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Usefulness of MOG-antibody titres at first episode to predict the future clinical course in adults

  • Alvaro Cobo-Calvo
  • María Sepúlveda
  • Hyacintha ’Indy
  • Thais Armangué
  • Anne Ruiz
  • Elisabeth Maillart
  • Caroline Papeix
  • Bertrand Audoin
  • Helene Zephir
  • Damien Biotti
  • Jonathan Ciron
  • Francoise Durand-Dubief
  • Nicolas Collongues
  • Xavier Ayrignac
  • Pierre Labauge
  • Eric Thouvenot
  • Alexis Montcuquet
  • Romain Deschamps
  • Nuria Solà-Valls
  • Sara Llufriu
  • Yolanda Blanco
  • Jerome de Seze
  • Sandra Vukusic
  • Albert Saiz
  • Romain Marignier
  • The OFSEP Group
  • The REEM Group
Original Communication

Abstract

Objective

To analyze whether myelin oligodendrocyte glycoprotein antibody (MOG-Ab) titres at onset of the disease were different according to the clinical phenotype at presentation, and to investigate whether the titres were associated with risk of further relapses or predicted clinical outcome in adult patients. Finally, we assessed an alternative method to the classical measurement of MOG-Ab levels by serial dilutions.

Methods

This is a retrospective study including 79 MOG-Ab-positive adult patients, whose samples were obtained at first episode. MOG-Ab were tested by cell-based assay. HEK293 cells were transfected (tHEK293) with human-MOG plasmid. Non-tHEK293 cells were used as negative controls. Assessment of antibody titres was performed by serial dilution, and delta mean fluorescence intensity ratio signal (MOG-ratio ΔMFI) by flow cytometry. MOG-ratio ΔMFI was calculated as follows: (MFI tHEK293cells- MFI non-tHEK293cells)/MFI non-tHEK293cells. MOG-ratio ΔMFI was calculated from the first serum dilution at 1:320. The association between MOG-Ab titres and risk of relapse was analyzed by Cox regression. The association between MOG-Ab titres and visual or motor disability at last follow-up was performed by binary logistic regression. Poor visual outcome was defined when patients displayed some degree of visual disability (visual acuity [VA] < 20/20) and poor motor outcome when patients displayed some degree of motor disability (Disability Status Scale [DSS] > 1). We also investigated correlations between MOG-Ab titres and MOG-ratio ΔMFI.

Results

MOG-Ab titres were higher in Caucasians than in those with other ethnicities, and in patients with a more severe VA (VA ≤ 20/100) or motor disability (DSS ≥ 3.0) at onset (p = 0.006, 0.034, and 0.058, respectively). MOG-Ab titres were not associated with risk of relapses or with the final clinical outcome. MOG-ratio ΔMFI correlated with MOG-Ab titres in the whole cohort (ρ = 0.90; p < 0.001), and when stratified by initial clinical phenotype.

Conclusion

High MOG-Ab titres at onset are associated with a more severe presentation, but do not predict the future disease course. MOG-ratio ΔMFI is an alternative and straightforward method to determine MOG-Ab levels.

Keywords

MOG antibodies Titre Prognosis Neuromyelitis optica Optic neuritis Myelitis 

Notes

Acknowledgements

The authors thank the group of NeuroBioTec from Hospices Civils de Lyon for supporting this study. Members of the OFSEP group: Alvaro Cobo- Calvo, Hyacintha d'Indy, Anne Ruiz, Elisabeth Maillart, Caroline Papeix, Bertrand Audoin, Helene Zephir, Damien Biotti, Jonathan Ciron, Francoise Durand-Dubief, Nicolas Collongues, Xavier Ayrignac, Pierre Labauge, Eric Thouvenot, Alexis Montcuquet, Romain Deschamps, Jerome de Seze, Sandra Vukusic, Romain Marignier. Members of the REEM group: María Sepúlveda, Thais Armangué, Nuria Solà- Valls, Sara Llufriu, Yolanda Blanco, Albert Saiz.

Funding

The present study is supported by a grant from ARSEP foundation and a grant provided by the French State and handled by the “Agence Nationale de la Recherche”, within the framework of the “Investments for the Future” programme, under the reference ANR-10-COHO-002 Observatoire Français de la Sclérose en Plaques (OFSEP), by the Eugene Devic Foundation against Multiple Sclerosis (EDMUS Foundation), by Red Española de Esclerosis Múltiple (REEM), Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER, “Otra manera de hacer Europa”) (RD16/0015/0002); and by Fundació Marató de TV3 (20141830).

Compliance with ethical standards

Conflicts of interest

Cobo-Calvo, Sepulveda, d’Indy, Armangué and Ruiz report no disclosures. Maillart has received consulting and lecturing fees, and travel grants from Biogen Idec, Genzyme, Novartis, Merck Serono, Roche, Sanofi Aventis and Teva Pharma, and research support from Novartis and Roche. Audoin reports no disclosures. Zephir reports no disclosures. Jonathan Ciron serves on scientific advisory board for Merck Serono and Roche, and has received funding for travel and honoraria from Biogen, Novartis, Genzyme, Teva Pharmaceuticals, Merck Serono and Roche, with no relation with the submitted work. Ayrignac and Thouvenot report no disclosures. Montcuquet has received funding for travel from Merck Serono, Teva, Novartis, Sanofi-Genzyme and Biogen. Solà Valls received consulting and travel grants from Biogen Idec, Genzyme-Sanofi, Merck Serono, and Bayer-Schering. Llufriu reports no disclosures. Papeix reports no disclosures. Biotti has received consulting and lecturing fees, and travel grants from Biogen Idec, Genzyme, Novartis, Merck Serono, Roche, Sanofi Aventis and Teva Pharma. Durand-Dubief serves on scientific advisory board for Merck Serono and has received funding for travel and honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, Roche and Teva. Collongues has received honoraria for consulting or presentation from Biogen Idec, Almirall, Novartis, Merck Serono, LFB, Teva Pharma, Sanofi-Genzyme, Roche, and is a member of the editorial board of the Journal de la Ligue Française contre la Sclérose en plaques, with no relation with the submitted work. Labauge reports no disclosure. Deschamps has received travels grants from Biogen Idec. De Seze reports no disclosures. Vukusic has received consulting and lecturing fees, travel grants and research support from Biogen, Geneuro, Genzyme, Novartis, Merck Serono, Roche, Sanofi Aventis and Teva Pharm. Blanco reports no disclosures. Saiz has received travel funding and/or speaker honoraria from Bayer-Schering, Merck-Serono, Biogen Idec, Sanofi-Aventis, Teva Pharmaceutical Industries, Novartis and Roche. Marignier has received consulting and lecturing fees, travel grants and research support from Bayer-Schering, Biogen Idec, Genzyme, Novartis, Merck Serono, Roche, Sanofi Aventis and Teva Pharma.

Supplementary material

415_2018_9160_MOESM1_ESM.tif (206 kb)
Supplementary Figure 1. MOG mean fluorescence intensity from different determinations. (a) non-transfected HEK293 cells, (b) transfected HEK293cells with MOG and green fluorescence protein (GFP), (c) serum from negative control, (d) serum from positive control, (e) MOG-ratio ΔMFI from one MOG-Ab- positive patient (TIF 199 KB)
415_2018_9160_MOESM2_ESM.tif (113 kb)
Supplementary Figure 2. Distribution of clinical phenotype regarding MOG-Ab titres (a) MOG-Ab titres at onset and, (b) at last follow-up (TIF 114 KB)
415_2018_9160_MOESM3_ESM.docx (19 kb)
Supplementary material 3 (DOCX 18 KB)

References

  1. 1.
    Sato DK, Callegaro D, Lana-Peixoto MA et al (2014) Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 82:474–481CrossRefGoogle Scholar
  2. 2.
    Höftberger R, Sepulveda M, Armangue T et al (2015) Antibodies to MOG and AQP4 in adults with neuromyelitis optica and suspected limited forms of the disease. Mult Scler 21:866–874CrossRefGoogle Scholar
  3. 3.
    Jurynczyk M, Messina S, Woodhall MR et al (2017) Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain 140:3128–3138CrossRefGoogle Scholar
  4. 4.
    Cobo-Calvo A, Ruiz A, Maillart E et al (2018) Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: the MOGADOR study. Neurology 90:e1858–e1869CrossRefGoogle Scholar
  5. 5.
    Hennes E-M, Baumann M, Schanda K et al (2017) Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology 89:900–908CrossRefGoogle Scholar
  6. 6.
    Baumann M, Sahin K, Lechner C et al (2015) Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein. J Neurol Neurosurg Psychiatry 86:265–272CrossRefGoogle Scholar
  7. 7.
    Cobo-Calvo Á, Ruiz A, D’Indy H et al (2017) MOG antibody-related disorders: common features and uncommon presentations. J Neurol 264:1945–1955CrossRefGoogle Scholar
  8. 8.
    Jarius S, Ruprecht K, Kleiter I et al (2016) MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 1: Frequency, syndrome specificity, influence of disease activity, long-term course, association with AQP4-IgG, and origin. J Neuroinflammation 13:279CrossRefGoogle Scholar
  9. 9.
    Hyun J-W, Woodhall MR, Kim S-H et al (2017) Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases. J Neurol Neurosurg Psychiatry 88:811–817CrossRefGoogle Scholar
  10. 10.
    López-Chiriboga AS, Majed M, Fryer J et al (2018) Association of MOG-IgG serostatus with relapse after acute disseminated encephalomyelitis and proposed diagnostic criteria for MOG-IgG-associated disorders. JAMA Neurol 75:1355–1363CrossRefGoogle Scholar
  11. 11.
    Wingerchuk DM, Banwell B, Bennett JL et al (2015) International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85:177–189CrossRefGoogle Scholar
  12. 12.
    Huppke P, Rostasy K, Karenfort M et al (2013) Acute disseminated encephalomyelitis followed by recurrent or monophasic optic neuritis in pediatric patients. Mult Scler 19:941–946CrossRefGoogle Scholar
  13. 13.
    Polman CH, Reingold SC, Banwell B et al (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302CrossRefGoogle Scholar
  14. 14.
    Cobo-Calvo Á, Sepúlveda M, Bernard-Valnet R et al (2016) Antibodies to myelin oligodendrocyte glycoprotein in aquaporin 4 antibody seronegative longitudinally extensive transverse myelitis: clinical and prognostic implications. Mult Scler 22:312–319CrossRefGoogle Scholar
  15. 15.
    Marignier R, Bernard-Valnet R, Giraudon P et al (2013) Aquaporin-4 antibody-negative neuromyelitis optica: distinct assay sensitivity-dependent entity. Neurology 80:2194–2200CrossRefGoogle Scholar
  16. 16.
    Sepúlveda M, Armangue T, Martinez-Hernandez E et al (2016) Clinical spectrum associated with MOG autoimmunity in adults: significance of sharing rodent MOG epitopes. J Neurol 263:1349–1360CrossRefGoogle Scholar
  17. 17.
    Kaneko K, Sato DK, Nakashima I et al (2016) Myelin injury without astrocytopathy in neuroinflammatory disorders with MOG antibodies. J Neurol Neurosurg Psychiatry 87:1257–1259CrossRefGoogle Scholar
  18. 18.
    Kaneko K, Sato DK, Nakashima I et al (2018) CSF cytokine profile in MOG-IgG + neurological disease is similar to AQP4-IgG + NMOSD but distinct from MS: a cross-sectional study and potential therapeutic implications. J Neurol Neurosurg Psychiatry 89:927–936CrossRefGoogle Scholar
  19. 19.
    Hasegawa M, Houdou S, Mito T et al (1992) Development of myelination in the human fetal and infant cerebrum: a myelin basic protein immunohistochemical study. Brain Dev 14:1–6CrossRefGoogle Scholar
  20. 20.
    Miller DJ, Duka T, Stimpson CD et al (2012) Prolonged myelination in human neocortical evolution. Proc Natl Acad Sci 109:16480–16485CrossRefGoogle Scholar
  21. 21.
    Fernandez-Carbonell C, Vargas-Lowy D, Musallam A et al (2016) Clinical and MRI phenotype of children with MOG antibodies. Mult Scler 22:174–184CrossRefGoogle Scholar
  22. 22.
    McKeon A, Lennon VA, Lotze T et al (2008) CNS aquaporin-4 autoimmunity in children. Neurology 71:93–100CrossRefGoogle Scholar
  23. 23.
    Bertsias G, Ioannidis J, Boletis J et al (2008) EULAR recommendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics. Ann Rheum Dis 67:195–205CrossRefGoogle Scholar
  24. 24.
    Verheul MK, Fearon U, Trouw LA, Veale DJ (2015) Biomarkers for rheumatoid and psoriatic arthritis. Clin Immunol 161:2–10CrossRefGoogle Scholar
  25. 25.
    Tremlett H, Zhao Y, Joseph J et al (2008) Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry 79:1368–1374CrossRefGoogle Scholar
  26. 26.
    Kitley J, Leite MI, Nakashima I et al (2012) Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 135:1834–1849CrossRefGoogle Scholar
  27. 27.
    Waters P, Woodhall M, O’Connor KC et al (2015) MOG cell-based assay detects non-MS patients with inflammatory neurologic disease. Neurol Neuroimmunol NeuroInflammation 2:e89CrossRefGoogle Scholar
  28. 28.
    Peschl P, Schanda K, Zeka B et al (2017) Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination. J Neuroinflammation 14:208CrossRefGoogle Scholar
  29. 29.
    Wilson R, Makuch M, Kienzler A-K et al (2018) Condition-dependent generation of aquaporin-4 antibodies from circulating B cells in neuromyelitis optica. Brain 141:1063–1074CrossRefGoogle Scholar
  30. 30.
    Jarius S, Paul F, Aktas O et al (2018) MOG encephalomyelitis: International recommendations on diagnosis and antibody testing. J Neuroinflammation 15:134CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Alvaro Cobo-Calvo
    • 1
    • 2
  • María Sepúlveda
    • 3
  • Hyacintha ’Indy
    • 2
  • Thais Armangué
    • 3
    • 4
  • Anne Ruiz
    • 2
  • Elisabeth Maillart
    • 5
  • Caroline Papeix
    • 5
  • Bertrand Audoin
    • 6
  • Helene Zephir
    • 7
  • Damien Biotti
    • 8
  • Jonathan Ciron
    • 8
  • Francoise Durand-Dubief
    • 1
  • Nicolas Collongues
    • 9
  • Xavier Ayrignac
    • 10
  • Pierre Labauge
    • 10
  • Eric Thouvenot
    • 11
  • Alexis Montcuquet
    • 12
  • Romain Deschamps
    • 13
  • Nuria Solà-Valls
    • 3
  • Sara Llufriu
    • 3
  • Yolanda Blanco
    • 3
  • Jerome de Seze
    • 9
  • Sandra Vukusic
    • 1
    • 14
    • 15
  • Albert Saiz
    • 3
  • Romain Marignier
    • 1
    • 2
    • 15
  • The OFSEP Group
  • The REEM Group
  1. 1.Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation and Centre de référence pour les maladies inflammatoires rares du cerveau et de la moelle (MIRCEM)Hôpital Neurologique Pierre Wertheimer Hospices Civils de LyonLyonFrance
  2. 2.Lyon’s Neuroscience Research Center, U1028 INSERM, UMR5292 CNRS, FLUID TeamLyonFrance
  3. 3.Institut d´Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Center of Neuroimmunology, Neurology DepartmentHospital ClínicBarcelonaSpain
  4. 4.Pediatric Neuroimmunology Unit, Department of NeurologySant Joan de Deu Children’s Hospital, University of BarcelonaBarcelonaSpain
  5. 5.Department of NeurologyPitié-Salpêtrière Hospital, APHPParisFrance
  6. 6.Pôle de Neurosciences Cliniques, Service de NeurologieAix Marseille Univ, APHM, Hôpital de La TimoneMarseilleFrance
  7. 7.Pôle des Neurosciences et de l’Appareil Locomoteur, CHU de LilleUniversité de Lille, LIRIC, UMR 995LilleFrance
  8. 8.Department of Neurology B4, Bâtiment Pierre-Paul RiquetUniversity Hospital of PurpanToulouseFrance
  9. 9.Department of Neurology and Clinical Investigation CenterStrasbourg University HospitalStrasbourgFrance
  10. 10.Multiple Sclerosis UnitMontpellier University HospitalMontpellierFrance
  11. 11.Department of Neurology, Hôpital CarémeauNimes University HospitalNimesFrance
  12. 12.Department of NeurologyHôpital de DupuytrenLimogesFrance
  13. 13.Department of NeurologyFondation A. De RothschildParisFrance
  14. 14.Lyon’s Neuroscience Research CenterObservatoire Français de la Sclérose en Plaques, INSERM 1028 et CNRS UMR5292LyonFrance
  15. 15.Université Claude Bernard Lyon 1, Université de LyonLyonFrance

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