Publications by authors named "Antonios Bayas"

37 Publications

Sunlight exposure exerts immunomodulatory effects to reduce multiple sclerosis severity.

Proc Natl Acad Sci U S A 2021 01;118(1)

Department of Neurology, Neuroimmunological Section, University of Rostock, 18051 Rostock, Germany.

Multiple sclerosis (MS) disease risk is associated with reduced sun-exposure. This study assessed the relationship between measures of sun exposure (vitamin D [vitD], latitude) and MS severity in the setting of two multicenter cohort studies ( = 946, = 990). Additionally, effect-modification by medication and photosensitivity-associated variants was assessed. High serum vitD was associated with a reduced MS severity score (MSSS), reduced risk for relapses, and lower disability accumulation over time. Low latitude was associated with higher vitD, lower MSSS, fewer gadolinium-enhancing lesions, and lower disability accumulation. The association of latitude with disability was lacking in IFN-β-treated patients. In carriers of :rs1805008(T), who reported increased sensitivity toward sunlight, lower latitude was associated with higher MRI activity, whereas for noncarriers there was less MRI activity at lower latitudes. In a further exploratory approach, the effect of ultraviolet (UV)-phototherapy on the transcriptome of immune cells of MS patients was assessed using samples from an earlier study. Phototherapy induced a vitD and type I IFN signature that was most apparent in monocytes but that could also be detected in B and T cells. In summary, our study suggests beneficial effects of sun exposure on established MS, as demonstrated by a correlative network between the three factors: Latitude, vitD, and disease severity. However, sun exposure might be detrimental for photosensitive patients. Furthermore, a direct induction of type I IFNs through sun exposure could be another mechanism of UV-mediated immune-modulation in MS.
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http://dx.doi.org/10.1073/pnas.2018457118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817192PMC
January 2021

Anti-CD20 therapies and pregnancy in neuroimmunologic disorders: A cohort study from Germany.

Neurol Neuroimmunol Neuroinflamm 2021 01 17;8(1). Epub 2020 Dec 17.

From the Institute of Clinical Neuroimmunology (T.K., I.M.), Biomedical Center and University Hospital, Ludwig-Maximilians Universitaet München, Munich; Department of Neurology (S.T., A.I.C., I.A., K.H.), Katholisches Klinikum, St. Josef Hospital, Ruhr University Bochum; Institute of Clinical Pharmacy and Pharmacotherapy (A.I.C.), Heinrich Heine University Düsseldorf; Department of Neurology (A.B.), University Hospital of Augsburg; Klinik für Neurologie (F.H.), Krankenhaus Martha-Maria Halle-Dölau gGmbH, Halle (Saale); Klinik für Neurologie (U.H.-v.O.), Knappschaftskrankenhaus Dortmund Klinikum Westfalen, Dortmund; Marianne-Strauß-Klinik (M.-M.H.), Berg; Department of Neurology (J.K.), Klinikum der Stadt Ludwigshafen gGmbH, Ludwigshafen; Department of Neurology (M.R., O.A.), Medical Faculty, Heinrich Heine University Düsseldorf; Department of Neurology (M.R.), Center for Neurology and Neuropsychiatry, LVR-Klinikum Düsseldorf; Department of Neurology (M.S.), University of Leipzig; Sektion Neuroimmunologie (A.W.), Klinik für Neurologie, Klinikum Herford; Institute of Neuropathology and Department of Neurology (M.S.W.), University Medical Center, Georg August University Göttingen, Germany.

Objective: To report pregnancy outcomes and disease activity (DA) in women with MS, neuromyelitis optica spectrum disorders (NMOSDs), and other neuroimmunologic diseases (ONID) after treatment with rituximab (RTX)/ocrelizumab (OCR) 12 months before or during pregnancy.

Methods: Data were collected in the German MS and pregnancy registry and centers from the Neuromyelitis Optica Study Group. Sixty-eight known outcomes of 88 pregnancies from 81 women (64 MS, 10 NMOSD, and 7 ONID) were included and stratified in 3 exposure groups: >6M-group = RTX/OCR >6 but ≤12 months before the last menstrual period (LMP) (n = 8); <6M group = RTX/OCR <6 months before the LMP (n = 47); preg group = RTX/OCR after the LMP (n = 13).

Results: Pregnancy outcomes were similar between groups, but significantly more preterm births (9.8% vs 45%) occurred after exposure during pregnancy. Overall, 2 major congenital abnormalities (3.3%), both in the preg group, were observed. Three women had severe infections during pregnancy. All women with MS (35) and 12/13 women with NMOSD, RTX/OCR exposure before the LMP and known pregnancy outcomes after gestational week 22 were relapse free during pregnancy. Five of 29 (17.2%) women with relapsing-remitting MS (RRMS) and 1 of 12 (8.3%) with NMOSD and at least 6 months postpartum follow-up experienced a relapse postpartum. Duration of RTX/OCR and early retreatment but not detection of B-cells were possible predictors for postpartum relapses in patients with RRMS/NMOSD.

Conclusions: Although RTX/OCR might be an interesting option for women with RRMS/NMOSD who plan to become pregnant to control DA, more data on pregnancy outcomes and rare risks are needed.
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http://dx.doi.org/10.1212/NXI.0000000000000913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757754PMC
January 2021

Alemtuzumab-associated diffuse alveolar damage - a case report.

BMC Neurol 2020 Sep 23;20(1):357. Epub 2020 Sep 23.

Neurology and Clinical Neurophysiology, University Hospital of Augsburg, Stenglinstrasse 2, 86156, Augsburg, Germany.

Background: Identifying causes of alemtuzumab induced respiratory symptoms in Multiple Sclerosis (MS) patients is crucial.

Case Presentation: We report a case of diffuse alveolar damage (DAD) in a patient with MS after the first course of alemtuzumab treatment. A 42-year-old female developed progressive non-productive cough and exertional dyspnea 2 months after alemtuzumab treatment. DAD was diagnosed histopathologically by lung biopsy. The patient recovered completely, alemtuzumab was not continued.

Conclusions: Our case highlights another pathomechanism for non-infective lung-disorders in alemtuzumab treated MS patients. DAD is a potential, albeit rare side effect of alemtuzumab, broadening the spectrum of non-infective lung disorders that should be considered in the diagnostic work-up.
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http://dx.doi.org/10.1186/s12883-020-01934-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510011PMC
September 2020

Genetic determinants of the humoral immune response in MS.

Neurol Neuroimmunol Neuroinflamm 2020 09 16;7(5). Epub 2020 Jul 16.

From the Department of Neurology (C.G., T.F.M.A., A. Keating, B.K., A. Klein, V.P., A. Berthele, B.H.), Klinikum rechts der Isar, School of Medicine, Technical University of Munich; Institute of Human Genetics (P.L.), Helmholtz Zentrum München, Neuherberg; Department of Neurology (R.G.), St. Josef Hospital, Ruhr-University Bochum; Department of Neurology, Focus Program Translational Neurosciences (FTN) and Research Center for Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2) (F.Z.), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology and Translational Center for Regenerative Medicine (F.T.B.), University of Leipzig; Clinical Neuroimmunology and Neurochemistry (M.S.), Department of Neurology, Hannover Medical School, Hannover; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Department of Neurology (B.W.), University Hospital Heidelberg; Department of Neurology (H.W.), University of Münster; Department of Neurology (A. Bayas), University Hospital Augsburg; Institute of Clinical Neuroimmunology (T.K.), University Hospital and Biomedical Center, Ludwig-Maximilians University Munich; Department of Neurology (U.K.Z.), Neuroimmunological Section, University of Rostock; Department of Neurology (R.A.L.), University Hospital Erlangen; Department of Neurology (R.A.L.), University of Regensburg; Department of Neurology & Stroke and Hertie-Institute for Clinical Brain Research (U.Z.), Eberhard-Karls-Universität Tübingen; Max Planck Institute of Psychiatry (M.K.), Munich; Department of Neurology (C.W.), Medical Faculty, Heinrich Heine University, Düsseldorf; Department of Neurology (C.W.), University Hospital Cologne; Institute of Neuroimmunology and Multiple Sclerosis (M.A.F), University Medical Centre Hamburg-Eppendorf, Hamburg; NeuroCure Clinical Research Center (F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin; Berlin Institute of Health and Experimental and Clinical Research Center (F.P.), Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin; and Center of Neuroimmunology (B.T.), Philipps-University Marburg; and Munich Cluster for Systems Neurology (SyNergy) (B.H.), Germany.

Objective: In this observational study, we investigated the impact of genetic factors at the immunoglobulin heavy chain constant locus on chromosome 14 and the major histocompatibility complex region on intrathecal immunoglobulin G, A, and M levels as well as on B cells and plasmablasts in the CSF and blood of patients with multiple sclerosis (MS).

Methods: Using regression analyses, we tested genetic variants on chromosome 14 and imputed human leukocyte antigen (HLA) alleles for associations with intrathecal immunoglobulins in 1,279 patients with MS or clinically isolated syndrome and with blood and CSF B cells and plasmablasts in 301 and 348 patients, respectively.

Results: The minor alleles of variants on chromosome 14 were associated with higher intrathecal immunoglobulin G levels (β = 0.58 [0.47 to 0.68], lowest adjusted = 2.32 × 10), and lower intrathecal immunoglobulin M (β = -0.56 [-0.67 to -0.46], = 2.06 × 10) and A (β = -0.42 [-0.54 to -0.31], = 7.48 × 10) levels. Alleles from the HLA-B*07:02-DRB1*15:01-DQA1*01:02-DQB1*06:02 haplotype were associated with higher (lowest = 2.14 × 10) and HLA-B*44:02 with lower (β = -0.35 [-0.54 to -0.17], = 1.38 × 10) immunoglobulin G levels. Of interest, different HLA alleles were associated with lower intrathecal immunoglobulin M (HLA-C*02:02, β = -0.45 [-0.61 to -0.28], = 1.01 × 10) and higher immunoglobulin A levels (HLA-DQA1*01:03-DQB1*06:03-DRB1*13:01 haplotype, β = 0.40 [0.21 to 0.60], = 4.46 × 10). The impact of HLA alleles on intrathecal immunoglobulin G and M levels could mostly be explained by associations with CSF B cells and plasmablasts.

Conclusion: Although some HLA alleles seem to primarily drive the extent of humoral immune responses in the CNS by increasing CSF B cells and plasmablasts, genetic variants at the immunoglobulin heavy chain constant locus might regulate intrathecal immunoglobulins levels via different mechanisms.
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http://dx.doi.org/10.1212/NXI.0000000000000827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371373PMC
September 2020

Long-term management of multiple sclerosis patients treated with cladribine tablets: an expert opinion.

Expert Opin Pharmacother 2020 Nov 13;21(16):1965-1969. Epub 2020 Jul 13.

Klinik für Neurologie, Juliusspital Würzburg Klinikum Würzburg Mitte gGmbH , Germany.

Introduction: Oral cladribine is a highly effective pulsed selective immune reconstitution therapy licensed for relapsing multiple sclerosis. A full treatment course comprises two treatment cycles given with 1 year of intermission. Further dosing is not routinely recommended in years 3 and 4.

Areas Covered: The long-term management of patients treated with oral cladribine has not been fully defined on the basis of clinical studies as of yet. The authors provide their expert opinion on this.

Expert Opinion: Based on available evidence and experience from routine clinical use, the authors suggest a structured approach to the long-term management of patients treated with cladribine tablets according to their responder type, i. e. the degree and timing of disease activity, if any, after treatment initiation. Informed treatment decisions require structured patient monitoring by established clinical and imaging parameters. In patients with relevant disease activity in year 3 or 4 and beyond, the use of additional cycle(s) of oral cladribine might become an option. For patients requiring a treatment switch, the choice of therapies primarily includes moderately to highly effective MS drugs.
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http://dx.doi.org/10.1080/14656566.2020.1792885DOI Listing
November 2020

Clinical implications of serum neurofilament in newly diagnosed MS patients: A longitudinal multicentre cohort study.

EBioMedicine 2020 Jun 24;56:102807. Epub 2020 May 24.

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany.

Background: We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients.

Methods: In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up.

Findings: Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels.

Interpretation: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions.

Funding: Supported the German Federal Ministry for Education and Research, the German Research Council, and Hertie-Stiftung.
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http://dx.doi.org/10.1016/j.ebiom.2020.102807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251380PMC
June 2020

Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis.

J Neurol Neurosurg Psychiatry 2020 07 5;91(7):681-686. Epub 2020 May 5.

Department of Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany

Objective: To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).

Methods: Serum samples were collected from 901 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.

Results: EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.

Conclusion: The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
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http://dx.doi.org/10.1136/jnnp-2020-322941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361012PMC
July 2020

Is ε4 associated with cognitive performance in early MS?

Neurol Neuroimmunol Neuroinflamm 2020 07 1;7(4). Epub 2020 May 1.

From the Department of Neurology and Focus Program Translational Neuroscience (FTN) (S.E., C.G., M.M., S.B., S.G., F.Z., C.M.L., F.L.), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Germany; Department of Neurology (A.S.), Inselspital, Bern University Hospital, University of Bern, Switzerland; Department of Neurology (A.S., B.A., R.G.), St. Josef-Hospital, Ruhr-University Bochum; Institute of Medical Biostatistics (G.T.), Epidemiology and Informatics (IMBEI), University Medical Center of the Johannes Gutenberg University Mainz; Department of Neurology (A. Bayas), Klinikum Augsburg; Department of Neurology (A. Berthele, B.H.), Klinikum rechts der Isar, Technical University of Munich; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf; Clinic of Neurology (L.K., S.G.M., H.W.), University Hospital Münster, Westphalian-Wilhelms-University Münster; Institute of Clinical Neuroimmunology (T.K.), Ludwig Maximilian University of Munich; Department of Neurology (R.A.L.), University Hospital Erlangen; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (F.P.), Charité - Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medicine; Department of Neurology (M.S.), Hannover Medical School; Department of Neurology (B.T.), Philipps-University Marburg; Department of Neurology (F.T.B.), University of Leipzig; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Neurology (F.W.), Max-Planck-Institute of Psychiatry, Munich; Neurological Clinic (F.W.), Sana Kliniken des Landkreises Cham; Department of Neurology (B.W.), University of Heidelberg; Department. of Neurology (U.K.Z.), University of Rostock; Central Information Office (CIO) (G.A.), Philipps-University Marburg; and Genetic and Molecular Epidemiology Group (C.M.L.), Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and Cardiogenetics, University of Lübeck, Germany.

Objective: To assess the impact of polymorphisms on cognitive performance in patients newly diagnosed with clinically isolated syndrome (CIS) or relapsing-remitting MS (RRMS).

Methods: This multicenter cohort study included 552 untreated patients recently diagnosed with CIS or RRMS according to the 2005 revised McDonald criteria. The single nucleotide polymorphisms rs429358 (ε4) and rs7412 (ε2) of the haplotype were assessed by allelic discrimination assays Cognitive performance was evaluated using the 3-second paced auditory serial addition test and the Multiple Sclerosis Inventory Cognition (MUSIC). Sum scores were calculated to approximate the overall cognitive performance and memory-centered cognitive functions. The impact of the carrier status on cognitive performance was assessed using multiple linear regression models, also including demographic, clinical, MRI, and lifestyle factors.

Results: ε4 homozygosity was associated with lower overall cognitive performance, whereas no relevant association was observed for ε4 heterozygosity or ε2 carrier status. Furthermore, higher disability levels, MRI lesion load, and depressive symptoms were associated with lower cognitive performance. Patients consuming alcohol had higher test scores than patients not consuming alcohol. Female sex, lower disability, and alcohol consumption were associated with better performance in the memory-centered subtests of MUSIC, whereas no relevant association was observed for carrier status.

Conclusion: Along with parameters of a higher disease burden, ε4 homozygosity was identified as a potential predictor of cognitive performance in this large cohort of patients with CIS and early RRMS.
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http://dx.doi.org/10.1212/NXI.0000000000000728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217661PMC
July 2020

Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German National Multiple Sclerosis Cohort study.

Pain 2020 04;161(4):787-796

Department of Neurology, Technical University of Munich (TUM), School of Medicine, Munich, Germany.

Pain is frequent in multiple sclerosis (MS) and includes different types, with neuropathic pain (NP) being most closely related to MS pathology. However, prevalence estimates vary largely, and causal relationships between pain and biopsychosocial factors in MS are largely unknown. Longitudinal studies might help to clarify the prevalence and determinants of pain in MS. To this end, we analyzed data from 410 patients with newly diagnosed clinically isolated syndrome or relapsing-remitting MS participating in the prospective multicenter German National MS Cohort Study (NationMS) at baseline and after 4 years. Pain was assessed by self-report using the PainDETECT Questionnaire. Neuropsychiatric assessment included tests for fatigue, depression, and cognition. In addition, sociodemographic and clinical data were obtained. Prevalence of pain of any type was 40% and 36% at baseline and after 4 years, respectively, whereas prevalence of NP was 2% and 5%. Pain of any type and NP were both strongly linked to fatigue, depression, and disability. This link was even stronger after 4 years than at baseline. Moreover, changes in pain, depression, and fatigue were highly correlated without any of these symptoms preceding the others. Taken together, pain of any type seems to be much more frequent than NP in early nonprogressive MS. Moreover, the close relationship between pain, fatigue, and depression in MS should be considered for treatment decisions and future research on a possible common pathophysiology.
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http://dx.doi.org/10.1097/j.pain.0000000000001767DOI Listing
April 2020

[Diagnostics and treatment of tuberculosis under immunotherapy for multiple sclerosis : Current status and recommendations in Germany].

Nervenarzt 2019 Dec;90(12):1245-1253

Klinik für Neurologie, Forschungszentrum Translationale Neurowissenschaften (FTN), Forschungszentrum für Immuntherapie (FZI), Rhine Main Neuroscience Network (rmn2), Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstr. 1, 55131, Mainz, Deutschland.

After years of low incidence, a large increase of new tuberculosis (TB) cases has been reported in Germany since 2015. New immunotherapies for the treatment of multiple sclerosis (MS) are associated with a reduced immune competence and a potential increased risk for infections. Most neurologists lack specific experiences with TB infections. This article summarizes specific recommendations for the diagnostics and treatment of TB under MS immunotherapies with a focus on the situation in Germany. Due to low case numbers and little experience with the risk of TB under the new immunotherapies, the clinical competence network for MS (KKNMS) consensus recommendations have a low grade of evidence.
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http://dx.doi.org/10.1007/s00115-019-0760-0DOI Listing
December 2019

Autoimmune encephalitis associated with antibodies against the metabotropic glutamate receptor type 1: case report and review of the literature.

Ther Adv Neurol Disord 2019 10;12:1756286419847418. Epub 2019 May 10.

Department of Neurology, University Hospital of Augsburg, Augsburg, Germany.

Autoimmune encephalitis associated with antibodies against the metabotropic glutamate receptor type 1 is a rare autoimmune disease with only 18 cases being described in the literature so far. Most patients present with subacute cerebellar ataxia. In more than one third of cases a paraneoplastic aetiology has been suspected. Here we report a case of a 45-year-old man without known malignancy, who presented with progressive dysarthria and subsequently developed subacute cerebellar ataxia. Immunotherapy with glucocorticoids, i.v. immunoglobulins and rituximab improved clinical symptoms and resulted in a stable disease course up to the present. The article describes the clinical course of the patient with a follow-up-period of approximately 24 months and reviews the cases reported in the literature so far.
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http://dx.doi.org/10.1177/1756286419847418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535747PMC
May 2019

Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis.

JAMA Neurol 2019 07;76(7):841-849

Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.

Importance: Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed.

Objective: To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome.

Design, Setting, And Participants: Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018.

Exposure: Patients were offered standard immunotherapies per national treatment guidelines.

Main Outcomes And Measures: A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated.

Results: Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found.

Conclusions And Relevance: Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.
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http://dx.doi.org/10.1001/jamaneurol.2019.0905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583696PMC
July 2019

Can we predict cognitive decline after initial diagnosis of multiple sclerosis? Results from the German National early MS cohort (KKNMS).

J Neurol 2019 Feb 4;266(2):386-397. Epub 2018 Dec 4.

Department of Neurology, University Hospital Münster, Westfälische-Wilhelms-University Münster, Münster, Germany.

Background: Cognitive impairment (CI) affects approximately one-third of the patients with early multiple sclerosis (MS) and clinically isolated syndrome (CIS). Little is known about factors predicting CI and progression after initial diagnosis.

Methods: Neuropsychological screening data from baseline and 1-year follow-up of a prospective multicenter cohort study (NationMS) involving 1123 patients with newly diagnosed MS or CIS were analyzed. Employing linear multilevel models, we investigated whether demographic, clinical and conventional MRI markers at baseline were predictive for CI and longitudinal cognitive changes.

Results: At baseline, 22% of patients had CI (impairment in ≥2 cognitive domains) with highest frequencies and severity in processing speed and executive functions. Demographics (fewer years of academic education, higher age, male sex), clinical (EDSS, depressive symptoms) but no conventional MRI characteristics were linked to baseline CI. At follow-up, only 14% of patients showed CI suggesting effects of retesting. Neither baseline characteristics nor initiation of treatment between baseline and follow-up was able to predict cognitive changes within the follow-up period of 1 year.

Conclusions: Identification of risk factors for short-term cognitive change in newly diagnosed MS or CIS is insufficient using only demographic, clinical and conventional MRI data. Change-sensitive, re-test reliable cognitive tests and more sophisticated predictors need to be employed in future clinical trials and cohort studies of early-stage MS to improve prediction.
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http://dx.doi.org/10.1007/s00415-018-9142-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373354PMC
February 2019

Adherence to Subcutaneous IFN β-1a in Multiple Sclerosis: Final Analysis of the Non-Interventional Study READOUTsmart Using the Dosing Log and Readout Function of RebiSmart.

Adv Ther 2019 01 28;36(1):175-186. Epub 2018 Nov 28.

Department of Neurology, Klinikum Augsburg, Augsburg, Germany.

Introduction: Patient adherence is a key determinant of treatment success in multiple sclerosis (MS). The RebiSmart autoinjector facilitates patient self-injection of subcutaneous interferon β-1a (sc IFN β-1a) and allows quantitative measurement of adherence via its automated dosing log. We evaluated patient adherence and patient-reported cognitive and health-economic outcomes over 2 years in patients using RebiSmart.

Methods: In this non-interventional, single-arm study, enrolled patients were 12-65 years of age, had relapsing-remitting MS or a single demyelinating event, and had been prescribed 44 or 22 μg sc IFN β-1a. Quantitative adherence (proportion of scheduled injections administered) and qualitative adherence (proportion of weeks with treatment schedule correctly followed) were monitored over 2 years. Other end points included self-assessed adherence, patient-reported outcomes (fatigue, depression and quality of life), cognitive outcomes and health-economic outcomes.

Results: A total of 368 of 392 (93.9%) enrolled patients were analyzed. Mean quantitative adherence was 85.3% overall (months 1-24), 89.6% for months 1-12 and 83.3% for months 13-24. No major impact on quantitative adherence was observed for sex, age (< 37 years vs. ≥ 37 years), prior medication or participation in the patient support program RebiSTAR. Mean qualitative adherence was 67.0% overall (months 1-24). Self-assessed adherence was reported as being higher than RebiSmart-monitored adherence. There was a trend toward more MS-related visits to physicians among patients with high adherence.

Conclusions: Patients using RebiSmart demonstrated high adherence to treatment that was associated with a slight improvement in information processing speed and working memory and an overall tendency for more intensive self-management.

Funding: Merck Serono GmbH, Germany, an affiliate of Merck KGaA, Darmstadt, Germany.
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http://dx.doi.org/10.1007/s12325-018-0839-1DOI Listing
January 2019

The NRF2 pathway as potential biomarker for dimethyl fumarate treatment in multiple sclerosis.

Ann Clin Transl Neurol 2018 Jun 16;5(6):668-676. Epub 2018 Apr 16.

Department of Neurology University Hospital Erlangen Friedrich-Alexander-University Erlangen-Nürnberg Erlangen 91054 Germany.

Objective: Immunological studies have demonstrated a plethora of beneficial effects of dimethyl fumarate (DMF) on various cell types. However, the cellular and molecular targets are incompletely understood and response markers are scarce. Here, we focus on the relation between nuclear factor (erythroid-derived 2)-like 2 (NRF2) pathway induction under DMF therapy and the composition of the blood immune cell compartment and clinical efficacy in relapsing-remitting multiple sclerosis (MS) patients.

Methods: We explored effects of DMF on peripheral immune cell subsets by flow cytometric and transcriptional analysis of serial blood samples obtained from 43 MS patients during the first year of therapy.

Results: Gene expression analysis proved activation of NRF2 signaling under DMF therapy that was paralleled by a temporal expansion of FoxP3 regulatory T cells, CD56 natural killer cells, plasmacytoid dendritic cells, and a decrease in CD8 T cells, B cells, and type 1 myeloid dendritic cells. In a subgroup of 28 patients with completely available clinical data, individuals with higher levels of the NRF2 target gene NAD(P)H quinone dehydrogenase 1 (NQO1) 4-6 weeks after DMF therapy initiation were more likely to achieve no evidence of disease activity status 1 year later. The degree of NQO1 induction further correlated with patient age.

Interpretation: We demonstrate that positive effects of DMF on the clinical outcome are paralleled by induction of the antioxidant NRF2 transcriptional pathway and a shift toward regulatory immune cell subsets in the periphery. Our data identify a role of the NRF2 pathway as potential biomarker for DMF treatment in MS.
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http://dx.doi.org/10.1002/acn3.553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989754PMC
June 2018

Tryptophan immunoadsorption during pregnancy and breastfeeding in patients with acute relapse of multiple sclerosis and neuromyelitis optica.

Ther Adv Neurol Disord 2018 28;11:1756286418774973. Epub 2018 May 28.

Department of Neurology, General Hospital Lüdenscheid, Märkische Kliniken GmbH, Germany.

Background: Up to every fourth woman with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) suffers a clinically relevant relapse during pregnancy. High doses of steroids bear some serious risks, especially within the first trimester of pregnancy. Immunoadsorption (IA) is an effective and more selective treatment option in disabling MS relapse than plasma exchange. Data on the use of IA during pregnancy and breastfeeding are scarce.

Methods: In this retrospective multicenter study, we analyzed the safety and efficacy of IA treatment in acute relapses during pregnancy or breastfeeding. The primary outcome parameter - change of acute relapse-related disability after IA - was assessed using Expanded Disability Status Scale (EDSS) and visual acuity (VA) measurements for patients with optic neuritis (ON).

Results: A total of 24 patients were analyzed, 23 with relapsing-remitting MS, and 1 with NMOSD. Twenty patients were treated with IA during pregnancy. Four patients received IA postnatally during the breastfeeding period. Treatment was started at a mean 22.5 [standard deviation (SD) 13.9] days after onset of relapse. Patients were treated with a series of 5.8 (mean, SD 0.7) IA treatments within 7-10 days. Sixteen patients received IA because of steroid-refractory relapse, eight were treated without preceding steroid pulse therapy. EDSS improved clinically relevant from 3.5 [median, interquartile range (IQR) 2] before IA to 2.5 (median, IQR 1.1) after IA, < 0.001. In patients with ON, VA improved in four out of five patients. Altogether, in 83% of patients, a rapid and marked improvement of relapse-related symptoms was observed after IA with either a decrease of ⩾1 EDSS grade or improvement in VA ⩾20%. No clinically relevant side effect was reported in 138 IA treatments.

Conclusions: Tryptophan-IA was found to be effective and well tolerated in MS/NMOSD relapses, both as an escalation option after insufficient response to steroid pulse therapy and as first-line relapse treatment during pregnancy and breastfeeding.
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http://dx.doi.org/10.1177/1756286418774973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974561PMC
May 2018

Alemtuzumab as rescue therapy in a cohort of 50 relapsing-remitting MS patients with breakthrough disease on fingolimod: a multi-center observational study.

J Neurol 2018 Jul 25;265(7):1521-1527. Epub 2018 Apr 25.

Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-University, Erlangen-Nürnberg, Germany.

Background: Relapsing-remitting multiple sclerosis (RRMS) requires efficient immunomodulatory treatment to reach "no evidence of disease activity" status at best. Alemtuzumab and fingolimod have proved to be efficient options in RRMS with active disease course. Yet, side effects and break-through disease may limit long-time treatment and necessitate switch of medication. Data on efficacy and safety of alemtuzumab following fingolimod treatment are limited, but useful for clinical practice.

Methods: Clinical and MRI data of 50 RRMS patients with a history of therapy switch from fingolimod to alemtuzumab were retrospectively analyzed. Data were acquired from nine large German MS Centers from 2013 to 2016 and analyzed using descriptive statistics.

Results: On average, patients with disease duration of 12.9 years and median EDSS of 3.0 at baseline switched to alemtuzumab after 68 weeks of fingolimod treatment. Thereafter, patients on alemtuzumab were followed for a mean of 64 weeks. The annualized relapse rate decreased from 2.2 in the year prior to 0.34 in the following year after switching to alemtuzumab and EDSS stabilized. In a subgroup of patients (n = 23), MRI data point to a reduction in enhancing (4.47 vs. 0.26) and new/enlarging T2 lesions (5.8 vs. 0.27) after treatment adjustment. Side effects were generally as expected from published data for alemtuzumab (autoimmunity 2/50, severe infections 1/50). One patient suffered combined lethal necrotizing leukoencephalopathy and hemolytic anemia.

Discussion: Therapy switch was highly effective in reducing clinical and MRI surrogates of disease activity and was mainly well tolerated within one year of follow-up. Hence, alemtuzumab constitutes a promising therapy in RRMS with refractory disease activity despite fingolimod treatment. Further studies are warranted to confirm these beneficial findings and to reveal safety concerns in the longer-term follow-up.
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http://dx.doi.org/10.1007/s00415-018-8871-2DOI Listing
July 2018

Treatment choices and neuropsychological symptoms of a large cohort of early MS.

Neurol Neuroimmunol Neuroinflamm 2018 May 1;5(3):e446. Epub 2018 Mar 1.

Department of Neurology (O.v.B., B.A., R.G., A.S.), St. Josef-Hospital, Ruhr-University Bochum; Institute of Medical Biometry and Statistics (T.D., N.H., A.Z.), University of Lübeck, University Hospital Schleswig-Holstein, Campus Lübeck; Central Information Office (CIO) (G.A.), Philipps-University Marburg, Germany; School of Mathematics (A.Z.), Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa; Department of Neurology (M.-M.H., L.A., B.H.), Klinikum rechts der Isar, Technical University of Munich; Munich Cluster for Systems Neurology (SyNergy) (L.A., B.H.); Department of Neurology (F.L., S.G., F.Z.), University Medicine Mainz, Johannes Gutenberg University Mainz; Department of Neurology (L.K., S.G.M., H.W.), University Hospital Münster; Department of Neurology (B.T.), Philipps-University Marburg; Department of Neurology (M.Stoppe, F.T.B.), University of Leipzig; Department of Neurology (H.T.), University of Ulm; Clinic of Neurology Dietenbronn (H.T.), Schwendi; Institute of Clinical Neuroimmunology (T.K.), Ludwig Maximilian University of Munich; Department of Neurology (M.Stangel), Hannover Medical School; Institut für Neuroimmunologie und Multiple Sklerose (C.H.), Universitätsklinikum Hamburg-Eppendorf; Department of Neurology (B.W.), University of Heidelberg; NeuroCure Clinical Research Center and Experimental and Clinical Research Center (F.P.), Charité-University Medicine Berlin and Max Delbrueck Center for Molecular Medicine; Department of Neurology (A.B.), Klinikum Augsburg; Department of Neurology (C.W.), Heinrich-Heine-University, Düsseldorf; Department of Neurology (C.W.), University Hospital Köln; Neurology (F.W.), Max-Planck-Institute of Psychiatry, Munich; Neurological Clinic (F.W.), MATERNUS Kliniken AG, Bad Oeynhausen; Department of Neurology (R.A.L.), University Hospital Erlangen; Department of Neurology & Stroke (U.Z.), Hertie Institute for Clinical Brain Research, Eberhard-Karls-University Tübingen; Department of Neurology (U.K.Z.), University of Rostock, Germany; and Department of Neurology (A.S.), Inselspital Bern, University Hospital and University of Bern, Switzerland.

Objective: To assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS.

Methods: The German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms.

Results: Of 1,124 patients, with a 2.2:1 female-to-male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06-40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded Disability Status Scale (EDSS) score at baseline was 1.5 (IQR: 1.0-2.0). A proportion of 67.8% of patients started DMT after a median time of 167.0 days (IQR 90.0-377.5) since the first manifestation. A total of 64.7% and 70.4% of the 762 patients receiving early DMT were classified as CIS and RRMS, respectively. Fatigue, depressive symptoms, and cognitive dysfunction were detected in 36.5%, 33.5%, and 14.7% of patients, respectively.

Conclusion: Baseline characteristics of this large cohort of patients with early, untreated MS corroborated with other cohorts. Most patients received early DMT within the first year after disease onset, irrespective of a CIS or RRMS diagnosis. Despite the low EDSS score, neuropsychological symptoms affected a relevant proportion of patients.
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http://dx.doi.org/10.1212/NXI.0000000000000446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833336PMC
May 2018

Role of Nuclear Factor (Erythroid-Derived 2)-Like 2 Signaling for Effects of Fumaric Acid Esters on Dendritic Cells.

Front Immunol 2017 22;8:1922. Epub 2017 Dec 22.

Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.

To date, the intracellular signaling pathways involved in dendritic cell (DC) function are poorly understood. The antioxidative transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) has been shown to affect maturation, function, and subsequent DC-mediated T cell responses of murine and human DCs. In experimental autoimmune encephalomyelitis (EAE), as prototype animal model for a T helper cell-mediated autoimmune disease, antigen presentation, cytokine production, and costimulation by DCs play a major role. We explore the role of Nrf2 in DC function, and DC-mediated T cell responses during T cell-mediated autoimmunity of the central nervous system using genetic ablation and pharmacological activation in mice and men to corroborate our data in a translational setting. In murine and human DCs, monomethyl fumarate induced Nrf2 signaling inhibits DC maturation and DC-mediated T cell proliferation by reducing inflammatory cytokine production and expression of costimulatory molecules. In contrast, Nrf2-deficient DCs generate more activated T helper cells (Th1/Th17) but fewer regulatory T cells and foster T cell proliferation. Transfer of DCs with Nrf2 activation during active EAE reduces disease severity and T cell infiltration. Our data demonstrate that Nrf2 signaling modulates autoimmunity in murine and human systems inhibiting DC maturation and function thus shedding further light on the mechanism of action of antioxidative stress pathways in antigen-presenting cells.
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http://dx.doi.org/10.3389/fimmu.2017.01922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5744071PMC
December 2017

Combination treatment of fingolimod with antidepressants in relapsing-remitting multiple sclerosis patients with depression: a multicentre, open-label study - REGAIN.

Ther Adv Neurol Disord 2016 Sep 3;9(5):378-88. Epub 2016 Jun 3.

Novartis Pharma, Nuremberg, Germany.

Objectives: Approximately one in two patients with multiple sclerosis (MS) suffer from comorbid depression. The primary objective of this study was to evaluate the safety and tolerability of fingolimod and antidepressant combination in relapsing-remitting MS patients with mild-to-moderate depression. Efficacy outcome variables were quality of life (QoL), fatigue, disability and depression.

Methods: Patients received open-label fingolimod 0.5 mg over 2 weeks, followed by fingolimod plus citalopram (40 mg), fluoxetine (40 mg) or venlafaxine (150 mg) over 16 weeks. The antidepressant was selected at the physician's discretion.

Results: In total, 54 patients were recruited at 25 centres across Germany. No new safety signals (including cardiac) emerged compared with previous clinical studies. Adverse events (mostly mild-to-moderate) were reported in 43 patients. A total of three patients had serious adverse events and 10 discontinued the study. QoL (mean [95% confidence interval]) improved by 2.2 (-3.3, -1.2; Patient Reported Indices for MS questionnaire), fatigue by 8.2 (-13.1, -3.3; modified Fatigue Impact Scale) and depression by 6.3 (-8.4, -4.2; Hamilton Depression Scale) points. However, the results must be interpreted cautiously owing to limited patient numbers.

Conclusions: Combination of fingolimod with antidepressant medication showed no unexpected safety signals. Patient-reported outcomes (QoL, disability, fatigue and depression) remained stable or improved.
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http://dx.doi.org/10.1177/1756285616651197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4994781PMC
September 2016

CEACAM1 mediates B cell aggregation in central nervous system autoimmunity.

Sci Rep 2016 07 20;6:29847. Epub 2016 Jul 20.

Department of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.

B cell aggregates in the central nervous system (CNS) have been associated with rapid disease progression in patients with multiple sclerosis (MS). Here we demonstrate a key role of carcinoembryogenic antigen-related cell adhesion molecule1 (CEACAM1) in B cell aggregate formation in MS patients and a B cell-dependent mouse model of MS. CEACAM1 expression was increased on peripheral blood B cells and CEACAM1(+) B cells were present in brain infiltrates of MS patients. Administration of the anti-CEACAM1 antibody T84.1 was efficient in blocking aggregation of B cells derived from MS patients. Along these lines, application of the monoclonal anti-CEACAM1 antibody mCC1 was able to inhibit CNS B cell aggregate formation and significantly attenuated established MS-like disease in mice in the absence of any adverse effects. CEACAM1 was co-expressed with the regulator molecule T cell immunoglobulin and mucin domain -3 (TIM-3) on B cells, a novel molecule that has recently been described to induce anergy in T cells. Interestingly, elevated coexpression on B cells coincided with an autoreactive T helper cell phenotype in MS patients. Overall, these data identify CEACAM1 as a clinically highly interesting target in MS pathogenesis and open new therapeutic avenues for the treatment of the disease.
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http://dx.doi.org/10.1038/srep29847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951702PMC
July 2016

Design of TRUST, a non-interventional, multicenter, 3-year prospective study investigating an integrated patient management approach in patients with relapsing-remitting multiple sclerosis treated with natalizumab.

BMC Neurol 2016 Jul 12;16:98. Epub 2016 Jul 12.

Department of Neurology and Center for Neuropsychiatry, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.

Background: Natalizumab provides rapid and high-efficacy control of multiple sclerosis disease activity with long-term stabilization. However, the benefits of the drug are countered by a risk of developing progressive multifocal leukoencephalopathy in patients infected with the John Cunningham Virus. Close monitoring is required in patients with increased progressive multifocal leukoencephalopathy risk receiving natalizumab in the long-term for an optimal benefit-risk evaluation. Standardized high-quality monitoring procedures may provide a superior basis for individual benefit and risk evaluation and thus improve treatment decisions. The non-interventional study TRUST was designed to capture natalizumab effectiveness under real-life conditions and to examine alternate approaches for clinical assessments, magnetic resonance imaging monitoring and use of biomarkers for progressive multifocal leukoencephalopathy risk stratification.

Methods/design: TRUST is a non-interventional, multicenter, prospective cohort study conducted at approximately 200 German neurological centers. The study is intended to enroll 1260 relapsing-remitting multiple sclerosis patients with ongoing natalizumab therapy for at least 12 months. Patients will be followed for a period of 3 years, irrespective of treatment changes after study start. Data on clinical, subclinical and patient-centric outcomes will be documented in order to compare the effectiveness of continuous versus discontinued natalizumab treatment. Furthermore, the type and frequency of clinical, magnetic resonance imaging and biomarker assessments, reasons for continuation or discontinuation of therapy and the safety profile of natalizumab will be collected to explore the impact of a systematic patient management approach and its potential impact on patient outcome. Specifically, the role of biomarkers, the use of expert opinions, the impact of high-frequency magnetic resonance imaging assessment for early progressive multifocal leukoencephalopathy detection and the role of additional radiological and clinical expert advice will be explored.

Discussion: TRUST was initiated in spring 2014 and enrollment is anticipated to be completed by mid 2016. Annual interim analyses will deliver continuous information and transparency with regard to the patient cohorts and the completeness and quality of data as well as closely monitor any safety signals in the natalizumab-treated cohort. The study's results may provide insights into opportunities to improve the benefit-risk assessment in clinical practice and support treatment decisions.
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http://dx.doi.org/10.1186/s12883-016-0625-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4942949PMC
July 2016

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

Sci Adv 2016 06 17;2(6):e1501678. Epub 2016 Jun 17.

Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, 35043 Marburg, Germany.

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.
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http://dx.doi.org/10.1126/sciadv.1501678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928990PMC
June 2016

The Correlation between the Virus- and Brain Antigen-Specific B Cell Response in the Blood of Patients with Multiple Sclerosis.

Viruses 2016 Apr 23;8(4):105. Epub 2016 Apr 23.

Department of Anatomy and Cell Biology, University of Wuerzburg, Koellikerstr. 6, 97070 Wuerzburg, Germany.

There is a largely divergent body of literature regarding the relationship between Epstein-Barr virus (EBV) infection and brain inflammation in multiple sclerosis (MS). Here, we tested MS patients during relapse (n = 11) and in remission (n = 19) in addition to n = 22 healthy controls to study the correlation between the EBV- and brain-specific B cell response in the blood by enzyme-linked immunospot (ELISPOT) and enzyme-linked immunosorbent assay (ELISA). Cytomegalovirus (CMV) was used as a control antigen tested in n = 16 MS patients during relapse and in n = 35 patients in remission. Over the course of the study, n = 16 patients were untreated, while n = 33 patients received immunomodulatory therapy. The data show that there was a moderate correlation between the frequencies of EBV- and brain-reactive B cells in MS patients in remission. In addition we could detect a correlation between the B cell response to EBV and disease activity. There was no evidence of an EBV reactivation. Interestingly, there was also a correlation between the frequencies of CMV- and brain-specific B cells in MS patients experiencing an acute relapse and an elevated B cell response to CMV was associated with higher disease activity. The trend remained when excluding seronegative subjects but was non-significant. These data underline that viral infections might impact the immunopathology of MS, but the exact link between the two entities remains subject of controversy.
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http://dx.doi.org/10.3390/v8040105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4848599PMC
April 2016

Successful Replication of GWAS Hits for Multiple Sclerosis in 10,000 Germans Using the Exome Array.

Genet Epidemiol 2015 Dec 26;39(8):601-8. Epub 2015 Oct 26.

Max-Planck-Institut für Psychiatrie, Munich, Germany.

Genome-wide association studies (GWAS) successfully identified various chromosomal regions to be associated with multiple sclerosis (MS). The primary aim of this study was to replicate reported associations from GWAS using an exome array in a large German study. German MS cases (n = 4,476) and German controls (n = 5,714) were genotyped using the Illumina HumanExome v1-Chip. Genotype calling was performed with the Illumina Genome Studio(TM) Genotyping Module, followed by zCall. Single-nucleotide polymorphisms (SNPs) in seven regions outside the human leukocyte antigen (HLA) region showed genome-wide significant associations with MS (P values < 5 × 10(-8) ). These associations have been reported previously. In addition, SNPs in three previously reported regions outside the HLA region yielded P values < 10(-5) . The effect of nine SNPs in the HLA region remained (P < 10(-5) ) after adjustment for other significant SNPs in the HLA region. All of these findings have been reported before or are driven by known risk loci. In summary, findings from previous GWAS for MS could be successfully replicated. We conclude that the regions identified in previous GWAS are also associated in the German population. This reassures the need for detailed investigations of the functional mechanisms underlying the replicated associations.
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http://dx.doi.org/10.1002/gepi.21933DOI Listing
December 2015

The brain antigen-specific B cell response correlates with glatiramer acetate responsiveness in relapsing-remitting multiple sclerosis patients.

Sci Rep 2015 Sep 21;5:14265. Epub 2015 Sep 21.

Department of Anatomy and Cell Biology, University of Würzburg, Würzburg, Germany.

B cells have only recently begun to attract attention in the immunopathology of multiple sclerosis (MS). Suitable markers for the prediction of treatment success with immunomodulatory drugs are still missing. Here we evaluated the B cell response to brain antigens in n = 34 relapsing-remitting MS (RRMS) patients treated with glatiramer acetate (GA) using the enzyme-linked immunospot technique (ELISPOT). Our data demonstrate that patients can be subdivided into responders that show brain-specific B cell reactivity in the blood and patients without this reactivity. Only in patients that classified as B cell responders, there was a significant positive correlation between treatment duration and the time since last relapse in our study. This correlation was GA-specific because it was absent in a control group that consisted of interferon-ß (IFN-β)-treated RRMS patients (n = 23). These data suggest that GA has an effect on brain-reactive B cells in a subset of patients and that only this subset benefits from treatment. The detection of brain-reactive B cells is likely to be a suitable tool to identify drug responders.
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http://dx.doi.org/10.1038/srep14265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4585696PMC
September 2015

Listeria Meningitis Complicating Alemtuzumab Treatment in Multiple Sclerosis--Report of Two Cases.

Int J Mol Sci 2015 Jun 29;16(7):14669-76. Epub 2015 Jun 29.

Department of Neurology, Klinikum Augsburg, Augsburg 86156, Germany.

Alemtuzumab, a humanized monoclonal antibody targeting the surface molecule CD52, leads to a rapid depletion of immune cells in the innate and adaptive immune system. In phase 2 and 3 trials in multiple sclerosis (MS), infections have been reported more frequently in alemtuzumab than in interferon beta treated patients. Here we report two patients treated with alemtuzumab for MS developing Listeria meningitis few days after the first infusion cycle. Both patients recovered completely after prompt diagnosis and adequate treatment. Physicians and patients should be aware of this serious, but treatable complication.
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http://dx.doi.org/10.3390/ijms160714669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519865PMC
June 2015

Adherence to, and effectiveness of, subcutaneous interferon β-1a administered by RebiSmart® in patients with relapsing multiple sclerosis: results of the 1-year, observational SMART study.

Expert Opin Drug Deliv 2015 Aug 22;12(8):1239-50. Epub 2015 Jun 22.

Department of Neurology, Klinikum Augsburg , Stenglinstr 2, D-86156, Augsburg , Germany +49 821 400 3892 ; +49 821 400 2691 ;

Background: Patients with multiple sclerosis who have poor adherence to treatment have a higher risk of relapse than adherent patients. This study assessed adherence to, and effectiveness and convenience of, treatment with subcutaneous (sc) interferon (IFN) β-1a (Rebif®, Merck Serono SA) 44 or 22 μg three times weekly in patients with relapsing multiple sclerosis (RMS) using the RebiSmart® electronic, multidose, autoinjector for 1 year.

Study Design: European, multicentre, observational study among neurologists: inclusion criteria included RMS, Expanded Disability Status Scale score ≤ 6, sc IFN β-1a administered by RebiSmart for ≤ 6 weeks. The primary endpoint was cumulative adherence recorded by RebiSmart.

Results: The safety population included 912 patients, 77.4% (n = 823) of whom completed the Month-12 visit. Mean (± standard deviation) cumulative adherence was 97.1 ± 7.3% (n = 791). The most common reason for missed injection was 'forgot to inject' (37.0%). At Month 12/ED, 79.5% of patients were relapse-free. Of 353 patients who rated the convenience of the device, 68.3% found injecting 'very easy'. No unknown safety issues were detected.

Conclusions: Patients with RMS self-injecting sc IFN β-1a with RebiSmart had excellent adherence at Month 12/ED, which was associated with good clinical outcomes and no unexpected safety issues. Patients rated RebiSmart as convenient and easy to use.
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http://dx.doi.org/10.1517/17425247.2015.1057567DOI Listing
August 2015
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