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Neutralizing 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

Duke University, Durham, North Carolina, United States
Neurology (Impact Factor: 8.3). 04/2007; 68(13):977-84. DOI: 10.1212/01.wnl.0000258545.73854.cf
Source: PubMed

ABSTRACT The clinical and radiologic impact of developing neutralizing antibodies (NAbs) to interferon beta (IFNbeta) while on this therapy for multiple sclerosis (MS) is assessed. On the basis of Class II and III evidence, it is concluded that treatment of patients with MS with IFNbeta (Avonex, Betaseron, or Rebif) is associated with the production of NAbs (Level A). NAbs in the serum are probably associated with a reduction in the radiographic and clinical effectiveness of IFNbeta treatment (Level B). In addition, the rate of NAb production is probably less with IFNbeta-1a treatment than with IFNbeta-1b treatment, although the magnitude and persistence of this difference is difficult to determine (Level B). Finally, it is probable that there is a difference in seroprevalence due to variability in the dose of IFNbeta injected or in the frequency or route of its administration (Level B). Regardless of the explanation, it seems clear that IFNbeta-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFNbeta preparations (either IFNbeta-1a or IFNbeta-1b) given multiple times per week subcutaneously (Level A). However, because NAbs disappear in some patients even with continued IFNbeta treatment (especially in patients with low titers), the persistence of this difference is difficult to determine (Level B). Although the finding of sustained high-titer NAbs (>100 to 200 NU/mL) is associated with a reduction in the therapeutic effects of IFNbeta on radiographic and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, or which cutoff titer to apply (Level U).

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    • "BAb screening has low false-negative rates and high sensitivity/specificity. There have been opposing assessments of the importance of BAb and NAb testing relative to clinical management of IFN-treated patients, specifically in Europe (European Federation of Neurologic Societies [EFNS]), America (American Academy of Neurology), and Canada [3,8,12]. "
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    ABSTRACT: Many patients with relapsing-remitting multiple sclerosis (MS) treated with high-dose interferon-beta (IFNbeta) develop serum binding antibodies (BAb) and neutralizing antibodies (NAb). NAb reduces the biological activity of IFNbeta, which contributes to clinical failure in these patients. We investigated whether access to antibody (Ab) test results would alter usual care of (IFNbeta)-treated patients and whether BAb could predict NAb. This was a randomized, controlled, open-label, parallel-group, multicenter study in patients with multiple sclerosis. Subjects (n = 1358) were randomly assigned to Ab testing or usual care. BAb and NAb titres were measured using standard assays. Primary and secondary outcomes were the proportion of patients whose IFNbeta therapy changed and the type of and reasons for therapy changes. Therapy changes differed between the Ab testing and usual care arms (19.6% and 14.0%, respectively; p = 0 . 004). Results from Ab testing were more frequently reported as the reason for therapy change in the Ab testing arm than in the usual care arm (p < 0.0001). NAb and BAb positivity significantly increased the likelihood of therapy change and reduced IFNbeta-associated adverse events. BAb titres were a significant predictor of NAb positivity (p = 0.0012). Initial BAb-positive and NAb-positive status in both study arms had a significant impact on the overall number of patients with a therapy change (p < 0.05). Access to Ab test results impacted therapy management. BAb titres can predict NAb positivity in patients on high-dose IFNbeta.
    BMC Neurology 04/2014; 14(1):73. DOI:10.1186/1471-2377-14-73 · 2.49 Impact Factor
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    • "Therapy with IFNβ should be discontinued in patients with high titres of NAbs at repeated measurements at intervals of 3–6 months (level A recommendation). In contrast, the 2007 recommendations by the American Academy of Neurology [Goodin et al. 2007a] concluded that there is probably a reduction in efficacy of treatment because of NAbs, and there is likely to be greater antibody production in response to IFNβ-1b than to IFNβ-1a, but they were unable to make definite recommendations for changing therapy. "
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    ABSTRACT: Biopharmaceuticals are drugs which are based on naturally occurring proteins (antibodies, receptors, cytokines, enzymes, toxins), nucleic acids (DNA, RNA) or attenuated microorganisms. Immunogenicity of these agents has been commonly described and refers to a specific antidrug antibody response. Such immunogenicity represents a major factor impairing the efficacy of biopharmaceuticals due to biopharmaceutical neutralization. Indeed, clinical experience has shown that induction of antidrug antibodies is associated with a loss of response to biopharmaceuticals and also with hypersensitivity reactions. The first disease-specific agent licensed to treat multiple sclerosis (MS) was interferon-β (IFNβ). In its various preparations, it remains the most commonly used first-line agent. The occurrence of antidrug antibodies has been extensively researched in MS, particularly in relation to IFNβ. However, much controversy remains regarding the significance of these antibodies and incorporation of testing into clinical practice. Between 2% and 45% of people treated with IFNβ will develop neutralizing antibodies, and this is dependent on the specific drug and dosing regimen. The aim of this review is to discuss the use of IFNβ in MS, the biological and clinical relevance of anti-IFNβ antibodies (binding and neutralizing antibodies), the incorporation of testing in clinical practice and ongoing research in the field.
    Therapeutic Advances in Neurological Disorders 01/2013; 6(1):3-17. DOI:10.1177/1756285612469264
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    • "Furthermore, in-vitro studies have demonstrated that NAbs can lead to alterations in the transcription rate of MS-relevant genes [3,4]. In contrast, other studies have indicated that the relapse rate is not significantly different between NAb-negative and NAb-positive patients [2]. Generally, the frequency of NAbs against IFNB diminishes over time, and especially patients who develop NAbs to IFNB-1b (Betaferon®, Chiron Corporation, Emeryville, CA, USA) often revert to NAb-negative status upon subsequent testing [5-9]. "
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    ABSTRACT: Interferon-beta (IFNB) therapy for multiple sclerosis can lead to the induction of neutralizing antibodies (NAbs) against IFNB. Various methods are used for detection and quantification of NAbs. Blood samples from 125 IFNB-1b-treated patients, which were tested NAb negative or NAb positive after conclusion of a clinical study, were retested three years after first being assessed in four different laboratories that offer routine NAb testing to practicing neurologists. The myxovirus protein A (MxA) induction assay, the cytopathic effect (CPE) assay (two laboratories), or the luciferase assay were used. Intra- and inter-laboratory agreement between assays with respect to NAb detection and NAb titer quantification were evaluated. High agreement for NAb detection (kappa coefficient, 0.86) and for titer levels was observed for the intra-laboratory comparison in the laboratory using the MxA induction assay performed three years ago and now. A similarly high agreement for NAb detection (kappa coefficient, 0.87) and for titer quantification was noted for the MxA assay of this laboratory with one of two laboratories using the CPE assay. All other inter-laboratory comparisons showed kappa values between 0.57 and 0.68 and remarkable differences in individual titer levels. There are considerable differences in the detection and quantification of IFNB-induced NAbs among laboratories offering NAb testing for clinical practice using different assay methods. It is important that these differences are considered when interpreting NAb results for clinical decision-making and when developing general recommendations for potentially clinically meaningful NAb titer levels.
    Journal of Neuroinflammation 06/2012; 9:129. DOI:10.1186/1742-2094-9-129 · 4.90 Impact Factor
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