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Worldwide, the beta interferons remain the most commonly prescribed disease-modifying drugs for multiple sclerosis. However, it is unclear if they alter survival. We investigated the association between beta interferon and mortality in the 'real-world' setting. This was a multi-centre population-based observational study of patients with relapsing-onset multiple sclerosis who were initially registered at a clinic in British Columbia, Canada (1980-2004) or Rennes, France (1976-2013). Data on this cohort were accessed from the clinical multiple sclerosis databases and from individually linked health administrative data; all data were collected prospectively. Participants were followed from the latter of their first multiple sclerosis clinic visit, 18th birthday or 1 January 1996; until death, emigration or 31 December 2013. Only those who were naïve to disease-modifying therapy and immunosuppressant treatment of multiple sclerosis at the start of their follow-up were included in the analysis. A nested case-control approach was used. Up to 20 controls, matched to cases (deaths) by country, sex, age ± 5 years, year and disability level at study entry, were randomly selected from the cohort by incidence density sampling. The associations between all-cause mortality and at least 6 months beta interferon exposure, and also cumulative exposure ('low', 6 months to 3 years; and 'high', >3 years), were estimated by conditional logistic regression adjusting for treatment with other disease-modifying therapies and age in years. Further analyses included separate analyses by sex and country, additional adjustment for comorbidity burden in the Canadian cohort, and estimation of the association between beta interferon and multiple sclerosis-related death in both countries. Among 5989 participants (75% female) with a mean age of 42 (standard deviation, SD 11) years at study entry, there were 742 deaths (70% female) and the mean age at death was 61 (SD 13) years. Of these cases, 649 were matched to between one and 20 controls. Results of the conditional logistic regression analyses are expressed as adjusted odds ratios with 95% confidence intervals. The odds of beta interferon exposure were 32% lower among cases than controls (0.68; 0.53-0.89). Increased survival was associated with >3 years beta interferon exposure (0.44; 0.30-0.66), but not between 6 months and 3 years exposure (1.00; 0.73-1.38). Findings were similar within sex and country, and for multiple sclerosis-related death. Beta interferon treatment was associated with a lower mortality risk among people with relapsing-onset multiple sclerosis. Findings were consistent between two geographically distinct regions in North America and Europe., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (EDSS) and utility) was set up, in conjunction with a risk-sharing agreement between payers and producers, to investigate this issue., Methods: The outcomes of the UK treated patients were compared with a modelled untreated control based on the British Columbia MS data set to assess the long-term effectiveness of these treatments. Two complementary analysis models were used: a multilevel model (MLM) and a continuous Markov model., Results: 4862 patients with MS were eligible for the primary analysis (mean and median follow-up times 8.7 and 10 years). EDSS worsening was reduced by 28% (MLM), 7% (Markov) and 24% time-adjusted Markov in the total cohort, and by 31% (MLM) and 14% (Markov) for relapsing remitting patients. The utility worsening was reduced by 23%-24% in the total cohort and by 24%-31% in the RR patients depending on the model used. All sensitivity analyses showed a treatment effect. There was a 4-year (CI 2.7 to 5.3) delay to EDSS 6.0. An apparent waning of treatment effect with time was seen. Subgroup analyses suggested better treatment effects in those treated earlier and with lower EDSS scores., Conclusions: This study supports a beneficial effect on long-term disability with first-line MS disease-modifying treatments, which is clinically meaningful. However the waning effect noted requires further study., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Beta-interferons (IFNβ) are the most widely prescribed drugs for patients with multiple sclerosis (MS). However, whether or not treatment with IFNβ can delay secondary progressive MS (SPMS) onset remains unknown. Our aim was to examine the association between IFNβ exposure and SPMS onset in patients with relapsing-remitting MS (RRMS)., Methods: A retrospective cohort study using British Columbia (Canada) population-based clinical and health administrative data (1985-2008) was conducted. RRMS patients treated with IFNβ (n = 794) were compared with untreated contemporary (n = 933) and historical (n = 837) controls. Cohort entry was the first clinic visit during which patients became eligible for IFNβ treatment (baseline). The outcome was time from baseline to SPMS onset. Cox regression models with IFNβ as a time-dependent exposure were adjusted for sex, and baseline age, disease duration, disability, *socioeconomic status and *comorbidities (*available for the contemporary cohorts only). Additional analyses included propensity score adjustment., Results: The median follow-up for the IFNβ-treated, untreated contemporary and historical controls were 5.7, 3.7 and 7.3 years, and the proportions of patients reaching SPMS were 9.2%, 11.8% and 32.9%, respectively. After adjustment for confounders, IFNβ exposure was not associated with the risk of reaching SPMS when either the contemporary or the historical untreated cohorts were considered (hazard ratio 1.07; 95% confidence interval 0.93-1.48, and hazard ratio 1.04; 95% confidence interval 0.74-1.46, respectively). Further adjustments and the propensity score yielded results consistent with the main analysis., Conclusions: Amongst patients with RRMS, use of IFNβ was not associated with a delayed onset of SPMS., (© 2015 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: In 2002, the UK's National Institute for Clinical Excellence (NICE) concluded that interferon beta and glatiramer acetate would be cost effective as disease-modifying therapies (DMTs) for multiple sclerosis only if the short-term disability benefits reported in clinical trials were maintained. The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established to assess whether disability progression was consistent with a cost-effectiveness target of £36 000 per quality-adjusted life-year projected over 20 years. We aimed to evaluate the long-term effectiveness and cost-effectiveness of these DMTs by comparing a cohort of patients with relapsing-remitting multiple sclerosis enrolled in the UK RSS with a natural history cohort from British Columbia, Canada., Methods: In our clinical cohort we included patients starting a DMT who were enrolled in the UK RSS who had relapsing multiple sclerosis at baseline and had at least one further clinical assessment. In our control cohort we included patients in the British Columbia multiple sclerosis database (BCMS; data collection 1980-96) who met the same eligibility criteria as for the RSS cohort. We compared disability progression at 6 years for RSS patients with untreated progression modelled from BCMS patients using continuous Markov and multilevel models. The primary outcomes were the progression ratio (treated vs untreated) measured both in Expanded Disability Status Scale (EDSS) score and utility. A ratio of less than 100% for EDSS implied slower than expected progression on treatment compared with off treatment; a utility ratio of 62% or less implied that the DMTs were cost effective., Findings: 5610 patients starting a DMT were enrolled in the UK RSS between Jan 14, 2002, and July 13, 2005 (72 sites), of whom 4137 were included in our clinical cohort. We included 898 BCMS patients in the control cohort who met the RSS inclusion criteria and had at least one EDSS score after baseline. RSS patients had a mean follow-up of 5·1 years (SD 1·4). Both models showed slower EDSS progression than predicted for untreated controls (Markov model, 75·8% [95% CI 71·4-80·2]; multilevel model, 60·0% [56·6-63·4]). Utility ratios were consistent with cost-effectiveness (Markov model, 58·5% [95% CI 54·2-62·8]; multilevel model, 57·1% [53·0-61·2])., Interpretation: Findings from this large observational study of treatment with interferon beta or glatiramer acetate provide evidence that their effects on disability in patients with relapsing-remitting multiple sclerosis are maintained and cost effective over 6 years. Similar modelling approaches could be applied to other chronic diseases for which long-term controlled trials are not feasible., Funding: Health Departments of England, Wales, Scotland, and Northern Ireland, Biogen Idec, Merck Serono, Bayer Schering Pharmaceuticals, Teva Pharmaceuticals Industries, UK National Institute of Health Research's Health Technology Assessment Programme., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

A proportion of multiple sclerosis (MS) patients treated with interferon-β (IFNβ) develop neutralizing antibodies (NAbs), which can reduce therapeutic efficacy. In the Betaseron/Betaferon in Newly Emerging MS for Initial Treatment (BENEFIT) study, 88/277 patients developed NAbs, 48 having transient positivity and 29 having sustained positivity. This study aimed to investigate the antibody binding characteristics of serial sera in a subset of these two patient groups. Using Biacore™, a surface plasmon resonance-based technology that monitors biomolecular interactions in real time, we immobilized pure IFNβ-1b and analyzed antibody binding responses and dissociation rates of these sera. NAb titers correlated directly with binding responses and inversely with dissociation rates, and sera from sustained NAb patients demonstrated significantly higher binding responses and slower dissociation rates than sera from transient NAb patients. Thus, transient and sustained NAbs are quantitatively and qualitatively different, and interestingly, binding responses and dissociation rates at month 12 could predict the NAb course., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: We examined (1) patient characteristics and disease-modifying drug (DMD) exposure in late-onset (LOMS, ≥50 years at symptom onset) versus adult-onset (AOMS, 18-<50 years) MS and (2) the association between interferon-beta (IFNβ) and disability progression in older relapsing-onset MS adults (≥50 years)., Methods: This retrospective study (1980-2004, British Columbia, Canada) included 358 LOMS and 5627 AOMS patients. IFNβ-treated relapsing-onset MS patients aged ≥50 (regardless of onset age, 90) were compared with 171 contemporary and 106 historical controls. Times to EDSS 6 from onset and from IFNβ eligibility were examined using survival analyses., Results: LOMS patients (6%) were more likely to be male, with motor onset and a primary-progressive course, and exhibit faster progression and were less likely to take DMDs. Nonetheless, 57% were relapsing-onset, of which 31% were prescribed DMDs, most commonly IFNβ. Among older relapsing-onset MS adults, no significant association between IFNβ exposure and disability progression was found when either the contemporary (hazard ratio [HR]: 0.46; 95% CI: 0.18-1.22) or historical controls (HR: 0.54; 95% CI: 0.20-1.42) were considered., Conclusion: LOMS differed clinically from AOMS. One-third of older relapsing-onset MS patients were prescribed a DMD. IFNβ exposure was not significantly associated with reduced disability in older MS patients.

Purpose: A systematic evaluation of hospital events can be an important surrogate measure for drug effectiveness or adverse effects. The purpose of this study was to examine the association between beta-interferon use and hospital events in a large cohort of patients with multiple sclerosis (MS)., Methods: Retrospective cohort study comparing beta-interferon exposed and unexposed patients using clinical data from the British Columbia MS (BCMS) database linked with health administrative databases, 1996-2008. For each patient, the primary outcome was the number of hospital events in each month, analyzed by quasi Poisson regression. Beta-interferon exposure was examined two ways: current and cumulative exposure. Secondary outcomes included whether a hospital event occurred in each month for each specific primary diagnoses, grouped by International Classification of Diseases categories., Results: Current exposure to beta-interferon was not associated with an altered rate of hospital events (adjusted incident rate ratio 1.018; 95% CI 0.803-1.290). Similarly, there was no association with cumulative exposure. Cumulative beta-interferon exposure was associated with a lower odds of respiratory disease-related hospital events compared to those never exposed to beta-interferon., Conclusions: Exposure to beta-interferon for MS was not associated with a change in overall hospital event rates. Preliminary evidence suggests that the beta-interferons may have a protective effect against respiratory diseases requiring hospitalization in MS patients., (Copyright © 2014 John Wiley & Sons, Ltd.)

Objective: The risk of cancer after exposure to the β-interferons (IFNβs) for multiple sclerosis (MS) has not been established. We assessed whether IFNβ treatment for MS is associated with cancer risk or the risk of specific cancers in a population-based observational study., Methods: The British Columbia MS database was linked to the provincial Cancer Registry, Vital Statistics death files and Health Registration files. Using a nested case-control design, MS cancer cases were matched with up to 20 randomly selected MS controls at the date of cancer diagnosis by sex, age (± 5 years) and study entry year using incidence density sampling. Associations between treatment exposure and overall or specific (breast, colorectal, lung and prostate) cancers were estimated by conditional logistic regression, adjusted for MS disease duration and age. Tumour size at cancer diagnosis was compared between treated and untreated patients using the stratified Wilcoxon test to explore potential lead time bias., Results: The cohort included 5146 relapsing-onset MS patients and 48,705 person-years of follow-up, during which 227 cancers were diagnosed. Exposure to IFNβ was not significantly different for cases and controls (OR 1.28; 95% CI 0.87 to 1.88). There was a non-significant trend towards an increased risk of IFNβ exposure in the breast cancer cases (OR 1.77; 95% CI 0.92 to 3.42), but no evidence of a dose-response effect. Tumour size was similar between IFNβ treated and untreated cases., Conclusions: There was no evidence of an increased cancer risk with exposure to IFNβ over a 12-year observation period. However, the trend towards an association between IFNβ and breast cancer should be investigated further., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Longitudinal observational data are required to assess the association between exposure to β-interferon medications and disease progression among relapsing-remitting multiple sclerosis (MS) patients in the "real-world" clinical practice setting. Marginal structural Cox models (MSCMs) can provide distinct advantages over traditional approaches by allowing adjustment for time-varying confounders such as MS relapses, as well as baseline characteristics, through the use of inverse probability weighting. We assessed the suitability of MSCMs to analyze data from a large cohort of 1,697 relapsing-remitting MS patients in British Columbia, Canada (1995-2008). In the context of this observational study, which spanned more than a decade and involved patients with a chronic yet fluctuating disease, the recently proposed "normalized stabilized" weights were found to be the most appropriate choice of weights. Using this model, no association between β-interferon exposure and the hazard of disability progression was found (hazard ratio = 1.36, 95% confidence interval: 0.95, 1.94). For sensitivity analyses, truncated normalized unstabilized weights were used in additional MSCMs and to construct inverse probability weight-adjusted survival curves; the findings did not change. Additionally, qualitatively similar conclusions from approximation approaches to the weighted Cox model (i.e., MSCM) extend confidence in the findings., (© The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2013 The Author(s) European Journal of Neurology © 2013 EAN.)

The appearance of neutralizing antibodies (NAbs) has significant clinical and regulatory consequences for interferons in patients with multiple sclerosis (MS). In a double blind, randomized clinical trial, 84 patients with relapsing remitting MS were enrolled in a 24month study period. Patients were randomly assigned into two groups receiving 30mcg weekly intramuscular injections of either Avonex® (Biogen Idec, USA; 42 patients) or CinnoVex® (CinnaGen Co, Iran; 42 patients). NAb titer was drawn for all patients every 6months and assayed using cytopathic effect assay (CPE) method in Tehran, Iran. To validate the measure done in the Iranian lab, 45 sera with adequate volume and proper storing condition were selected and sent to be rechecked using luciferase reporter gene assay (LA) method for verification in 2 phases in Vancouver, Canada. The cut-off point of 20 TRU was considered for positivity. The two labs found the same three samples to be positive (2 samples from patients received Avonex and 1 received CinnoVex) and 42 to be negative. They had the following values using the Kawade formula as recommended by international standards; 2238, 89 and 302 (TRu/ml) using CPE assay versus 2464, 290 and 169 (TRu/ml) using LA method. As similar results were obtained from CinnoVex or Avonex in our study, we suggest that both medications will have a similar immunogenetic profile., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Context: Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established., Objective: To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS., Design, Setting, and Patients: Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts., Main Outcome Measures: The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication., Results: The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results., Conclusion: Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.

Objective: To examine the effects of interferon beta (IFNβ)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments., Methods: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNβ-1b 250 μg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary., Results: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNβ-1b 250 μg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNβ-1b 250 μg-treated patients (46.0% among IFNβ-1b 50 μg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect., Conclusions: There was a significant survival advantage in this cohort of patients receiving early IFNβ-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNβ-1b benefit on all-cause mortality., Classification of Evidence: This study provides Class III evidence that early treatment with IFNβ-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

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.

Patients with multiple sclerosis (MS) treated with interferon β (IFNβ) preparations develop varying levels of antibodies that neutralize the biological effects of IFNβ, reduce its in vivo bioavailability, and diminish its therapeutic efficacy. The aim was to determine as distinct measures of immunogenicity the occurrence (frequency) and the magnitude (level) of IFNβ neutralizing antibody (NAb) formation in a large Canadian population as a cross-sectional study of patients with MS treated in a clinical practice setting with different, equally available IFNβ products: Avonex(®) (intramuscular IFNβ-1a), Rebif(®) (subcutaneous (SC) IFNβ-1a) at 22 and 44 μg, and Betaseron(®) (SC IFNβ-1b). Over a 3-year period 3,124 serum samples from 2,711 patients with MS were submitted by neurologists in MS clinics distributed across Canada and tested for NAbs in a single independent laboratory, utilizing a quantitative, standardized NAb bioassay. NAb frequency was greatest (35%) with Rebif (SC IFNβ-1a) 44 μg and least (7.5%) with Avonex (intramuscular IFNβ-1a), whereas Betaseron (IFNβ-1b) and Rebif 22 μg were in between (22%). NAb serum levels at magnitudes considered high, ≥100 tenfold reduction units (TRU)/mL, were found in 65%-83% of patients with detectable NAbs. Nearly half (42%-47%) of NAb-positive patients given IFNβ-1a preparations had very high titers (≥ 1,000 TRU/mL), whereas only 22% of NAb-positive patients on Betaseron had titers >1,000 TRU/mL. Differences in patterns of NAb formation among the four IFNβ product-dose combinations became more evident in patients with MS when both NAb frequency and the full range of NAb titer magnitude were measured.

The identification of factors that can affect the efficacy of immunomodulatory drugs in relapsing-remitting multiple sclerosis (MS) is important. For the available interferon-beta products, neutralising antibodies (NAb) have been shown to affect treatment efficacy. In June, 2009, a panel of experts in MS and NAbs to interferon-beta therapy convened in Amsterdam, Netherlands, under the auspices of the Neutralizing Antibodies on Interferon beta in Multiple Sclerosis consortium, a European-based project of the 6th Framework Programme of the European Commission, to review and discuss data on NAbs and their practical consequences for the treatment of patients with MS on interferon beta. The panel believed that information about NAbs and other markers of biological activity of interferons (ie, myxovirus resistance protein A [MxA]) can be integrated with clinical and imaging indicators to guide individual treatment decisions. In cases of sustained high-titre NAb positivity and/or lack of MxA bioactivity, a switch to a non-interferon-beta therapy should be considered. In patients who are doing poorly clinically, therapy should be switched irrespective of NAb or MxA bioactivity., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The study of antibodies against Interferon-beta (IFN-beta) in treated multiple sclerosis (MS) patients has focused primarily on detection and quantification, with no single method of detection providing a comprehensive characterization. We assessed serial samples of 18 MS patients, treated with IFN-beta for between 66 and 198 months, to characterize the affinity maturation of these antibodies using a biosensor-based approach (Biacore). Biacore utilizes the principles of surface plasmon resonance (SPR) with data from the dissociation phase of the antigen-antibody reaction being inversely proportional to relative antibody affinity. In patients with neutralizing antibodies (NAbs+), mean antibody dissociation rates decreased from 0.00118 +/- 0.00030 s(-1) at month 6 to 0.00021 +/- 0.00008 s(-1) at month 36, followed by a slight increase to 0.00027 +/- 0.00003 s(-1) at month 60. In NAb- patients, mean antibody dissociation rates decreased only very slightly from 0.00130 +/- 0.00025 s(-1) to 0.00105 +/- 0.00020 s(-1) at month 18, followed by a gradual increase to 0.00243 +/- 0.00099 s(-1) at month 60. Our study shows little improvement in antibody affinity in NAb- patients, in contrast to a marked increase in antibody affinity over time in NAb+ patients with a significant correlation between NAb titers and relative antibody dissociation rates (Spearman's correlation, R(2) = -0.374, p < 0.001). The evaluation of relative antibody affinities will contribute to a thorough understanding of the anti-IFN-beta antibody response.

Neutralizing antibodies (NAbs) can occur in some multiple sclerosis (MS) patients receiving interferon beta (IFNbeta) therapy. NAbs reduce drug bioavailabity and high NAb titers reduce drug efficacy. We describe the validation of the R. Farrell and G. Giovannoni luciferase reporter gene assay to measure NAbs to INFbeta. We assayed 163 sera from IFNbeta treated MS patients with an optimized luciferase method and compared the results to those obtained with the reference cytopathic effect (CPE) method using A549 cells and an encephalomyocarditis virus (EMCV). Binding antibodies (BAbs) were measured using a capture ELISA as a screening test for NAbs in the CPE assay. NAb status measured by the luciferase and the ELISA/CPE method did not yield a significant difference. Log10 NAb titers obtained from the luciferase assay and the A549/EMCV CPE methods correlated very well. The inter-assay coefficient of variation for titers was between 17.8-29.3%, and the intra-assay coefficient of variation was between 6.3-15.2%. The luciferase assay is reliable, appropriately sensitive and requires less time than the currently available NAb methods.

Adverse drug reaction (ADR) reporting is essential in the post-marketing surveillance of drugs, detection of serious adverse reactions, and has been the basis for drug withdrawals. The study aimed to examine ADR reporting patterns to the multiple sclerosis (MS) immunomodulatory drugs (IMD) in Canada. All ADRs reported to the Canadian ADR Monitoring Program (CADRMP) from 1965 to March 2006 (n=193 208) were accessed and ADRs in which an IMD for MS (beta-interferon or glatiramer acetate) was the suspected drug extracted (n=888 reports were dated March/96-March/06). Almost half of all IMD ADRs reports (438/888) were sourced through the patient compared to 14.9% (10 649/71 373) of all ADRs reported to CADRMP over the same period. Of IMD ADR reports, 88.7% (788/888) were directed through the manufacturer compared to 57.7% (41197/71373) of all ADRs. Encouragement to others involved in patient care, such as pharmacists, nurses and physicians might enhance reporting of MS ADRs. Despite the limitations of ADR reporting data, previously unpublished case reports in several understudied MS populations were detailed: paediatrics (or= 65 years, n=23) and during pregnancy (n=12). In addition, 46 deaths suspected by the reporter as being related to IMD treatment were detailed as well as three possible drug interactions.

Multiple sclerosis (MS) patients treated with interferon-beta (IFN-beta) often form anti-IFN-beta antibodies accompanied by a reduction in IFN-beta 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-beta prescriptions. We have identified at the UBC MS clinic a cohort of 262 patients, each having been treated with a single IFN-beta preparation more than three years, some for nearly a decade. Of 119 patients treated with Betaseron (IFN-beta1b), 18 (15.1%) were neutralizing antibody positive (NAb+) at the time of the study, whereas of 131 treated with subcutaneous Rebif (IFN-beta1a SC), 16 (12.2%) were NAb+, but none of 12 treated with intramuscular Avonex (IFN-beta1a) 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.

Anti-Interferon beta (IFNbeta) antibodies are frequently produced during treatment with IFNbeta in Multiple Sclerosis (MS) patients. In recent years, it has become clear that these antibodies cause a decrease in IFNbeta-induced biomarkers and in IFNbeta clinical efficacy. Anti-IFNbeta antibodies are mainly of the IgG isotype, which consists of 4 subclasses. In this study, we tested whether changes occurred in IgG subclasses over time. A series of sera from 21 IFNbeta-treated patients (11 IFNbeta-1a, 10 IFNbeta-1b) were analysed longitudinally using a capture ELISA. IFNbeta-1a treated patients had a restricted subclass distribution, whilst IFNbeta-1b-treated patients demonstrated a wider distribution. When compared to IFNbeta-1b-treated patients, IFNbeta-1a-treated patients had lower levels of total and subclass-specific IgGs against IFNbeta. In particular, antibody levels were markedly lower in the neutralizing antibody (NAb) negative (-) category of IFNbeta-1a-treated patients in comparison to the NAb-IFNbeta-1b-treated patients. The most striking observation of this study were the very low levels or complete absence of IgG3 subclass-specific antibodies to IFNbeta in IFNbeta-1a-treated patients. This difference in the levels of IgG3 may help to clarify the differences in the overall pattern of development of anti-IFNbeta antibodies in IFNbeta-1a-and IFNbeta-1b-treated patients.

Background: Recent guidelines have recommended the use of validated assays for the measurement of neutralizing antibodies (NABs) to interferon beta (IFNbeta) in patients with multiple sclerosis (MS). In an attempt of validation, we studied the analytical performance of a bioassay based on antiviral cytopathic effect (CPE) using WISH cells and the vesicular stomatitis virus (WISH/VSV CPE)., Methods: NAB titres measured with the WISH/VSV CPE assay in 63 sera from IFNbeta-treated MS patients were compared to those obtained with the reference CPE method using A549 cells and the encephalomyocarditis virus. Binding antibodies (BABs) were measured using a capture ELISA as a screening test for NABs., Results: No false-negative BAB was obtained in our patients. The between-run coefficients of variation (CVs) determined with log10 titres of the NIH anti-IFNbeta (G038-501-572) yielded good results (

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.

This review explores the salient issues surrounding liver injury and liver monitoring associated with beta-interferon (IFNB) treatment for multiple sclerosis (MS). Post-marketing studies have found a higher proportion of IFNB-treated MS patients with elevated aminotransferases than reported in the pivotal clinical trials. Although the risk of severe liver injury appears small, the true incidence is unknown. Post-marketing studies have shown that the greatest period of risk for the development of liver test abnormalities appears to be in the first year of IFNB treatment. The risk also increases with the more frequently administered, higher-dosage IFNBs. Males are more likely than females to develop elevated aminotransferases (> upper normal limit), although females appear at a greater risk of severe liver injury. Of the commonly used biochemical liver tests, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP) and bilirubin appear the most useful for routine monitoring of IFNB treatment. Whilst many other factors can affect liver test results, including obesity, alcohol, concomitant medications, co-morbidities and theoretically even MS itself, regular liver testing both prior and during IFNB therapy might help minimise Type A or dose/frequency dependent aminotransferase elevations. However, testing will probably not prevent the Type B idiosyncratic reactions which can result in severe hepatic injury; hence patients need to be aware, and to report hepatic side effects promptly.

The authors report further analysis of a six-year retrospective chart review of multiple sclerosis (MS) patients prescribed interferon-beta (IFNB) in British Columbia, Canada. Actions and outcomes taken when 284/835 (34%) of the patients developed de novo elevated aminotransferases are presented; 239/284 (84%) of patients were continued on treatment despite these elevations; 216/246 (88%) of patients reaching grade 1 toxicity (greater than the upper limit of normal) continued IFNB treatment; of these, 167/216 (77%) returned to within normal limits. Of the 22/29 (76%) reaching grade 2 toxicity (> 2.5 times the upper limit of normal) and continuing treatment, 14/22 (64%) returned to within the normal range. One of the nine patients reaching grade 3 toxicity ( > 5 times the upper limit of normal) was allowed continue treatment and their aminotransferase levels returned to within normal limits. However, one patient reaching grade 3 toxicity went on to develop liver failure (previously reported).

Background: A new liquid formulation of Avonex (interferon beta-1a [IFNbeta-1a]) in a prefilled syringe has been developed to make administration of the drug easier for patients with multiple sclerosis (MS). This formulation does not contain human serum albumin (HSA), often added to interferon (IFN) products for stabilization. However, formulation changes may alter the secondary, tertiary, and quaternary structures of IFNbeta products. These kinds of structural changes could lead to the formation of antibodies directed against IFNbeta. Some of these anti-IFN antibodies may neutralize the biologic activity of IFNbeta., Objective: This study was designed to determine the immunogenicity and safety of the new prefilled syringe (liquid) HSA-free formulation of Avonex in patients with relapsing MS., Methods: This was a multicenter, single-arm, open-label study. Patients with relapsing MS received liquid, HSA-free Avonex 30 microg by IM injection from a prefilled syringe once weekly for up to 24 months. Immunogenicity and safety were assessed every 3 months. Serum levels of neutralizing antibodies (NAbs) were measured at baseline and every 3 months using a 2-step enzyme-linked immunosorbent assay and antiviral cytopathic effect assay., Results: A total of 153 patients (121 women, 32 men; mean [SD] age, 39.6 [9.9] years; age range, 19.0-59.0 years) were enrolled in the study. Sera were available for analysis from 125 and 119 patients after 18 and 24 months of treatment, respectively. By 18 months, 1 patient (1%) had > or =2 consecutive titers of > or =20, a level at which the persistent presence of NAbs has been shown in some studies to have clinical consequences. By 24 months, 1 additional patient (total 2%) had > or =2 consecutive titers of > or =20. At 18 months, 5 patients (4%) had > or =1 NAb titer of > or =5; at 24 months, 6 patients (5%) had > or =1 NAb titer of > or =5. The safety profile of liquid Avonex was comparable to the lyophilized form containing HSA., Conclusions: The prefilled syringe (liquid) HSA-free formulation of Avonex was well tolerated and showed a low level of immunogenicity. Over 24 months, 2% of patients developed persistent NAbs (> or =2 consecutive titers of > or =20).

A population-based retrospective chart review of the biochemical liver tests of 844 patients with multiple sclerosis prescribed a beta-interferon (IFNbeta) product in British Columbia, Canada was performed between 1995 and 2001. Overall, 36.9% (243/659) of patients developed new elevations of alanine aminotransferase. All the IFNbetas caused elevated aminotransferase levels compared with pretreatment levels (p < 0.005) and were higher than reported in clinical trials. Their relative effect on aminotransferases can be approximated as IFNbeta-1b(subcutaneous [SC]) = IFNbeta-1a(SC) > IFNbeta-1a(IM).

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.

A retrospective chart review of patients in British Columbia with multiple sclerosis prescribed beta-interferon (IFNbeta) between 1995 and 2001 was carried out to investigate reasons for the interruption of therapy. The highest proportion of interruptions (76/281; 27%) occurred in the first 6 months. The single most common reason was perceived lack of efficacy, cited by 84 of 281 (30%). Gender, disability, and disease duration were identified as factors influencing interruption of IFNbeta therapy.

Background: The Canadian Burden of Illness Study Group reported that the quality of life (QoL) of multiple sclerosis (MS) patients falls drastically, early in the disease. With disability progression, the physical functioning scales of the Short Form 36 (SF-36) showed further decreases in QoL. The objective of this study is to describe the QoL of MS patients treated with interferon beta-1b (IFNB-1b) and to compare it to the QoL observed in a group of patients who had not been treated with IFNB-1b., Methods: Treated patients were prospectively recruited and were seen at their regular visit to the MS clinic. They self-completed the SF-36 questionnaire and their QoL was described and retrospectively compared to that of historical controls., Results: When IFNB-1b treated patients were compared to historical control patients with the same relapsing forms of MS, the treated patients with an Expanded Disability Status Scale (EDSS) score lower than 3.0 had a significantly better QoL. This was significant for four of the eight SF-36 domains: Physical Function (+22%, p = 0.0102), Role-Physical (+100%, p = 0.0022), General Health (+27%, p = 0.0070) and Social Function (+19%, p = 0.0287). The average QoL difference was 8% in the EDSS 3.0-6.0 group and 10% in the EDSS > 6 group., Conclusion: Patients with relapsing forms of MS treated with IFNB-1b have better QoL than patients who are not treated, especially those with an EDSS < 3.0.

The fate of the neutralizing antibody (NAB) in MS patients treated with interferons remains unclear. We conducted a follow-up survey of NAB titers in 59 long-term treated patients from the London and Vancouver cohorts of the pivotal trial of interferon alpha-1b. NAB were measured with the myxovirus protein A assay and an ELISA, at a mean follow-up that exceeded 8 years. NAB disappeared in the majority of patients.

Regulation of class II MHC (Ia) antigen expression by interferons beta and gamma was studied in an in vitro model of the blood-brain barrier. Primary cultures of human brain microvessel endothelial cells were incubated with IFN-beta, gamma or a combination of the two cytokines and surface expression of class II MHC molecules was investigated with the immunogold silver staining technique and enzyme-linked immunosorbent assay. Treatment of monolayers with IFN-beta (100-6000 U/ml) failed to induce Class II MHC molecules. Co-incubation with IFN-gamma (100 U/ml), with or without pretreatment with IFN-beta, significantly inhibited the IFN-gamma-induced de novo expression in a concentration-dependent manner. Downregulation was less significant when incubation with both cytokines was preceded by 2-day treatment with IFN-gamma and was not observed in cultures incubated for an additional 4 days with IFN-gamma. Endothelial cells treated with IFN-gamma exhibited prominent morphological changes and frequent overlapping. These changes were not observed in the presence of either IFN-beta or both cytokines in the media. IFN-beta alone, or in combination with IFN-gamma, significantly inhibited the growth of endothelial cells, while only slight inhibition was observed with IFN-gamma. The results of these studies suggest that IFN-beta may function in modulating IFN-gamma-mediated immune responses in the human central nervous system at the level of the blood-brain barrier and this negative regulatory mechanism may be, at least in part, responsible for the recently reported beneficial effect of IFN-beta in relapsing-remitting multiple sclerosis.