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Background: Some multiple sclerosis (MS) patients treated with interferon beta (IFN beta) develop antibodies to the drug. Neutralising antibody (NAB) assays for IFN beta are expensive and the clinical relevance of the results has been debated.Objective: To establish a cheap, sensitive, and reliable assay for antibodies to (125)I-IFN beta, and to correlate levels of antibodies with clinical response to IFN beta treatment.Methods: We established a radioimmunoprecipitation assay (RIPA) using (125)I-IFN beta. We tested NAB positive sera, healthy control sera, and serial samples of 33 IFN beta-1b treated MS patients from the Vancouver cohort of the Berlex pivotal trial who had a high incidence of NABs.Results: We found that the RIPA was highly sensitive for the detection of antibodies to IFN beta-1a and -1b, and that there was a strong correlation between reactivity of NAB positive sera for (125)I-IFN beta-1b and for (125)I-IFN beta-1a. The RIPA was more sensitive and consistent than the NAB. Moreover, there was a trend towards poorer MRI outcomes in RIPA positive patients, but not in NAB-positive patients.Conclusions: The RIPA assay is sensitive and easy to perform. It should be of value in assessing the clinical impact of IFN beta antibodies, and its use could help target expensive INF beta treatments to those who will respond best. [ABSTRACT FROM AUTHOR]

Background and purpose It was recently reported that there was no significant overall association between interferon beta exposure and disability progression in relapsing−remitting multiple sclerosis ( RRMS) patients in an observational study from Canada. In the current study, the potential for heterogeneity in the association between exposure to interferon beta and disability progression across patients' baseline characteristics was investigated. Methods RRMS patients treated with interferon beta ( n = 868) and two cohorts of untreated patients (829 contemporary and 959 historical controls) were included. The main outcome was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained Expanded Disability Status Scale ( EDSS) score 6 using a multivariable Cox model, with treatment as a time-varying predictor, testing interaction effects for five pre-specified baseline characteristics: sex, age, disease duration, EDSS and annualized relapse rate ( ARR) based on the previous 2 years. Results Significant heterogeneity was found in the association of interferon beta exposure and disability progression only across ARR, and only when treated patients were compared with historical controls ( P = 0.005 at a Bonferroni-adjusted alpha of 0.01). For patients with ARR>1, treatment-exposed time was associated with a hazard ratio of 0.38 (95% CI 0.20-0.75) for disability progression compared with the unexposed time. Conclusions RRMS patients with more frequent relapses at baseline may be more likely to benefit from interferon beta treatment with respect to long-term disability progression. [ABSTRACT FROM AUTHOR]

Background: Post-marketing studies and case reports have linked beta-interferon (IFNβ) treatment with liver enzyme abnormalities and liver injuries in patients with multiple sclerosis (MS). Few predictors of risk exist.Objective: We investigated the effect of IFNβ and other patient characteristics on levels of the liver enzyme, alanine aminotransferase (ALT).Method: Repeated ALT test results were reviewed retrospectively for 1064 MS patients prescribed an IFNβ as their first immunomodulatory drug. Liver enzyme abnormality was defined as an ALT elevation twice the upper limit of normal (≥2 ULN). The Generalized Estimating Equation (GEE) was used to analyze the effect of age (≤35, >35—40, >40—45, >45 years), gender, disease duration, IFNβ product, and duration of treatment (≤5, >5—15, >15—40, >40 months) on de novo liver enzyme abnormality.Results: Over a mean treatment period of 38.7 months (SD = 34.9), 12.4% (95/766) of MS patients developed de novo liver enzyme abnormality. Multivariable GEE results showed a dose frequency response effect of IFNβs on liver enzyme abnormality: OR = 3.8(95% CI: 1.6—9.2) for IFNβ-1a 44 μg SC, and OR = 3.4 (95% CI: 1.5—7.9) for IFNβ-1b 250 μg SC compared with the lower frequency IFNβ-1a 30 μg IM. Younger age (≤40 years), male gender, and ≤15 months of IFNβ exposure were also independent predictors.Conclusion: A dose frequency response effect was observed, with high-frequency IFNβs having the greatest risk. The first 15 months of treatment, men, and younger patients were also associated with elevated risk. Regular ALT monitoring in MS patients appears prudent; long-term consequences of ALT elevations should be further investigated. [ABSTRACT FROM PUBLISHER]

Binding antibodies (BAbs) and neutralizing antibodies (NAbs) develop following the use of interferon beta (IFNß) in patients with relapsing-remitting multiple sclerosis (RRMS). The appearance of anti-IFNß antibodies has been associated with reduction of the therapeutic efficacy of IFNß therapy; however, while BAbs and NAbs arise from exposure to IFNß, they have different characteristics and different impacts on clinical outcomes. Not all patients develop BAbs and NAbs, and patients who do may revert to seronegative status for each of these antibodies, even with continued IFNß treatment. This review examines the potential clinical and biological effect of BAbs and NAbs on therapeutic efficacy in the treatment of RRMS. [ABSTRACT FROM AUTHOR]

Abstract: The efficacy of interferon (IFN) beta has been shown in several placebo-controlled, parallel-group studies in relapsing–remitting multiple sclerosis (RRMS). PRISMS, the largest such study to date, clearly demonstrated the efficacy of IFN beta-1a on all outcome measures over 2 years during the placebo-controlled, parallel-group phase. However, this study''s placebo-crossover design also provided us with a unique opportunity to conduct a prospective within-group assessment, eliminating the impact of inter-patient variability. At the start of year 3, patients receiving placebo during years 1–2 were re-randomized in a dose-blinded fashion to receive IFN beta-1a, 22 or 44 mcg subcutaneously three times weekly, during years 3 and 4. Clinic visits occurred 3–6 monthly and T2 MRI scans were obtained after 1 and 2 years on therapy. Comparison of the mean relapse count per patient over 2 years (the primary outcome measure) during time on placebo (years 1 and 2) with that during active treatment (years 3 and 4) revealed a decrease from 2.6 to 1.2 in both dose groups (54% relative reduction; p <0.001). Disability progression, T2 MRI lesion activity and accumulation of T2 lesion burden were also significantly improved with therapy (p <0.01). No new safety issues were noted. These data provide further support for IFN beta-1a''s efficacy in RRMS. The ability to detect significant treatment effects with reduced patient numbers in this type of before/after analysis, may be due to the reduction in inter-patient variability. [Copyright &y& Elsevier]

Pokeweed-mitogen-induced IgG secretion. Con A suppression and T cell surface markers were measured in 30 chronic progressive multiple sclerosis (MS) patients and 21 healthy controls. Mean IgG secretion was higher in the MS patients than in the controls (2392±270 vs 1499±243); Con A suppression was lower (4 ±5% vs 24±4%) and the CD4/CD8 ratio was higher (4.1 ± 0. 4 vs 2 9 ± 0.4), The above assays were used in vitro to monitor the effects of Wellferon (lymphoblastoid interferon) injections on this group of MS patients. Before treatment the INF-group (n = 14) did not differ from the PLA-group (n = 16), After 1 week of daily injections the level of lgG secreted was dramatically reduced in the INF group (629 ±96 ng/ml) compared to the PLA-group (1756 ± 319 ng/ml). There was no change in either Con A suppression or T cell surface markers, IgG secretion remained lower in the INF-group for the 6 month treatment period. Following cessation of the injections and a 6 month washout period, IgG secretion in the INF-group rose and was equivalent to that observed in the PLA-group, A series of lymphocyte subset mixing experiments implicates the B lymphocyte subset as being directly affected by interferon injections in vivo. [ABSTRACT FROM AUTHOR]

The article discusses the significance of neutralizing antibodies (NAbs) and interferon on the treatment for multiple sclerosis (MS). The interferon beta therapies signified clear disease-modifying activity in MS that reduced relapse rate and magnetic resonance imaging disease burden. It is recognized that methodologic issues are the most significant problem in interpreting studies on the effects of NAb.