THE INFLUENCE OF NEUTRALIZING ANTIBODIES TO INTERFERON-BETA ON PROGRESSION OF MULTIPLE SCLEROSIS

Cover Page

Cite item

Abstract

Background: Neutralizing antibodies (NAbs) affect the effectiveness of interferon therapy in patients with multiple sclerosis; however, this influence cannot be considered as unequivocal. NAbs formation is determined by several factors, such as frequency and duration of administration, interferon-β (IFN-β) formulation and the patient's genotype. It has been found that NAb titers vary over time. Aim: To assess the levels of NAbs to IFN-β in patients with multiple sclerosis and to investigate their relationship to disease progression. Materials and methods: We analyzed serum samples from 83  multiple sclerosis patients after a  long-term IFN-β-1b treatment; NAbs detection reaction was performed by assessment of their cytopathic effect. Results: NAbs were found in 63.9%  (53  of 83) of patients with dura￾tion of IFN-β-1b treatment of 33.3±17.6 months. All NAb-positive patients were treated with high￾dose IFN-β. Patients with titers>800  LU (n=28) demonstrated a  trend towards more advanced neurologic deficit on the Expanded Disability Status Scale (EDSS), compared to the patients with normal NAbs titers (0  to 20  LU, n=30) and intermediate titers (20 to 800 LU, n=25) (p>0.05). The exacerbation rate in the group with NAbs titers from 20  to 800  LU was insignificantly lower than that in the group with NAbs>800 and in the NAb-negative patients (p>0.05). Conclusion: Testing for NAbs may be a promising method for monitoring of IFN-β therapy in multiple sclerosis. There was a trend towards more pronounced neurological deficit in patients with high NAbs titers, but paradoxical data on a high rate of exacerbations in NAb-negative patients requires further study. 

About the authors

V. Yu. Lizhdvoy

Moscow Regional Research and Clinical Institute (MONIKI)

Author for correspondence.
Email: lijdvoy@mail.ru

MD, Senior Research Fellow, Department of Neurology

61/2–10 Shchepkina ul., Moscow, 129110

Tel.: +7 (495) 684 57 38

Russian Federation

T. P. Ospel'nikova

N.F. Gamaleya Research Institute of Epidemiology and Microbiology

Email: fake@neicon.ru

MD, Senior Research Fellow, Laboratory of Interferonogenesis

18 Gamalei ul., Moscow, 123098

Russian Federation

S. V. Kotov

Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

MD, PhD, Professor; Head of Department of Neurology; Head of Chair of Neurology, Postgraduate Training Faculty

61/2 Shchepkina ul., Moscow, 129110

Russian Federation

References

  1. Ziemssen T, De Stefano N, Pia Sormani M, Van Wijmeersch B, Wiendl H, Kieseier BC. Optimizing therapy early in multiple sclerosis: an evidence-based view. Mult Scler Relat Disord. 2015;4(5):460–9. doi: 10.1016/j. msard.2015.07.007.
  2. Bridel C, Lalive PH. Update on multiple sclerosis treatments. Swiss Med Wkly. 2014;144:w14012. doi: 10.4414/smw.2014.14012.
  3. Farrell RA, Marta M, Gaeguta AJ, Souslova V, Giovannoni G, Creeke PI. Development of resistance to biologic therapies with reference to IFN-β. Rheumatology (Oxford). 2012;51(4):590–9. doi: 10.1093/rheumatology/ ker445.
  4. Fox E, Green B, Markowitz C, Murray R, Goodman AD, Glenski SJ, Loupe P, Cogburn JN. The effect of scheduled antibody testing on treatment patterns in interferon-treated patients with multiple sclerosis. BMC Neurol. 2014;14:73. doi: 10.1186/1471-2377-14-73.
  5. Bertolotto A, Capobianco M, Amato MP, Capello E, Capra R, Centonze D, Di Ioia M, Gallo A, Grimaldi L, Imberti L, Lugaresi A, Mancinelli C, Marrosu MG, Moiola L, Montanari E, Romano S, Musu L, Paolicelli D, Patti F, Pozzilli C, Rossi S, Salvetti M, Tedeschi G, Tola MR, Trojano M, Zaffaroni M, Malucchi S; Italian Multiple Sclerosis Study group. Guidelines on the clinical use for the detection of neutralizing antibodies (NAbs) to IFN beta in multiple sclerosis therapy: report from the Italian Multiple Sclerosis Study group. Neurol Sci. 2014;35(2):307–16. doi: 10.1007/s10072-013-1616-1.
  6. Seres E, Vécsei L. Significance of neutralizing antibodies to immunomodulatory therapy and their laboratory analysis in multiple sclerosis. Ideggyogy Sz. 2006;59(5–6):156–62.
  7. Hartung HP, Polman C, Bertolotto A, Deisenhammer F, Giovannoni G, Havrdova E, Hemmer B, Hillert J, Kappos L, Kieseier B, Killestein J, Malcus C, Comabella M, Pachner A, Schellekens H, Sellebjerg F, Selmaj K, Sorensen PS. Neutralising antibodies to interferon beta in multiple sclerosis: expert panel report. J Neurol. 2007;254(7):827–37. doi: 10.1007/s00415- 006-0486-3.
  8. Оспельникова ТП, Морозова ОВ, Исаева ЕИ, Лиждвой ВЮ, Колодяжная ЛВ, Андреева СА, Котов СВ, Ершов ФИ. Мониторинг цитокинов у больных рассеянным склерозом в процессе лечения препаратом IFNβ-1a. Журнал неврологии и психиатрии им. С.С. Корсакова. 2015;115(8–2):71.
  9. Hegen H, Millonig A, Bertolotto A, Comabella M, Giovanonni G, Guger M, Hoelzl M, Khalil M, Killestein J, Lindberg R, Malucchi S, Mehling M, Montalban X, Polman CH, Rudzki D, Schautzer F, Sellebjerg F, Sørensen PS, Deisenhammer F. Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development. Mult Scler. 2014;20(5):577–87. doi: 10.1177/1352458513503597.
  10. Creeke PI, Farrell RA. Clinical testing for neutralizing antibodies to interferon-β in multiple sclerosis. Ther Adv Neurol Disord. 2013;6(1):3– 17. doi: 10.1177/1756285612469264.
  11. Kappos L, Clanet M, Sandberg-Wollheim M, Radue EW, Hartung HP, Hohlfeld R, Xu J, Bennett D, Sandrock A, Goelz S; European Interferon Beta-1a IM Dose-Comparison Study Investigators. Neutralizing antibodies and efficacy of interferon beta-1a: a 4-year controlled study. Neurology. 2005;65(1):40–7. doi: 10.1212/01. wnl.0000171747.59767.5c.
  12. Pachner AR, Warth JD, Pace A, Goelz S; INSIGHT investigators. Effect of neutralizing antibodies on biomarker responses to interferon beta: the INSIGHT study. Neurology. 2009;73(18):1493– 500. doi: 10.1212/WNL.0b013e3181bf98db.
  13. Deisenhammer F. Neutralizing antibodies to interferon-beta and other immunological treatments for multiple sclerosis: prevalence and impact on outcomes. CNS Drugs. 2009;23(5):379–96. doi: 10.2165/00023210- 200923050-00003.
  14. Noronha A. Neutralizing antibodies to interferon. Neurology. 2007;68(24 Suppl 4):S16–22. doi: 10.1212/01.wnl.0000277705.63813.84.
  15. Hegen H, Schleiser M, Gneiss C, Di Pauli F, Ehling R, Kuenz B, Lutterotti A, Berger T, Deisenhammer F. Persistency of neutralizing antibodies depends on titer and interferon-beta preparation. Mult Scler. 2012;18(5):610–5. doi: 10.1177/1352458511426738.
  16. van der Voort LF, Gilli F, Bertolotto A, Knol DL, Uitdehaag BM, Polman CH, Killestein J. Clini￾cal effect of neutralizing antibodies to interferon beta that persist long after cessation of therapy for multiple sclerosis. Arch Neurol. 2010;67(4):402–7. doi: 10.1001/archneurol.2010.21.
  17. Sørensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J, Polman C, Pozzilli C, Ross C; EFNS Task Force on Anti-IFN-beta Antibodies in Multiple Sclerosis. Guidelines on use of anti-IFN-beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol. 2005;12(11):817–27. doi: 10.1111/j.1468-1331.2005.01386.x.
  18. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Montalban X, O'Connor P, Sandberg-Wollheim M, Thompson AJ, Waubant E, Weinshenker B, Wolinsky JS. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302. doi: 10.1002/ ana.22366.

Copyright (c) 2016 Lizhdvoy V.Y., Ospel'nikova T.P., Kotov S.V.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies