Effect Of Glatiramer Acetate Research Articles

The effect of glatiramer acetate, IFNβ-1a, fingolimod, and dimethyl fumarate on the expression of T-bet, IFN-γ, and MEG3 in PBMC of RRMS patients

ObjectiveMultiple sclerosis (MS) is a progressing neurodegenerative disease marked by chronic central nervous system inflammation and degeneration.This study investigates gene expression profiles of T-box transcription factor TBX21 (T-bet), interferon-gamma (IFN-γ), and long non-coding RNA MEG3 in peripheral blood mononuclear cells (PBMCs) from treatment-naïve Relapsing-Remitting Multiple Sclerosis patients (RRMS), healthy controls, and RRMS patients on different Disease Modifying Therapies (DMTs). The aim is to understand the role of T-bet, IFN-γ, and MEG3 in MS pathogenesis and their potential as diagnostic and therapeutic targets.ResultsElevated T-bet expression is observed in treatment-naïve RRMS patients compared to healthy individuals. RRMS patients treated with Interferon beta-1alpha (IFNβ-1a) and fingolimod exhibit downregulated T-bet and MEG3 expression levels, respectively, with more pronounced effects in females. Healthy individuals show a moderate positive correlation between T-bet and MEG3 and between IFN-γ and T-bet. In RRMS patients treated with Glatiramer Acetate (GA), a strong positive correlation is observed between MEG3 and IFN-γ. Remarkably, RRMS patients treated with Dimethyl Fumarate (DMF) exhibit a significant positive correlation between T-bet and MEG3. These findings underscore the diagnostic potential of T-bet in RRMS, warranting further exploration of MEG3, T-bet, and IFN-γ interplay in RRMS patients.

Deficits in Monocyte Function in Age Related Macular Degeneration: A Novel Systemic Change Associated With the Disease.

Age-related macular degeneration (AMD) is characterized by the accumulation of debris in the posterior eye. In this study we evaluated peripheral blood monocyte phagocytic function at various stages of AMD and in aged matched control participants. Real-time tri-color flow cytometry was used to quantify phagocytic function of peripheral blood monocyte subsets (non-classic, intermediate and classic) isolated from subjects with intermediate or late AMD and compared with age matched healthy controls. Assessment of phagocytic function of monocytes isolated from those with and without reticular pseudodrusen was also made, and the effect of glatiramer acetate on phagocytic function assessed. Phagocytic function was reduced in all subjects with AMD, irrespective of stage of disease. However, there was no correlation between phagocytic function and drusen load, nor any difference between the level of phagocytosis in those with or without reticular pseudodrusen. Treatment with glatiramer acetate increased phagocytosis of classical and non-classical monocytes, normalizing the reduction in phagocytosis observed in those with AMD. These findings suggest that defective systemic phagocytosis is associated with both intermediate and late stages of AMD, highlighting a potential role in the accumulation of debris that occurs early in the disease process. Assessing peripheral monocyte phagocytic function provides further insights into the etiology of this disease and offer a novel therapeutic target.

Effectiveness of glatiramer acetate in neutralizing antibody-positive patients previously treated with interferon-β

BackgroundSome patients with multiple sclerosis who are treated with interferon-β(IFNβ) develop neutralizing antibodies (NAbs), which reduce or abolish the therapeutic effects of the treatment. These patients are usually switched to a non-IFNβ treatment, such as glatiramer acetate (GA).It is unknown whether a patient's previous disease activity in combination with their NAb-status can provide further insights on their risk of future disease activity. Consequently, we investigated treatment outcomes in patients switching from IFNβ to GA according to NAb-status and clinical disease activity, while on IFNβ. MethodsWe identified all patients switching from IFNβ to GA and having information on NAb-status from the Danish Multiple Sclerosis Registry and compared treatment outcomes while on GA according to previous disease activity and the presence of NAbs. ResultsWe included 568 patients in the study: 107 NAb-negative patients switched due to adverse events (group 1), 24 NAb-negative patients switched with disease activity (group 2), 397 NAb-positive patients switched without disease activity (group 3) and 40 NAb-positive patients switched with disease activity (group 4).Compared to the reference (group 1), group 2 had an increased risk of future relapses (HR 1.79 95% Confidence interval (CI): 1.00–3.19). Group 3 showed a trend of a lower risk of future relapses (HR 0.74, 95%CI: 0.53–1.04). Group 4 had, on average, a similar risk of future relapses (HR 1.15 95% CI: 0.69–1.92). Similarly, group 2 had a higher probability of treatment discontinuation due to disease activity compared to the other groups. ConclusionWhile on GA, patients switched from IFNβ in the context of disease activity and no NAbs had the highest risk of future disease activity, while NAb positive patients without previous activity had the lowest. We did not find any average difference between NAb-positive patients switching in a context of disease activity and NAb-negative patients switched due to adverse events, although carefulness in the interpretation of this result is advised.

Interferon-beta, but not Glatiramer Acetate treatment induces gender-specific increase in BDNF serum levels in relapsing-remitting multiple sclerosis female patients

Neuroprotection is considered a major therapeutic target in Multiple Sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS). Accordingly, current disease modifying drugs (DMDs) for MS have been revaluated for their ability to stimulate production of neurotrophic factors that may provide support to neural cells against neurodegeneration. Brain-derived neurotrophic factor (BDNF) is considered the best candidate for such neuroprotective effects in MS. In the present study, we explored a potential effects of Glatiramer Acetate (GA), and Interferon-beta (IFN-b), the first two available treatments of MS, on circulating levels of BDNF considering the different BDNF forms. Using ELISA assays, we quantified mature and total BDNF in the serum of 20 relapsing-remitting MS (RR-MS) patients treated with GA and 31 with INF-beta compared with 20 age-matched RR-MS patients without any DMD. Mature BDNF but not total BDNF was significantly increased by treatment with IFN-b in female patients only, while GA had no effect. These results support a gender-specific role of BDNF in the treatment of RR-MS with INF-b. Of note, the present study was carried out with standardized ELISA assays which are commercially available and, prospectively, might be routinely used in the common clinical practice to monitor the individual response to the therapy with IFN-b.

Effect of glatiramer acetate on cerebral grey matter pathology in patients with relapsing-remitting multiple sclerosis

IntroductionIn this two year longitudinal study we compare the progression of grey matter (GM) damage in MS patients treated with glatiramer acetate (GA) for relapsing-remitting multiple sclerosis (RRMS) respect to untreated patients. MethodsWe studied thirty-five treated with GA and thirty-five untreated RRMS subjects matched for age, gender, disease duration and EDSS. Each patient underwent neurological examination every 6 months and 3-Tesla MRI at study entry (T0), after 1 year (T1) and 2 years (T2). At T0, T1 and T2, the number of new cortical lesions (CLs) was assessed on double inversion recovery images. By using the longitudinal stream of FreeSurfer, the cortical thickness and volume changes of several cerebral structures were evaluated after 2 years. ResultsThe mean number of new CLs was significantly lower in GA group compared to untreated patients both at T1 (0.9 ± 1.0 vs 1.7 ± 1.0, p < 0.05) and at T2 (1.4 ± 1.3 vs 2.9 ± 1.8, p < 0.001). Volume loss of thalamus (−0.5% ± 0.2% vs. −1.1% ± 0.4%; p < 0.001), globus pallidus (−4.4% ± 3.1% vs. −8.2% ± 4.5%; p < 0.001), hippocampus (−0.7% ± 0.3% vs. −1.5% ± 0.5%; p < 0.001) and cerebellum (−0.5% ± 0.3% vs. −0.9% ± 0.4%; p < 0.001) was also lower in the GA group. A more pronounced cortical thinning was observed in cingulate (p = 0.04), cuneus and frontomarginal gyrus (p = 0.01 for both comparisons) of the untreated patients. ConclusionOur findings suggest that GA exerts its immunomodulatory action at the level of GM either reducing the accumulation of CLs and slowing down the GM atrophy progression. Despite a confirmation in a larger sample size is required, our results suggest a possible effect of GA on GM damage.

Disease-modifying therapies modulate retinal atrophy in multiple sclerosis: A retrospective study.

To retrospectively investigate whether disease-modifying therapies (DMTs) exert differential effects on rates of retinal atrophy in relapsing-remitting multiple sclerosis (RRMS), as assessed using optical coherence tomography (OCT). A total of 402 patients with RRMS followed at the Johns Hopkins MS Center who underwent Cirrus-HD OCT were assessed for eligibility. Inclusion criteria included at least 1 year of OCT follow-up and adherence to a single DMT during the period of follow-up. Combined thickness of the ganglion cell + inner plexiform (GCIP) and other retinal layers was computed utilizing automated macular segmentation. Retinal thickness changes were analyzed using mixed-effects linear regression. The effects of glatiramer acetate (GA; n = 48), natalizumab (NAT; n = 46), and interferon-β-1a subcutaneously (IFNSC; n = 35) and intramuscularly (IFNIM; n = 28) were assessed. Baseline analyses revealed no significant differences between groups in terms of age, sex, optic neuritis history, or follow-up duration. During follow-up, relative to NAT-treated patients, IFNSC- and GA-treated patients exhibited 0.37 μm/y (p < 0.001) and 0.14 μm/y (p = 0.035) faster rates of GCIP thinning, respectively, adjusting for the interval between initiation of DMT and OCT monitoring (gap time), age, sex, relapses, and disease duration. In the IFNSC group, GCIP thinning was 1.53 μm/y faster during the first year of therapy vs during the time interval afterwards (p < 0.001). Rates of GCIP atrophy in patients with RRMS vary according to DMT utilization. Our findings support OCT for monitoring neurodegenerative treatment effects in the retina, an easily accessible tissue, and as a practical outcome measure in RRMS clinical trials.

The Effect of Glatiramer Acetate on Spinal Cord Volume in Relapsing-Remitting Multiple Sclerosis.

ABSTRACTBACKGROUNDSpinal cord atrophy occurs early in the multiple sclerosis (MS) disease course, is closely related to physical disability, and is a putative neuroprotective therapeutic outcome measure.OBJECTIVEThis pilot study explored glatiramer acetate (GA)’s effect on spinal cord volume in patients with relapsing‐remitting MS (RRMS).METHODSFifteen patients receiving daily subcutaneous GA were prospectively followed. At baseline, age was 43.6 ± 7.4 years, Expanded Disability Status Scale (EDSS) score was 1.4 ± 1.5, timed 25‐foot walk (T25FW) was 4.7 ± 1.1 seconds, and time on GA was 2.1 ± 3.1 years. Healthy controls (n = 10) with similar age and sex to the patients were also enrolled. The spinal cord was imaged at baseline and one year later with 3T magnetic resonance imaging. An active surface method measured the C1–C7 spinal cord volume from which we calculated the normalized area.RESULTSThe spinal cord area showed no significant change in the MS group over one year (P = .19). Furthermore, the change in the spinal cord area did not differ significantly between the MS and control groups over one year (P = .26). In the MS group, the EDSS score (P = .44) and T25FW (P = .92) did not change significantly on‐study.CONCLUSIONIn this pilot study of RRMS, GA therapy was not associated with any ongoing spinal cord atrophy or any difference in the one‐year rate of spinal cord area change versus healthy controls. These results paralleled the lack of clinical worsening and may reflect a treatment effect of GA. Further studies are needed to confirm these preliminary findings.

Effect of glatiramer acetate on short-term memory impairment induced by lipopolysaccharide in male mice.

Glatiramer acetate (GA) demonstrates neuroprotective, neurogenesis, and anti-inflammatory properties. This study examines the probable protective effect of acute GA on lipopolysaccharide (LPS)-induced memory impairment in male mice and further explores which routes of administration [subcutaneous (s.c.) or intracerebroventricular (i.c.v.)] exert optimum effect. Memory performance was evaluated in two-trial recognition Y-maze and passive-avoidance tasks evaluating special recognition memory and fear memory, respectively. Memory impairment was induced by LPS [100 μg/kg, intraperitoneally (i.p.)], 4 h before training. In Y-maze, GA (10, 2.5, 0.625, 0.153, and 0.03 mg/kg, s.c.; 250 μg/mouse; i.c.v.) was administered 10 min following LPS, and special memory was assayed in Y-maze apparatus. In passive avoidance, LPS (100, 250 μg/kg; i.p.) was injected 4 h before receiving foot shock, and GA (10, 2.5; s.c.) or (250 μg/mouse; i.c.v.) was administered 4 h before the shock. Following 24 h, the fear memory was evaluated. Memory impaired significantly following LPS (100, 250 μg/kg; i.p.) in Y-maze and passive-avoidance tasks, P < 0.001 and P < 0.05, respectively. The data revealed that GA (250 μg/mouse, i.c.v.) and GA (10, 2.5 mg/kg; s.c.) in Y-maze reversed memory impairment (LPS 100 μg/kg, i.p.) (P < 0.01). In passive-avoidance task, GA (2.5, 10 mg/kg; s.c.) reversed LPS-induced impairment and the mice showed significantly longer latency times during the retention trial (P < 0.01). GA improved memory impairment both centrally and systemically. It improved spatial recognition memory increasing the average time in the novel arm and improved fear memory increasing latency time. GA administration improved memory impairment profoundly through both systemic and central routs.

GLATIRAMER ACETATE AND PREGNANCY IN WOMEN WITH MULTIPLE SCLEROSIS – RESULTS FROM THE GERMAN MULTIPLE SCLEROSIS AND PREGNANCY REGISTRY

ObjectiveTo determine the effect of glatiramer acetate (GLAT) exposure during pregnancy on perinatal outcome in women with multiple sclerosis (MS).BackgroundMS is one of the most common neurological diseases of the central nervous system, which mainly affects young women of reproductive age.Only limited data are available on whether GLAT exposure during pregnancy has an effect on perinatal outcome.MethodsWe compared the outcome of pregnancies of patients with MS exposed to GLAT with pregnancies of unexposed controls. Women with MS were enrolled into the German Multiple Sklerosis and pregnancy registry. Data were assessed with a standardized questionnaire during pregnancy and the postpartum year. Detailed information on course of MS, concomitant medication, pregnancy course and outcome was obtained.ResultsWe collected data on 230 pregnancies: 135 with exposure to GLAT and 95 MS controls unexposed to disease-modifying therapies (DMTs) during pregnancy.While 25 of the exposed pregnancies are still ongoing we did not document any malformation in the first 110 GLAT exposed pregnancies with at least 6 months postpartum follow up. The rate of spontaneous abortions did not differ compared to unexposed controls. 3 (3.15%) infants of the DMT unexposed women were born with malformations of non-genetic origin and 1 (0.95%) newborn was diagnosed with Wolf Hirschhorn syndrome.ConclusionsGLAT exposure does not constitute a major human teratogen or influence outcome of pregnancy negatively compared to untreated women with MS. Final data including the outcome of ongoing pregnancies will be presented at the time of the meeting.

Multiple sclerosis and pregnancy

Multiple sclerosis (MS) is a chronic, neurodegenerative disease that has a high impact on patients׳ quality of life. The majority of diagnosed patients are women of childbearing age, making pregnancy-related issues (conception, contraception, childbirth, lactation) a key concern. MS typically stabilizes during pregnancy, particularly in the last trimester. Evidence suggests that the disease does not affect fertility, delivery, fetal health or pregnancy itself and does not cause birth defects. There is no increase in spontaneous abortions although a decreased birth weight has been reported. Epidural analgesia is safe in women with MS and hasn´t worsened disability in the postpartum period. Small differences in MS risk according to month of birth have been reported (higher in spring, lower in autumn). MS risk is lower among women born to mothers with high vitamin D intake during pregnancy, supplementing vitamin D-deficient mothers could be useful. No single gene produces MS . The risk for MS is about 2% for a child with one MS parent, and 6–12% for children where both parents have MS. Regarding the course of the disease, pregnancy had no effect on disability and no negative long-term impact. It seems that pregnancy could accelerate disease in RIS patients. High relapse rate or disability before pregnancy as well as relapse during pregnancy, have been associated with increased risk for postpartum attacks. An increase in new or enlarging MRI lesions post-partum was reported in several studies.MS itself does not pose any obstacles to breastfeeding and there is no risk of disease transmission through breast milk. Conflicting data indicate either no effect from breast-feeding or a positive benefit in reducing MS activity. The FDA has said that DMTs should not be used in MS patients who are pregnant, trying to become pregnant, or breast-feeding. Even though studies which have considered this aspect have found no effect of glatiramer acetate and only minor adverse effects of interferons. Glatiramer acetate has the most favorable pregnancy rating (class B). Natalizumab, fingolimod and BG12 have been given a pregnancy category C rating by the FDA based on results of animal studies and teriflunomide has been designated pregnancy category X. It is also recommended to discontinue symptomatic therapies prior to conception if they are not absolutely necessary. A short course of high-dose corticosteroids to hasten recovery from disabling relapses appears relatively safe during pregnancy, but there is a possible increased risk of fetal cleft palate associated with their use in the first trimester. There is little information regarding effects of MS disease modifying treatments on human male fertility or pregnancy outcomes in fathers receiving treatment

Effect of glatiramer acetate on disease reactivation in MS patients discontinuing natalizumab

Multiple sclerosis (MS) patients discontinuing natalizumab are at risk of rebound of disease activity. In the present multi-center, open-label, non-randomized, prospective, pilot study, we tested whether treatment with glatiramer acetate (GA) is safe and effective after natalizumab in MS patients. The study was performed at academic tertiary medical centers. Forty active relapsing-remitting MS patients who never failed GA therapy and who discontinued natalizumab after 12-18months of therapy were enrolled. GA was initiated 4weeks after the last dose of natalizumab. 62.5% of patients were relapse-free 12months after GA initiation. Annualized relapse rate and time to relapse were significantly lower than before natalizumab. Notably, the frequency of relapses was significantly lower amongst those patients who had experienced ≤2 relapses the year before initiation of natalizumab therapy, compared with patients who had had three or more relapses. No evidence of rebound was observed in magnetic resonance imaging scans. Furthermore, Expanded Disability Status Scale and Multiple Sclerosis Functional Composite were stable in our patients, again suggesting that 12months of post-natalizumab-GA therapy is not associated with clinical deterioration. Following discontinuation of natalizumab, 12 months of therapy with GA is safe and well tolerated in MS patients. GA can reduce the risk of early reactivation/rebound of disease activity in this setting.

Comparison of Standard 1.5 T vs. 3 T Optimized Protocols in Patients Treated with Glatiramer Acetate. A Serial MRI Pilot Study

This study explored the effect of glatiramer acetate (GA, 20 mg) on lesion activity using the 1.5 T standard MRI protocol (single dose gadolinium [Gd] and 5-min delay) or optimized 3 T protocol (triple dose of Gd, 20-min delay and application of an off-resonance saturated magnetization transfer pulse). A 15-month, phase IV, open-label, single-blinded, prospective, observational study included 12 patients with relapsing-remitting multiple sclerosis who underwent serial MRI scans (Days −45, −20, 0; the minus ign indicates the number of days before GA treatment; and on Days 30, 60, 90, 120, 150, 180, 270 and 360 during GA treatment) on 1.5 T and 3 T protocols. Cumulative number and volume of Gd enhancing (Gd-E) and T2 lesions were calculated. At Days −45 and 0, there were higher number (p < 0.01) and volume (p < 0.05) of Gd-E lesions on 3 T optimized compared to 1.5 T standard protocol. However, at 180 and 360 days of the study, no significant differences in total and cumulative number of new Gd-E and T 2 lesions were found between the two protocols. Compared to pre-treatment period, at Days 180 and 360 a significantly greater decrease in the cumulative number of Gd-E lesions (p = 0.03 and 0.021, respectively) was found using the 3 T vs. the 1.5 T protocol (p = NS for both time points). This MRI mechanistic study suggests that GA may exert a greater effect on decreasing lesion activity as measured on 3 T optimized compared to 1.5 T standard protocol.

Magnetic Resonance Imaging (MRI) Characterization of the Therapeutic Effect of Glatiramer Acetate in Different Models of Experimental Autoimmune Encephalomyelitis (EAE) (P05.109)

Objective: To study the different pathological manifestations in chronic versus relapsing-remitting experimental autoimmune encephalomyelitis (EAE) and the in situ therapeutic effect of glatiramer acetate (GA, Copaxoneâ) using advanced magnetic resonance imaging (MRI) parameters. Background The respective roles of inflammatory and neurodegenerative processes in multiple sclerosis and its EAE models are controversial. The immunomodulator GA alleviates MS/EAE pathological inflammation and induces neuroprotective repair processes within the CNS. MRI is an essential noninvasive tool for in vivo evaluation of MS therapies. Design/Methods: Mice inflicted with chronic MOG or relapsing-remitting PLP peptide-induced EAE were treated with GA (7 daily injections) starting after disease induction (prevention) or after clinical symptoms development (suppression). Brain MRI measurements were performed at several time points along disease progression. MRI protocols included transverse T2, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI), analyzed both by whole brain histograms and by voxel based analysis. Results: Brains of EAE mice of both models revealed increased T2-values with associated enlargement of ventricle size indicating substantial CNS inflammation. Ventricle swelling was characteristic to the PLP-induced model in which 5-fold elevation of ventricle size was detected. Decreased MTR values and increased apparent diffusion coefficient (ADC) were observed mainly in MOG-induced mice indicative of macromolecular loss and structural CNS damage involvement in the chronic disease. GA applied by both prevention and suppression regimens affected all the MRI pathological manifestations, resulting in significant reduction of T2 values and ventricle volume, elevated MTR and decreased ADC in comparison to sham-treated mice. Furthermore, following GA treatment, histogram peaks of all MRI parameters were statistically not different from naive controls. Conclusions: Inflammatory manifestations are involved in both EAE models, whereas macromolecular loss and structural CNS damage are more prominent in chronic EAE. GA improves MRI parameters: T2-relaxation, ventricle swelling, MTR and ADC indicating its in situ anti-inflammatory and repair consequences. Supported by: Teva. Disclosure: Dr. Aharoni has nothing to disclose. Dr. Sason has nothing to disclose. Dr. Sela has received royalty payments from Teva Neuroscience. Dr. Sela holds stock and/or stock options in Teva Neuroscience. Dr. Sela has received research support from Teva Neuroscience. Dr. Arnon has received royalty payments from Teva Neuroscience. Dr. Arnon has received research support from Teva Neuroscience.

Glatiramer Acetate Reverses Plasticity and Cognitive Deficits Associated with Acute Inflammation in MS (P04.118)

Objective: Evaluating the effects of Glatiramer acetate (GA) therapy on inflammation, cognitive performance and synaptic plasticity in MS. Background Cognitive dysfunction is frequent in multiple sclerosis (MS). It is associated with gray matter pathology, brain atrophy, and altered connectivity. Recent evidence showed that acute inflammation alters amyloid-beta metabolism reducing its concentration in the CSF and leading to impairment of synaptic plasticity and cognitive function. Design/Methods: Paced Auditory Serial Addition Test (PASAT) and responses to intermittent Theta Burst Stimulation (iTBS, a Transcranial Magnetic Stimulation (TMS) protocol able to induce LTP-like responses in the human cortex) were measured before and after 3 months of GA in 30 drug-naive MS patients. Patients were stratified according to the presence of gadolinium enhancing lesions (Gd+ or Gd-) at brain MRI performed at recruitment and after 3 months. Moreover patients were genotyped according to the BDNF Val66Met genetic polymorphism, known to influence both cognition and responses to iTBS. Results: Before treatment iTBS induced LTP, measured immediately and 15 minutes after stimulation, was decreased in Gd+ patients at both timepoints (1.09±0.13 (mean±SE) and 1.19±0.14) compared to Gd- patients (1.57±0.12 and 1.68±0.19; all p Conclusions: These results suggest that GA is useful to ameliorate cognitive deficits in MS by interfering with the inflammatory mechanisms responsible for beta-amyloid alteration within the CNS. Disclosure: Dr. Mori has nothing to disclose. Dr. Kusayanagi has nothing to disclose. Dr. Buttari has nothing to disclose. Dr. Nicoletti has nothing to disclose. Dr. Bernardi has nothing to disclose. Dr. Centonze has received personal compensation for activities with Teva Neuroscience, Merck Serono, and Bayer Schering. Dr. Centonze has received research support from Teva Neuroscience.

Glatiramer Acetate Mediated Expression of 4 1integrin (VLA-4) on T and B Regulatory Cells in EAE Mice (P02.109)

Objective: To evaluate the effect of glatiramer acetate (GA) on the induction of α4β1 (VLA-4) on regulatory T/B cells in EAE mice. Background α4β1 expressing B cells and CD4+ T cells are important in the effector phase of EAE. Regulatory cells (CD4+CD25+ or CD19+CD5+) impact disease progression in EAE and perhaps human MS. Both B and Treg cells protect against disease by the secretion of specific anti-inflammatory cytokines including IL-10 as well as important trafficking molecules. Design/Methods: An immunosuppression assay was performed using GA sensitized lymphocytes at varying ratios in the presence of mAb to a4. Cellular isolates were obtained from GA treated EAE mice and phenotyped for T/B regulatory cell expression by FACS and mRNA secretory expression for various chemokines (CXCR4, 5, MIP1 alpha) cytokines and neurotrophic factors including BDNF. Results: Higher expression of both T and B regulatory phenotypes were observed in GA treated mice. Lymphocyte suppression (50% at 1:1 ratio) by regulatory cells was unaffected by exposure to anti-α4. Increased IL-10 and decreased IFNγ was measured in T and B cells from GA treated mice. No significant difference in α4β1 expression was observed on regulatory T or B cell obtained from GA immunized mice compared to control mice. An increase in MZ B cells (B220+CD21hiCD23lo) was observed in GA treated mice. Further studies are underway that will focus on the identification of these cells within the CNS. Conclusions: GA may influence the conditioning of the Treg/Breg response that appears independent of α4β1 expression. The increased number of T/B regulatory cells represents an important mechanism in the suppression of EAE pathogenesis. GA conditioned B cells have a significant down regulatory effect on chemokines CXCR4, CXCR5 and TLR9 expression in spleen and within the CNS that may be responsible for mediating anti-inflammatory effects in EAE induced mice. Supported by: Teva Neuroscience and NIAID-AI061938, and CA1027A1/3 - National Multiple Sclerosis Society. Disclosure: Dr. Begum-Haque has received research support from Teva Neuroscience. Dr. Christy has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Telesford has nothing to disclose. Dr. Haque has nothing to disclose. Dr. Kasper has received personal compensation for activities with Teva Neuroscience, Serono, Inc., Bayer Pharmaceuticals Corporation, Genentech, Inc., Mederex as a consultant and participant on a scientifc advisory board. Dr. Kasper has received research support from Teva Neuroscience, Serono, Inc. and Bayer Pharmaceutical Corporation.

Monocytes P2X7 purinergic receptor is modulated by glatiramer acetate in multiple sclerosis

The aim of this study is to investigate the expression of P2X7R, IL-1beta and the ATP activity modulating ecto-apyrase CD39 on peripheral blood monocytes of MS patients and to observe the possible effects of Glatiramer Acetate (GA) on such expression.Twelve RR treatment-free MS patients were selected and peripheral blood monocytes were obtained. The expression of P2X7R, IL-1beta and CD39 on monocytes was investigated by qrt-PCR. The in vitro effects of GA on the expression of monocytes stimulated with BzATP (a potent P2X7R agonist)—were evaluated. Ten healthy donors (HDs) were similarly studied. Finally, 5 MS patients were given GA therapy and the monocytes obtained before treatment, after 3 and 12months of GA treatment were similarly investigated.No differences were found in P2X7R, IL-1beta and CD39 expression between patients and controls. In MS Bz-ATP stimulated monocytes, GA pre-conditioning clearly downregulated P2X7R (p=0.003) but IL-1beta expression also showed a decreasing trend (p=0.07). Conversely, CD39 showed an increasing trend (p=0.07). Similar evidence was found in HDs. GA in vivo treatment induced a reduction in the expression that was clear for P2X7R and CD39 (p<0.05) but only not significant for IL-1beta after 12months of treatment.Monocytes from both MS and control subjects express P2X7R, IL-1beta and CD39, and GA seems to interfere with such expression.

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial

Effects of glatiramer acetate on spasticity in previously interferon-β-treated and treatment-naive patients with relapsing-remitting multiple sclerosis: A prospective, nonrandomized, open-label, uncontrolled, observational pilot study

Background: Treatment with interferon-β (IFN-β) has been related to worsening of muscle spasticity in patients with multiple sclerosis (MS). However, there are no specific data on the effects of glatiramer acetate (GA) on spasticity. Objective: The aim of the present study was to assess the effects of GA on spasticity in patients with relapsing-remitting MS who had been previously treated with IFN-β or were treatment naive. Methods: Two cohorts of MS patients with spasticity who were about to begin treatment with GA at the approved dosage (20 mg/d) were enrolled in the study: patients who were being switched from IFN-β due to adverse events or lack of efficacy (cohort 1) and patients who were treatment naive (cohort 2). The follow-up periods for cohorts 1 and 2 were 18 and 12 months, respectively. Patients' physical condition was assessed at baseline and at the end of follow-up using the Modified Ashworth Scale (MAS), Penn Spasm Frequency Scale (PSFS), Global Pain Score (GPS), Adductor Tone Rating Scale, Expanded Disability Status Scale (EDSS), and neurophysiologic tests (latency and amplitude of the Hoffmann reflex [H reflex] in the soleus, and ratio of maximum H reflex to maximum motor response [H/M ratio] in the lower limb). The frequency and severity of adverse events were recorded throughout follow-up, and investigators rated the causal relationship to GA (unrelated, unlikely, possibly, or probably). Results: Twenty-eight patients were included in the study, 13 in cohort 1 and 15 in cohort 2. All patients were white. Cohort 1 was 76.9% female, with a mean (SD) age of 39.85 (9.25) years; cohort 2 was 66.7% female, with a mean age of 40.73 (11.52) years. Cohort 1 had significant reductions from baseline to the end of follow-up in mean scores on the MAS for the right hemibody (from 1.85 [0.61] to 1.18 [0.60]; P = 0.002) and left hemibody (from 1.86 [0.55] to 1.27 [0.65]; P = 0.045), PSFS (from 2.00 [0.91] to 0.36 [0.81]; P = 0.002), and GPS (from 47.69 [13.94] to 24.09 [17.15] mm; P = 0.002). The changes from baseline were not significant on the mean Adductor Tone Rating Scale, EDSS, H-reflex latency or amplitude on either side, or lower-limb H/M ratio on either side. Cohort 2 had significant reductions from baseline in H-reflex latency on the left side (from 30.31 [2.44] to 28.75 [2.01]; P = 0.005) and H/M ratio on the right side (from 0.45 [0.15] to 0.35 [0.19]; P = 0.025). There were no significant changes in mean scores on the MAS for either hemibody, PSFS, GPS, Adductor Tone Rating Scale, EDSS, H-reflex latency on the right side, H-reflex amplitude on either side, or lower-limb H/M ratio on the left side. Sixteen patients experienced a total of 28 adverse events. Seven mild adverse events were considered related to GA: local reaction at the injection site (3 patients); headache/migraine, anxiety, and skin reaction (1 patient each); and an unspecified adverse drug reaction (1 patient). Two serious adverse events (pyelonephritis and pyrexia) occurred during the study, neither of them considered related to GA. Conclusions: In this pilot study in patients with relapsing-remitting MS, GA treatment did not increase spasticity. Furthermore, the results suggest that GA may reduce spasticity in patients previously treated with IFN-β. These findings support the conduct of large randomized controlled trials of the effects of GA on spasticity.

Glatiramer acetate delayed conversion to multiple sclerosis in patients with clinically isolated syndrome

Source Citation Comi G, Martinelli V, Rodegher M, et al. Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe ...

The mechanism of action of glatiramer acetate treatment in multiple sclerosis

Glatiramer acetate (formerly known as copolymer 1) is the major noninterferon immunomodulatory agent used in the treatment of relapsing-remitting multiple sclerosis. Its mechanism of action over the past 40 years has evolved with our understanding of the immune response. We review the various mechanisms that have been proposed for this random polymer over the years, with emphasis on recent methods that utilize modern immunologic techniques. Studies describing processes such as immune deviation and effects on regulatory T cells and antigen-presenting cells are presented. Effects of glatiramer acetate on the immune response have evolved as our technical abilities and knowledge of the immune response itself have developed.