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.
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We compared demographic and clinical features, including outcome defined by a failure time analysis of disability, in 143 patients with a family history of multiple sclerosis (familial MS) compared with 956 patients without such a history (sporadic MS). Patients with familial MS did not differ from those with sporadic MS even when patients with 1st-degree relatives or multiple relatives with MS were considered separately. An intraclass correlation analysis of 13 pairs of affected 1st-degree relatives, both members of which were followed in our clinic, failed to reveal heterogeneity among different families. We were unable to find any support for differences between familial and sporadic MS.
Two microsatellite markers, tightly linked to CACNA1A, were genotyped in migraine with aura (MA) families to determine if this gene, which underlies the 19p13 linked forms of familial hemiplegic migraine, is also linked to MA. Two-point parametric lod and nonparametric linkage scores did not support linkage. Transmission disequilibrium testing provided no evidence for linkage of MA to CACNA1A. In a large dataset of 64 Canadian MA families, the authors did not find evidence to support an MA susceptibility gene in the region of 19p13.
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: The primary question is whether interferon beta is more effective than placebo in decreasing the number of SPMS patients who experience disability progression during follow‐up. We also aim to evaluate the incidence and seriousness of side effects and adverse events. The secondary objectives are to examine the effect of interferon beta on relapses during follow‐up, on patient activities of daily living and quality of life, and reducing the need for other treatments. We will also evaluate change in MRI parameters during follow‐up.
An abstract is not available for this content so a preview has been provided. As you have access to this content, a full PDF is available via the ‘Save PDF’ action button.
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Multiple sclerosis (MS) susceptibility is characterized by maternal parent-of-origin effects and increased female penetrance.In 7796 individuals from 1797 MS families (affected individuals n 5 2954), we further implicate epigenetic modifications within major histocompatibility complex (MHC) class II haplotypes as mediating these phenomena.Affected individuals with the main MS-associated allele HLA-DRB1 * 15 had a higher female-to-male ratio versus those lacking it (P 5 0.00023).Distorted transmission of MHC haplotypes by both parent-of-origin and gender-of-affected-offspring was most evident in the maternal HLA-DRB1 * 15 transmission to affected female offspring (OR 5 3.31, 95% CI 5 2.59 -4.24) contrasting with similarity among maternal transmission to affected male offspring (OR 5 2.13, 95% CI 5 1.44 -3.14), paternal transmissions to affected female (OR 5 2.14, 95% CI 5 1.64 -2.78) and male (OR 5 2.16, 95% CI 5 1.37 -3.39) offspring.Significant parent-of-origin effects were observed in affected females (maternal: P 5 9.33 3 10 242 ; paternal: P 5 1.12 3 10 215 ; comparison: P 5 0.0014), but not in affected males (maternal: P 5 6.70 3 10 28 ; paternal: P 5 2.54 3 10 26 ; comparison: P 5 0.95).Conditional logistic regression analysis revealed further differential risk of HLA diplotypes.Risks for HLA-DRB1 * 15 and likely for other HLA-DRB1 haplotypes were restricted by (i) parent-of-origin, (ii) gender-of-offspring and (iii) trans epistasis in offspring.These findings may illuminate the gender bias characterizing autoimmunity overall.They raise questions about the concept of restricted antigen presentation in autoimmunity and suggest that gender-specific epigenetic interactions may be the driving forces behind the MHC haplotypic associations.Haplotype-specific epigenetic modifications at MHC class II and their decay appear to be at the heart of MS pathogenesis and inheritance of risk, providing the focus for gene -environment interactions that determine susceptibility and resistance.
Four patients with progressive demyelinating myelopathy with symptoms spanning six to 25 years are described. There was no clinical evidence of dissemination of lesions in the central nervous system. Radiological evidence of dissemination was present in two cases; in one this was absent at the time of presentation and was only demonstrated after six years of progressive unifocal disease. In one case, pathological examination revealed a solitary area of chronic demyelination. In all cases but one, oligoclonal bands were detected on cerebrospinal fluid (CSF) electrophoresis. Some cases of chronically progressive myelopathy result from focal demyelination in the absence of a second lesion demonstrable by clinical, radiographic or necropsy examination.
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