Approved Beta interferons in relapsing-remitting multiple sclerosis: is there an odd one out?
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ABSTRACT:
SUBMITTER: Clapin A
PROVIDER: S-EPMC3619495 | biostudies-literature | 2012
REPOSITORIES: biostudies-literature
Publications
Approved Beta interferons in relapsing-remitting multiple sclerosis: is there an odd one out?
Journal of central nervous system disease 20120903
Three interferons are marketed for the treatment of relapsing-remitting multiple sclerosis. In its pivotal trial, one of them demonstrated impressive efficacy as a once-weekly regimen, but later head-to-head studies and reviews questioned its superiority. Analysis of this pivotal trial in publications and health authority reviews has shown that its early termination might have caused attrition bias. Censored patients were different from those completing the study on magnetic resonance imaging pa ...[more]
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Project description:Changes of intestinal permeability (IP) have been extensively investigated in inflammatory bowel diseases (IBD) and celiac disease (CD), underpinned by a known unbalance between microbiota, IP and immune responses in the gut. Recently the influence of IP on brain function has greatly been appreciated. Previous works showed an increased IP that preceded experimental autoimmune encephalomyelitis development and worsened during disease with disruption of TJ. Moreover, studying co-morbidity between Crohn's disease and MS, a report described increased IP in a minority of cases with MS. In a recent work we found that an alteration of IP is a relatively frequent event in relapsing-remitting MS, with a possible genetic influence on the determinants of IP changes (as inferable from data on twins); IP changes included a deficit of the active mechanism of absorption from intestinal lumen. The results led us to hypothesize that gut may contribute to the development of MS, as suggested by another previous work of our group: a population of CD8+CD161high T cells, belonging to the mucosal-associated invariant T (MAIT) cells, a gut- and liver-homing subset, proved to be of relevance for MS pathogenesis. We eventually suggest future lines of research on IP in MS: studies on IP changes in patients under first-line oral drugs may result useful to improve their therapeutic index; correlating IP and microbiota changes, or IP and blood-brain barrier changes may help clarify disease pathogenesis; exploiting the IP data to disclose co-morbidities in MS, especially with CD and IBD, may be important for patient care.
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2015-03-10 | GSE66573 | GEO
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2015-03-10 | E-GEOD-66573 | biostudies-arrayexpress
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| S-EPMC4431469 | biostudies-literature
Project description:BACKGROUND:We systematically reviewed the comparative effectiveness of injectable beta-interferons (IFN-?) and glatiramer acetate (GA) on annualised relapse rate (ARR), progression and discontinuation due to adverse events (AEs) in RRMS, using evidence from within the drugs' recommended dosages. METHODS:We updated prior comprehensive reviews, checked references of included studies, contacted experts in the field, and screened websites for relevant publications to locate randomised trials of IFN-? and GA with recommended dosages in RRMS populations, compared against placebo or other recommended dosages. Abstracts were screened and assessed for inclusion in duplicate and independently. Studies were appraised using the Cochrane risk of bias tool. Rate ratios for ARR, hazard ratios for time to progression, and risk ratios for discontinuation due to AEs were synthesised in separate models using random effects network meta-analysis. RESULTS:We identified 24 studies reported in 42 publications. Most studies were at high risk of bias in at least one domain. All drugs had a beneficial effect on ARR as compared to placebo, but not compared to each other, and findings were robust to sensitivity analysis. We considered time to progression confirmed at 3 months and confirmed at 6 months in separate models; while both models suggested that the included drugs were effective, findings were not consistent between models. Discontinuation due to AEs did not appear to be different between drugs. CONCLUSIONS:Meta-analyses confirmed that IFN-? and GA reduce ARR and generally delay progression as defined in these trials, though there was no clear 'winner' across outcomes. Findings are additionally tempered by the high risk of bias across studies, and the use of an impairment/mobility scale to measure disease progression. Future research should consider more relevant measures of disability and, given that most trials have been short-term, consider a longitudinal approach to comparative effectiveness. REVIEW REGISTRATION:PROSPERO CRD42016043278 .
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| S-EPMC4473119 | biostudies-literature
Project description:BackgroundSurveillance of integrity of the basic elements of the cell including DNA, RNA, and proteins is a critical element of cellular physiology. Mechanisms of surveillance of DNA and protein integrity are well understood. Surveillance of structural RNAs making up the vast majority of RNA in a cell is less well understood. Here, we sought to explore integrity of processing of structural RNAs in relapsing remitting multiple sclerosis (RRMS) and other inflammatory diseases.ResultsWe employed mononuclear cells obtained from subjects with RRMS and cell lines. We used quantitative-PCR and whole genome RNA sequencing to define defects in structural RNA surveillance and siRNAs to deplete target proteins. We report profound defects in surveillance of structural RNAs in RRMS exemplified by elevated levels of poly(A) + Y1-RNA, poly(A) + 18S rRNA and 28S rRNAs, elevated levels of misprocessed 18S and 28S rRNAs and levels of the U-class of small nuclear RNAs. Multiple sclerosis is also associated with genome-wide defects in mRNA splicing. Ro60 and La proteins, which exist in ribonucleoprotein particles and play different roles in quality control of structural RNAs, are also deficient in RRMS. In cell lines, silencing of the genes encoding Ro60 and La proteins gives rise to these same defects in surveillance of structural RNAs.ConclusionsOur results establish that profound defects in structural RNA surveillance exist in RRMS and establish a causal link between Ro60 and La proteins and integrity of structural RNAs.
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Project description:Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and mainly affects young adults. Its natural history has changed in recent years with the advent of disease-modifying drugs, which have been available since the early 1990s. The increasing number of first-line and second-line treatment options, together with the variable course of the disease and patient lifestyles and expectations, makes the therapeutic decision a real challenge. The aim of this review is to give a comprehensive overview of the main present and some future drugs for relapsing-remitting MS, including risk-benefit considerations, to enable readers to draw their own conclusions regarding the risk-benefit assessment of personalized treatment strategies, taking into account not only treatment-related but also disease-related risks. We performed a Medline literature search to identify studies on the treatment of MS with risk stratification and risk-benefit considerations. We focused our attention on studies of disease-modifying, immunomodulating, and immunosuppressive drugs, including monoclonal antibodies. Here we offer personal considerations, stemming from long-term experience in the treatment of MS and thorough discussions with other neurologists closely involved in the care of patients with the disease. MS specialists need to know not only the specific risks and benefits of single drugs, but also about drug interactions, either in simultaneous or serial combination therapy, and patient comorbidities, preferences, and fears. This has to be put into perspective, considering also the risks of untreated disease in patients with different clinical and radiological characteristics. There is no single best treatment strategy, but therapy has to be tailored to the patient. This is a time-consuming task, rich in complexity, and influenced by the attitude towards risk on the parts of both the patient and the clinical team. The broader the MS drug market becomes, the harder it will be for the clinician to help the patient decide which therapeutic strategy to opt for.
| S-EPMC3699254 | biostudies-other