Publications by authors named "Tobias Derfuss"

104 Publications

Impact of COVID-19 on multiple sclerosis care and management: Results from the European Committee for Treatment and Research in Multiple Sclerosis survey.

Mult Scler 2021 Mar 25:13524585211005339. Epub 2021 Mar 25.

Department of Neurofarba, University of Florence, Florence, Italy/IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Background: The spread of Coronavirus disease-19 (COVID-19) poses unique challenges in the management of people with multiple sclerosis (PwMS).

Objectives: To collect data about the impact of COVID-19 emergency on access to care for PwMS and on MS treatment practices.

Methods: Between March and July 2020, the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) promoted an online survey covering patient access to care, management of relapses and visits, disease-modifying therapy (DMT) and experience with COVID-19.

Results: Three-hundred and sixty neurologists from 52 countries (68% from Europe) completed the survey. 98% reported COVID-19-related restrictions. Telemedicine was adopted to overcome the limited access to care and was newly activated (73%) or widely implemented (17%). 70% reported changes in DMT management. Interferons and glatiramer were considered safe. Dimethyl fumarate, teriflunomide and fingolimod were considered safe except for patients developing lymphopenia. No modifications were considered for natalizumab in 64%, cladribine in 24%, anti-CD20 in 22% and alemtuzumab in 17%; 18% (for alemtuzumab and cladribine) and 43% (for anti-CD20) considered postponing treatment.

Conclusion: The ECTRIMS survey highlighted the challenges in keeping standards of care in clinical practice. Telemedicine clearly needs to be implemented. Gathering data on DMT safety will remain crucial to inform treatment decisions.
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http://dx.doi.org/10.1177/13524585211005339DOI Listing
March 2021

Mass Cytometry of CSF Identifies an MS-Associated B-cell Population.

Neurol Neuroimmunol Neuroinflamm 2021 03 15;8(2). Epub 2021 Feb 15.

From the Department of Biomedicine (D.J., J.R., E.G., I.C., M.D., J.K., T.D., N.S.R.S.), University Hospital Basel, University of Basel; Novartis Institutes for BioMedical Research (C. Rauld, C. Regairaz, L.R., A.W., R.C., G.R., J.M.C.); Swiss Institute of Bioinformatics (J.R.), Basel; Institute of Experimental Immunology (E.G., B.B.), University of Zurich; and Department of Medicine (E.G., M.D., J.K., T.D.), Neurologic Clinic and Policlinic, University Hospital and University of Basel, Switzerland.

Objective: To identify an MS-specific immune cell population by deep immune phenotyping and relate it to soluble signaling molecules in CSF.

Methods: We analyzed surface expression of 22 markers in paired blood/CSF samples from 39 patients using mass cytometry (cytometry by time of flight). We also measured the concentrations of 296 signaling molecules in CSF using proximity extension assay. Results were analyzed using highly automated unsupervised algorithmic informatics.

Results: Mass cytometry objectively identified a B-cell population characterized by the expression of CD49d, CD69, CD27, CXCR3, and human leukocyte antigen (HLA)-DR as clearly associated with MS. Concentrations of the B cell-related factors, notably FCRL2, were increased in MS CSF, especially in early stages of the disease. The B-cell trophic factor B cell activating factor (BAFF) was decreased in MS. Proteins involved in neural plasticity were also reduced in MS.

Conclusion: When analyzed without a priori assumptions, both the soluble and the cellular compartments of the CSF in MS were characterized by markers related to B cells, and the strongest candidate for an MS-specific cell type has a B-cell phenotype.
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http://dx.doi.org/10.1212/NXI.0000000000000943DOI Listing
March 2021

Combination of teriflunomide and interferon as follow-up therapy after fingolimod-associated PML.

Neurol Neuroimmunol Neuroinflamm 2021 01 3;8(1). Epub 2020 Dec 3.

From the Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland.

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http://dx.doi.org/10.1212/NXI.0000000000000927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803336PMC
January 2021

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium.

PLoS Med 2020 10 30;17(10):e1003348. Epub 2020 Oct 30.

CESP, INSERM UMR 1018, Faculty of Medicine, Paris-Sud University, UVSQ, Paris-Saclay University, Villejuif, France.

Background: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited.

Methods And Findings: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings.

Conclusion: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.
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http://dx.doi.org/10.1371/journal.pmed.1003348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598520PMC
October 2020

Comparative analysis of dimethyl fumarate and fingolimod in relapsing-remitting multiple sclerosis.

J Neurol 2021 Mar 24;268(3):941-949. Epub 2020 Sep 24.

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing-remitting multiple sclerosis (RRMS).

Objective: To compare the effectiveness of dimethyl fumarate and fingolimod in a real-world setting, where both agents are licensed as a first-line DMT for the treatment of RRMS.

Methods: We identified patients with RRMS commencing dimethyl fumarate or fingolimod in the Swiss Federation for Common Tasks of Health Insurances (SVK) Registry between August 2014 and July 2019. Propensity score-matching was applied to select subpopulations with comparable baseline characteristics. Relapses and disability outcomes were compared in paired, pairwise-censored analyses.

Results: Of the 2113 included patients, 1922 were matched (dimethyl fumarate, n = 961; fingolimod, n = 961). Relapse rates did not differ between the groups (incident rate ratio 1.0, 95%CI 0.8-1.2, p = 0.86). Moreover, no difference in the hazard of 1-year confirmed disability worsening (hazard ratio [HR] 0.9; 95%CI 0.6-1.6; p = 0.80) or disability improvement (HR 0.9; 95%CI 0.6-1.2; p = 0.40) was detected. These findings were consistent both for treatment-naïve patients and patients switching from another DMT.

Conclusion: Dimethyl fumarate and fingolimod have comparable effectiveness regarding reduction of relapses and disability worsening in RRMS.
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http://dx.doi.org/10.1007/s00415-020-10226-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914245PMC
March 2021

Lymphocyte recovery after fingolimod discontinuation in patients with MS.

Neurol Neuroimmunol Neuroinflamm 2020 11 14;7(6). Epub 2020 Aug 14.

From the Department of Neurology (S.N., J.K., T.D.), University Hospital Basel, University of Basel; Division of Developmental- and Neuropaediatrics (S.N.), University Children's Hospital of Basel (UKBB), University of Basel; and Department of Biomedicine (J.K., T.D.), University Hospital Basel, Switzerland.

Objective: To investigate the dynamics of immune cells recovery after treatment discontinuation of fingolimod in real-life clinical practice, we analyzed the course of lymphocyte reconstitution and its potential influencing factors in patients with multiple sclerosis (MS).

Methods: We analyzed leukocyte, lymphocyte, and granulocyte counts of 58 patients at 3, 6, and 12 months after fingolimod cessation and the following parameters as potential risk factors for a prolonged lymphopenia up to 12 months: age; sex; Expanded Disability Status Scale, and disease duration at the time of fingolimod start; type and number of previous immunomodulatory treatments; fingolimod treatment duration; lymphocyte count at baseline before fingolimod, at fingolimod stop, and at the time of therapy switch; time interval between fingolimod cessation and new treatment initiation; type of the follow-up immunomodulatory treatment; and corticosteroid administration after fingolimod cessation.

Results: All patients showed a drop of the lymphocyte count under fingolimod with no relevant leukopenia or neutropenia. One year after discontinuation, still 22% of the patients were lymphopenic and 54% of them did not reach 80% of the baseline lymphocyte value. Low lymphocyte counts before fingolimod start, under fingolimod, and at therapy switch, successive treatment with rituximab, and pretreatment with mitoxantrone were significantly associated with a prolonged immune cell recovery.

Conclusions: Prolonged lymphopenia after fingolimod cessation exists in a subgroup of patients with MS and should be considered in clinical practice, particularly when changing treatment regimens.
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http://dx.doi.org/10.1212/NXI.0000000000000874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641093PMC
November 2020

Aggressive multiple sclerosis (1): Towards a definition of the phenotype.

Mult Scler 2020 06 12:1352458520925369. Epub 2020 Jun 12.

Department of Clinical Neuroscience, Division of Neurology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden.

While the major phenotypes of multiple sclerosis (MS) and relapsing-remitting, primary and secondary progressive MS have been well characterized, a subgroup of patients with an active, aggressive disease course and rapid disability accumulation remains difficult to define and there is no consensus about their management and treatment. The current lack of an accepted definition and treatment guidelines for aggressive MS triggered a 2018 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on aggressive MS. The aim of the workshop was to discuss approaches on how to describe and define the disease phenotype and its treatments. Unfortunately, it was not possible to come to consensus on a definition because of unavailable data correlating severe disease with imaging and molecular biomarkers. However, the workshop highlighted the need for future research needed to define this disease subtype while also focusing on its treatment and management. Here, we review previous attempts to define aggressive MS and present characteristics that might, with additional research, eventually help characterize it. A companion paper summarizes data regarding treatment and management.
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http://dx.doi.org/10.1177/1352458520925369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412876PMC
June 2020

Aggressive multiple sclerosis (2): Treatment.

Mult Scler 2020 06 12:1352458520924595. Epub 2020 Jun 12.

Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Vall d'Hebron Institut de Recerca, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

The natural history of multiple sclerosis (MS) is highly heterogeneous. A subgroup of patients has what might be termed aggressive MS. These patients may have frequent, severe relapses with incomplete recovery and are at risk of developing greater and permanent disability at the earlier stages of the disease. Their therapeutic window of opportunity may be narrow, and while it is generally considered that they will benefit from starting early with a highly efficacious treatment, a unified definition of aggressive MS does not exist and data on its treatment are largely lacking. Based on discussions at an international focused workshop sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), we review our current knowledge about treatment of individuals with aggressive MS. We analyse the available evidence, identify gaps in knowledge and suggest future research needed to fill those gaps. A companion paper details the difficulties in developing a consensus about what defines aggressive MS.
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http://dx.doi.org/10.1177/1352458520924595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412878PMC
June 2020

Disability progression multiple sclerosis patients on fingolimod versus interferon-beta/glatiramer acetate.

Mult Scler 2021 03 28;27(3):439-448. Epub 2020 May 28.

Neurologic Clinic and Policlinic, Departments of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland.

Background: Disability progression independent of relapses (PIRA) has been described as a frequent phenomenon in relapsing-remitting multiple sclerosis (RRMS).

Objective: To compare the occurrence of disability progression in relapse-free RRMS patients on interferon-beta/glatiramer acetate (IFN/GA) versus fingolimod.

Methods: This study is based on data from the Swiss association for joint tasks of health insurers. Time to relapse and 12-month confirmed disability progression were compared between treatment groups using multivariable Cox regression analysis with confounder adjustment. Inverse-probability weighting was applied to correct for the bias that patients on fingolimod have a higher chance to remain relapse-free than patients on IFN/GA.

Results: We included 1640 patients (64% IFN/GA, 36% fingolimod, median total follow-up time = 4-5 years). Disease-modifying treatment (DMT) groups were well balanced with regard to potential confounders. Disability progression was observed in 155 patients (8.8%) on IFN/GA and 51 (7.6%) on fingolimod, of which 44 and 23 were relapse-free during the initial DMT, respectively. Adjusted standard regression analysis on all patients indicated that those on fingolimod experience less frequently disability progression compared with IFN/GA (hazard ratio = 0.53 (95% confidence interval = 0.37-0.76)). After bias correction, this was also true for patients without relapses (hazard ratio=0.56 (95% confidence interval = 0.32-0.98).

Conclusion: Our analysis indicates that fingolimod is superior to IFN/GA in preventing disability progression in both relapsing , young, newly diagnosed RRMS patients.
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http://dx.doi.org/10.1177/1352458520918489DOI Listing
March 2021

Selective inhibition of anti-MAG IgM autoantibody binding to myelin by an antigen-specific glycopolymer.

J Neurochem 2020 09 23;154(5):486-501. Epub 2020 Jun 23.

Institute of Molecular Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.

Anti-myelin-associated glycoprotein (MAG) neuropathy is a disabling autoimmune peripheral neuropathy that is caused by circulating monoclonal IgM autoantibodies directed against the human natural killer-1 (HNK-1) epitope. This carbohydrate epitope is highly expressed on adhesion molecules such as MAG, a glycoprotein present in myelinated nerves. We previously showed the therapeutic potential of the glycopolymer poly(phenyl disodium 3-O-sulfo-β-d-glucopyranuronate)-(1→3)-β-d-galactopyranoside (PPSGG) in selectively neutralizing anti-MAG IgM antibodies in an immunological mouse model and ex vivo with sera from anti-MAG neuropathy patients. PPSGG is composed of a biodegradable backbone that multivalently presents a mimetic of the HNK-1 epitope. In this study, we further explored the pharmacodynamic properties of the glycopolymer and its ability to inhibit the binding of anti-MAG IgM to peripheral nerves. The polymer selectively bound anti-MAG IgM autoantibodies and prevented the binding of patients' anti-MAG IgM antibodies to myelin of non-human primate sciatic nerves. Upon PPSGG treatment, neither activation nor inhibition of human and murine peripheral blood mononuclear cells nor alteration of systemic inflammatory markers was observed in mice or ex vivo in human peripheral blood mononuclear cells. Intravenous injections of PPSGG to mice immunized against the HNK-1 epitope removed anti-MAG IgM antibodies within less than 1 hr, indicating a fast and efficient mechanism of action as compared to a B-cell depletion with anti-CD20. In conclusion, these observations corroborate the therapeutic potential of PPSGG for an antigen-specific treatment of anti-MAG neuropathy. Read the Editorial Highlight for this article on page 465.
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http://dx.doi.org/10.1111/jnc.15021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497077PMC
September 2020

Advances in oral immunomodulating therapies in relapsing multiple sclerosis.

Lancet Neurol 2020 04 11;19(4):336-347. Epub 2020 Feb 11.

Neurology Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedicine University Hospital Basel, University of Basel, Basel, Switzerland; Department of Biomedical Engineering, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Oral treatment options for disease-modifying therapy in relapsing multiple sclerosis have substantially increased over the past decade with four approved oral compounds now available: fingolimod, dimethyl fumarate, teriflunomide, and cladribine. Although these immunomodulating therapies are all orally administered, and thus convenient for patients, they have different modes of action. These distinct mechanisms of action allow better adaption of treatments according to individual comorbidities and offer different mechanisms of treatment such as inhibition of immune cell trafficking versus immune cell depletion, thereby substantially expanding the available treatment options.

Recent Developments: New sphingosine-1-phosphate receptor (S1PR) modulators with more specific S1PR target profiles and potentially better safety profiles compared with fingolimod were tested in patients with relapsing multiple sclerosis. For example, siponimod, which targets S1PR1 and S1PR5, was approved in March, 2019, by the US Food and Drug Administration for the treatment of relapsing multiple sclerosis including active secondary progressive multiple sclerosis. Ozanimod, another S1P receptor modulator in the approval stage that also targets S1PR1 and S1PR5, reduced relapse rates and MRI activity in two phase 3 trials of patients with relapsing multiple sclerosis. Blocking of matrix metalloproteinases or tyrosine kinases are novel modes of action in the treatment of relapsing multiple sclerosis, which are exhibited by minocycline and evobrutinib, respectively. Minocycline reduced conversion to multiple sclerosis in patients with a clinically isolated syndrome. Evobrutinib reduced MRI activity in a phase 2 trial, and a phase 3 trial is underway, in patients with relapsing multiple sclerosis. Diroximel fumarate is metabolised to monomethyl fumarate, the active metabolite of dimethyl fumarate, reduces circulating lymphocytes and modifies the activation profile of monocytes, and is being tested in this disease with the aim to improve gastrointestinal tolerability. The oral immunomodulator laquinimod did not reach the primary endpoint of reduction in confirmed disability progression in a phase 3 trial of patients with relapsing multiple sclerosis. In a phase 2 trial of patients with primary progressive multiple sclerosis, laquinimod also did not reach the primary endpoint of a reduction in brain volume loss, as a consequence the development of this drug will probably not be continued in multiple sclerosis. WHERE NEXT?: Several new oral compounds are in late-stage clinical development. With new modes of action introduced to the treatment of multiple sclerosis, the question of how to select and sequence different treatments in individual patients arises. Balancing risks with the expected efficacy of disease-modifying therapies will still be key for treatment selection. However, risks as well as efficacy can change when moving from the controlled clinical trial setting to clinical practice. Because some oral treatments, such as cladribine, have long-lasting effects on the immune system, the cumulative effects of sequential monotherapies can resemble the effects of a concurrent combination therapy. This treatment scheme might lead to higher efficacy but also to new safety concerns. These sequential treatments were largely excluded in phase 2 and 3 trials; therefore, monitoring both short-term and long-term effects of sequential disease-modifying therapies in phase 4 studies, cohort studies, and registries will be necessary.
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http://dx.doi.org/10.1016/S1474-4422(19)30391-6DOI Listing
April 2020

PARP-1 deregulation in multiple sclerosis.

Mult Scler J Exp Transl Clin 2019 Oct-Dec;5(4):2055217319894604. Epub 2019 Dec 16.

Departments of Biomedicine and Neurology, University Hospital Basel, Switzerland.

Background: Poly (ADP-ribose) polymerase 1 (PARP-1) plays pivotal roles in immune and inflammatory responses. Accumulating evidence suggests PARP-1 as a promising target for immunomodulation in multiple sclerosis and natalizumab-associated progressive multifocal leukoencephalopathy.

Objective: This study explores expression of PARP-1 and downstream effectors in multiple sclerosis and during natalizumab treatment.

Methods: Transcriptional expressions were studied by real-time reverse transcriptase polymerase chain reaction on CD4T/CD8T/CD14/B cells and peripheral blood mononuclear cells from healthy volunteers, untreated and natalizumab-treated non-progressive multifocal leukoencephalopathy and progressive multifocal leukoencephalopathy multiple sclerosis patients.

Results: PARP-1 expression was higher in CD4T, CD8T and B cells from untreated patients compared to healthy volunteers. Natalizumab treatment restored deregulated PARP-1 expression in T cells but not in B cells. Sustained upregulation of PARP-1 was associated with decreased expression of downstream PARP-1 factors such as TGFBR1/TGFBR2/BCL6 in B cells. Notably, a higher expression of PARP-1 was detected in progressive multifocal leukoencephalopathy patients.

Conclusions: Given the importance of PARP-1 in inflammatory processes, its upregulation in multiple sclerosis lymphocyte populations suggests a potential role in the immune pathogenesis of multiple sclerosis. Strikingly higher PARP-1 expression in progressive multifocal leukoencephalopathy cases suggests its involvement in progressive multifocal leukoencephalopathy disease pathomechanisms. These results further support the value of PARP-1 inhibitors as a potential novel therapeutic strategy for multiple sclerosis and natalizumab-associated progressive multifocal leukoencephalopathy.
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http://dx.doi.org/10.1177/2055217319894604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6918498PMC
December 2019

New and enlarging white matter lesions adjacent to the ventricle system and thalamic atrophy are independently associated with lateral ventricular enlargement in multiple sclerosis.

J Neurol 2020 Jan 14;267(1):192-202. Epub 2019 Oct 14.

Neurologic Clinic and Policlinic, Departments of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland.

Objective: To investigate the association between new or enlarging T2-weighted (w) white matter (WM) lesions adjacent to the ventricle wall, deep grey matter (DGM) atrophy and lateral ventricular enlargement in multiple sclerosis (MS).

Methods: Patients derived from the Genetic Multiple Sclerosis Associations study. Lateral ventricles and DGM were segmented fully automated at baseline and 5 years follow-up using Automatic Lateral Ventricle delineation (ALVIN) and Multiple Automatically Generated Templates brain segmentation algorithm (MAgeT), respectively. T2w and T1w lesions were manually segmented. To investigate the association between lesion distance to the ventricle wall and the lateral ventricle volume, we parcellated the WM into concentric periventricular bands using FMRIB Software Library. Associations between clinical and MRI parameters were assessed in generalized linear models using generalized estimating equations for repeated measures.

Results: We studied 127 MS patients. Lateral ventricles enlarged on average by 2.4%/year. Patients with new/enlarging T2w WM lesions between baseline and follow-up at 5 years had accelerated lateral ventricular enlargement compared with patients without (p = 0.004). This was true in a multivariable analysis adjusted for age, gender, and whole brain atrophy. When looking at the T2w lesions in different periventricular bands, we found the strongest association between new/enlarging T2w lesions and lateral ventricle enlargement for WM lesions adjacent to the ventricle system (p < 0.001). Moreover, and indepedent of new/enlarging WM lesions, DGM atrophy was associated with ventricular enlargement. In a multivariable analysis, this was driven by thalamic atrophy (p < 0.001).

Conclusion: New/enlarging T2w lesions adjacent to the ventricle system and thalamic atrophy are independently associated with lateral ventricular enlargement in MS.
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http://dx.doi.org/10.1007/s00415-019-09565-wDOI Listing
January 2020

Hepatitis E virus infections in patients with MS on oral disease-modifying treatment.

Neurol Neuroimmunol Neuroinflamm 2019 09 11;6(5). Epub 2019 Jul 11.

From the Departments of Medicine, University Hospital Basel, Neurologic Clinic and Policlinic, Clinical Research and Biomedicine, University of Basel, Petersgraben, Switzerland.

Objective: To test whether patients with MS on disease-modifying treatments (DMTs) are at a higher risk of acute or chronic hepatitis E virus (HEV) infections or extrahepatic manifestations, we monitored approximately 1,100 persons with MS (pwMS) during 3 years for HEV infection.

Methods: This is an observational case series study. All pwMS were followed in our MS center between January 2016 and December 2018 with at least annual standardized clinical and laboratory assessments. Patients with unexplained liver enzyme elevations were routinely screened for HEV infection.

Results: Four cases of acute HEV under DMT (fingolimod [n = 3]; dimethyl fumarate [n = 1]) were identified. Two presented with fulminant icteric hepatitis and one with a HEV-associated neurologic manifestation (neuralgic amyotrophy). No chronic HEV courses were observed. DMT was continued after clearing of HEV or normalization of liver function tests in all cases.

Conclusion: HEV infection is an important differential diagnosis of drug-induced liver injury in pwMS under DMT. Our data do not suggest an increased incidence of acute HEV infections or chronification in pwMS. However, epidemiologic studies in immunomodulatory-treated patients are needed to further investigate HEV disease courses and extrahepatic manifestations.
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http://dx.doi.org/10.1212/NXI.0000000000000594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705628PMC
September 2019

PML with dimethyl fumarate-No convincing case against natalizumab.

Mult Scler 2019 10 22;25(12):1687-1688. Epub 2019 Aug 22.

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

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http://dx.doi.org/10.1177/1352458519872894DOI Listing
October 2019

GM-CSF and CXCR4 define a T helper cell signature in multiple sclerosis.

Nat Med 2019 08 22;25(8):1290-1300. Epub 2019 Jul 22.

Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.

Cytokine dysregulation is a central driver of chronic inflammatory diseases such as multiple sclerosis (MS). Here, we sought to determine the characteristic cellular and cytokine polarization profile in patients with relapsing-remitting multiple sclerosis (RRMS) by high-dimensional single-cell mass cytometry (CyTOF). Using a combination of neural network-based representation learning algorithms, we identified an expanded T helper cell subset in patients with MS, characterized by the expression of granulocyte-macrophage colony-stimulating factor and the C-X-C chemokine receptor type 4. This cellular signature, which includes expression of very late antigen 4 in peripheral blood, was also enriched in the central nervous system of patients with relapsing-remitting multiple sclerosis. In independent validation cohorts, we confirmed that this cell population is increased in patients with MS compared with other inflammatory and non-inflammatory conditions. Lastly, we also found the population to be reduced under effective disease-modifying therapy, suggesting that the identified T cell profile represents a specific therapeutic target in MS.
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http://dx.doi.org/10.1038/s41591-019-0521-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689469PMC
August 2019

A case of progressive multifocal leukoencephalopathy under dimethyl fumarate treatment without severe lymphopenia or immunosenescence.

Mult Scler 2019 10 18;25(12):1682-1685. Epub 2019 Jun 18.

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Progressive multifocal leukoencephalopathy (PML) is the main safety concern for dimethyl fumarate (DMF) treatment in persons with multiple sclerosis (pwMS). Risk stratification under DMF is currently based on age above 50 years and prolonged lymphopenia below 500 cells/μL.

Objective: To report a case of PML under DMF without severe lymphopenia or immunosenescence.

Methods: Case report.

Results: A 39-year-old female pwMS developed DMF-associated oligosymptomatic PML. The patient had not experienced any repeated lymphocyte counts below 800 cells/μL and was 15 years younger than previously described cases.

Conclusion: Despite risk stratification, vigilance for PML is advised in all pwMS under DMF. Severe CD8-lymphopenia is a common feature of all published DMF-associated cases.
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http://dx.doi.org/10.1177/1352458519852100DOI Listing
October 2019

Antigen Extraction and B Cell Activation Enable Identification of Rare Membrane Antigen Specific Human B Cells.

Front Immunol 2019 16;10:829. Epub 2019 Apr 16.

Department of Medicine, Neurologic Clinic and Policlinic, University Hospital and University of Basel, Basel, Switzerland.

Determining antigen specificity is vital for understanding B cell biology and for producing human monoclonal antibodies. We describe here a powerful method for identifying B cells that recognize membrane antigens expressed on cells. The technique depends on two characteristics of the interaction between a B cell and an antigen-expressing cell: antigen-receptor-mediated extraction of antigen from the membrane of the target cell, and B cell activation. We developed the method using influenza hemagglutinin as a model viral membrane antigen, and tested it using acetylcholine receptor (AChR) as a model membrane autoantigen. The technique involves co-culturing B cells with adherent, bioorthogonally labeled cells expressing GFP-tagged antigen, and sorting GFP-capturing, newly activated B cells. Hemagglutinin-specific B cells isolated this way from vaccinated human donors expressed elevated CD20, CD27, CD71, and CD11c, and reduced CD21, and their secreted antibodies blocked hemagglutination and neutralized viral infection. Antibodies cloned from AChR-capturing B cells derived from patients with myasthenia gravis bound specifically to the receptor on cell membrane. The approach is sensitive enough to detect antigen-specific B cells at steady state, and can be adapted for any membrane antigen.
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http://dx.doi.org/10.3389/fimmu.2019.00829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477023PMC
September 2020

A case of concomitant psoriasis and multiple sclerosis: Secukinumab and rituximab exert dichotomous effects in two autoimmune conditions.

Mult Scler Relat Disord 2019 Jun 9;31:38-40. Epub 2019 Mar 9.

Neurological Clinic and Policlinic, University Hospital and University of Basel, Basel, Switzerland.

Background: Multiple sclerosis (MS) and psoriasis vulgaris (PV) are two disorders with autoimmune pathophysiology and a supposed altered T helper (T) cell response.

Objective: To report a case of concomitant relapsing remitting MS and PV treated with different immunomodulatory medications, particularly secukinumab and rituximab.

Methods: Case report.

Results: In a 68-year-old woman diagnosed with MS and PV, secukinumab alleviated the dermatological condition, but could not control neuroinflammation. Rituximab treatment halted MS activity, but led to a flare-up of dermatological inflammation.

Conclusion: The presented case suggests that the pathomechanisms of MS and PV differ regarding involvement of T and B cells with implications for therapeutic approaches.
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http://dx.doi.org/10.1016/j.msard.2019.03.009DOI Listing
June 2019

Quantitative 7T MRI does not detect occult brain damage in neuromyelitis optica.

Neurol Neuroimmunol Neuroinflamm 2019 05 7;6(3):e541. Epub 2019 Mar 7.

Neurologic Clinic and Policlinic (B.P., T.J.D., T.S.), Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland; NeuroCure Clinical Research Center (N.B., L.R., J.B.-S., F.P., T.S.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Department of Neurology (N.B., J.B.-S., K.R., F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Experimental and Clinical Research Center (F.P.), Charité-Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine; Clinical and Experimental Multiple Sclerosis Research Center (K.R., F.P.), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Berlin Ultrahigh Field Facility (T.N.), Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Germany; Medical Image Analysis Center AG (J.W., T.S.); and qbig (J.W.), Department of Biomedical Engineering, University of Basel, Basel, Switzerland.

Objective: To investigate and compare occult damages in aquaporin-4 (AQP4)-rich periependymal regions in patients with neuromyelitis optica spectrum disorder (NMOSD) vs healthy controls (HCs) and patients with multiple sclerosis (MS) applying quantitative T1 mapping at 7 Tesla (T) in a cross-sectional study.

Methods: Eleven patients with NMOSD (median Expanded Disability Status Scale [EDSS] score 3.5, disease duration 9.3 years, age 43.7 years, and 11 female) seropositive for anti-AQP4 antibodies, 7 patients with MS (median EDSS score 1.5, disease duration 3.6, age 30.2 years, and 4 female), and 10 HCs underwent 7T MRI. The imaging protocol included T2*-weighted (w) imaging and an MP2RAGE sequence yielding 3D T1w images and quantitative T1 maps. We semiautomatically marked the lesion-free periependymal area around the cerebral aqueduct and the lateral, third, and fourth ventricles to finally measure and compare the T1 relaxation time within these areas.

Results: We did not observe any differences in the T1 relaxation time between patients with NMOSD and HCs (all > 0.05). Contrarily, the T1 relaxation time was longer in patients with MS vs patients with NMOSD (lateral ventricle = 0.056, third ventricle = 0.173, fourth ventricle = 0.016, and cerebral aqueduct = 0.048) and vs HCs (third ventricle = 0.027, fourth ventricle = 0.013, lateral ventricle = 0.043, and cerebral aqueduct = 0.005).

Conclusion: Unlike in MS, we did not observe subtle T1 changes in lesion-free periependymal regions in NMOSD, which supports the hypothesis of a rather focal than diffuse brain pathology in NMOSD.
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http://dx.doi.org/10.1212/NXI.0000000000000541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410932PMC
May 2019

The monoclonal antibody GNbAC1: targeting human endogenous retroviruses in multiple sclerosis.

Ther Adv Neurol Disord 2019 7;12:1756286419833574. Epub 2019 Mar 7.

Neurological Policlinic and Clinic, University Hospital and University of Basel, Petersgraben 4, Basel, 4031, Switzerland.

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disorder of the central nervous system (CNS). Despite improvements of immunomodulatory therapies in relapsing-remitting MS, the pathomechanisms of progressive disease are poorly understood and therapeutically addressed to date. A pathophysiological role for proteins encoded by human endogenous retroviruses (HERVs) has been proposed. GNbAC1 is a monoclonal antibody directed against the envelope protein of a HERV with postulated involvement in MS.

Methods: This review addresses the treatment concept of GNbAC1, the design, preclinical and clinical development of the antibody, as published by November 2018. All four in-human trials (of which two addressed MS) are discussed.

Conclusion: The treatment concept of GNbAC1 is appealing but remains controversial due to conflicting results regarding the hypothesized underlying pathomechanism. Anticipated immunomodulatory effects were not observed in clinical or pharmacodynamic analyses of the currently available data. However, a magnetic resonance imaging sign compatible with the remyelinating potential of GNbAC1 encouraged further development of this antibody in progressive MS. No relevant issues with tolerability or safety have been described to date.
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http://dx.doi.org/10.1177/1756286419833574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407165PMC
March 2019

Association of Rituximab Treatment With Disability Progression Among Patients With Secondary Progressive Multiple Sclerosis.

JAMA Neurol 2019 03;76(3):274-281

Neurologic Clinic and Policlinic, University Hospital and University of Basel, Basel, Switzerland.

Importance: Therapeutic options for patients with secondary progressive multiple sclerosis (SPMS) are limited.

Objective: To analyze disability progression in patients with SPMS treated with rituximab compared with matched control patients never treated with rituximab.

Design, Setting, And Participants: This retrospective cohort study analyzed data obtained from patients with SPMS at 3 multiple sclerosis centers located in Basel and Lugano, Switzerland, and Amsterdam, the Netherlands, from 2004 to 2017. Patients were included for analysis if they had received a diagnosis of SPMS, were treated (57 eligible; 54 included) or never treated (504 eligible; 59 included) with rituximab, and had at least 1 follow-up visit. The variables used for propensity score matching were sex, age, Expanded Disability Status Scale (EDSS) score, and disease duration. Follow-up duration was up to 10 years, with a mean (SD) of 3.5 (2.6) years for rituximab-treated patients and 5.4 (2.4) years for controls in the total cohort and a mean (SD) of 3.5 (2.7) years for rituximab-treated patients and 4.8 (2.2) years for controls in the matched cohort.

Exposures: Comparing EDSS score progression in patients with SPMS (treated with rituximab vs not treated with rituximab) using propensity score matching.

Main Outcomes And Measures: The primary end point was progression of EDSS score after baseline, and the secondary end point was time to confirmed disability progression.

Results: After 1:1 propensity score matching, 44 matched pairs (88 patients) were included in the analysis. At baseline, patients treated with rituximab had a mean (SD) age of 49.7 (10.0) years, mean (SD) disease duration of 18.2 (9.4) years, and mean (SD) EDSS score of 5.9 (1.4), and 26 (59%) were women, whereas controls had a mean (SD) age of 51.3 (7.4) years, mean (SD) disease duration of 19.4 (8.7) years, and mean (SD) EDSS score of 5.70 (1.29), and 27 (61%) were women. In the covariate-adjusted analysis of the matched set, patients with SPMS who were treated with rituximab had a significantly lower EDSS score during a mean (SD) follow-up of 3.5 (2.7) years (mean difference, -0.52; 95% CI, -0.79 to -0.26; P < .001). Time to confirmed disability progression was significantly delayed in the rituximab-treated group (hazard ratio, 0.49; 95% CI, 0.26-0.93; P = .03).

Conclusions And Relevance: In this study, patients with SPMS treated with rituximab had a significantly lower EDSS score for up to 10 years of follow-up and a significantly delayed confirmed progression compared with matched controls, suggesting that B-cell depletion by rituximab may be therapeutically beneficial in these patients. A prospective randomized clinical trial with a better level of evidence is needed to confirm the efficacy of rituximab in such patients.
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http://dx.doi.org/10.1001/jamaneurol.2018.4239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439730PMC
March 2019

Central Slab versus Whole Brain to Measure Brain Atrophy in Multiple Sclerosis.

Eur Neurol 2018 3;80(3-4):207-214. Epub 2019 Jan 3.

Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel, Switzerland,

Background: Structural Image Evaluation using Normalization of Atrophy (SIENA) is used to measure brain atrophy in multiple sclerosis (MS). However, brain extraction is prone to artefacts in the upper and lower parts of the brain. To overcome these shortcomings, some pivotal MS trials used a central slab instead of the whole brain as input for SIENA. The aim of this study was to compare the internal consistency and statistical dispersion of atrophy measures, associations with clinical outcomes and required sample sizes in clinical trials between these two approaches.

Methods: Brain volume change was assessed using SIENA in 119 MS patients with 5-years follow-up on 3D T1-weighted Magnetization Prepared Rapid Gradient Echo datasets using the whole brain or a central slab ranging from -10 to +60 mm Montreal Neurological Institute atlas coordinates. The statistical analysis included the quartile coefficient of dispersion, partial correlations with clinical outcomes and sample size calculations. Clinical outcome measures comprised the Expanded Disability Status Scale, MS Functional Composite and Symbol Digit Modalities Test.

Results: Annualized brain atrophy rates were higher using central slab than whole brain as input for SIENA (-0.51 ± 0.49 vs. -0.37 ± 0.39% per year, p < 0.001). Central and whole brain volume change showed comparable statistical dispersion and similarly correlated with clinical outcomes at 5-years follow-up. Sample size calculations estimated 14% fewer patients required to detect a given treatment effect when using the central slab instead of the whole brain option in SIENA.

Conclusion: Central slab and whole brain SIENA produced comparable statistical dispersion with similar associations to clinical outcomes.
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http://dx.doi.org/10.1159/000495798DOI Listing
March 2019

Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis. Results from the ABIRISK prospective cohort study.

J Neuroimmunol 2019 01 7;326:19-27. Epub 2018 Nov 7.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. Electronic address:

Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-β) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-β-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-β ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.
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http://dx.doi.org/10.1016/j.jneuroim.2018.11.002DOI Listing
January 2019

Association of antibodies against myelin and neuronal antigens with neuroinflammation in systemic lupus erythematosus.

Rheumatology (Oxford) 2019 05;58(5):908-913

Neurologic Clinic and Policlinic, Department of Medicine, University Hospital Basel, Basel.

Objectives: To determine frequency and syndrome specificity of novel and known nervous system (NS)-directed antibodies in a large, unbiased cohort of SLE patients in the Swiss SLE Cohort Study.

Methods: This retrospective pilot study included 174 patients in a cross-sectional and 102 in a longitudinal study. Antibodies against 12 NS antigens [myelin oligodendrocyte glycoprotein (MOG), neurofascin 186 (NF186), aquaporin-4 (AQP4), N-methyl-D-aspartate receptor (subunit NR1) (NMDAR-NR1), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (subunits 1 and 2) (AMPAR1/2), gamma-aminobutyric acid B receptor (subunits B1 and B2) (GABABR1/2), glutamate decarboxylase 65 (GAD65), glycine receptor (GlyR), contactin-associated protein-like 2 (CASPR2), leucine-rich glioma-inactivated 1 (LGI1), metabotropic glutamate receptor 5 (mGluR5) and dipeptidyl-peptidase-like protein 6 (DPPX)] were screened with validated cell-based assays and correlated with clinical and diagnostic findings.

Results: Twenty-three of one hundred and seventy-four (13.2%) patients harboured antibodies against MOG (n = 14), NF186 (n = 6), GAD65 (n = 2), AQP4 and GlyR (n = 1). Anti-MOG antibodies were most frequently found in the cohort (8%). Thirteen of the anti-NS antibody-positive patients showed clinical symptoms of NS involvement, a subgroup of which (n = 8) resembled the syndrome associated with the antibody. Nine patients harboured antibodies without neurological symptoms and one patient was lost to follow-up. The frequency of NPSLE was significantly higher in the anti-NS antibody-positive patients (13/23, 56.5%: MOG 6/14, 42.9%; NF186 5/6, 83.3%; GAD65 2/2, 100%; AQP4/GlyR 0/1, 0%) compared with the antibody-negative cohort (21/151, 13.9%) (chi-square test, P < 0.0001).

Conclusion: Anti-NS antibodies, most prevalently anti-MOG antibodies, are significantly associated with NPSLE and manifest with the distinct neurological syndrome associated with the antibody in a subgroup. Follow-up studies in large, independent cohorts will reveal whether these anti-NS antibodies could serve as a diagnostic and prognostic biomarker for NPSLE and enable tailored treatment decisions in this challenging and diverse patient cohort.
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http://dx.doi.org/10.1093/rheumatology/key282DOI Listing
May 2019

Anti-Myelin Oligodendrocyte Glycoprotein Antibody-Associated Central Nervous System Demyelination-A Novel Disease Entity?

JAMA Neurol 2018 08;75(8):909-910

Institute of Neuropathology, University Medical Center, Göttingen, Germany.

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http://dx.doi.org/10.1001/jamaneurol.2018.1055DOI Listing
August 2018

Testosterone and estrogen in multiple sclerosis: from pathophysiology to therapeutics.

Expert Rev Neurother 2018 06 6;18(6):515-522. Epub 2018 Jun 6.

d Departments of Neurology and Biomedicine , University Hospital Basel , Basel , Switzerland.

Introduction: Neuroprotection and remyelination are two unmet needs in the treatment of multiple sclerosis (MS). Therapeutic potential has been identified with sexual hormones, supported in women by a decrease in MS activity during the pregnancy, in men by a greater severity of symptoms and a faster progression than in women. Areas covered: The therapeutic effect of testosterone and estrogens is reviewed. Both hormones have demonstrated an anti-inflammatory effect. Testosterone has an effect in protecting neurons in culture against glutamate-induced toxicity and oxidative stress, and stimulates myelin formation and regeneration mediated through the neural androgen receptor. In experimental autoimmune encephalomyelitis model, estrogens significantly decrease inflammation in the central nervous system via ERα, while its action on ERβ leads to myelin and axon reparation. Estriol therapy in two phase 2 trials showed a decrease in clinical disease activity and inflammatory parameters in MRI. However, evidence of a therapeutic effect of testosterone is scarce. Expert commentary: Phase 3 trials with estriol as an add-on supplementation are now mandatory. Testosterone is another candidate to be tested in phase 2 trials. These hormones should be considered as an adjunctive therapy. New validated tools are needed to assess their effect on neuroprotection and remyelination.
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http://dx.doi.org/10.1080/14737175.2018.1481390DOI Listing
June 2018

Comparative analysis of natalizumab versus fingolimod as second-line treatment in relapsing-remitting multiple sclerosis.

Mult Scler 2018 05 24;24(6):777-785. Epub 2018 Apr 24.

Neurologic Clinic and Policlinic, Department of Neurology, University Hospital Basel, Basel, Switzerland.

Background: No randomized controlled trials have compared the efficacy of fingolimod or natalizumab as second-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS).

Objective: To compare clinical outcomes after escalation to fingolimod versus natalizumab in patients with clinically active RRMS.

Methods: Using the registry of the Swiss Federation for Common Tasks of Health Insurances, we identified patients with RRMS and ≥1 relapse in the year before switching from interferon beta or glatiramer acetate to fingolimod or natalizumab. Propensity score matching was used to select patients with comparable baseline characteristics. Relapse and Expanded Disability Status Scale (EDSS) outcomes were compared in paired, pairwise-censored analyses.

Results: Of the 547 included patients, 358 were matched (fingolimod, n = 179; natalizumab, n = 179). Median follow-up time was 1.8 years (interquartile range 0.9-2.9). Patients switching to natalizumab had a lower risk of relapses (incidence rate ratio 0.5, 95% confidence interval (CI) 0.3-0.8, p = 0.001) and were more likely to experience EDSS improvement (hazard ratio (HR) 1.8, 95% CI 1.1-2.7, p = 0.01) compared to fingolimod. We found no differences in the proportion of patients free from EDSS progression (HR 0.9, 95% CI 0.5-1.5, p = 0.62).

Conclusion: Natalizumab seems to be more effective in reducing relapse rate and improving disability compared with fingolimod.
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http://dx.doi.org/10.1177/1352458518768433DOI Listing
May 2018

Extensive bilateral brain lesions in neuromyelitis optica spectrum disorders.

Mult Scler 2018 08 20;24(9):1262-1263. Epub 2018 Apr 20.

Neurological Clinic and Policlinic, University Hospital Basel, Basel, Switzerland.

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http://dx.doi.org/10.1177/1352458518771888DOI Listing
August 2018

Defining distinct features of anti-MOG antibody associated central nervous system demyelination.

Ther Adv Neurol Disord 2018 29;11:1756286418762083. Epub 2018 Mar 29.

Institute of Neuropathology, University Medical Center, Göttingen, Germany.

Extensive research over the last decades basically failed to identify a common cause of noninfectious inflammatory central nervous system (CNS) demyelinating disease. To a great extent, this may reflect that the group of inflammatory CNS demyelinating disorders likely contains multiple pathogenetically distinct disease entities. Indeed, the greatest success so far in deciphering the pathogenesis of a CNS demyelinating disorder resulted from the discovery of anti-aquaporin (AQP)-4 antibodies (ab), which allowed progressive delineation of neuromyelitis optica (NMO), formerly considered a variant of the most common CNS demyelinating disorder, multiple sclerosis (MS), as a distinct disease. Nowadays, AQP-4 NMO is considered an autoimmune astrocytopathy, in which CNS demyelination occurs only as a consequence of a primary destruction of astrocytes. Delineating these patients concomitantly revealed that not all patients presenting with clinically NMO-suggestive disease phenotype express AQP-4 ab, which created the pathogenetically undefined category of NMO spectrum disorders (NMOSD). Recent investigations discovered that a subgroup of these AQP-4 NMOSD patients produce an ab response against myelin oligodendrocyte glycoprotein (MOG), a molecule expressed on the outer lamella of the myelin sheath. Using pathophysiologically meaningful cell-based assays, this humoral response is extremely rare in adult MS and absent in classical AQP-4 NMO, sharply differentiating the evolving group from both established disorders. In this review, we summarize available clinical, immunological and histopathological data on patients with MOG CNS demyelinating disease. By comparing this clearly distinct cohort to AQP-4 NMO as well as MS, we propose that MOG CNS demyelinating disease represents a distinct novel disease entity. In addition to its diagnostic value, we furthermore provide mechanistic insight on how this peripheral anti-MOG ab response may be of pathogenetic relevance in triggering acute flares of inflammatory CNS demyelination.
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http://dx.doi.org/10.1177/1756286418762083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5881972PMC
March 2018