Glatiramer acetate for multiple sclerosis
ABSTRACT This is an updated Cochrane review of the previous version published (Cochrane Database of Systematic Reviews 2004 , Issue 1 . Art. No.: CD004678. DOI: 10.1002/14651858.CD004678)Previous studies have shown that glatiramer acetate (Copaxone (R)), a synthetic amino acid polymer is effective in experimental allergic encephalomyelitis (EAE), and improve the outcome of patients with multiple sclerosis (MS).
To verify the clinical efficacy of glatiramer acetate in the treatment of MS patients with relapsing remitting (RR) and progressive (P) course.
We searched the Cochrane MS Group Trials Register (26 March 2009), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2009), MEDLINE (PubMed) (January 1966 to 26 March 2009), EMBASE (January 1988 to 26 March 2009) and hand searching of symposia reports (1990-2009).
All randomised controlled trials (RCTs) comparing glatiramer acetate and placebo in patients with definite MS, whatever the administration schedule and disease course, were eligible for this review.
Both patients with RR and P MS were analysed. Study protocols were comparable across trials. No major flaws were found in methodological quality. However, efficacy of blinding should be balanced against side effects, including injection-site reactions.
Among 409 retrieved references, we identified 16 RCTs; six of them, published between 1987 and 2007, met the selection criteria and were included in this review. Five hundred and forty RR patients and 1049 PMS contributed to the analysis. In RR MS, a decrease in the mean EDSS score (-0.33 and -0.45), was found respectively at 2 years and 35 months without any significant effect on sustained disease progression. The reduction of mean number of relapse was evident at 1 year (-0.35 ) 2 years (-0.51 ) and 35 months (-0.64), but significant studies ' heterogeneity was found. The number of hospitalisations and steroid courses were significantly reduced. No benefit was shown in P MS patients. No major toxicity was found. The most common systemic adverse event was a transient and self-limiting patterned reaction of flushing, chest tightness, sweating, palpitations, anxiety. Local injection-site reactions were observed in up to a half of patients treated with glatiramer acetate, thus making a blind assessment of outcomes questionable.
Glatiramer acetate did show a partial efficacy in RR MS in term of relapse -related clinical outcomes, without any significant effect on clinical progression of disease measured as sustained disability. The drug is not effective in progressive MS patients.
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ABSTRACT: Multiple sclerosis (MS) is a chronic progressive, neurological disease characterized by the targeted immune system-mediated destruction of central nervous system (CNS) myelin. Autoreactive CD4+ T helper cells have a key role in orchestrating MS-induced myelin damage. Once activated, circulating Th1-cells secrete a variety of inflammatory cytokines that foster the breakdown of blood-brain barrier (BBB) eventually infiltrating into the CNS. Inside the CNS, they become reactivated upon exposure to the myelin structural proteins and continue to produce inflammatory cytokines such as tumor necrosis factor α (TNFα) that leads to direct activation of antibodies and macrophages that are involved in the phagocytosis of myelin. Proliferating oligodendrocyte precursors (OPs) migrating to the lesion sites are capable of acute remyelination but unable to completely repair or restore the immune system-mediated myelin damage. This results in various permanent clinical neurological disabilities such as cognitive dysfunction, fatigue, bowel/bladder abnormalities, and neuropathic pain. At present, there is no cure for MS. Recent remyelination and/or myelin repair strategies have focused on the role of the neurotrophin brain-derived neurotrophic factor (BDNF) and its upstream transcriptional repressor methyl CpG binding protein (MeCP2). Research in the field of epigenetic therapeutics involving histone deacetylase (HDAC) inhibitors and lysine acetyl transferase (KAT) inhibitors is being explored to repress the detrimental effects of MeCP2. This review will address the role of MeCP2 and BDNF in remyelination and/or myelin repair and the potential of HDAC and KAT inhibitors as novel therapeutic interventions for MS.Molecular Neurobiology 01/2015; DOI:10.1007/s12035-014-9074-1 · 5.29 Impact Factor
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ABSTRACT: A series of controlled clinical trials have shown that exogenous interferon-beta (IFN-β) benefits patients with relapsing-remitting multiple sclerosis (RRMS) by reducing relapse rate, disability progression, and the formation of new brain and spinal cord lesions on magnetic resonance imaging (MRI) scans. Unfortunately, however, the effectiveness of IFN-β is limited in this setting by the occurrence of treatment non-responsiveness in nearly 25% of patients. Furthermore, clinicians who care for RRMS patients remain unable to accurately identify IFN-β non-responders prior to the initiation of therapy, causing delays in the use of alternative treatments and sometimes requiring that patients turn to medications with more significant side effects to control their disease. Progress has been made toward understanding how both endogenous and exogenous IFN-β act to slow RRMS as well as the related mouse model, experimental autoimmune encephalomyelitis (EAE). Most studies point to its inhibitory actions on circulating immune cells as being important for suppressing both disorders, but multiple potential target cells and inflammatory pathways have been implicated and those essential to confer its benefits remain undefined. This review focuses on the role of both endogenous and exogenous IFN-β in RRMS, paying particular attention to the issue of why certain individuals appear refractory to its disease-modifying effects. A continued goal in this field remains the identification of a convenient biomarker that accurately predicts IFN-β treatment non-responsiveness in individual RRMS patients. Development of such an assay will allow clinicians to customize therapy for patients with this complex disorder. Copyright © 2015 Elsevier Ltd. All rights reserved.Cytokine 02/2015; DOI:10.1016/j.cyto.2015.01.004 · 2.87 Impact Factor
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ABSTRACT: Background The Evaluate Patient OutComes (EPOC) study assessed physician- and patient-reported outcomes in individuals with relapsing multiple sclerosis who switched directly from injectable disease-modifying therapy (iDMT; glatiramer acetate, intramuscular or subcutaneous interferon beta-1a, or interferon beta-1b) to once-daily, oral fingolimod. Post hoc analyses evaluated the impact of a switch to fingolimod versus staying on each of the four individual iDMTs.Methods Overall, 1053 patients were randomized 3:1 to switch to fingolimod or remain on iDMT. The primary endpoint was the change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction score. Secondary endpoints included changes in scores for TSQM Effectiveness, Side Effects and Convenience subscales, Beck Depression Inventory-II (BDI-II), Fatigue Severity Scale (FSS), Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS) Activities, 36-item Short-Form Health Survey (SF-36) Mental Component Summary (MCS) and Physical Component Summary (PCS) and mean investigator-reported Clinical Global Impressions of Improvement (CGI-I). All outcomes were evaluated after 6 months of treatment.ResultsChanges in TSQM Global Satisfaction scores were superior after a switch to fingolimod when compared with scores in patients remaining on any of the iDMTs (all p <0.001). Likewise, all TSQM subscale scores improved following a switch to fingolimod (all p <0.001), except when compared with glatiramer acetate for the TSQM Side Effects subscale (p =0.111). FSS scores were found to be superior for fingolimod versus remaining on subcutaneous interferon beta-1a and interferon beta-1b, BDI-II scores were significantly improved for fingolimod except for the comparison with intramuscular interferon beta-1a, and SF-36 scores were superior with fingolimod compared with remaining on interferon beta-1b (MCS and PCS; p =0.030 and p =0.022, respectively) and subcutaneous interferon beta-1a (PCS only; p =0.024). Mean CGI-I scores were superior with fingolimod when compared with continuing treatment with any of the iDMTs (all p <0.001).Conclusions After 6 months, a switch to fingolimod showed superiority compared with remaining on each iDMT for a range of patient- and physician-reported outcomes, including global satisfaction with treatment.Trial registrationClinicalTrials.gov NCT01216072.BMC Neurology 11/2014; 14(1):220. DOI:10.1186/s12883-014-0220-1 · 2.49 Impact Factor