Interferon-beta: the neutralizing antibody (NAb) titre predicts reversion to                 NAb negativity

Gneiss, Claudia; Reindl, Markus; Lutterotti, Andreas; Ehling, Rainer; Egg, R.; Khalil, Michael; Berger, Thomas; Deisenhammer, Florian

doi:10.1191/1352458504ms1074oa

Cited by 58 publications

(44 citation statements)

References 20 publications

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“…Spontaneous seroreversion has been described in the presence of low BAbs/ NAbs titers [39,40]. In these patients, IFNb treatment does not need to be discontinued, but MxA should be regularly monitored.…”

Section: Discussionmentioning

confidence: 98%

“…Categorizing patients has different clinical implications: in patients with complete inhibition in MxA gene expression, NAbs and BAbs evaluations have to be performed, and IFNb treatment should be stopped in patients with high BAbs and NAbs titers, because they are associated with persistent sero-positivity [38,39]. Spontaneous seroreversion has been described in the presence of low BAbs/ NAbs titers [39,40].…”

Section: Discussionmentioning

confidence: 99%

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One-year evaluation of factors affecting the biological activity of interferon beta in multiple sclerosis patients

et al. 2010

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MxA is an antiviral protein induced by type I interferons (IFN) and some viruses; MxA gene expression is an appropriate marker for measuring biologic activity of exogenous IFNβ, as its induction indicates IFNAR receptor stimulation. A recent study has shown that measurement of MxA mRNA, after 1 year of treatment, predicts clinical responsiveness to IFNβ therapy. Loss of IFNβ bioactivity is mostly due to anti-IFNβ antibodies (both neutralizing and binding), non-compliance and receptor saturation. The aim of this study was to evaluate all possible causes of loss of IFNβ bioactivity after 1 year in treated patients. One hundred sixty-seven multiple sclerosis (MS) patients were included. One year after beginning IFNβ therapy, each patient underwent a blood test; MxA gene expression was measured by real time PCR, antiviral CPE assay to detect neutralizing antibodies (NAbs), and capture-ELISA (cELISA) to measure binding antibodies (BAbs). For MxA an upper normal threshold of 87 (RE) was considered, 20 TRU/mL was the threshold for NAbs, and 1 U for BAbs positivity. Thirty-seven out of 167 patients (22%) were MxA-negative; of these, 22 were both BAbs and NAbs+, whereas 12 were BAbs+ but Nabs-, and three were both BAbs and NAbs-. The following conclusions were drawn from the study: (1) MxA mRNA should be measured after 1 year of IFNβ therapy; (2) after 1 year of IFNβ treatment, absence of IFNβ bioactivity was detected in 22% of the patients; (3) different biological phenomena and reduced compliance explain this absence; (4) identification of the reason for absence of IFN bioactivity improves patients' management.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

One-year evaluation of factors affecting the biological activity of interferon beta in multiple sclerosis patients

et al. 2010

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“…Another recent study assessing the predictive value of NAb titres showed that the discrimination between those patients who remained NAb+ (non-reverters) and those who eventually reverted to NAb) status was best at 24 months of IFNb treatment. At that time, the magnitude of titres in non-reverters was significantly higher than that of reverters [45]. It has been suggested that NAb levels should be viewed as a continuum with regard to biological relevance.…”

Section: Detection Of Ifnb Binding Antibodiesmentioning

confidence: 97%

Neutralising antibodies to interferon β in multiple sclerosis

et al. 2007

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Interferon beta (IFNbeta) therapy for multiple sclerosis (MS) is associated with a potential for the development of neutralising antibodies (NAbs) that negatively affect therapy. Several factors influence the development of NAbs, such as lack of complete sequence homology with the endogenous IFNbeta sequence, frequency of administration, level of dose and formulation of IFNbeta. Taken together, the evidence that NAb status reduces clinical efficacy in MS patients is strong. Standardised assays for NAbs are lacking, and titres vary over time. NAb testing is a critical component of care for MS patients because it provides information on one of the most important factors determining clinical responsiveness to IFNbeta therapy. This expert panel report attempts to move the field towards resolution of the remaining issues and considers several aspects of NAbs, including their clinical relevance, factors influencing immunogenicity, assays to quantify NAbs and the definition of clinically relevant titres.

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“…Approximately 30 % will revert to being NAB-negative over a period of several years. It appears that patients treated with IFN β-1b are more likely to revert to NAB-negative status [12] and, similarly, patients with a low NAB titre (< 75-100 NU/mL) are also more likely to revert to being NAB-negative than patients with higher NAB titres [13,14].…”

Section: The Issue Of Nab Persistencementioning

confidence: 86%

Optimising MS disease-modifying therapies: antibodies in perspective

Giovannoni

2004

J Neurol

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A proportion of people with multiple sclerosis (MS) treated with interferon (IFN) a develop neutralising anti-IFN beta antibodies (NABs). The immunogenicity of the available commercial compounds relates to the genetic structure of the IFN beta molecule, its mode of production, glycosylation status, aggregate formation, commercial formulation, potency, dose, frequency and, possibly, route of administration. At present, it is not possible to predict who will develop NABs usually appear within the first 2 years of starting therapy. In patients treated with IFN beta in whom NABs persist for a significant period of time, their presence is associated with a reduction in both the biological effects and clinical efficacy. Approximately one third of NAB-positive patients with a titre > 20 NU/mL will revert to NAB-negative status with long-term follow-up. The persistence of NABs appears to be linked to the type of IFN beta treatment as well as the titre of antibodies. The overall efficacy of IFN beta and, hence, of any biological disease-modifying treatment (DMT) would be substantially improved if the development of NABs could be prevented or reversed. Although the overall efficacy of IFN beta in MS is relatively modest, the efficacy in individuals who remain NAB-negative is considerably better than in those who become persistently NAB-positive. One could argue that when comparing the 'true' clinical efficacy of different IFN beta products, the comparisons should be limited to the cohorts that remain NAB-negative. As a corollary, the therapeutic efficacy of IFN beta could be maximised if patients who tolerate higher-dose preparations could be prevented from developing persistent NABs. Strategies employed to prevent or reverse the development of NABs with other biological compounds (e. g. insulin, factor VIII, IFN beta, recombinant human erythropoietin) include improvements in the manufacturing process, immunosuppression, induction of tolerance and deimmunisation, and these should be considered in relation to biological DMT therapy as part of future clinical studies.

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Interferon-beta: the neutralizing antibody (NAb) titre predicts reversion to NAb negativity

Abstract: The NAb titre might support treatment decisions in patients with MS whose test results are positive for NAbs.

Cited by 58 publications

References 20 publications

One-year evaluation of factors affecting the biological activity of interferon beta in multiple sclerosis patients

One-year evaluation of factors affecting the biological activity of interferon beta in multiple sclerosis patients

Neutralising antibodies to interferon β in multiple sclerosis

Optimising MS disease-modifying therapies: antibodies in perspective

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