21 results on '"Willison, Alice"'
Search Results
2. Inter-alpha-trypsin inhibitor heavy chain H3 is a potential biomarker for disease activity in myasthenia gravis
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Schroeter, Christina B., Nelke, Christopher, Stascheit, Frauke, Huntemann, Niklas, Preusse, Corinna, Dobelmann, Vera, Theissen, Lukas, Pawlitzki, Marc, Räuber, Saskia, Willison, Alice, Vogelsang, Anna, Marina, Adela Della, Hartung, Hans-Peter, Melzer, Nico, Konen, Felix F., Skripuletz, Thomas, Hentschel, Andreas, König, Simone, Schweizer, Michaela, Stühler, Kai, Poschmann, Gereon, Roos, Andreas, Stenzel, Werner, Meisel, Andreas, Meuth, Sven G., and Ruck, Tobias
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- 2024
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3. Review and meta-analysis of neuropsychological findings in autoimmune limbic encephalitis with autoantibodies against LGI1, CASPR2, and GAD65 and their response to immunotherapy
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Mueller, Christoph, Elben, Saskia, Day, Gregory S., Alves, Pedro, Hebert, Julien, Tang-Wai, David F., Holtmann, Olga, Iorio, Raffaele, Perani, Daniela, Titulaer, Maarten J., Hansen, Niels, Bartsch, Thorsten, Johnen, Andreas, Illes, Zsolt, Borm, Leah, Willison, Alice G., Wiendl, Heinz, Meuth, Sven G., Kovac, Stjepana, Bölte, Jens, and Melzer, Nico
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- 2023
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4. Real-world evidence on siponimod treatment in patients with secondary progressive multiple sclerosis
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Regner-Nelke, Liesa, Pawlitzki, Marc, Willison, Alice, Rolfes, Leoni, Oezalp, Sinem-Hilal, Nelke, Christopher, Kölsche, Tristan, Korsen, Melanie, Grothe, Matthias, Groppa, Sergiu, Luessi, Felix, Engel, Sinah, Nelles, Gereon, Bonmann, Eckhard, Roick, Holger, Friedrich, Anke, Knorn, Philipp, Landefeld, Harald, Biro, Zoltan, Ernst, Michael, Bayas, Antonios, Menacher, Martina, Akgün, Katja, Kleinschnitz, Christoph, Ruck, Tobias, Ziemssen, Tjalf, Pul, Refik, and Meuth, Sven G.
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- 2022
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5. Myositis in Germany: epidemiological insights over 15 years from 2005 to 2019
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Pawlitzki, Marc, Acar, Laura, Masanneck, Lars, Willison, Alice, Regner-Nelke, Liesa, Nelke, Christopher, L’hoest, Helmut, Marschall, Ursula, Schmidt, Jens, Meuth, Sven G., and Ruck, Tobias
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- 2022
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6. “A second birthday”? Experiences of persons with multiple sclerosis treated with autologous hematopoietic stem cell transplantation—a qualitative interview study.
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Volz, Timo, Sippel, Anna, Fischbach, Felix, Richter, Johanna, Willison, Alice Grizzel, Häußler, Vivien, and Heesen, Christoph
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HEMATOPOIETIC stem cell transplantation ,STEM cell transplantation ,MULTIPLE sclerosis ,PHYSIOLOGICAL stress ,QUALITATIVE research ,PSYCHOLOGICAL stress - Abstract
Introduction and objective: Autologous hematopoietic stem cell transplantation (aHSCT) is a promising treatment option for persons with multiple sclerosis (pwMS). Patients undergoing aHSCT face unique challenges in all aspects of life. In this study, we explored the lived experiences of pwMS undergoing aHSCT. Methods: Semi-structured interviews of 12 pwMS treated with aHSCT were conducted using a maximum variation sampling strategy. Interviews were transcribed verbatim and analyzed thematically using inductive and deductive categories. Results: Three major themes were identified: (1) preparing for aHSCT, (2) experiencing the procedure, and (3) post-treatment time. A difficult decision-making process, organizational effort, and funding difficulties characterized the preparation for transplantation. AHSCT was seen as a life-changing event accompanied by both psychological and physical stress, with an associated feeling of regaining control. The transplantation had a lasting positive effect on the lives of the interviewed pwMS. However, the early post-treatment time was characterized by successes and failures alike. Particularly the independently organized medical aftercare was perceived as challenging. Retrospective revaluation has led most pwMS to wish for earlier information provision about the treatment option of aHSCT during their treatment history. Conclusion: AHSCT had a clear impact on patients’ physical and psychosocial health, influencing their perception of life and its quality. Assessing and attending to unmet needs of patients before, during, and after transplantation may positively influence their experience of aHSCT. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Ofatumumab-induced severe reactivation of psoriasis in a patient with multiple sclerosis.
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Kölsche, Tristan, Willison, Alice Grizzel, Meuth, Sven G, Pawlitzki, Marc, Horbrügger, Marc, Skripuletz, Thomas, Meller, Stephan, and Pfeuffer, Steffen
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REGULATORY B cells , *DIMETHYL fumarate , *MAGNETIC resonance imaging , *SYMPTOMS , *CERVICAL cord , *PSORIATIC arthritis , *AUTOIMMUNE diseases - Abstract
This letter discusses the case of a 58-year-old woman with relapsing remitting multiple sclerosis (RRMS) who experienced a severe exacerbation of psoriasis after being treated with ofatumumab, an anti-CD20 monoclonal antibody. Despite discontinuing ofatumumab and trying various treatments, her psoriasis continued to worsen. Eventually, she was treated with secukinumab, a fully human monoclonal IL-17A antibody approved for psoriasis, which resulted in significant improvement. The letter highlights the potential risk of worsening psoriasis with B-cell-depleting therapies in RRMS patients and suggests that anti-IL17 antibodies may be a good alternative treatment option. [Extracted from the article]
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- 2024
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8. SARS-CoV-2 Vaccination and Neuroimmunological Disease: A Review.
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Willison, Alice Grizzel, Pawlitzki, Marc, Lunn, Michael Peter, Willison, Hugh John, Hartung, Hans-Peter, and Meuth, Sven Günther
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- 2024
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9. The Use of Nitrosative Stress Molecules as Potential Diagnostic Biomarkers in Multiple Sclerosis.
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Räuber, Saskia, Förster, Moritz, Schüller, Julia, Willison, Alice, Golombeck, Kristin S., Schroeter, Christina B., Oeztuerk, Menekse, Jansen, Robin, Huntemann, Niklas, Nelke, Christopher, Korsen, Melanie, Fischer, Katinka, Kerkhoff, Ruth, Leven, Yana, Kirschner, Patricia, Kölsche, Tristan, Nikolov, Petyo, Mehsin, Mohammed, Marae, Gelenar, and Kokott, Alma
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CEREBROSPINAL fluid examination ,NATALIZUMAB ,MULTIPLE sclerosis ,CENTRAL nervous system diseases ,NEUROLOGICAL disorders ,BIOMARKERS - Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) of still unclear etiology. In recent years, the search for biomarkers facilitating its diagnosis, prognosis, therapy response, and other parameters has gained increasing attention. In this regard, in a previous meta-analysis comprising 22 studies, we found that MS is associated with higher nitrite/nitrate (NOx) levels in the cerebrospinal fluid (CSF) compared to patients with non-inflammatory other neurological diseases (NIOND). However, many of the included studies did not distinguish between the different clinical subtypes of MS, included pre-treated patients, and inclusion criteria varied. As a follow-up to our meta-analysis, we therefore aimed to analyze the serum and CSF NOx levels in clinically well-defined cohorts of treatment-naïve MS patients compared to patients with somatic symptom disorder. To this end, we analyzed the serum and CSF levels of NOx in 117 patients (71 relapsing–remitting (RR) MS, 16 primary progressive (PP) MS, and 30 somatic symptom disorder). We found that RRMS and PPMS patients had higher serum NOx levels compared to somatic symptom disorder patients. This difference remained significant in the subgroup of MRZ-negative RRMS patients. In conclusion, the measurement of NOx in the serum might indeed be a valuable tool in supporting MS diagnosis. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Gathering Global Perspectives to Establish the Research Priorities and Minimum Data Sets for Degenerative Cervical Myelopathy:Sampling Strategy of the First Round Consensus Surveys of AO Spine RECODE-DCM
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Mowforth, Oliver D, Khan, Danyal Z, Wong, Mei Yin, Pickering, George A E, Dean, Lydia, Magee, Joe, Mullarkey, Laura, Hirayama, Yuri, Rihova, Martina, Butler, Max, Stewart, Max, Goulson, Beth, Ahmed, Shahzaib, Fricke, Kai, Popa-Nimigean, Vladimir, Millar, Zack, Venkatesh, Ashwin, Willison, Alice, Senthil, Keerthi, Hazenbiller, Olesja, Sarewitz, Ellen, Sadler, Iwan, Gronlund, Toto, Tetreault, Lindsay, Harrop, James S, Aarabi, Bizhan, Rahimi-Movaghar, Vafa, Kurpad, Shekar N, Guest, James D, Wilson, Jefferson R, Kwon, Brian K, Fehlings, Michael G, McNair, Angus G K, Davies, Benjamin M, and Kotter, Mark R N
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spondylosis ,surveys and questionnaires ,Orthopedics and Sports Medicine ,Surgery ,Neurology (clinical) ,cervical vertebrae ,spinal osteophytosis ,spinal cord diseases - Abstract
Study Design Survey. Introduction AO Spine Research Objectives and Common Data Elements for Degenerative Cervical Myelopathy (AO Spine RECODE-DCM) is an international initiative that aims to accelerate knowledge discovery and improve outcomes by developing a consensus framework for research. This includes defining the top research priorities, an index term and a minimum data set (core outcome set and core data elements set – core outcome set (COS)/core data elements (CDE)). Objective To describe how perspectives were gathered and report the detailed sampling characteristics. Methods A two-stage, electronic survey was used to gather and seek initial consensus. Perspectives were sought from spinal surgeons, other healthcare professionals and people with degenerative cervical myelopathy (DCM). Participants were allocated to one of two parallel streams: (1) priority setting or (2) minimum dataset. An email campaign was developed to advertise the survey to relevant global stakeholder individuals and organisations. People with DCM were recruited using the international DCM charity Myelopathy.org and its social media channels. A network of global partners was recruited to act as project ambassadors. Data from Google Analytics, MailChimp and Calibrum helped optimise survey dissemination. Results Survey engagement was high amongst the three stakeholder groups: 208 people with DCM, 389 spinal surgeons and 157 other healthcare professionals. Individuals from 76 different countries participated; the United States, United Kingdom and Canada were the most common countries of participants. Conclusion AO Spine RECODE-DCM recruited a diverse and sufficient number of participants for an international PSP and COS/CDE process. Whilst PSP and COS/CDE have been undertaken in other fields, to our knowledge, this is the first time they have been combined in one process.
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- 2021
11. Degenerative cervical myelopathy education in UK medical schools: a national cross-sectional survey of medical students.
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Brannigan, Jamie F. M., Davies, Benjamin M., Stewart, Max, Smith, Sam, Willison, Alice, Ahmed, Shahzaib, Sadler, Iwan, Sarewitz, Ellen, Francis, Jibin, Stacpoole, Sybil R. L., Kotter, Mark R. N., and Mowforth, Oliver D.
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MEDICAL students ,MEDICAL education ,MEDICAL schools ,SPINAL cord diseases ,STUDENT surveys ,CANCER education - Abstract
Degenerative cervical myelopathy (DCM) is a common and progressive neurological condition caused by injury of the cervical spinal cord by degenerative spinal pathology. Delayed diagnosis leading to avoidable and irreversible disability is a major current problem limiting patient outcomes. Lack of sufficient representation of DCM in undergraduate and postgraduate medical curricula may contribute to poor recognition of DCM by non-specialist doctors. The objective of this study was to assess the DCM teaching provision in UK medical schools and the DCM knowledge of UK medical students. UK medical students completed a web-based survey distributed nationally through university social media pages, university email bulletins and the national student network of Myelopathy.org. The survey comprised a 19-item questionnaire capturing data on student demographics, myelopathy teaching and myelopathy knowledge. Advertisements were repeated monthly over a 12-month recruitment period and participation was incentivised by entry into an Amazon voucher prize draw. Ethical approval for the study was granted by the Psychology Research Ethics Committee, University of Cambridge (PRE.2018.099). A total of 751 medical students from 32 British medical schools completed the survey. Medical students from all year groups participated. Most students (520; 72%) had not received any medical school teaching about DCM. When students had received DCM teaching, the duration of teaching was minimal (75% < 1 h). A total of 350 students (47%) reported conducting private study on DCM. Modal student self-rating of their own knowledge of DCM was 'terrible' (356; 47%). There was no correlation between a student's subjective rating of their knowledge and their answers to objective questions. A total of 723 (96%) of students expressed interest in learning more about DCM, with lectures the preferred format. DCM appears to be a neglected condition in medical education which has implications for clinical practice. However, student enthusiasm to undertake private study suggests future teaching interventions will be well-received. Future work is necessary to characterise the format of DCM teaching that is most effective and to subsequently measure how educational interventions translate into clinical benefits. [ABSTRACT FROM AUTHOR]
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- 2022
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12. Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity.
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Ruck, Tobias, Barman, Sumanta, Schulte-Mecklenbeck, Andreas, Pfeuffer, Steffen, Steffen, Falk, Nelke, Christopher, Schroeter, Christina B., Willison, Alice, Heming, Michael, Müntefering, Thomas, Melzer, Nico, Krämer, Julia, Lindner, Maren, Riepenhausen, Marianne, Gross, Catharina C., Klotz, Luisa, Bittner, Stefan, Muraro, Paolo A., Schneider-Hohendorf, Tilman, and Schwab, Nicholas
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RESEARCH ,RESEARCH methodology ,AUTOIMMUNE diseases ,EVALUATION research ,PROTEOMICS ,COMPARATIVE studies ,IMMUNITY ,PHENOTYPES - Abstract
Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing-remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity. [ABSTRACT FROM AUTHOR]
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- 2022
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13. The neurodevelopmental spectrum seen with CHD2 variants.
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Willison, Alice G and Thomas, Rhys H
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NEURAL development - Published
- 2022
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14. Detecting ongoing disease activity in mildly affected multiple sclerosis patients under first-line therapies.
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Masanneck, Lars, Rolfes, Leoni, Regner-Nelke, Liesa, Willison, Alice, Räuber, Saskia, Steffen, Falk, Bittner, Stefan, Zipp, Frauke, Albrecht, Philipp, Ruck, Tobias, Hartung, Hans-Peter, Meuth, Sven G., and Pawlitzki, Marc
- Abstract
• Even among MS patients considered mildly affected, most showed disease activity • Driven by MRI activity, loss of NEDA-3 was the most frequent marker of disease activity • PIRA occurred in 50% of patients and was often not accompanied by loss of NEDA-3 • MRI and clinical measurements often did not show disease activity simultaneously • Measuring different disease activity outcome measures could improve monitoring 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. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]
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- 2022
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15. Gathering Global Perspectives to Establish the Research Priorities and Minimum Data Sets for Degenerative Cervical Myelopathy: Sampling Strategy of the First Round Consensus Surveys of AO Spine RECODE-DCM.
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Mowforth, Oliver D., Khan, Danyal Z, Wong, Mei Yin, Pickering, George A. E., Dean, Lydia, Magee, Joe, Mullarkey, Laura, Hirayama, Yuri, Rihova, Martina, Butler, Max, Stewart, Max, Goulson, Beth, Ahmed, Shahzaib, Fricke, Kai, Popa-Nimigean, Vladimir, Millar, Zack, Venkatesh, Ashwin, Willison, Alice, Senthil, Keerthi, and Hazenbiller, Olesja
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- 2022
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16. Platelet Inhibition by Low-Dose Acetylsalicylic Acid Reduces Neuroinflammation in an Animal Model of Multiple Sclerosis.
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Vogelsang, Anna, Eichler, Susann, Huntemann, Niklas, Masanneck, Lars, Böhnlein, Hannes, Schüngel, Lisa, Willison, Alice, Loser, Karin, Nieswandt, Bernhard, Kehrel, Beate E., Zarbock, Alexander, Göbel, Kerstin, and Meuth, Sven G.
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ASPIRIN ,NEUROINFLAMMATION ,MULTIPLE sclerosis ,ANIMAL disease control ,T cells ,ANIMAL models in research ,BLOOD platelets - Abstract
Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4
+ T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28% in ASA-treated mice compared to 56.11 ± 1.46% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A2 were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS. [ABSTRACT FROM AUTHOR]- Published
- 2021
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17. An optimized and validated protocol for inducing chronic experimental autoimmune encephalomyelitis in C57BL/6J mice.
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Huntemann, Niklas, Vogelsang, Anna, Groeneweg, Linda, Willison, Alice, Herrmann, Alexander M., Meuth, Sven G., and Eichler, Susann
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LABORATORY mice , *MYELIN oligodendrocyte glycoprotein , *PERTUSSIS toxin , *ENCEPHALOMYELITIS , *ANIMAL welfare , *AUTOIMMUNE diseases - Abstract
Myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model of multiple sclerosis. However, variations in the induction protocol can affect EAE progression, and may reduce the comparability of data. In the present study, we investigated the influence of the different components used for EAE induction in C57BL/6J mice on disease progression. In the present study, MOG 35–55 -induced chronic EAE in C57BL/6J mice has been applied as a model to challenge optimal pertussis toxin (PTx) dosing, while considering variations in batch potency. We demonstrate that the dosage of PTx, adjusted to its potency, influences EAE development in a dose-dependent manner. Our data show that with our protocol, which considers PTx potency, C57BL/6J mice consistently develop symptoms of EAE. The mice show a typical chronic course with symptom onset after 10.5 ± 1.08 days and maximum severity around day 16 postimmunization followed by a mild remission of symptoms. Previously studies reveal that alterations in PTx dosing directly modify EAE progression. Our present study highlights that PTx batches differ in potency, resulting in inconsistent EAE induction. We also provide a clear protocol that allows a reduction in the number of mice used in EAE experiments, while maintaining consistent results. Higher standards for comparability and reproducibility are needed to ensure and maximize the generation of reliable EAE data. Specifically, consideration of PTx potency. With our method of establishing consistent EAE pathogenesis, improved animal welfare standards and a reduction of mice used in experimentation can be achieved. • Pertussis toxin lots may vary in its potency, influencing the pathogenesis of EAE. • We titrated pertussis toxin to an optimal dose for a consistent EAE induction. • We provide a reliable protocol to achieve a higher degree of comparability. • This protocol helps to reduce the number of mice used in preclinical research. [ABSTRACT FROM AUTHOR]
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- 2022
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18. Eculizumab treatment alters the proteometabolome beyond the inhibition of complement.
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Nelke C, Schroeter CB, Stascheit F, Huntemann N, Pawlitzki M, Willison A, Räuber S, Melzer N, Distler U, Tenzer S, Stühler K, Roos A, Meisel A, Meuth SG, and Ruck T
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- Humans, Complement System Proteins, Complement Activation, Receptor, Anaphylatoxin C5a, Leukotrienes, Complement C5, Myasthenia Gravis drug therapy
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Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify off-target effects shaping long-term outcomes. For this reason, we studied a cohort of patients with MG treated with either eculizumab or azathioprine as well as treatment-naive patients using a combined proteomics and metabolomics approach. This strategy validated known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients, including the oxidative stress response, mitogen-activated protein kinase signaling, and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct off-target effects induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes.
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- 2023
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19. Effect of Previous Disease-Modifying Therapy on Treatment Effectiveness for Patients Treated With Ocrelizumab.
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Pfeuffer S, Rolfes L, Ingwersen J, Pul R, Kleinschnitz K, Korsen M, Räuber S, Ruck T, Schieferdecker S, Willison AG, Aktas O, Kleinschnitz C, Hartung HP, Kappos L, and Meuth SG
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- Humans, Male, United States, Adult, Female, Prospective Studies, Treatment Outcome, Antilymphocyte Serum, Recurrence, Multiple Sclerosis, Relapsing-Remitting drug therapy, Multiple Sclerosis drug therapy
- Abstract
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.)
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- 2023
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20. Vaccine-based clinical protection against SARS-CoV-2 infection and the humoral immune response: A 1-year follow-up study of patients with multiple sclerosis receiving ocrelizumab.
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Räuber S, Willison A, Korsen M, Kölsche T, Golombeck KS, Plaack B, Schüller J, Huntemann N, Rolfes L, Schroeter CB, Nelke C, Regner-Nelke L, Förster M, Ringelstein M, Barnett MH, Hartung HP, Aktas O, Albrecht P, Ruck T, Melzer N, Meuth SG, and Kremer D
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- Humans, Follow-Up Studies, SARS-CoV-2, COVID-19 Vaccines, Retrospective Studies, Antibodies, Monoclonal, Humanized therapeutic use, COVID-19 prevention & control, Multiple Sclerosis drug therapy, Vaccines
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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.)
- Published
- 2022
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21. Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity.
- Author
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Ruck T, Barman S, Schulte-Mecklenbeck A, Pfeuffer S, Steffen F, Nelke C, Schroeter CB, Willison A, Heming M, Müntefering T, Melzer N, Krämer J, Lindner M, Riepenhausen M, Gross CC, Klotz L, Bittner S, Muraro PA, Schneider-Hohendorf T, Schwab N, Meyer Zu Hörste G, Goebels N, Meuth SG, and Wiendl H
- Subjects
- Alemtuzumab adverse effects, Humans, Phenotype, Proteomics, Autoimmune Diseases chemically induced, Autoimmunity
- Abstract
Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing-remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2022
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