Anti-interferon-beta antibodies in Polish multiple sclerosis patients: prevalence and clinical significance in a long-term prospective study
, 2, 2, 3, 1, 2
Abstract
Aim of the study. To determine the prevalence of anti-interferon-β binding (BAb) and neutralising antibodies (NAb), and to investigate whether NAb measured by luciferase-based cell assay can predict treatment response in multiple sclerosis (MS) patients treated with interferon-β-1b (IFNβ-1b).
Clinical rationale for the study. A subgroup of IFNβ-treated MS patients develop NAb directed against the drug. The clinical significance remains controversial, which could be explained to some extent by technical difficulties in NAb detection and quantification. A simple, specific and reproducible test for NAb might help elucidate these uncertainties.
Materials and methods. Sera from 101 consecutive MS patients initiating treatment with IFNβ-1b were collected at baseline and during the first two years, and assessed for BAbNAb with a novel luciferase-based cell assay. Median clinical follow-up lasted 5.1 years.
Results. BAb were present in 97% and NAb in 88% of the study cohort. Unexpectedly, 92% of patients tested positive for Bab and 12.5% for NAb at baseline, before drug exposure. Patients with baseline NAb positivity were more likely to remain free of disease activity in the first three years of treatment. When baseline-positive cases were grouped together with those who remained NAb-negative, and the resulting group was compared to those who became positive after drug exposure, NAb positivity was associated with a higher risk of disease activity during the entire follow-up. Direct comparison of BAb/Nab-positive and BAb/Nab-negative patients only revealed an association of BAb positivity with more active disease after four years of treatment, while NAb failed to predict the outcome.
Conclusions and clinical implications. Antibodies developed after treatment initiation are associated with a worse outcome. Naturally- occurring antibodies appear to predict more benign disease. Their prevalence and specificity require further investigation.
Keywords: multiple sclerosisinterferon-betaneutralising antibodiestreatment outcome
References
- Ross C, Clemmesen KM, Svenson M, et al. Immunogenicity of interferon-beta in multiple sclerosis patients: influence of preparation, dosage, dose frequency, and route of administration. Danish Multiple Sclerosis Study Group. Ann Neurol. 2000; 48(5): 706–712.
- Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first three years. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology. 1996; 47(4): 889–894.
- Sorensen PS, Koch-Henriksen N, Ross C, et al. Danish Multiple Sclerosis Study Group. Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology. 2005; 65(1): 33–39.
- Cocco E, Marrosu MG. Profile of PEGylated interferon beta in the treatment of relapsing-remitting multiple sclerosis. Ther Clin Risk Manag. 2015; 11: 759–766.
- Gneiss C, Reindl M, Lutterotti A, et al. Interferon-beta: the neutralizing antibody (NAb) titre predicts reversion to NAb negativity. Mult Scler. 2004; 10(5): 507–510.
- Malucchi S, Sala A, Gilli F, et al. Neutralizing antibodies reduce the efficacy of betaIFN during treatment of multiple sclerosis. Neurology. 2004; 62(11): 2031–2037.
- Perini P, Calabrese M, Biasi G, et al. The clinical impact of interferon beta antibodies in relapsing-remitting MS. J Neurol. 2004; 251(3): 305–309.
- Tomassini V, Paolillo A, Russo P, et al. Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis. J Neurol. 2006; 253(3): 287–293.
- Malucchi S, Gilli F, Caldano M, et al. One-year evaluation of factors affecting the biological activity of interferon beta in multiple sclerosis patients. J Neurol. 2011; 258(5): 895–903.
- Petkau AJ, White RA, Ebers GC, et al. IFNB Multiple Sclerosis Study Group. Longitudinal analyses of the effects of neutralizing antibodies on interferon beta-1b in relapsing-remitting multiple sclerosis. Mult Scler. 2004; 10(2): 126–138.
- Paolicelli D, D'Onghia M, Pellegrini F, et al. The impact of neutralizing antibodies on the risk of disease worsening in interferon β-treated relapsing multiple sclerosis: a 5 year post-marketing study. J Neurol. 2013; 260(6): 1562–1568.
- Paolicelli D, Manni A, Iaffaldano A, et al. The role of neutralizing antibodies to interferon-β as a biomarker of persistent MRI activity in multiple sclerosis: a 7-year observational study. Eur J Clin Pharmacol. 2016; 72(8): 1025–1029.
- WHO Expert Committee on Biological Standardization. Thirty-fifth report. World Health Organ Tech Rep Ser. 1985; 725: 1–140.
- Bertolotto A, Sala A, Caldano M, et al. Development and validation of a real time PCR-based bioassay for quantification of neutralizing antibodies against human interferon-beta. J Immunol Methods. 2007; 321(1-2): 19–31.
- Farrell R, Kapoor R, Leary S, et al. Neutralizing anti-interferon beta antibodies are associated with reduced side effects and delayed impact on efficacy of Interferon-beta. Mult Scler. 2008; 14(2): 212–218.
- Lallemand C, Meritet JF, Erickson R, et al. Quantification of neutralizing antibodies to human type I interferons using division-arrested frozen cells carrying an interferon-regulated reporter-gene. J Interferon Cytokine Res. 2008; 28(6): 393–404.
- Lam R, Farrell R, Aziz T, et al. Validating parameters of a luciferase reporter gene assay to measure neutralizing antibodies to IFNbeta in multiple sclerosis patients. J Immunol Methods. 2008; 336(2): 113–118.
- Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005; 58(6): 840–846.
- Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69(2): 292–302.
- Kappos L, De Stefano N, Freedman MS, et al. Inclusion of brain volume loss in a revised measure of 'no evidence of disease activity' (NEDA-4) in relapsing-remitting multiple sclerosis. Mult Scler. 2016; 22(10): 1297–1305.
- Wencel-Warot A, Michalak S, Warot M, et al. The cross-reactivity of binding antibodies with different interferon beta formulations used as disease-modifying drugs in multiple sclerosis patients. Medicine (Baltimore). 2016; 95(45): e5337.
- TIBCO Software Inc. StatSoft STATISTICA. ; 2017.
- MedCalc Software bvba. MedCalc statistical software. Ostend, Belgium 2015. https://www.medcalc.org/ (May 13, 2017).
- Sorensen PS, Koch-Henriksen N, Bendtzen K. Are ex vivo neutralising antibodies against IFN-beta always detrimental to therapeutic efficacy in multiple sclerosis? Mult Scler. 2007; 13(5): 616–621.
- Rudick RA, Simonian NA, Alam JA, et al. Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG). Neurology. 1998; 50(5): 1266–1272.
- PRISMS Study Group and the University of British Columbia MS/MRI Analysis Group.. PRISMS-4: Long-term efficacy of interferon-beta-1a in relapsing MS. Neurology. 2001; 56(12): 1628–1636.
- Rotstein DL, Healy BC, Malik MT, et al. Evaluation of no evidence of disease activity in a 7-year longitudinal multiple sclerosis cohort. JAMA Neurol. 2015; 72(2): 152–158.
