Constantinescu CS, Freitag P, Kappos L
Mult Scler 2000 Dec;6(6):378-81
University Hospital, Queen's Medical Centre, Division of Clinical Neurology, Nottingham, UK
PMID# 11212132; UI# 21079636
Free radicals including Peroxynitrite are induced in Multiple Sclerosis (MS). Antioxidant and Peroxynitrite inhibitor Uric Acid (UA), suppresses the MS animal model Experimental AutoImmune Encephalomyelitis (EAE).
MS patients have lower average serum UA than controls. An inverse relationship exists between MS and Gout, Glatiramer Acetate (GA) suppresses EAE and is beneficial in Relapsing MS.
We investigated Serum UA changes during open-label treatment of Relapsing MS with GA. Ten patients (six females, four males, aged 19 to 39 years, mean age 32 years) completed 6 months of GAA (Copaxone 20 mg s.c daily).
Of these, nine completed 12 months. After 6 months on GA, serum UA (normal, 173359 micromol/ml for women, 258-491 micromol/ml for men) increased in nine and marginally decreased (302 to 300 micromol/ml) in a single patient.
Mean UA significantly increased from 240 to 303 micromol/ml (P=0.0014). At 12 months, UA remained significantly higher than at start (P=0.006) decreasing in only one patient.
In contrast, we found no significant UA changes after 6 and 12 months of treatment in 21 MS patients treated with Interferon-ß-1a (Avonex), or in 11 treated with Interferon-ß-1a (Rebif), or in five placebo-treated controls.
Increasing UA, a natural inhibitor of free radicals, may represent a mechanism of action of Glatiramer Acetate in MS.
Fusco C, Andreone V, Coppola G, Luongo V, Guerini F, Pace E, Florio C, Pirozzi G, Lanzillo R, Ferrante P, Vivo P, Mini M, Macri M, Orefice G, Lombardi ML
Neurology 2001 Dec 11;57(11):1976-9
Universita Fedrico II, Servizio Immunoematologia e Trasfusione, Napoli, Italy
PMID# 11739812; UI# 21603061
Copolymer-1 (Cop-1) is a random synthetic Amino Acid copolymer, effective in the treatment of the Relapsing/Remitting form of MS (RRMS).
In vitro and in vivo studies suggest that the mechanism of Cop-1 involves its binding to Major Histocompatibility Complex Class II molecules as an initial step.
To assess a possible relationship between Human Leukocyte Antigen (HLA) Alleles and response to Cop-1 therapy.
Eighty-three patients with RRMS, 44 treated with Cop-1 and 39 with Interferon-beta-1a (IFN-beta-1a) for 2 years, were typed by molecular methods for HLA Class II Genes and subgrouped according to clinical outcome.
Data have shown a possible positive correlation between presence of DRB1*1501 and response to Cop-1 therapy (p = 0.008). No relationship between HLA Alleles and therapy has been found in IFN-beta-1a treated patients.
Results suggest that DRB1*1501 might be relevant for the clinical outcome in Cop-1 treated patients and, if confirmed in larger studies, it could be helpful in the selection of RRMS patients for different therapeutic options.
PolyReactive AntiBodies To Glatiramer Acetate Promote Myelin Repair In Murine Model Of DeMyelinating Disease
Ure DR, Rodriguez M
FASEB J 2002 Aug 1;16(10):1260-1262
Mayo Medical and Graduate School, Departments of, Immunology and, Neurology, Rochester, Minnesota, USA
Using a murine model of DeMyelinating disease, we demonstrate that ReMyelination of Spinal Cord Axons is promoted by AntiBodies to Glatiramer Acetate (GA, Copolymer-1, Copaxone), a therapeutic agent for Multiple Sclerosis (MS).
Glatiramer Acetate is a mixture of randomly synthesized Peptides that induces both T-Cell activation and AntiBody production in all treated individuals.
These observations prompted us to compare the independent effects of adoptively transferred GA-reactive T-Cells and AntiBodies in mice with chronic inflammatory DeMyelination induced by Theiler's Virus.
Transferred T-Cells had no effect on lesion load or the extent of ReMyelination. Purified polyclonal GA AntiBodies also did not alter lesion load, which suggests that neither GA T-Cells or AntiBodies were pathogenic.
On the contrary, GA AntiBodies enhanced the normally low level of ReMyelination in chronic lesions.
The AntiBodies, which were primarily ImmunoGlobulin (Ig) G1 and IgG2, cross-reacted with Oligodendrocytes, PeriVascular infiltrating cells, Astrocytes, and Neurons in Spinal Cord sections.
In Glial cultures they bound subsets of early lineage Oligodendrocytes and Microglia. Thus, several mechanisms may have contributed to the promotion of ReMyelination.
These results support the hypothesis that the AntiBody response in GA-treated patients is beneficial by facilitating repair of DeMyelinated lesions.
Caon C, Din M, Ching W, Tselis A, Lisak R, Khan O
Eur J Neurol 2006 May;13(5):471-4
Wayne State University School of Medicine, Multiple Sclerosis Center, Department of Neurology, Detroit, MI, USA
We examined the clinical course after switching Disease-Modifying Therapy (DMT) in patients with Relapsing/Remitting Multiple Sclerosis (RRMS).
Eighty-five consecutive RRMS patients who received weekly Interferon-beta-1a (IFN-beta-1a) 6 MU i.m. for at least 18 months were enrolled.
Baseline annualized relapse rate (ARR) for the 2 years prior to initiating therapy with IFN-beta-1a was obtained from charts.
All 85 patients received treatment with IFN beta-1a at 6 MU i.m. weekly for 18-24 months (mean 19.7 months). Treatment with IFN-beta-1a reduced the mean ARR from 1.41 to 1.23 (P=0.005).
All 85 patients were then switched to Glatiramer Acetate (GA) 20 mg s.c. daily and prospectively followed up for 36-42 months (mean 37.5 months).
Patients were switched because of persistent clinical disease activity (n=62) or persistently unacceptable toxicity (n=23) as determined by the treating Neurologist.
Treatment with GA reduced the mean ARR from 1.23 to 0.53 (P=0.0001).
Subgroup analysis showed that in patients who were switched because of lack of efficacy (n=62), the mean ARR was reduced from 1.32 on IFN beta-1a to 0.52 on GA (P=0.0001).
In contrast, in patients who switched because of persistent toxicity (n=23), the mean ARR was reduced from 0.61 on IFN-beta-1a to 0.47 on GA (P, non-significant).
Our observations suggest that clinical observations such as relapse rate and tolerability may be used as criteria for switching DMT in clinical practice.
More definitive consensus criteria incorporating Magnetic Resonance Imaging and clinical observations for defining optimal response and tolerability need to be developed for the routine clinical management of RRMS patients receiving DMT.