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Original research
Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis
  1. Sargis Abrahamyan1,2,
  2. Bettina Eberspächer3,
  3. Muna-Miriam Hoshi4,
  4. Lilian Aly4,
  5. Felix Luessi5,
  6. Sergiu Groppa5,
  7. Luisa Klotz6,
  8. Sven G Meuth6,
  9. Christoph Schroeder7,
  10. Thomas Grüter7,
  11. Björn Tackenberg8,
  12. Friedemann Paul1,9,
  13. Florian Then-Bergh10,
  14. Tania Kümpfel11,
  15. Frank Weber12,
  16. Martin Stangel13,
  17. Antonios Bayas14,
  18. Brigitte Wildemann15,
  19. Christoph Heesen16,
  20. Uwe Zettl17,
  21. Clemens Warnke18,19,
  22. Gisela Antony20,
  23. Nicole Hessler21,
  24. Heinz Wiendl6,
  25. Stefan Bittner5,
  26. Bernhard Hemmer4,
  27. Ralf Gold7,
  28. Anke Salmen22,
  29. Klemens Ruprecht1
  30. on behalf of the German Competence Network Multiple Sclerosis (KKNMS)
    1. 1 Department of Neurology, Charité – Universitätsmedizin Berlin, Berlin, Germany
    2. 2 Yerevan State University, Yerevan, Armenia
    3. 3 Labor Berlin Charité-Vivantes GmbH, Berlin, Germany
    4. 4 Department of Neurology, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
    5. 5 Department of Neurology, University Medicine Mainz, Johannes Gutenberg University Mainz, Mainz, Germany
    6. 6 Department of Neurology with Institute of Translational Neurology, University of Münster, Münster, Germany
    7. 7 Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany
    8. 8 Department of Neurology, Philipps-Universität Marburg, Marburg, Germany
    9. 9 NeuroCure Clinical Research Center, Charité – Universitätsmedizin Berlin, Berlin, Germany
    10. 10 Department of Neurology, University of Leipzig, Leipzig, Germany
    11. 11 Institute of Clinical Neuroimmunology, Ludwig-Maximilians-Universität, Munich, Germany
    12. 12 Neurological Clinic, Sana Kliniken des Landkreises Cham, Cham, Germany
    13. 13 Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany
    14. 14 Department of Neurology, Universitätsklinikum Augsburg, Augsburg, Germany
    15. 15 Department of Neurology, University of Heidelberg, Heidelberg, Germany
    16. 16 Department of Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
    17. 17 Department of Neurology, University of Rostock, Rostock, Germany
    18. 18 Department of Neurology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
    19. 19 Department of Neurology, University of Düsseldorf, Düsseldorf, Germany
    20. 20 Central Information Office (CIO), Philipps-Universität Marburg, Marburg, Germany
    21. 21 Institute of Medical Biometry and Statistics, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
    22. 22 Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
    1. Correspondence to Dr Klemens Ruprecht, Department of Neurology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; klemens.ruprecht{at}charite.de

    Abstract

    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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    Footnotes

    • Presented at This paper was presented at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 12 October 2018, Berlin, Germany (https://doi.org/10.1177/1352458518799980).

    • Collaborators Katrin Pape, Department of Neurology, University Medicine Mainz, Johannes Gutenberg University Mainz, Germany; Gerd Meyer zu Hörste, Department of Neurology with Institute of Translational Neurology, University of Münster, Germany; Maria Seipelt, Department of Neurology, Philipps-Universität Marburg, Germany; Sandra Nischwitz and Matthias Knop, Department of Neurology, Max-Planck-Institute of Psychiatry, Munich, Germany; Susanne Rothacher, Department of Neurology, Universitätsklinikum Augsburg, Germany; Hayrettin Tumani, Department of Neurology, University of Ulm, Germany, and Clinic of Neurology Dietenbronn, Schwendi, Germany; Ulf Ziemann, Department of Neurology, Eberhard-Karls-Universität Tübingen, Germany; Ralf A Linker, Department of Neurology, University Hospital Regensburg, Germany.

    • Contributors SA and BE participated in study design, performed antibody measurements and analysed the data. M-MH, LA, FL, SG, LK, SGM, CS, TG, BT, FP, FT-B, TK, FW, MS, AB, BW, CH, UZ, CW, GA, NH, HW, SB, BH, RG and AS contributed patients and clinical data. GA, RG, BH, AS and HW designed and conceptualised the German National MS cohort. KR conceived the study, participated in the study design, analysed the data and drafted the manuscript. All authors reviewed and revised the manuscript.

    • Funding The German National MS Cohort and the Kompetenznetz Multiple Sklerose are supported by grants from the German Federal Ministry for Education and Research, grant number 01GI0914 (Bochum), 01GI0916, 01GI1601G (Lübeck) and 01GI1601B (Marburg). This study was supported by the Charité Research Fund and Stiftung Charité (BIH Clinical Fellow Program).

    • Competing interests SA reports no disclosures. BE reports no disclosures. M-MH received travel expenses from Bayer Health Care and honoraria for an advisory board from Merck Serono GmbH. LA reports no disclosures. FL serves as an advisory board member for Roche Pharma and has received travel grants from Teva Pharma. SG reports no disclosures. LK received compensation for serving on scientific advisory boards (Genzyme, Novartis Pharma); speaker honoraria and travel support (CSL Behring, Merck Serono, Roche, Novartis Pharma); research support (Biogen, Novartis Pharma). SGM receives honoraria for lecturing, and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Bundesinstitut für Risikobewertung (BfR), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, Gemeinsamer Bundesausschuss (G-BA), German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and Alexion, Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, HERZ Burgdorf, Merck Serono, Novartis, ONO Pharma, Roche, and Teva.CS reports no disclosures.TG received travel reimbursement from Biogen Idec; not related to this work. BT received personal speaker honoraria and consultancy fees as a speaker and advisor from Bayer Healthcare, Biogen, CSL Behring, GRIFOLS, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, TEVA und UCB Pharma. His University received unrestricted research grants from Biogen-idec, Novartis, TEVA, Bayer Healthcare, CSL-Behring, GRIFOLS, Octapharma, Sanofi Genzyme und UCB Pharma; none related to this work.FP serves on the scientific advisory board for Novartis; received speaker honoraria and travel funding from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an academic editor for PLoS ONE; is an associate editor for Neurology® Neuroimmunology & Neuroinflammation; consulted for SanofiGenzyme, Biogen Idec, MedImmune, Shire, and Alexion; and received research support from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis/Genzyme, Alexion, Merck Serono, German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Guthy Jackson Charitable Foundation, and National Multiple Sclerosis of the USA; none related to this work. FTB received personal compensation for speaking and attending advisory boards from Actelion, Bayer, Biogen, Genzyme, Merck, Novartis, Teva and Roche; financial support, through his institution, to attend scientific meetings or for investigator initiated studies from Actelion, Bayer, Biogen, Genzyme, Merck, Novartis and Teva. TK received travel expenses and personal compensations from Bayer Healthcare, Teva Pharma, Merck-Serono, Novartis, Sanofi-Aventis/Genzyme, Roche and Biogen, as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma; and none related to this work. FW received honoraria from Genzyme, Novartis, TEVA, Bayer and Biogen for speaking or for serving on a scientific advisory board, a travel grant for the attention of a scientific meeting from Merck-Serono and Novartis and grant support from Merck-Serono, Novartis and from the Federal Ministry of Education and Research (BMBF, Projects Biobanking and Omics in ControlMS as part of the Competence Network Multiple Sclerosis). MS received honoraria for scientific lectures or consultancy from Bayer Healthcare, Biogen, Baxter/Baxalta, CSL Behring, Euroimmune, Grifols, Merck-Serono, Novartis, Roche, Sanofi-Aventis, and Teva. His institution received research support from Bayer Healthcare, Biogen Idec, Genzyme, Merck-Serono, Novartis, and Teva; and none related to this work. AB received personal compensation from Merck Serono, Biogen, Bayer, Novartis, TEVA, Roche, Sanofi/Genzyme, Celgene, Alexion and grants for congress trips and participation from Biogen, TEVA, Novartis, Sanofi/Genzyme, Merck Serono, Celgene; none related to this work. BW reports grants from Deutsche Forschungsgemeinschaft, grants from Bundesministerium für Forschung und Technologie, grants from Dietmar Hopp Stiftung, grants from Klaus Tschira Stiftung, grants and personal fees from Merck Serono, personal fees from Biogen, personal fees from Bayer Healthcare, personal fees from TEVA, grants and personal fees from Novartis, grants and personal fees from Sanofi Genzyme, personal fees from Roche, outside the submitted work. CH received research grants and speaker honoraria from Biogen, Genzyme, Roche, and Merck; none related to this work. UKZ received speaker fees from Aventis, Almirall, Biogen, Bayer, Merck, Novartis, Roche, and Teva. CW has received institutional fees for consultancy, speaking, or research from Novartis, Biogen, Sanofi-Genzyme and Roche. GA reports no disclosures.NH reports no disclosures.HW receives honoraria for acting as a member of scientific advisory boards and as a consultant for Biogen, Evgen, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd, Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Sanofi-Genzyme, TEVA, and WebMD Global. Professor Wiendl is acting as a paid consultant for Abbvie, Actelion, Biogen, IGES, Novartis, Roche, Sanofi-Genzyme, and the Swiss Multiple Sclerosis Society. His research is funded by the BMBF, DFG, Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen GmbH, GlaxoSmithKline GmbH, and Roche Pharma AG, Sanofi-Genzyme. SB has received honoria and compensation for travel from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Roche. BH served on scientific advisory boards for F. Hoffmann-La Roche Ltd, Novartis, Bayer AG, and Genentech; he has served as DMSC member for Allergy Care and TG Therapeutics; he or his institution have received speaker honoraria from Biogen Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, Desitin, and F. Hoffmann-La Roche Ltd; his institution has received research support from Chugai Pharmaceuticals; holds part of two patents; one for the detection of antibodies and T cells against KIR4.1 in a subpopulation of patients with MS and one for genetic determinants of neutralizing antibodies to interferon β during the last 3 years. RG serves on scientific advisory boards for Teva Pharmaceutical Industries Ltd, Biogen Idec, Bayer Schering Pharma, and Novartis; has received speaker honoraria from Biogen Idec, Teva Pharmaceutical Industries Ltd., Bayer Schering Pharma, and Novartis; serves as editor for Therapeutic Advances in Neurological Diseases and on the editorial boards of Experimental Neurology and the Journal of Neuroimmunology; and receives research support from Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, and Novartis; none related to this work. AS received speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; none related to this work. KR received research support from Novartis, Merck Serono, German Ministry of Education and Research, European Union, Stiftung Charité (BIH Clinical Fellow), Arthur Arnstein Stiftung Berlin, as well as speaking fees and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, Roche, Novartis, and Guthy Jackson Charitable Foundation.

    • Patient consent for publication Not required.

    • Ethics approval The study protocol, including collection of biospecimens for scientific purposes, was approved by the lead ethics committee, Ruhr-University Bochum (registration number 3714-10), and local ethics committees of all participating centres.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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