Glatiramer Acetate Treatment Research Articles

Benefit of endermology on indurations and panniculitis/lipoatrophy during relapsing-remitting multiple sclerosis long-term treatment with glatiramer acetate.

Use of endermology (Endermologie®), which consists of a deep mechanical massage, in patients with multiple sclerosis receiving glatiramer acetate suggested improvements in injection-site indurations and panniculitis/lipoatrophy in our previous pilot experience. We aimed to assess the effect of endermology in a larger population of patients with multiple sclerosis receiving glatiramer acetate in clinical practice. This was the extension phase of our pilot experience, carried out in patients with relapsing-remitting multiple sclerosis (RRMS) and indurations and/or panniculitis/lipoatrophy associated with long-term glatiramer acetate administration. Patients underwent endermology sessions twice per week, for 6 weeks, according to clinical practice. Seventy evaluable patients were included (mean age, 42.7±9.3 years; female, 95.7%; mean multiple sclerosis duration, 9.2±8.6 years; mean glatiramer acetate duration, 46.7±29.9 months). Fifty (71.4%) patients showed indurations and 58 (82.9%) panniculitis/lipoatrophy. After 12 endermology sessions, the number of patients with indurations significantly decreased (71.4% vs. 28.6%; p<0.001), as did the number of their indurations (4.2±3.6 vs. 3.7±3.4; p<0.001). Although the number of patients with panniculitis/lipoatrophy did not significantly decrease, there was a significant reduction in the number of areas of panniculitis/lipoatrophy (4.3±2.6 vs. 3.9±2.2; p<0.05). Forty-nine (98.0%) patients with indurations and 57 (98.3%) patients with panniculitis/lipoatrophy felt satisfied/very satisfied with treatment and considered endermology useful/very useful. Endermology was well tolerated, as some pain was reported in eight (11.4%) patients, discomfort in three (4.3%) patients, and local blotch/swelling and transient bruise in one (1.4%) patient each. Endermology enabled glatiramer acetate tolerance to be enhanced in 42 (60.0%) patients. This project represents the largest experience available supporting the benefit of endermology in the reduction/disappearance of indurations and improvement in panniculitis/lipoatrophy in patients with RRMS receiving long-term glatiramer acetate treatment. Moreover, these benefits also contributed to enhancing glatiramer acetate tolerance.

Glatiramer acetate desensitisation in multiple sclerosis patients ‐ the case report

Background Glatiramer acetate (GA) is immunomodulatory drug widely prescribed for the treatment of multiple sclerosis (MS). GA treatment is frequently associated with local site reactions and generalized urticaria. The systemic reaction approximately occurs in 10% of patients. The desensitization could help to return GA to MS treatment. Objective Our aim was to evaluate the safety and efficiency of GA desensitisation. Eight days of the GA treatment MS female patient came with adverse reactions. Twelve hours after GA administration itching in the injection site, feeling of swelling tongue, swallowing difficulty and cough appeared. Methods

Effects of Glatiramer Acetate in a Spontaneous Model of Autoimmune Neuroinflammation

Glatiramer acetate (GA) (Copaxone), a well-established drug for the treatment of multiple sclerosis, is believed to modulate numerous pathways including antigen-presenting cells or cytokine responses. A new generation of spontaneous experimental autoimmune encephalomyelitis mouse models has been developed that mimic certain aspects of multiple sclerosis spectrum disorders. We assessed the effects of GA in the opticospinal encephalomyelitis model, which involves MOG35-55 peptide-specific T cells and B cells. A nonsignificant trend toward lower disease incidence was found for GA treatment (started on postnatal day 20). Immunohistochemical evaluations revealed no significant differences for inflammatory lesions and demyelination, cytokine production, proliferation, and cell surface markers of immune cells between GA-treated and PBS-treated (control) mice. Although a good correlation was found between the disease score of individual mice and some readout parameters (eg, immunohistochemical staining), this was not the case for others (eg, IFN-γ production). It seems plausible that a major effect of GA lies on alternative immunological pathways, such as initiating of an immune response that is not sufficiently reflected in this spontaneous experimental autoimmune encephalomyelitis model. Thus, the main advantage of the opticospinal encephalomyelitis model in our hands lies in the elucidation of factors influencing the onset of experimental autoimmune encephalomyelitis (eg, susceptibility factors). The model seems less suitable for investigation of disease severity modifications after therapeutic interventions.

Fatigue and health-related quality of life in relapsing-remitting multiple sclerosis after 2 years glatiramer acetate treatment are predicted by changes at 6 months: An observational multi-center study

Fatigue and health-related quality of life in relapsing-remitting multiple sclerosis after 2 years glatiramer acetate treatment are predicted by changes at 6 months: An observational multi-center study

Glatiramer acetate reverses cognitive deficits from cranial-irradiated rat by inducing hippocampal neurogenesis

Patients received cranial-irradiation can be affected with cognitive deficits and decreasing hippocampal neurogenesis. In this work, we characterized the cognitive ability and immune-induced neurogenesis of the pre- and post-treated cranial-irradiated rats with Glatiramer acetate (GA), known as a weak CNS auto-antigen. The GA-treated rats displayed better cognitive abilities in Morris water maze (MWM). The numbers of Iba-I-positive microglia, BrdU+/DCX+ cells and BrdU+/NeuN+ cells in hippocampus increased, which are accompanied with increased IFN-γ and decreased IL-6, IL-4. Furthermore, GA reverted the Th1/Th2 balance. GA treatment can reverse the cognitive deficits caused by cranial irradiation through a mechanism that likely involves immunomodulation.

Thyroid autoimmunity and dysfunction in multiple sclerosis patients during long-term treatment with interferon beta or glatiramer acetate: an Italian multicenter study

Few long-term follow-up data are available on thyroid dysfunction (TD) in multiple sclerosis (MS) patients treated with glatiramer acetate (GA) or with interferon-beta (IFNb). In a cohort of 787 relapsing–remitting MS (RRMS) patients whom were followed up for 8 years, we observed an increased prevalence of TD and thyroid autoimmunity (TA) within the first year of IFNb treatment, regardless of the dose or frequency of administration, while no change was observed with GA treatment. The increased prevalence of TD and TA within the first year of IFNb treatment suggested the need for close monitoring of thyroid function and autoimmunity, though only during the first year of IFNb treatment.

Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS)

BackgroundFingolimod demonstrated superior efficacy compared with interferon β-1a intramuscular in relapsing multiple sclerosis. The impact of treatment history on fingolimod efficacy is unknown. ObjectivesThis post-hoc analysis of phase 3 TRANSFORMS data compared the efficacy and safety of fingolimod and interferon β-1a intramuscular among patient subgroups defined by prior treatment history. MethodsAnnualized relapse rate and safety of once-daily oral fingolimod 0.5mg, 1.25mg, or once-weekly interferon β-1a 30μg intramuscular for 12 months were analyzed in 1292 patients with relapsing multiple sclerosis according to prior disease-modifying therapy, reason for prior disease-modifying therapy discontinuation (adverse events or unsatisfactory therapeutic effect), and prior disease-modifying therapy duration. ResultsCompared with interferon β-1a intramuscular, fingolimod 0.5mg significantly reduced annualized relapse rate in patients who were treatment naive, received prior interferon-β treatment, discontinued prior disease-modifying therapy for unsatisfactory therapeutic effect, or had prior disease-modifying therapy duration of ≥1 year (P≤0.05, all comparisons). Similar trends were observed in patients with prior glatiramer acetate treatment. Significant reductions were also seen with fingolimod 1.25mg for treatment-naive and prior interferon-β-treated patients. ConclusionsThis analysis demonstrates superiority of fingolimod over interferon β-1a intramuscular regardless of prior (interferon-β) treatment and prior treatment efficacy and duration. ClinicalTrials.gov identifier: NCT00340834.

Impact of Delayed Diagnosis and Treatment in Clinically Isolated Syndrome and Multiple Sclerosis

Multiple sclerosis (MS) is a progressive inflammatory disease with several possible clinical courses; before the development of definite MS, some patients may have clinically isolated syndrome (CIS), which is a single attack of neurological symptoms caused by inflammation or demyelination. Disease-modifying treatments (DMTs) have been extensively used for the management of MS, resulting in improvements in the clinical presentation and decreases in MS-associated neurological damage. Earlier initiation of DMT in the course of MS is associated with better outcomes. For patients with CIS, initiation of interferon-beta or glatiramer acetate treatment after an initial clinical event indicative of MS has been associated with delays in the progression to clinically definite MS as well as improvements in measures of neurological damage via magnetic resonance imaging. The initiation of treatment for patients with CIS should be considered, and nurses play a vital role in educating patients about the risks of conversion to MS and the benefits of early DMT.

Glatiramer acetate ameliorates experimental autoimmune neuritis

Glatiramer acetate (GA) is one of the first-line disease-modifying medications that have been approved for the treatment of multiple sclerosis via immune modulatory mechanisms. However, it remains unclear whether the immunomodulation effect of GA is central nervous system (CNS) antigen specific. Here, we explored the mechanism of action of GA by subcutaneously injecting GA in experimental autoimmune neuritis (EAN) rats, an animal model for Guillain-Barré syndrome (GBS). Clinical, electrophysiological and histological findings showed that neurological deficits, demyelination and axonal injury of sciatic nerves were all significantly attenuated in Lewis rats when GA was administered before immunization with peripheral nervous system antigen P0. Our results further demonstrated that GA treatment inhibited either P0 or myelin basic protein (MBP) (CNS antigen)-stimulated auto-immune T-cell proliferation in vitro. GA administrated at 10 days after induction of EAN when neurological sign became apparent also ameliorated the severity of disease, inhibited T-cell response to P0 and MBP and induced shift of proinflammatory and immune modulatory cytokines. Collectively, our findings suggested that GA attenuated neurological deficits in EAN rats and that the immune modulatory mechanisms of GA were not CNS antigen specific.

Glatiramer acetate treatment effects on gene expression in monocytes of multiple sclerosis patients

BackgroundGlatiramer acetate (GA) is a mixture of synthetic peptides used in the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this study was to investigate the effects of GA therapy on the gene expression of monocytes.MethodsMonocytes were isolated from the peripheral blood of eight RRMS patients. The blood was obtained longitudinally before the start of GA therapy as well as after one day, one week, one month and two months. Gene expression was measured at the mRNA level by microarrays.ResultsMore than 400 genes were identified as up-regulated or down-regulated in the course of therapy, and we analyzed their biological functions and regulatory interactions. Many of those genes are known to regulate lymphocyte activation and proliferation, but only a subset of genes was repeatedly differentially expressed at different time points during treatment.ConclusionsOverall, the observed gene regulatory effects of GA on monocytes were modest and not stable over time. However, our study revealed several genes that are worthy of investigation in future studies on the molecular mechanisms of GA therapy.

Comparative effectiveness of fingolimod versus interferons or glatiramer acetate for relapse rates in multiple sclerosis: a retrospective US claims database analysis

Objective:Disease-modifying therapies, such as fingolimod, interferon (IFN) and glatiramer acetate (GA), have differing effects on relapse rates in patients with multiple sclerosis (MS), but little is known about the real-world differences in relapse rates with these treatments. This retrospective study assessed relapse rates in patients with active MS initiating fingolimod, IFN or GA therapy in a real-world setting.Methods:Using administrative claims data from the US PharMetrics Plus database, we identified previously treated and untreated patients with MS who initiated fingolimod, IFN or GA treatment between 1 October 2010 and 31 March 2011 and had experienced a relapse in the previous year. A claims-based algorithm was used to identify relapses over the persistence period in patients with 540 days of post-index continuous enrolment. A logistic regression model assessed the probability of having at least one relapse and a generalized linear model estimated differences in annualized relapse rates (ARRs).Results:The study enrolled 525 patients (fingolimod, n = 128; combined IFN/GA cohort, n = 397) of the 31,041 initially identified. Similar findings for fingolimod and IFN/GA were observed for the unadjusted proportion of patients experiencing relapses (31.3% vs. 34.0%, respectively; p = 0.5653) and ARRs (0.50 vs. 0.55, respectively) while persistent to treatment. After adjusting for baseline differences, fingolimod was associated with a 52% reduction in the probability of having a relapse (odds ratio, 0.48; 95% confidence interval [CI], 0.28–0.84; p = 0.0097) and a 50% reduction in ARR (rate ratio, 0.50; 95% CI, 0.34–0.75; p = 0.0006) compared with IFN/GA.Limitations:Identification of relapses is based on the claims in the database rather than on a clinical assessment.Conclusions:In a real-world setting, fingolimod was shown to be associated with significantly lower relapse rates than IFN/GA in patients with MS who had a history of relapses.

Glatiramer acetate attenuates the pro-migratory profile of adhesion molecules on various immune cell subsets in multiple sclerosis

An altered expression pattern of adhesion molecules (AM) on the surface of immune cells is a premise for their extravasation into the central nervous system (CNS) and the formation of acute brain lesions in multiple sclerosis (MS). We evaluated the impact of glatiramer acetate (GA) on cell-bound and soluble AM in the peripheral blood of patients with relapsing-remitting MS (RRMS). Fifteen patients treated de novo with GA were studied on four occasions over a period of 12 months. Surface levels of intracellular cell adhesion molecule (ICAM)-1, ICAM-3, lymphocyte function-associated antigen (LFA)-1 and very late activation antigen (VLA)-4 were assessed in T cells (CD3(+) CD8(+) , CD3(+) CD4(+) ), B cells, natural killer (NK) cells, natural killer T cells (NK T) and monocytes by five-colour flow cytometry. Soluble E-selectin, ICAM-1, ICAM-3, platelet endothelial cell adhesion molecule (PECAM)-1, P-selectin and vascular cell adhesion molecule (VCAM)-1 were determined with a fluorescent bead-based immunoassay. The pro-migratory pattern in RRMS was verified by comparison with healthy controls and was characterized by up-regulation of LFA-1 (CD3(+) CD4(+) T cells, B cells), VLA-4 (CD3(+) CD8(+) T cells, NK cells), ICAM-1 (B cells) and ICAM-3 (NK cells). Effects of GA treatment were most pronounced after 6 months and included attenuated levels of LFA-1 (CD3(+) CD4(+) ) and VLA-4 (CD3(+) CD4(+) , CD3(+) CD8(+) , NK, NK T, monocytes). Further effects included lowering of ICAM-1 and ICAM-3 levels in almost all immune cell subsets. Soluble AM levels in RRMS did not differ from healthy controls and remained unaltered after GA treatment. The deregulated pro-migratory expression profile of cell-bound AM is altered by GA treatment. While this alteration may contribute to the beneficial action of the drug, the protracted development and unselective changes indicate more secondary immune regulatory phenomena related to these effects.

Glatiramer acetate–induced acute hepatotoxicity in an adolescent with MS

Glatiramer acetate (GA), a synthetic copolymer, is a frequently used first-line treatment for relapsing-remitting multiple sclerosis (RRMS). Probable autoimmune hepatotoxicity during GA treatment has been reported,(1-4) but GA hepatotoxicity in the absence of positive autoimmune markers has not previously been described. Here, we report GA-induced hepatotoxicity in a pediatric patient with multiple sclerosis (MS).

Necrotizing skin lesion and radial nerve palsy in a patient treated with glatiramer acetate

Glatiramer acetate (GA) is an approved and well tolerated drug for the treatment of relapsing–remitting multiple sclerosis. We report a case of a 52year-old man with psoriasis and relapsing–remitting multiple sclerosis who developed, after 21months of GA treatment, an injection-site cutaneous necrosis that involved both subcutaneous and muscular tissue with massive edema, followed, 3days later, by radial nerve palsy. After few days another similar lesion appeared in another injection-site. We hypothesize that cutaneous necrosis could be due to a local dis-immune reaction and, probably, psoriasis could have played an important role in its pathogenesis.

Swiss Analysis of Multiple Sclerosis: A Multicenter, Non-Interventional, Retrospective Cohort Study of Disease-Modifying Therapies

Background: There is a scarcity of reports comparing efficacy and tolerability of the multiple sclerosis (MS) disease-modifying therapies [DMTs; intramuscular interferon-β1a (IM IFNβ-1a), subcutaneous (SC) IFNβ-1a, SC IFNβ-1b, SC glatiramer acetate (GA)] in a real-world setting. Methods: This multicenter, non-interventional, retrospective cohort study analyzed data from 546 patients with clinically isolated or relapsing-remitting MS constantly treated with one DMT for 2 years. Annualized relapse rate (ARR), Expanded Disability Status Scale (EDSS) scores, and DMT tolerability were assessed. Results: Demographic data were comparable across DMTs. There were no significant differences between DMT groups in ARR during study year 1 (p = 0.277) or study year 2 (p = 0.670), or in EDSS change between years 1 and 2 (p = 0.624). Adverse events were frequent (39-56%) in all groups. Flu-like symptoms were less frequent with GA treatment (2.3% vs. IM IFNβ-1a, 46.7%; SC IFNβ-1a, 39.8%; SC IFNβ-1b, 25.8%; p < 0.05). Injection site reactions were less often reported with IM IFNβ-1a (10.5% vs. SC IFNβ-1a, 33.9%; SC IFNβ-1b, 38.3%; GA, 26.1%; p < 0.05). Conclusions: All DMTs showed comparable effects on MS relapse rate and EDSS change, with IM IFNβ-1a and GA being more tolerable with respect to injection site reactions and flu-like symptoms, respectively.

Glatiramer Acetate Treatment-Related Effects on Visual EPs and P300 Wave in Patients Suffering from Multiple Sclerosis

Multiple sclerosis is an inflammatory neurological disease of young adults that leads to numerous therapeutic problems and to severe disability. Glatiramer acetate (GA) is a disease-modifying drug used frequently for long-term treatment of the disease. We investigated the impact of GA treatment on the parameters of reversal-pattern visual evoked potentials and event-related P300 wave (reflecting visual acuity and cognitive dysfunction). Relapsing-remitting multiple sclerosis patients either subjected to one-year-long continuous treatment with GA or without any disease-modifying therapy and also healthy controls were involved in the study. The above-mentioned parameters were analyzed at two time points, at the first recording and after one year. It was found that GA did not exert a significant influence on the phenomena studied at least during the one-year follow-up. This finding is in contrast to most of the clinical observations.

A One Year Follow-Up Study of Natural Killer and Dendritic Cells Activities in Multiple Sclerosis Patients Receiving Glatiramer Acetate (GA)

BackgroundMultiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease. It is thought to be mediated by CD4+ Th1/Th17 cells. More recently, cells of the innate immune system such as dendritic cells (DCs) and natural killer (NK) cells have been in focus. Glatiramer acetate (GA) is an approved drug for treating MS patients.Methodology/Principal FindingsIn the current study we examined the activities of NK and DCs in nine relapsing remitting MS patients for up to one year after initiation of GA treatment. We observed that NK cells isolated from most of these patients have increased cytotoxic activity against K562 cells. Further analysis showed that the same NK cells lysed both autologous immature (i) and mature (m) DCs. In most patients this increased activity was correlated with increased NK cell activating cytotoxicity receptors such as NKp30, NKp44, NKp46 and NKG2D, and reduced expression of the inhibitory molecule CD158 on the surface of these NK cells. The expression of HLA-DR was increased on iDCs and mDCs in the majority of the patients, but no consistency was observed for the expression of HLA-I or HLA-E. Also, the co-stimulatory receptors CD80, CD83 or CD86 expression was down-regulated on iDCs and mDCs in most cases. Further, the expression of CCR6 was increased on mDCs at later time points of therapy (between 32–48 weeks).Conclusions/SignificanceOur results are the first showing the effects of GA treatment on NK cells in MS patients, which may impact future use of this and other drugs to treat this disease.

Glatiramer acetate, an anti-demyelination drug, reduced rats’ epileptic seizures induced by pentylenetetrazol via protection of myelin sheath

Glatiramer acetate (GA) is a clinically prescribed immunomodulator drug used to treat demyelinating disease like multiple sclerosis (MS). Persistent down-regulation in the expression of myelin sheath proteins has been observed in both rats with pentylenetetrazol (PTZ) induced chronic epilepsy and some clinical epilepsy patients. Hypothetically, protection of myelin sheath by pharmaceutical means in the process of epilepsy might, to some extent, be helpful to control epileptic seizures. Therefore, we tried to use GA to treat PTZ-induced epilepsy rats. GA treatment successfully protected rats’ myelin sheath from demyelination in the process of PTZ-induced epileptic seizures. Notably, electroencephalogram (EEG) monitoring demonstrated that GA-treated epilepsy rats showed significantly lowered epileptiform discharges. Correspondingly, behavioral recording showed reduced frequency of seizures in GA-treated epilepsy rats. The results indicate that epilepsy associated demyelination may be a contributing factor in seizures behavior, and early intervention with anti-demyelination drugs may be beneficial to reduce the severity of seizures behavior.

Adherence to monthly online self-assessments for short-term monitoring: a 1-year study in relapsing-remitting multiple sclerosis patients after start of disease modifying treatment.

BackgroundThe participation of neurologists and patients in studies on the effectiveness and safety of newly authorized drugs in multiple sclerosis (MS) is insufficient. Monthly online self-assessments using patient-reported outcomes may help in short-term monitoring of neurological changes and side effects.ObjectiveInvestigate in relapsing-remitting (RR) MS patients the adherence to monthly online self-assessments after the start of disease modifying treatment.MethodsObservational study in 39 neurological departments in The Netherlands. Patients starting glatiramer acetate treatment were instructed to complete online the Modified Fatigue Impact Scale 5-item version and the 8-item Leeds Multiple Sclerosis Quality of Life scale every month during 1 year (T0 toT12).ResultsSixty-three investigators included 163 analyzable patients. At T3, 148 (90.8%) patients had completed all questionnaires; at T6, 142 (87.1%); at T9, 133 (81.6%); and at T12, 123 (75.5%). Eight (4.9%) patients did not complete any questionnaire. Median values for inter-assessment intervals ranged from 32 to 34 days (first quartile [Q1] 30 days, third quartile [Q3] 41 days), and the final assessment was at 417 days (median: Q1 385 days, Q3 480 days). Forty-three (26.3%) patients completed the questionnaires at all time points (completion adherent) with their final assessment within 30 days after the scheduled T12 (interval adherent). Eighty (49.1%) patients were completion adherent, but not interval adherent. Forty (24.5%) patients were not completion adherent, as they discontinued assessments prematurely. Men were more interval adherent than women (47.5% vs 20.0%; P = 0.001).ConclusionThe observation that three out of four (75.5%) RRMS patients completed two short questionnaires at all monthly time points during 1 year after the start of disease modifying treatment suggests that intensive online monitoring in this patient group is feasible. As only one in five (19.6%) patients adhered to the time intervals between self-assessments, measures are needed that improve the timely completion of questionnaires.

Modulation of immune function occurs within hours of therapy initiation for multiple sclerosis

Daily administration of FDA-approved glatiramer acetate (GA) has beneficial effects on clinical course of relapsing remitting multiple sclerosis (RRMS). Although mechanisms of GA-action have been widely investigated and partially understood, immediate immune dynamics following GA-therapy are unknown. In the present study, we characterized the immediate effects of GA on phenotype, quantity and function of immune cells in MS patients. Prominent changes in immune cells were detected within 4-12h post-first GA-injection. T-cell modulation included significantly decreased CD4/CD8 ratio, perturbed homeostasis of predominantly CD8+ T-cells, significant enhancement in CD8+ T-cell mediated suppression and inhibitory potential of induced CD4-suppressors. Changes in APC were restricted to monocytes and included reduced stimulatory capacity in MLR and significantly increased IL-10 and TNF-α production. Our study provides the first evidence that GA treatment induces rapid immunologic changes within hours of first dose. Interestingly, these responses are not only restricted to innate immune cells but also include complex modulation of T-cell functionality.