Increased disability and MRI lesions after discontinuation of IFN-beta-1a in secondary progressive MS
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Abstract:
To examine neurological and magnetic resonance imaging (MRI) changes following discontinuation of interferon (IFN)-beta-1a treatment in secondary progressive multiple sclerosis (SPMS).The study involved 21 SPMS patients who received subcutaneous (s.c.) IFN-beta-1a 44 microg three times weekly (t.i.w.) for 12 months and were thereafter followed up without treatment for a further 12 months. The number of relapses, disability on the Expanded Disability Status Scale (EDSS) and MRI were recorded at baseline, at 12 months of IFN-beta-1a 44 microg t.i.w. and 1 year after discontinuation of treatment.During the 12-month treatment EDSS score and volumes of brain T2- and T1-weighted lesions remained without significant progression, but at 12 months after treatment discontinuation both EDSS score and the volumes of cerebral lesions increased significantly. Cerebrospinal fluid fraction increased significantly both during the treatment and during follow-up.Discontinuation of IFN-beta-1a 44 microg t.i.w. in SPMS may be associated with an increase in neurological disability and brain lesions on MRI.Keywords:
Discontinuation
Interferon beta-1b
Interferon beta-1a
Objective: To evaluate the efficacy and safety of interferon beta- 1b (IFNβ - 1b) in subjects with secondary progressive multiple sclerosis (SPMS). Methods: This 3- year, multicenter, double- blind, placebo- controlled, randomized trial of IFNβ - 1b included 939 subjects from the United States and Canada with SPMS and Expanded Disability Status Scale (EDSS) scores ranging from 3.0 to 6.5. Subjects were randomly assigned to receive either placebo or IFNβ - 1b (250 μ g or 160 μ g/m2 body surface area), administered subcutaneously every other day. The primary outcome was time to progression by ≥ 1.0 EDSS point (0.5 point if EDSS score was 6.0 to 6.5 at entry)- confirmed at 6 months. Secondary outcomes included mean change in EDSS score from baseline, relapse- related measures, MRI activity, and a standardized neuropsychological function test. Results: There was no significant difference in time to confirmed progression of EDSS scores between placebo- treated patients and either of the IFNβ - 1b treatment groups. However, IFNβ - 1b treatment resulted in improvement on secondary outcome measures involving clinical relapses, newly active MRI lesions, and accumulated burden of disease on T2- weighted MRI. Effects were similar for both IFNβ - 1b treatment groups. Neutralizing antibodies to IFNβ - 1b were detected in 23% of 250- μ g and 32% of 160- μ g/m2 recipients, but their presence did not consistently affect clinical or MRI outcomes. IFNβ - 1b was also well tolerated at both doses. Conclusions: Although no treatment benefit was seen on the time to confirmed progression of disability, relapse- and MRI- related outcomes showed significant benefit with both dosing regimens tested, a result consistent with the outcomes of earlier clinical trials.
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To examine neurological and magnetic resonance imaging (MRI) changes following discontinuation of interferon (IFN)-beta-1a treatment in secondary progressive multiple sclerosis (SPMS).The study involved 21 SPMS patients who received subcutaneous (s.c.) IFN-beta-1a 44 microg three times weekly (t.i.w.) for 12 months and were thereafter followed up without treatment for a further 12 months. The number of relapses, disability on the Expanded Disability Status Scale (EDSS) and MRI were recorded at baseline, at 12 months of IFN-beta-1a 44 microg t.i.w. and 1 year after discontinuation of treatment.During the 12-month treatment EDSS score and volumes of brain T2- and T1-weighted lesions remained without significant progression, but at 12 months after treatment discontinuation both EDSS score and the volumes of cerebral lesions increased significantly. Cerebrospinal fluid fraction increased significantly both during the treatment and during follow-up.Discontinuation of IFN-beta-1a 44 microg t.i.w. in SPMS may be associated with an increase in neurological disability and brain lesions on MRI.
Discontinuation
Interferon beta-1b
Interferon beta-1a
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Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established.To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS.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.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.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.Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.
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Objective: Interferon (IFN) beta has repeatedly shown benefit in multiple sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with magnetic resonance imaging and, to some degree, the progression of disability; however, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage. This multicentre, double blind, placebo controlled study explored the dose−response curve by examining the clinical benefit of low dose IFN beta-1a (Rebif®), 22 μg subcutaneously once weekly, in patients with secondary progressive MS. Methods: A total of 371 patients with clinically definite SPMS were randomised to receive either placebo or subcutaneous IFN beta-1a, 22 μg once weekly, for 3 years. Clinical assessments were performed every 6 months. The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate. Results: Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 μg v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67). Other disability measures were also not significantly affected by treatment. Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted. Conclusions: This patient population was less clinically active than SPMS populations studied in other trials. Treatment with low dose, IFN beta-1a (Rebif®) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses. These results add a point at one extreme of the dose−response spectrum of IFN beta therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.
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Clinically isolated syndrome
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Interferon beta-1b
Interferon beta-1a
McDonald criteria
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Background and Objective: A phase III double-blind, placebo-controlled clinical trial demonstrated that interferon beta-la (IFNβ-1a) (Avonex, Biogen) significantly delayed progression of disability in relapsing MS patients. The primary clinical outcome was time from study entry until disability progression, defined as≥1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months. The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance. Methods: Post hoc analyses related to disability outcomes using data collected during the double-blind, placebo-controlled phase III clinical trial. Results: (1) Clinical efficacy related to disability did not depend on the definition of disability progression. A significant benefit in favor of IFNβ-1a was observed when ≥2.0 point worsening from baseline EDSS was required or when worsening was required to persist for ≥1.0 year. (2) Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFNβ-1a recipients who reached the primary study outcome. (3) Significantly fewer IFNβ-1a recipients progressed to EDSS milestones of 4.0 (relatively severe impairment) or 6.0(unilateral assistance needed to walk). (4) Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to disability progression was IFNβ-1a treatment. Conclusions: The primary clinical outcome for the IFNβ-1a clinical trial underestimated clinical benefits of treatment. Results in this report demonstrate that IFNβ-1a treatment is associated with robust, clinically important beneficial effects on disability progression in relapsing MS patients.
Interferon beta-1b
BETA (programming language)
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Objective: To evaluate the efficacy and safety of interferon beta-1b (IFNβ-1b) in subjects with secondary progressive multiple sclerosis (SPMS). Methods: This 3-year, multicenter, double-blind, placebo-controlled, randomized trial of IFNβ-1b included 939 subjects from the United States and Canada with SPMS and Expanded Disability Status Scale (EDSS) scores ranging from 3.0 to 6.5. Subjects were randomly assigned to receive either placebo or IFNβ-1b (250 μg or 160 μg/m2 body surface area), administered subcutaneously every other day. The primary outcome was time to progression by ≥1.0 EDSS point (0.5 point if EDSS score was 6.0 to 6.5 at entry) confirmed at 6 months. Secondary outcomes included mean change in EDSS score from baseline, relapse-related measures, MRI activity, and a standardized neuropsychological function test. Results: There was no significant difference in time to confirmed progression of EDSS scores between placebo-treated patients and either of the IFNβ-1b treatment groups. However, IFNβ-1b treatment resulted in improvement on secondary outcome measures involving clinical relapses, newly active MRI lesions, and accumulated burden of disease on T2-weighted MRI. Effects were similar for both IFNβ-1b treatment groups. Neutralizing antibodies to IFNβ-1b were detected in 23% of 250-μg and 32% of 160-μg/m2 recipients, but their presence did not consistently affect clinical or MRI outcomes. IFNβ-1b was also well tolerated at both doses. Conclusions: Although no treatment benefit was seen on the time to confirmed progression of disability, relapse- and MRI-related outcomes showed significant benefit with both dosing regimens tested, a result consistent with the outcomes of earlier clinical trials.
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Proposed beta-interferon (IFNβ) treatment failure criteria for patients with relapsing-remitting multiple sclerosis (RRMS) have not been validated in clinical practice. This study aimed to establish (a) whether IFNβ attenuated accumulation of fixed disability in comparison to a cohort of matched historical control subjects from the Sylvia Lawry centre for MS research, and (b) whether relapse-based treatment failure criteria or clinical and demographic variables had predictive value for the accumulation of fixed disability. Of the 175 IFNβ-treated RRMS patients, 60 (34%) developed accumulation of fixed disability over a median of five years follow-up, which was significantly less than the rate of accumulation of fixed disability in the control group (P<0.0001). Any relapse in the treatment period predicted accumulation of fixed disability with a sensitivity of 80% and specificity of 43%; patients totally relapse free were less likely to develop accumulation of fixed disability (P <0.002). Multivariate analysis confirmed that a greater risk of accumulation of fixed disability was conferred by a higher Expanded Disability Status Scale (EDSS) score starting IFNβ (P=0.02), and by failure of IFNβ to completely suppress relapses (P=0.004). In conclusion, IFNβ therapy reduced the accumulation of fixed disability in a cohort of RRMS patients, followed for a median of five years. Higher baseline EDSS and failure of complete relapse suppression were associated with a significantly greater likelihood of accumulation of fixed disability. Multiple Sclerosis 2007; 13: 336-342. http://msj.sagepub.com
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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.Interquartile range
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The treatment effects of recent immunomodulatory therapies on disease progression in relapsing-remitting multiple sclerosis (MS) have been mostly established from 'confirmed progression' endpoints. However, the reliability of this outcome measure is poor and a significant proportion of patients may be erroneously classified. We previously proposed the area under disability/time curves to quantify in-trial disability changes, but although these have advantages, they lack information on the direction of change. We have therefore performed disease trend analyses and categorical classifications using serial Expanded Disability Status Scale (EDSS) scores from the 533 complete datasets in a double-blind, randomized, placebo-controlled, phase III trial of subcutaneous interferon β-1a (IFNβ-1a) (PRISMS study). We found significant treatment benefits for IFNβ-1a on in-trial disability course (P=0.002). Therapeutic advantages remained when relapse-related assessments were excluded (P=0.018). Post hoc analyses demonstrated that IFNβ-la was mainly effective in both increasing the proportion of patients with a 'stable' course and reducing those with prolonged, disabling deteriorations. Baseline disease duration and EDSS levels, but not MRI lesion load, predicted the subsequent disability trends. Mean 'numbers needed to treat' (NNTs) to obtain preferred disability courses were reduced in patients with shorter disease duration. These results have important implications for the targeting of immunomodulatory therapies in MS. Multiple Sclerosis (2002) 8, 10-14
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