Top

Published in:

01-06-2013 | Original Communication

The impact of neutralizing antibodies on the risk of disease worsening in interferon β–treated relapsing multiple sclerosis: a 5 year post-marketing study

Authors: D. Paolicelli, M. D’Onghia, F. Pellegrini, V. Direnzo, P. Iaffaldano, V. Lavolpe, M. Trojano

Published in: Journal of Neurology | Issue 6/2013

Abstract

The impact of neutralizing antibodies (NAbs) on interferon β (IFNβ) efficacy in MS patients is still an object of controversy. To evaluate the clinical response to IFNβ during NAb-positive (NAb+) and NAb-negative (NAb−) statuses on a large population of relapsing remitting (RR) MS patients were followed up to 5 years. Sera from 567 RR MS patients treated with IFNβ for 2–5 years were collected every 6–12 months and evaluated for NAb presence by a cytopathic effect assay. The relapse rate and expanded disability status scale (EDSS) score were assessed at baseline and every 6 months for each patient. A NAb+ status was defined after two consecutive positive titers of NAbs >/= 20 neutralizing units (NU)/mL. Multivariate models were used to analyze the relapse rate, the time to first relapse, the time to confirmed EDSS score 4 during NAb+ and NAb− statuses. A propensity score (PS) matching analysis was performed to assess the robustness of the multivariate models. Fourteen percent of patients became NAb+ during the follow-up. A significant increase of the relapse rate (IRR = 1.38; p = 0.0247) and decrease of the time to 1st relapse (IRR = 1.51; p = 0.0111) were found during NAb+ periods. The PS matching analysis, in a selected cohort of patients, demonstrated a negative trend of NAbs on the time to reach the milestone EDSS 4 (IRR = 2.94; p = 0.0879). This long-term post-marketing observational study further confirms that the occurrence of NAbs significantly affects the risk of disease worsening in IFNβ- treated RRMS.

The IFNB Multiple Sclerosis Study Group I (1993) Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 43:655–661CrossRef

The Multiple Sclerosis Collaborative Research Group (MSCRG) (1996) Intramuscolar interferon beta 1-a for disease progression in relapsing multiple sclerosis. Ann Neurol 39:285–294CrossRef

PRISMS Study Group (1998) Randomized, double-blind, placebo-controlled study of interferon beta-1a in relapsing-remitting multiple sclerosis. Lancet 352:1498–1504CrossRef

Bermel RA, Weinstock-Guttman B, Bourdette D et al (2010) Intramuscular interferon beta-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study. Mult Scler 16(5):588–596PubMedCrossRef

Kappos L, Traboulsee A, Constantinescu C et al (2006) Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology 67:944–953PubMedCrossRef

Goodin DS, Reder AT, Ebers GC, Cutter G, Kremenchutzky M, Oger J, Langdon D, Rametta M, Beckmann K, DeSimone TM, Knappertz V (2012) Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNβ-1b trial. Neurology 78(17):1315–1322PubMedCrossRef

Trojano M, Pellegrini F, Fuiani A et al (2007) New natural history of interferon beta treated relapsing multiple sclerosis. Ann Neurol 61:300–306PubMedCrossRef

Pachner AR (1997) Anticytokine antibodies in beta interferons-treated MS patients and the need for testing: plight of the practicing neurologist. Neurology 49:647–650PubMedCrossRef

Runkel L, deDios C, Karpusas M, Baker D, Li Z, Zafari M et al (2001) Mapping of interferonβ epitopes important for receptor binding and activation: comparison of results achieved using antibody-based methods and alanine substitution mutagenesis. J Interferon Cytokine Res 21:931–941PubMedCrossRef

10.

The IFNB Multiple Sclerosis Study Group I (1996) Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. Neurology 47:889–894

11.

Rudick RA, Simonian NA, Alam JA, Campion M, Scaramucci JO, Jones W et al (1998) Incidence and significance of neutralizing antibodies to IFNβ-1a in multiple sclerosis. Multiple sclerosis collaborative research group (MSCRG). Neurology 50:1266–1272PubMedCrossRef

12.

Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O’Connor P et al (2002) Randomized comparative study of interferon β-1a treatment regimens in MS: the EVIDENCE trial. Neurology 59:1496–1506PubMedCrossRef

13.

Ross C, Clemmesen KM, Svenson M, Sørensen PS, Koch-Henriksen N, Skovgaard GL et al (2000) Immunogenicity of interferon β in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Ann Neurol 48:706–712PubMedCrossRef

14.

Hesse D, Sorensen PS (2007) Using measurements of neutralizing antibodies: the challenge of IFNβ therapy. Eur J Neurol 14:850–859PubMedCrossRef

15.

Van der Voort L, Gilli F, Bertolotto A, Knol DL, Uitdehaag B, Polman CH, Killestein J (2010) Clinical effect of neutralizing antibodies to interferon beta that persist long after cessation of therapy for multiple sclerosis. Arch Neurol 67(4):402–407PubMedCrossRef

16.

Petkau AJ, White RA, Ebers GC, Reder AT, Sibley WA, Lublin FD et al (2004) Longitudinal analyses of the effects of neutralizing antibodies on interferonβ-1 in relapsing remitting multiple sclerosis. Mult Scler 10:126–138PubMedCrossRef

17.

Sorensen PS, Koch-Hendriksen N, Ross C, Clemmesen KM, Bendtzen K, Danish Multiple Sclerosis Study Group (2005) Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology 65:33–39PubMedCrossRef

18.

Goodin DS, Frohman EM, Hurwitz B, O’Connor PW, Oger JJ, Reder AT et al (2007) Neutralising antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report. Report of the therapeutics and technology assessment subcommittee of the American academy of neurology. Neurology 68:977–984PubMedCrossRef

19.

Hesse D, Sellebjerg F, Sorensen PS (2009) Absence of MxA induction by interferon beta in patients with MS reflects complete loss of bioactivity. Neurology 73(5):372–377PubMedCrossRef

20.

Bertolotto A, Gilli F, Sala A, Capobianco M, Malucchi S, Milano E et al (2003) Persistent neutralizing antibodies abolish the interferon beta bioavailability in MS patients. Neurology 60:634–639PubMedCrossRef

21.

Pachner AR, Cadavid D, Wolansky L, Skurnick J (2009) Effect of anti-IFNβ antibodies on MRI lesions of MS patients in the BECOME study. Neurology 73(18):1485–1492PubMedCrossRef

22.

Koch-Henriksen N, Sorensen P, Bendtzen K, Flachs E (2009) The clinical effect of neutralizing antibodies against interferon-beta is independent of the type of interferon-beta used for patients with relapsing-remitting multiple sclerosis. Mult Scler 15:601–606PubMedCrossRef

23.

Cutter G (2003) Statistical issues in neutralizing antibodies. Neurology 61(S5): S38–S39

24.

Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L et al (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 58(6):840–846PubMedCrossRef

25.

Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33(11):1444–1452PubMedCrossRef

26.

Hansen MB, Ross C, Berg K (1990) A sensitive antiviral neutralization bioassay for measuring antibodies to interferons. J Immunol Methods 127:241–248PubMedCrossRef

27.

Kawade Y (1986) Quantitation of neutralization of interferon by antibody. Meth Enzymol 119:558–573PubMedCrossRef

28.

Sorensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr K-M, Palace J et al (2005) Guidelines on use of anti-IFNβ antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFNβ antibodies in multiple sclerosis. Eur J Neurol 12(11):817–827PubMedCrossRef

29.

Singer JD, Willett JB (2003) Applied longitudinal data analysis: modelling change and event occurrence. Oxford University Press, New YorkCrossRef

30.

Parsons LS (2004) Reducing bias in a propensity score matched-pair sample using greedy matching techniques. In: Proceedings of the twenty-sixth annual SAS users group international conference, Cary

31.

Boz C, Oger J, Gibs E, Grossberg SE, Neurologists of the UBC MS clinic (2007) Reduced effectiveness of long-term interferon β treatment on relapses in neutralizing antibody-positive multiple sclerosis patients: a Canadian multiple sclerosis clinic-based study. Mult Scler 13:1127–1137PubMedCrossRef

32.

Goodin DS, Hurwitz B, Noronha A (2007) Neutralizing antibodies to interferonβ-1b are not associated with disease worsening in multiple sclerosis. J Inter Med Res 35(2):173–187CrossRef

33.

Hartung HP, Freedman M, Polman CH, Edan G, Kappos L, Miller D, Montalban X et al (2007) Interferon β-1b-neutralizing antibodies 5 years after clinically isolated syndrome. Neurology 77(9):835–843PubMedCrossRef

34.

Rice GP, Paszner B, Oger J, Lesaux J, Paty D, Eber G (1999) The evolution of neutralizing antibodies in multiple sclerosis patients treated with interferon beta-1b. Neurology 52:1277–1279PubMedCrossRef

35.

Malucchi S, Sala A, Gilli F, Bottero R, Di Sapio A, Capobianco M et al (2004) Neutralizing antibodies reduce the efficacy of betaIFN during treatment of multiple sclerosis. Neurology 62:2031–2037PubMedCrossRef

36.

Sorensen PS, Ross C, Clemmesen KM, Bendtzen K, Frederiksen JL, Jensen K et al (2003) Clinical importance of neutralising antibodies against Interferon beta in patients with relapsing remittent multiple sclerosis. Lancet 362:1184–1191PubMedCrossRef

37.

Goodin D, Hartung HP, O’Connor P, Filippi M, Arnason B, Comi G, Cook S et al (2012) Neutralizing antibodies to interferon beta-1b multiple sclerosis: a clinico-radiographic paradox in the BEYOND trial. Mult Scler 18(2):181–195PubMedCrossRef

38.

Rosenbaum PR (1983) The central role of the propensity score in observational studies for causal effects. Biometrika 70:41–55CrossRef

39.

Sorensen PS (2009) Management of patients with neutralizing antibodies against interferon-beta: stop IFN-beta therapy or wait for the antibodies to go away? Eur J Neurol 16(1):1–2PubMedCrossRef

40.

Polman CH, Bertolotto A, Deisenhammer F, Giovannoni G, Hartung HP, Hemmer B, Killestein J et al (2010) Recommendations for clinical use of data on neutralising antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol 9:740–750PubMedCrossRef

Title: The impact of neutralizing antibodies on the risk of disease worsening in interferon β–treated relapsing multiple sclerosis: a 5 year post-marketing study
Authors: D. Paolicelli
M. D’Onghia
F. Pellegrini
V. Direnzo
P. Iaffaldano
V. Lavolpe
M. Trojano
Publication date: 01-06-2013
Publisher: Springer-Verlag
Published in: Journal of Neurology / Issue 6/2013
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-012-6829-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

The impact of neutralizing antibodies on the risk of disease worsening in interferon β–treated relapsing multiple sclerosis: a 5 year post-marketing study

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2013

Thank you Jan van Gijn

Cytomegalovirus and multiple sclerosis risk

Treatment of cognitive impairment in multiple sclerosis: position paper

Clinical determinants of primary and secondary fatigue in patients with Parkinson’s disease

Generalized myoclonus as a prominent symptom in a patient with FTLD-TDP

Faciobrachial dystonic seizures arise from cortico–subcortical abnormal brain areas