Magnetic Resonance Imaging Effects of Interferon Beta-1b in the BENEFIT Study

Barkhof, Frederik; Polman, Chris H.; Radue, Ernst‐Wilhelm; Kappos, Ludwig; Freedman, Mark S.; Edan, Gilles; Hartung, Hans‐Peter; Miller, David H.; Montalbán, Xavier; Poppe, Peter; Vos, Marlieke de; Lasri, Fatiha; Bauer, Lars; Dahms, S.; Wagner, Klaus; Pohl, Christoph; Sandbrink, Rupert

doi:10.1001/archneur.64.9.1292

Cited by 45 publications

(25 citation statements)

References 23 publications

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“…6,8 The longer observation period allowed for a more comprehensive analysis of the role of neutralising antibodies to interferon beta but failed to show any negative eff ect on the main outcomes. 35 As in the fi rst 2 years, 36 MRI fi ndings over 5 years are in accordance with the clinical observations. In both groups, overall disease burden, as depicted by T2-lesion volumes, was lower at 5 years than at baseline, indicating recovery from the initial infl ammatory event.…”

Section: Main Clinical Outcomessupporting

confidence: 77%

Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

Kappos

Freedman

Polman

et al. 2009

The Lancet Neurology

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334

283

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BACKGROUND:The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. METHODS: Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 microg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment a...

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Section: Main Clinical Outcomessupporting

confidence: 77%

Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

Kappos

Freedman

Polman

et al. 2009

The Lancet Neurology

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334

283

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“…Attacks were defined as in the original study, 13 as episodes of clinical worsening associated with an objective change on examination in a patient who was otherwise stable neurologically for 30 days prior to the onset of new signs and symptoms. A subset of 18 subjects received brief bouts of steroid treatment (average 4.6 Ϯ 5.0 days, range 1-21 days, median number of treatments per patient 4, range [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. The potential effect of this treatment on the study variables was considered in analysis.…”

Section: Methods Subjects and Mri Examinations This Was Amentioning

confidence: 99%

“…The nonuniform observation frequency across seasons or subjects was addressed by dividing the number of new lesions by the total number of scans for each subject, producing a rate of occurrence, a common measure used in clin- ical trials. 16 To account for individual levels of disease activity we also divided each new activity count (active examinations or lesions) by the total number of observations (examinations), yielding an annual fraction that reports the fraction of a patient's total annual disease activity falling within a given period. Variable coverage of the calendar year was addressed by adjusting all fractional measures based on a 1-year reference.…”

mentioning

confidence: 99%

Seasonal prevalence of MS disease activity

Meier¹,

Balashov²,

Healy³

et al. 2010

Neurology

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Objective: This observational cohort study investigated the seasonal prevalence of multiple sclerosis (MS) disease activity (likelihood and intensity), as reflected by new lesions from serial T2-weighted MRI, a sensitive marker of subclinical disease activity. Methods:Disease activity was assessed from the appearance of new T2 lesions on 939 separate brain MRI examinations in 44 untreated patients with MS. Likelihood functions for MS disease activity were derived, accounting for the temporal uncertainty of new lesion occurrence, individual levels of disease activity, and uneven examination intervals. Both likelihood and intensity of disease activity were compared with the time of year (season) and regional climate data (temperature, solar radiation, precipitation) and among relapsing and progressive disease phenotypes. Contrast-enhancing lesions and attack counts were also compared for seasonal effects.Results: Unlike contrast enhancement or attacks, new T2 activity revealed a likelihood 2-3 times higher in March-August than during the rest of the year, and correlated strongly with regional climate data, in particular solar radiation. In addition to the likelihood or prevalence, disease intensity was also elevated during the summer season. The elevated risk season appears to lessen for progressive MS and occur about 2 months earlier. Conclusion:This study documents evidence of a strong seasonal pattern in subclinical MS activity based on noncontrast brain MRI. The observed seasonality in MS disease activity has implications for trial design and therapy assessment. The observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity. This study tested the hypothesis that untreated multiple sclerosis (MS) disease activity, as observed by new lesions on noncontrast MRI, is not uniformly distributed over the calendar year, but shows greater prevalence during a particular season. Patterns of such seasonal variation have been observed mostly for clinical markers, with peaks in exacerbation rates during summer for the United States (Ohio, 1 Arizona 2 ) and Japan, 3 and during the spring in Switzerland. 4 A study of seasonal prevalence of optic neuritis in Sweden found higher incidence in spring than winter and correlations of incidence rates with solar radiation and temperature. 5Significant seasonal variation of immunologic activity was found by 2 studies in Boston and Amsterdam, with peaking concentrations of proinflammatory cytokines interferon-␥ and tumor necrosis factor-␣ in autumn. 6,7 Similarly, the immunosuppressive cytokine interleukin-10 was found to be elevated in the summer months in Australia. 8 On MRI, however, studies are very rare and findings elusive. Out of only 3 studies looking at MRI markers, 9-11 one found a seasonal effect. 9 All 3 studies were very limited in longitudinal

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“…In such circumstances, an immunosuppressive role of a-and b-IFNs was suggested by several reports (Decker et al, 2005;Jensen et al, 1992;Shahangian et al, 2009). Second, a number of studies show the effectiveness of this family of cytokines in reducing inflammation in different experimental settings and, most importantly, type I IFN is successfully used in the clinic, not only for the treatment of diseases of viral origin but also for the management of diseases such as multiple sclerosis (MS) (Barkhof et al, 2007;Billiau, 2006;Comi et al, 2001;Giovannoni and Miller, 1999). For patients suffering from MS in the relapsing-remitting phase (RR-MS), IFN-b markedly attenuates the course and the severity of the disease, contributing to the maintenance of the bloodbrain barrier integrity and reducing the occurrence of relapses.…”

Section: Introductionmentioning

confidence: 99%

Type I Interferon Inhibits Interleukin-1 Production and Inflammasome Activation

et al. 2011

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Type I interferon (IFN) is a common therapy for autoimmune and inflammatory disorders, yet the mechanisms of action are largely unknown. Here we showed that type I IFN inhibited interleukin-1 (IL-1) production through two distinct mechanisms. Type I IFN signaling, via the STAT1 transcription factor, repressed the activity of the NLRP1 and NLRP3 inflammasomes, thereby suppressing caspase-1-dependent IL-1β maturation. In addition, type I IFN induced IL-10 in a STAT1-dependent manner; autocrine IL-10 then signaled via STAT3 to reduce the abundance of pro-IL-1α and pro-IL-1β. In vivo, poly(I:C)-induced type I IFN diminished IL-1β production in response to alum and Candida albicans, thus increasing susceptibility to this fungal pathogen. Importantly, monocytes from multiple sclerosis patients undergoing IFN-β treatment produced substantially less IL-1β than monocytes derived from healthy donors. Our findings may thus explain the effectiveness of type I IFN in the treatment of inflammatory diseases but also the observed "weakening" of the immune system after viral infection.

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Magnetic Resonance Imaging Effects of Interferon Beta-1b in the BENEFIT Study

Cited by 45 publications

References 23 publications

Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

Seasonal prevalence of MS disease activity

Type I Interferon Inhibits Interleukin-1 Production and Inflammasome Activation

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