The Multiple Sclerosis Collaborative Research Group trial was a double-blind, randomized, multicenter, phase III, placebo-controlled study of interferon beta-1a (IFNbeta-1a; AVONEX) in relapsing forms of multiple sclerosis. Initial magnetic resonance imaging results have been published; this report provides additional results. Treatment with IFNbeta-1a, 30 microg once weekly by intramuscular injection, resulted in a significant decrease in the number of new, enlarging, and new plus enlarging T2 lesions over 2 years. The median increase in T2 lesion volume in placebo and IFNbeta-1a patients was 455 and 152 mm3, respectively, at 1 year and 1,410 and 628 mm3 at 2 years, although the treatment group differences did not reach statistical significance. For active patients, defined as those with gadolinium enhancement at baseline, the median change in T2 lesion volume in placebo and IFNbeta-1a patients was 1,578 and -12 mm3 and 2,980 and 1,285 mm3 at 1 and 2 years, respectively. Except for a minimal correlation of 0.30 between relapse rate and the number of gadolinium-enhanced lesions, correlations between MR and clinical measures at baseline and throughout the study were in general poor. Once weekly intramuscular IFNbeta-1a appears to impede the development of multiple sclerosis lesions at an early stage and has a favorable impact on the long-term sequelae of these inflammatory events as indicated by the slowed accumulation of T2 lesions.
"Interferon-β1a (Avonex) was approved by the FDA in 1996 for the treatment of patients with relapsing form of MS, and similar to Rebif, it is made by Chinese hamster ovarian cells. The FDA approval of this medication followed the results obtained from a clinical trial which was designed by the Multiple Sclerosis Collaborative Research Group (MSCRG) [32–34]. During this phase 3, multicenter, double-blind, placebo-controlled clinical trial, 301 patients with RRMS were randomized to be treated with IFN-β1a (30 Mg intramuscularly once weekly) or placebo, for 24 months. "
[Show abstract][Hide abstract] ABSTRACT: With the introduction of interferon- β 1b in 1993 as the first FDA-approved treatment for multiple sclerosis, the era of treatment of this incurable disease began, and its natural course was permanently changed. Currently, seven different treatments for patients with multiple sclerosis with different mechanisms of action and dissimilar side effect profiles exist. These medications include interferon- β 1a intramuscular (Avonex), interferon- β 1a subcutaneous (Rebif), interferon- β 1b subcutaneous (Betaseron/Extavia), glatiramer acetate (Copaxone), natalizumab (Tysabri), fingolimod (Gilenya), teriflunomide (Aubagio), and mitoxantrone (Novantrone). In addition, a large number of clinical trials are being conducted to assess the safety and efficacy of various experimental agents in patients with multiple sclerosis, including alemtuzumab, dimethyl fumarate, laquinimod, rituximab, daclizumab, and cladribine. In this paper, the author presents a concise and comprehensive review of present and potential treatments for this incurable disease.
"Placebo-controlled clinical studies have shown that IM IFNβ-1a reduces T2 LV , slows disability progression, , and prevents development of brain atrophy [33–36]. However, despite these known effects of treatment with IM IFNβ-1a, both the early and late disease duration groups of MS patients exhibited loss of brain tissue and, in particular, developed cortical atrophy over the 2 years in the present study. "
[Show abstract][Hide abstract] ABSTRACT: We investigated the evolution of cortical atrophy in patients with early relapsing-remitting (RR) multiple sclerosis (MS) and its association with lesion volume (LV) accumulation and disability progression. 136 of 181 RRMS patients who participated in the Avonex-Steroids-Azathioprine study were assessed bimonthly for clinical and MRI outcomes over 2 years. MS patients with disease duration (DD) at baseline of ≤24 months were classified in the early group (DD of 1.2 years, n = 37), while patients with DD > 24 months were classified in the late group (DD of 7.1 years, n = 99). Mixed effect model analysis was used to investigate the associations. Significant changes in whole brain volume (WBV) (P < 0.001), cortical volume (CV) (P < 0.001), and in T2-LV (P < 0.001) were detected. No significant MRI percent change differences were detected between early and late DD groups over 2 years, except for increased T2-LV accumulation between baseline and year 2 in the early DD group (P < 0.01). No significant associations were found between changes in T2-LV and CV over the followup. Change in CV was related to the disability progression over the 2 years, after adjusting for DD (P = 0.01). Significant cortical atrophy, independent of T2-LV accumulation, occurs in early RRMS over 2 years, and it is associated with the disability progression.
"The production of CXCL13 is pathogenic during EAE by sustaining myelin-specific CD4+ T-cell responses, and in vivo neutralization of CXCL13 ameliorates disease (Bagaeva et al., 2006). Since subcutaneous or intramuscular administration of IFNβ has been convincingly shown to reduce relapse rate, disability progression and the formation of new brain and spinal cord lesions in patients with RRMS (The IFNB Multiple Sclerosis Study Group, 1993; UBC MS/MRI Study Group and The IFNB Multiple Sclerosis Study Group, 1993; The Multiple Sclerosis Collaborative Research Group, 1996; Prevention of Relapses and Disability by IFNβ1a Subcutaneously in Multiple Sclerosis Study Group, 1998; The Multiple Sclerosis Collaborative Research Group, 1998), its capacity to regulate CXCL13 production may be an explanation for its mechanism of action in this complex neuroinflammatory disease. Further studies are underway to address this important question. "
[Show abstract][Hide abstract] ABSTRACT: Microglia express multiple TLRs (Toll-like receptors) and provide important host defence against viruses that invade the CNS (central nervous system). Although prior studies show these cells become activated during experimental alphavirus encephalitis in mice to generate cytokines and chemokines that influence virus replication, tissue inflammation and neuronal survival, the specific PRRs (pattern recognition receptors) and signalling intermediates controlling microglial activation in this setting remain unknown. To investigate these questions directly in vivo, mice ablated of specific TLR signalling molecules were challenged with NSV (neuroadapted Sindbis virus) and CNS viral titres, inflammatory responses and clinical outcomes followed over time. To approach this problem specifically in microglia, the effects of NSV on primary cells derived from the brains of wild-type and mutant animals were characterized in vitro. From the standpoint of the virus, microglial activation required viral uncoating and an intact viral genome; inactivated virus particles did not elicit measurable microglial responses. At the level of the target cell, NSV triggered multiple PRRs in microglia to produce a broad range of inflammatory mediators via non-overlapping signalling pathways. In vivo, disease survival was surprisingly independent of TLR-driven responses, but still required production of type-I IFN (interferon) to control CNS virus replication. Interestingly, the ER (endoplasmic reticulum) protein UNC93b1 facilitated host survival independent of its known effects on endosomal TLR signalling. Taken together, these data show that alphaviruses activate microglia via multiple PRRs, highlighting the complexity of the signalling networks by which CNS host responses are elicited by these infections.
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