Efficacy of glatiramer acetate in neuromyelitis optica spectrum disorder: a multicenter retrospective study
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Glatiramer acetate (GA) is an approved therapy for relapsing–remitting multiple sclerosis, but its efficacy for the prevention of attacks in neuromyelitis optica spectrum disorder (NMOSD) remains unknown. We did a multicenter retrospective analysis of GA-treated patients with NMOSD, identified through a national registry. Annualized relapse rate and expanded disability status scale (EDSS) were the main outcome measures. We identified 23 GA-treated patients (21 female, 16 aquaporin-4 antibody-positive). GA was given for <6 months in seven patients; reasons for stopping were relapses (n = 3), confirmation of NMOSD (n = 2) and side effects (n = 2). Of 16 patients treated ≥6 months with GA (15 female, 11 aquaporin-4 antibody-positive), 14 experienced at least one relapse. There was no reduction in the mean annualized relapse rate in the total group (1.9 ± 1.1 before vs. 1.8 ± 1.4 during GA therapy), as well as in those patients who were aquaporin-4 antibody-positive, or had a history of prior immunotherapy or not. The median EDSS increased (2.5 start vs. 3.5 finish of GA, P < 0.05). GA therapy was discontinued in 15/16 patients; reasons were therapeutic inefficacy in 13 and post-injection skin reactions in two patients. We conclude that GA is not beneficial for preventing attacks in most patients with NMOSD, particularly in aquaporin-4 antibody-positive cases.
KeywordsNeuromyelitis optica spectrum disorder Devic’s disease Glatiramer acetate Aquaporin-4 antibody Optic neuritis Myelitis
There was no specific funding for this study.
Members of the Neuromyelitis Optica Study Group (NEMOS) in alphabetical order. All institutions are in Germany, unless otherwise indicated
P. Albrecht, University of Düsseldorf; O. Aktas, University of Düsseldorf; K. Angstwurm, University of Regensburg; I. Ayzenberg, Ruhr-University Bochum; A. Berthele, Technical University Munich; F. Bischof, University of Tübingen; N. Borisow, Charité University Medicine Berlin; T. Böttcher, Bonhoeffer Klinikum Neubrandenburg; J. Brettschneider, Klinikum Herford; M. Buttmann, University of Würzburg; B. Ettrich, University of Leipzig; J. Faiss, Asklepios Klinik Teupitz; A. Gass, University Hospital Mannheim; C. Geis, University of Jena; K. Guthke, Klinikum Görlitz; J. Havla, Ludwig Maximilians University Munich; H-P. Hartung, University of Düsseldorf; K. Hellwig, Ruhr-University Bochum; B. Hemmer, Technical University Munich; F. Hoffmann, Krankenhaus Martha-Maria Halle; U. Hofstadt-van Oy, Klinikum Westfalen Dortmund; S. Jarius, University of Heidelberg; M. Kaste, Nordwest-Krankenhaus Sanderbusch; P. Kermer, Nordwest-Krankenhaus Sanderbusch; P. Kern, Asklepios Klinik Teupitz; C. Kleinschnitz, University of Würzburg; I. Kleiter, Ruhr-University Bochum; W. Köhler, Fachkrankenhaus Hubertusburg; E. Kolesilova, Asklepios Klinik Teupitz; M. Krumbholz, Ludwig Maximilians University Munich; T. Kümpfel, Ludwig Maximilians University Munich; S. Langel, Landeskrankenhaus Rheinhessen; F. Lauda, University of Ulm; M. Liebetrau, Evangelische Bathildiskrankenhaus Bad Pyrmont gGmbH; R. Linker, University of Erlangen; W. Marouf, Heliosklinik Stralsund; M. Marziniak, Isar-Amper Klinik Ost Munich; A. Melms, University of Erlangen; I. Metz, University of Göttingen; C. Mayer, University of Frankfurt; C. Münch, Charité University Medicine Berlin; O. Neuhaus, SRH Krankenhaus Sigmaringen; S. Niehaus, Klinikum Dortmund; F. Pache, Charité University Medicine Berlin; F. Paul, Charité University Medicine Berlin, H. Pellkofer, University of Göttingen; A. Riedlinger, Asklepios Klinik Teupitz; M. Ringelstein, University of Düsseldorf; L. Röpke, University of Jena; S.P. Rommer, University of Vienna (Austria); K. Ruprecht, Charité University Medicine Berlin; C. Ruschil, University of Tübingen; S. Schippling, University of Zürich (Switzerland); S. Schuster, University of Hamburg; M. Schwab, University of Jena; M. Stangel, Hannover Medical School, J. Stellmann, University of Hamburg; M. Stoppe, University of Leipzig; F. Then-Bergh, University of Leipzig; C. Trebst, Hannover Medical School; J. Tünnerhoff, University of Tübingen; H. Tumani, University of Ulm; C. Veauthier, Charité University Medicine Berlin; A. Walter, Klinikum Herford; KP. Wandinger, University of Schleswig–Holstein; M. Weber, University of Göttingen; R. Weissert, University of Regensburg; B. Wildemann, University of Heidelberg; C. Wilke, Nervenzentrum Potsdam; A. Winkelmann, University of Rostock; K. Young, University of Hamburg; L. Zeltner, University of Tübingen; C. Zentner, Martha Maria, University of Halle; U. Zettl, University of Rostock; U. Ziemann, University of Tübingen.
Compliance with ethical standards
Conflicts of interest
Ilya Ayzenberg has received travel grants from the International Headache Society. Joanna Schöllhammer has no conflicts of interest. Robert Hoepner has no conflicts of interest. Kerstin Hellwig has received grants from the German Research Foundation. She received honoraria for speaking and research grants from Biogen Idec, Bayer, Teva, Merck, Novartis, and Genzyme. Marius Ringelstein has received speaker honoraria from Novartis and travel reimbursement from Bayer Schering, Biogen Idec and Genzyme. Orhan Aktas has received honoraria for speaking/consultation and travel grants from Bayer Healthcare, Biogen Idec, Chugai, Novartis, Merck Serono, and Teva and research grants from Bayer Healthcare, Biogen Idec, Novartis, and Teva as well as from the German Science Foundation (DFG) and the Federal Ministry of Education and Research (BMBF, EDEN/EU-FP7). None of this interfered with the current report. Markus Krumbholz has received grant support, traveling expenses and scientific advisory board honoraria from Novartis, the Novartis foundation and Genzyme. Tania Kümpfel has received travel expenses and speaking honoraria from Bayer Healthcare, Genzyme, Teva Pharma, Merck-Serono, Novartis, Sanofi-Aventis, and Biogen-Idec as well as grant support from Bayer-Schering AG and Novartis. Corinna Trebst has received honoraria for speaking, consultation and expert testimony and participation in advisory boards from Bayer Vital GmbH, Biogen Idec, Genzyme GmbH, Novartis Pharmaceuticals and Sanofi Aventis Deutschland GmbH. None of this interfered with the current report. Friedemann Paul has received honoraria for speaking/consultation and travel grants from Bayer Healthcare, Biogen Idec, Novartis, MedImmune, Merck Serono, Genzyme, and Teva, and research grants from the German Research Foundation, the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis), and the Guthy Jackson Charitable Foundation. Florence Pache was supported by the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis) and has received funding from a research grant from Novartis Pharmaceuticals and travel grants from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and Genzyme, a Sanofi Company. None of this interfered with the current report. Mark Obermann was supported by the German Ministry of Education and Research (BMBF/KKNMS, Competence Network Multiple Sclerosis) and has received funding from a research grant from Novartis Pharmaceuticals and travel grants from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and Genzyme, a Sanofi Company. None of this interfered with the current report. Lena Zeltner has no conflicts of interest. Matthias Schwab has no conflicts of interest. Achim Berthele has received a research grant on NMO from Bayer Healthcare and participates in a clinical phase III study on NMO sponsored by Alexion Pharmaceuticals. He has received honoraria for speaking/consultation and travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Genzyme, Novartis, and Teva. Ingo Kleiter has received honoraria for speaking/consultation and/or travel grants from Bayer Healthcare, Biogen Idec, Chugai, Merck Serono, and the Guthy Jackson Charitable Foundation, and research grants from Bayer Healthcare, Biogen Idec, and Novartis Pharmaceuticals, as well as from the MERCUR Foundation.
This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Ethics approval was obtained from the institutional review board of the Ruhr University Bochum (#4573-13) and by the institutional review boards of the participating academic centers.
- 3.Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, de Seze J, Fujihara K, Greenberg B, Jacob A, Jarius S, Lana-Peixoto M, Levy M, Simon JH, Tenembaum S, Traboulsee AL, Waters P, Wellik KE, Weinshenker BG (2015) International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85:177–189. doi: 10.1212/WNL.0000000000001729 CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Shimizu J, Hatanaka Y, Hasegawa M, Iwata A, Sugimoto I, Date H, Goto J, Shimizu T, Takatsu M, Sakurai Y, Nakase H, Uesaka Y, Hashida H, Hashimoto K, Komiya T, Tsuji S (2010) IFNβ-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology 75:1423–1427. doi: 10.1212/WNL.0b013e3181f8832e CrossRefPubMedGoogle Scholar
- 7.Kira J, Itoyama Y, Kikuchi S, Hao Q, Kurosawa T, Nagato K, Tsumiyama I, von Rosenstiel P, Zhang-Auberson L, Saida T (2014) Fingolimod (FTY720) therapy in Japanese patients with relapsing multiple sclerosis over 12 months: results of a phase 2 observational extension. BMC Neurol 14:21. doi: 10.1186/1471-2377-14-21 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Trebst C, Jarius S, Berthele A, Paul F, Schippling S, Wildemann B, Borisow N, Kleiter I, Aktas O, Kümpfel T, Neuromyelitis Optica Study Group (NEMOS) (2014) Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS). J Neurol 261:1–16. doi: 10.1007/s00415-013-7169-7 CrossRefPubMedPubMedCentralGoogle Scholar
- 10.Ringelstein M, Ayzenberg I, Harmel J, Lauenstein A-S, Lensch E, Stögbauer F, Hellwig K, Ellrichmann G, Stettner M, Chan A, Hartung H-P, Kieseier B, Gold R, Aktas O, Kleiter I (2015) Long-term therapy with interleukin 6 receptor blockade in highly active neuromyelitis optica spectrum disorder. JAMA Neurol 72:756–763. doi: 10.1001/jamaneurol.2015.0533 CrossRefPubMedGoogle Scholar
- 11.Johnson KP, Brooks BR, Cohen JA, Ford CC, Goldstein J, Lisak RP, Myers LW, Panitch HS, Rose JW, Schiffer RB (1995) Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group. Neurology 45:1268–1276CrossRefPubMedGoogle Scholar
- 13.Begum-Haque S, Sharma A, Christy M, Lentini T, Ochoa-Reparaz J, Fayed IF, Mielcarz D, Haque A, Kasper LH (2010) Increased expression of B cell-associated regulatory cytokines by glatiramer acetate in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 219:47–53. doi: 10.1016/j.jneuroim.2009.11.016 CrossRefPubMedGoogle Scholar
- 14.Begum-Haque S, Sharma A, Kasper IR, Foureau DM, Mielcarz DW, Haque A, Kasper LH (2008) Downregulation of IL-17 and IL-6 in the central nervous system by glatiramer acetate in experimental autoimmune encephalomyelitis. J Neuroimmunol 204:58–65. doi: 10.1016/j.jneuroim.2008.07.018 CrossRefPubMedGoogle Scholar
- 15.Jarius S, Ruprecht K, Wildemann B, Kuempfel T, Ringelstein M, Geis C, Kleiter I, Kleinschnitz C, Berthele A, Brettschneider J, Hellwig K, Hemmer B, Linker RA, Lauda F, Mayer CA, Tumani H, Melms A, Trebst C, Stangel M, Marziniak M, Hoffmann F, Schippling S, Faiss JH, Neuhaus O, Ettrich B, Zentner C, Guthke K, Hofstadt-van Oy U, Reuss R, Pellkofer H, Ziemann U, Kern P, Wandinger KP, Bergh FT, Boettcher T, Langel S, Liebetrau M, Rommer PS, Niehaus S, Münch C, Winkelmann A, Zettl UUK, Metz I, Veauthier C, Sieb JP, Wilke C, Hartung HP, Aktas O, Paul F (2012) Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation 9:14. doi: 10.1186/1742-2094-9-14 CrossRefPubMedPubMedCentralGoogle Scholar
- 20.Ireland SJ, Guzman AA, O’Brien DE, Hughes S, Greenberg B, Flores A, Graves D, Remington G, Frohman EM, Davis LS, Monson NL (2014) The effect of glatiramer acetate therapy on functional properties of B cells from patients with relapsing-remitting multiple sclerosis. JAMA Neurol 71:1421–1428. doi: 10.1001/jamaneurol.2014.1472 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Araki M, Matsuoka T, Miyamoto K, Kusunoki S, Okamoto T, Murata M, Miyake S, Aranami T, Yamamura T (2014) Efficacy of the anti-IL-6 receptor antibody tocilizumab in neuromyelitis optica: a pilot study. Neurology 82:1302–1306. doi: 10.1212/WNL.0000000000000317 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Kitley J, Elsone L, George J, Waters P, Woodhall M, Vincent A, Jacob A, Leite MI, Palace J (2013) Methotrexate is an alternative to azathioprine in neuromyelitis optica spectrum disorders with aquaporin-4 antibodies. J Neurol Neurosurg Psychiatry 84:918–921. doi: 10.1136/jnnp-2012-304774 CrossRefPubMedGoogle Scholar
- 24.Cabre P, Olindo S, Marignier R, Jeannin S, Merle H, Smadja D, Aegis of French National Observatory of Multiple Sclerosis (2013) Efficacy of mitoxantrone in neuromyelitis optica spectrum: clinical and neuroradiological study. J Neurol Neurosurg Psychiatry 84:511–516. doi: 10.1136/jnnp-2012-303121 CrossRefPubMedGoogle Scholar
- 33.Kleiter I, Gold R (2015) Present and future therapies in neuromyelitis optica spectrum disorders. Neurotherapeutics. doi: 10.1007/s13311-015-0400-8
- 34.Comi G, Filippi M, Wolinsky JS (2001) European/Canadian multicenter, double-blind, randomized, placebo-controlled study of the effects of glatiramer acetate on magnetic resonance imaging–measured disease activity and burden in patients with relapsing multiple sclerosis. European/Canadian Glatiramer Acetate Study Group. Ann Neurol 49:290–297CrossRefPubMedGoogle Scholar