scholarly journals Impression of Clinical Worsening Fails to Predict Interferon-β Neutralizing Antibody Status

2008 ◽  
Vol 36 (6) ◽  
pp. 1418-1425 ◽  
Author(s):  
U Rot ◽  
A Sominanda ◽  
A Fogdell-Hahn ◽  
J Hillert
Keyword(s):  
Multiple Sclerosis ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Poor Response ◽  
Clinical Impression ◽  
Interferon Β ◽  
Routine Testing ◽  
Testing Facility ◽  
Testing Group ◽  
Clinical Worsening

The development of neutralizing antibodies (NAbs) against interferon-β (IFNβ) reduces clinical efficacy and markers of bioactivity in patients with multiple sclerosis (MS), although it has also been shown that a poor response to IFNβ coincided with unexpectedly low NAb levels. To try and resolve this incoherency, this study investigated 2822 patients referred to a NAb testing facility. The reason for NAb testing was indicated for 2506 patients: routine testing (76%), worsening of disease (14%) and other reasons (10%). Overall, 31% of patients were NAb positive and 17% had titres high enough to obliterate IFNβ bioactivity. The frequency of NAbs was similar in patients in the routine testing group compared with the worsening group. Samples showing high titres failed to be associated with worsening of symptoms. The study failed to show low NAb levels in patients responding poorly to IFNβ. It is concluded that it is not possible to predict NAb status by clinical impression of treatment response. This is likely to be an effect of the partial efficacy of IFNβ. Thus routine testing for NAbs must be carried out in order to identify NAb status in patients with MS.

Neutralizing antibody (NAb) assays in multiple sclerosis patients receiving interferon-β therapy

2007 ◽  
Vol 13 (1_suppl) ◽  
pp. 44-48 ◽  
Author(s):  
Florian Deisenhammer
Keyword(s):  
Multiple Sclerosis ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Diagnostic Value ◽  
Diagnostic Methods ◽  
Type I ◽  
Interferon Β ◽  
First Line Therapy ◽  
Multiple Sclerosis Patients ◽  
Relapsing Remitting Multiple Sclerosis

Interferon-β (IFN-β), a type I cytokine, is first-line therapy for relapsing-remitting multiple sclerosis (RRMS), a progressive neurological disease that can result in severe disability. As with all protein-based therapies, treatment with IFN-β can result in the development of neutralizing antibodies (NAbs), which has been shown to reduce the efficacy of the regimen. Recently, assays that evaluate patients for the presence of NAbs have received increased attention as a potentially valuable diagnostic tool in assessing the therapeutic effect of a chosen IFN-β regimen. However, despite the clinical desire to consistently monitor NAb levels in these patients, no standardized NAb assay has yet been identified. A lack of method standardization can lead to confusion when comparing NAb results over time and reduces the overall diagnostic value of assessing NAb status. This review will offer a summary of current NAb diagnostic methods and the factors that limit their consistency and practicality in the clinical setting. Alternatives to current methods for assessing NAb status will also be briefly discussed. Multiple Sclerosis 2007; 13: S44—S48. http://msj.sagepub.com

Reduced effectiveness of long-term interferon-β treatment on relapses in neutralizing antibody-positive multiple sclerosis patients: a Canadian multiple sclerosis clinic-based study

2007 ◽  
Vol 13 (9) ◽  
pp. 1127-1137 ◽  
Author(s):  
C. Boz ◽  
J. Oger ◽  
E. Gibbs ◽  
S.E. Grossberg ◽  
Keyword(s):  
Multiple Sclerosis ◽  
Relapse Rate ◽  
Neutralizing Antibodies ◽  
Clinical Effect ◽  
Neutralizing Antibody ◽  
Interferon Β ◽  
Pre Treatment ◽  
Multiple Sclerosis Patients ◽  
Relapse Rates

Multiple sclerosis (MS) patients treated with interferon-beta (IFN-β) often form anti-IFN-β antibodies accompanied by a reduction in IFN-β bioavailability. The clinical effect of these antibodies remains controversial. MS patients in British Columbia, Canada, must be diagnosed and evaluated annually by neurologists in an MS clinic in order to be reimbursed for their IFN-β prescriptions. We have identified at the UBC MS clinic a cohort of 262 patients, each having been treated with a single IFN-β preparation more than three years, some for nearly a decade. Of 119 patients treated with Betaseron® (IFN-β1b), 18 (15.1%) were neutralizing antibody positive (NAb+) at the time of the study, whereas of 131 treated with subcutaneous Rebif® (IFN-β1a SC), 16 (12.2%) were NAb+, but none of 12 treated with intramuscular Avonex ® (IFN-β1a) had detectable neutralizing antibodies. During the first two years of treatment, the relapse rate was significantly reduced from pre-treatment rates ( P < 0.001) and appeared to be unaffected by the subsequent NAb status. However, the relapse rates in the NAb+ patients were significantly greater than in the NAb— patients during years 3 ( P < 0.010) and 4 ( P < 0.027). Betaseron ®-treated NAb+ patients tended to have more relapses than NAb — patients during year 3 and this almost reached significance ( P = 0.056) but their relapse rate did not differ in year 4 and later. In contrast, Rebif ®-treated NAb+ patients tended to have more relapses in year 3 than Rebif ® -treated NAb — patients ( P = 0.074), but in year 4 they clearly ( P = 0.009) had more relapses than Rebif ®-treated NAb — patients. There was no convincing effect on progression of disability in any group. Multiple Sclerosis 2007; 13: 1127—1137. http://msj.sagepub.com

Neutralizing antibodies in multiple sclerosis: a complex impact on interferon responses, magnetic resonance imaging findings and clinical outcomes

2007 ◽  
Vol 13 (1_suppl) ◽  
pp. 53-62 ◽  
Author(s):  
A.T. Reder
Keyword(s):  
Multiple Sclerosis ◽  
Neutralizing Antibodies ◽  
Interferon Beta ◽  
Clinical Effect ◽  
First Year ◽  
Trial Duration ◽  
Cross Sectional ◽  
Immune Biomarkers ◽  
Interferon Responses ◽  
Clinical Worsening

Interferon beta (IFN-β) therapy reduces relapse rate, MRI lesion development, and delays the progression of disability in relapsing forms of multiple sclerosis. As with other protein therapies, some patients develop neutralizing antibodies (NAbs) that could limit the efficacy of IFN-β. The clinical impact of NAbs is hotly debated. Non-standardized NAb assays, NAb persistence and disappearance, plus a six-month lag before a clinical effect, different IFN-β species and formulations, variable trial duration, have made interpretation of the significance of NAbs a challenging task. There is a correlation between the presence of NAb and reduced efficacy of IFN-β therapy in two- to four-year trials. However, patients destined to become NAb positive do better in the first year of IFN-β therapy. Patients with clinical worsening have surprisingly low NAb frequency and titers. Understanding the true clinical implications of NAbs will require well-controlled longitudinal studies instead of simple cross-sectional analyses, plus innovative trial designs with immune biomarkers. Multiple Sclerosis 2007; 13: S53—S62. http://msj.sagepub.com

Treatment with azathioprine and cyclic methylprednisolone has little or no effect on bioactivity in anti-interferon beta antibody-positive patients with multiple sclerosis

2009 ◽  
Vol 15 (3) ◽  
pp. 323-328 ◽  
Author(s):  
M Ravnborg ◽  
K Bendtzen ◽  
O Christensen ◽  
PEH Jensen ◽  
D Hesse ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Neutralizing Antibodies ◽  
Primary Outcome ◽  
Protein A ◽  
Control Group ◽  
Interferon Β ◽  
Gene Assay ◽  
Resistance Protein ◽  
Polymerase Chain

Background It is unknown whether immunosuppression of patients who have developed interferon-β (IFN-β) neutralizing antibodies (NAbs) hastens disappearance of NAbs in the blood. Objective We wanted to test whether immunosuppression with cyclic methylprednisolone (MP) in combination with azathioprine (AZA) for 6 months accelerates recovery of IFN-β bioactivity in patients with multiple sclerosis (MS) with abolished in-vivo myxovirus resistance protein A (MxA) mRNA response to IFN-β. Methods We included 13 patients with MS with NAbs and a low IFN-β bioavailability detected by the MxA-mRNA response in a descriptive, non-randomized trial. Another 14 NAb-positive patients with a low MxA-mRNA response served as controls. The primary outcome was the fraction of patients who regained an MxA-mRNA response to IFN-β. NAbs were measured by means of a clinically validated cytopathic effect assay and a new reporter gene assay. The in-vivo MxA-mRNA response was measured by real-time polymerase chain reaction. Results A total of 11 patients in the treatment group completed the trial. In all, two of these 11 patients regained an in-vivo MxA-mRNA response as compared to one of 14 patients in the control group. Conclusion Treatment with AZA and cyclic MP for 6 months has little or no effect on IFN-β bioactivity in NAb-positive patients with MS.

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