Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 23, 2023
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Glatiramer acetate, formerly called copolymer-1, is one of a series of polypeptide preparations developed to stimulate myelin basic protein, a natural component of the myelin sheath. Myelin basic protein suppresses experimental allergic encephalomyelitis (the animal model of multiple sclerosis); a better suppression effect was demonstrated by the use of a synthetic basic copolymer (27). This provided the rationale for the use of copolymer in multiple sclerosis. Glatiramer acetate was developed for commercial use, and results of the first clinical trial were published in 1987. The United States Food and Drug Administration approved it in 1996 for use in multiple sclerosis patients.
Glatiramer acetate consists of synthetic polypeptides containing four naturally occurring amino acids: (1) L-glutamic acid, (2) L-lysine, (3) L-alanine, and (4) L-tyrosine.
Pharmacology. The exact mode of action is not known, but glatiramer is thought to modify the immune disturbances believed to be involved in the pathogenesis of multiple sclerosis. Principal mechanisms of action are:
(1) Glatiramer acetate binds to the major histocompatibility complex (MHC) class 2 molecules, thereby competing with the major histocompatibility complex binding of other antigens.
(2) Glatiramer acetate-major histocompatibility competes with myelin basic protein (MBP), which is one of the major autoantigens in the pathogenesis of multiple sclerosis for binding to the antigen-specific surface receptor of T cells.
(3) Glatiramer acetate, which is structurally like myelin basic protein, along with nanny proteins (negatively charged proteins that interact with myelin basic protein), restricts access of myelin basic protein to the 26S proteasome to protect its intracellular degradation (19).
(4) Glatiramer acetate affects several aspects of dysregulated B-cell function in multiple sclerosis that contribute to the mechanism of action (13).
(5) Glatiramer inhibits the activation of MBP-reactive T cells, which are believed to have access to the CNS, where they can exert anti-inflammatory and possibly neuroprotective effects.
(6) Glatiramer acetate promotes oligodendrogenesis and remyelination by elevating levels of growth factors that promote repair.
(7) Glatiramer enhances cytolysis of human natural killer cells against autologous and allogeneic immature and mature monocyte-derived dendritic cells, as well as inhibits the release of cytokine interferon-gamma.
(8) Multiple sclerosis patients treated with glatiramer show significant changes in circulating antigen-presenting cells and CD4+ T cells (24). Expression of CD40 on dendritic cells is significantly lower and is associated with relapse risk in multiple sclerosis patients treated with glatiramer.
(9) Increase of anti-inflammatory monocytes and restoration of Treg (T regulatory cell) level are characteristic of responder patients, not only in short-term but even after as long as a decade of treatment with glatiramer acetate (26).
(10) Findings of a 2-year longitudinal study suggested that glatiramer acetate exerts its immunomodulatory action at the level of grey matter by reducing the accumulation of cortical lesions and slowing down the progression of grey matter atrophy (09).
The remarkable reduction of the number of lesions (as demonstrated by gadolinium-enhanced MRI during treatment with glatiramer) suggests that this is due to pharmacological activity of the drug rather than spontaneous regression of the lesions. Glatiramer is considered to have a dual mechanism of action. In addition to immunoregulation, glatiramer acetate stimulates neurotrophin secretion in the central nervous system that may promote neuronal repair (03). Glatiramer acetate effectively reduces multiple sclerosis activity regardless of the severity of the MRI-detectable inflammatory process.
Pharmacokinetics. Pharmacokinetic studies have not been carried out in humans because the drug is not detectable in systemic blood circulation. Based on animal studies, it is assumed that the injected material is hydrolyzed locally, and a fraction of it enters the lymphatic circulation to reach the lymph nodes and then somehow enters the systemic circulation intact.
Pharmacogenomics/pharmacogenetics. Genotyping studies have revealed genetic biomarkers that can predict response to glatiramer acetate for relapsing multiple sclerosis. This could enable the development of pharmacogenomics-based personalized treatment for multiple sclerosis.
A study to investigate biomarkers of response to glatiramer acetate in relapsing-remitting multiple sclerosis patients found that the probability of accurately detecting response to glatiramer acetate was 85% for Response Gene to Complement 32, 90% for FasL, and 85% for interleukin-21 (18). These data suggest that these could serve as potential biomarkers for the detection of multiple sclerosis relapse and response to glatiramer therapy.
Results of a pharmacogenetic study of glatiramer acetate in late-phase clinical-trial cohorts of multiple sclerosis have shown that gene regions underlying the 4-SNP (rs80191572, rs28724893, rs1789084, and rs139890339) signature, in approximately 10% of patients who showed clinical improvements, have been linked with pathways associated with either the drug’s mechanism of action or the pathophysiology of disease (22).
Original evidence of clinical efficacy is based mainly on three controlled clinical trials. In a double-blind, randomized, placebo-controlled pilot trial involving 50 patients, 56% of the glatiramer acetate-treated patients remained relapse-free, compared to 26% in the placebo group (04). In a 2-year, multicenter, randomized, double-blind, placebo-controlled trial of 251 patients, glatiramer was shown to reduce relapses by an average of 29% when compared with placebo (16). A 2-year, longitudinal neuropsychological study of patients in a multicenter clinical trial showed no effect of glatiramer therapy on cognitive function in relapsing-remitting multiple sclerosis (28). There was, however, no decline in cognitive function, and this lack of deterioration is significant in a gradually progressive disease where some deterioration over a 2-year period is expected.
A randomized, double-blind clinical trial in patients with relapsing-remitting multiple sclerosis has shown that early treatment with glatiramer acetate is effective in delaying conversion to clinically definite multiple sclerosis and brain lesions detected by MRI. A systematic review of randomized trials concluded that glatiramer acetate is partially effective in relapsing-remitting multiple sclerosis but does not halt clinical progression of the disease (20).
Results of a randomized phase 3 dose-comparison study of glatiramer acetate showed that both the currently approved glatiramer acetate doses, 20 mg and 40 mg, were well-tolerated in patients with relapsing-remitting multiple sclerosis, with no gain in efficacy for the higher dose (08).
Results of a double-blind, randomized, controlled study of combined use of interferon beta-1a 30 μg intramuscularly weekly and glatiramer acetate 20 mg daily did not show significantly greater clinical benefit over 3 years than either agent alone in relapsing-remitting multiple sclerosis (21). The effect of combined use was associated with reduction of lesion size on MRI and a higher proportion of patients that attained disease activity-free status but whether this would translate into clinical benefit at a later stage remains to be determined by an extension study.
A multicenter, open-label, non-randomized, prospective, pilot study has shown that following discontinuation of natalizumab, 1 year of therapy with glatiramer acetate is safe and well tolerated in multiple sclerosis patients and can reduce the risk of early rebound of disease (23).
A phase 3 multicenter, randomized, placebo-controlled trial, PreCISe, assessed effects of glatiramer acetate in patients with clinically isolated syndromes that were suggestive of multiple sclerosis (02). Measurement of N-acetylaspartate (NAA) by proton magnetic resonance spectroscopy, a biomarker of neuronal integrity, and increase of NAA/creatine ratio indicated a neuroprotective effect of glatiramer acetate.
A randomized, double-blind clinical trial showed that a glatiramer acetate dose of 40 mg subcutaneously three times a week was safe and effective for patients with relapsing-remitting multiple sclerosis and provided the convenience of fewer injections (17).
Glatiramer acetate is indicated for a reduction in frequency of relapses in patients with relapsing-remitting multiple sclerosis.
• Glatiramer acetate has been shown to inhibit the development of experimental autoimmune uveoretinitis in mice.
• Glatiramer has been used for a case of relapsing neuromyelitis optica.
• Dry, age-related macular degeneration.
• Administration of glatiramer acetate leads to elevation of levels of brain-derived neurotrophic factor in the rat brain, and this has been proposed as a treatment for Rett syndrome as deficiency of this neurotrophic factor plays a role in the pathophysiology of the syndrome.
Patients with known hypersensitivity to either glatiramer acetate or mannitol should not take this drug.
The duration of glatiramer acetate treatment is indefinite. The goal is to reduce relapses of multiple sclerosis. Glatiramer acetate is a first-line therapy for the treatment of relapsing-remitting multiple sclerosis with a well-characterized safety profile and establish efficacy up to 20 years of continuous use (29). Whether prolonged treatment with glatiramer acetate reduces brain atrophy development in multiple sclerosis has not yet been established. Review of data from immunological and imaging studies that quantify axonal injury in the brain indicates a neuroprotective effect of glatiramer acetate. In a pilot study of relapsing-remitting multiple sclerosis, patients treated with glatiramer acetate did not have any clinical deterioration or spinal cord atrophy at 1 year as assessed by measurement of spinal cord volume by MRI as well as comparison with healthy controls (25). Because spinal cord atrophy occurs early during the course of multiple sclerosis and is closely related to physical disability, lack of atrophy is a possible neuroprotective therapeutic outcome measure.
Results of an observational study showed that glatiramer acetate slows the progression of Expanded Disability Status Scale scores more than other multiple sclerosis therapies and achieves a greater reduction in relapses as well as improvement in patients' quality of life (14). Switching from glatiramer acetate to other multiple sclerosis therapies did not improve response to treatment.
A retrospective study of relapsing-remitting multiple sclerosis patients has shown that glatiramer acetate is safe and useful, with low rates of serious adverse events and low rates of breakthrough disease, but development of intolerance to injection proved a major limitation to glatiramer acetate use (10). Patients who had been previously treated with interferons presented a lower probability of glatiramer acetate discontinuation than treatment-naive patients.
Phosphorylated SIRT1 is a potential biomarker of relapse and predictor of response to glatiramer acetate treatment in patients with relapsing-remitting multiple sclerosis and its downstream activation effects are shown by measuring the trimethylation of histone 3 at lysine 9. Findings of a clinical study showed that phosphorylated SIRT1 and histone 3 at lysine 9 are potential biomarkers for relapse and histone 3 at lysine 9 is a possible biomarker for predicting response to treatment of multiple sclerosis with glatiramer acetate (07).
Data from two independent multiple sclerosis trials, a randomized study (the Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis [CombiRx] trial, evaluating glatiramer acetate vs IFN-β-1a) and an observational cohort extracted from MSBase, were used to build and validate a treatment response score, regressing annualized relapse rates on a set of baseline predictors (05). It was possible to select criteria, based on patients' characteristics, to choose whether to treat with glatiramer acetate or IFN-β-1a, which has implications for clinical decisions in everyday clinical practice.
JNK and phospho-Bcl-2 are possible biomarkers of multiple sclerosis relapse and therapeutic response to glatiramer acetate in relapsing-remitting multiple sclerosis patients. One study found significantly higher levels of JNK1 p54 as well as JNK2 p54 and significantly lower levels of p-Bcl-2 in relapse patients and in non-responders to glatiramer acetate (01). These biomarkers may be useful for the personalized therapy of multiple sclerosis with glatiramer acetate.
Both 20 mg and 40 mg doses are approved, but usually 20 mg/day is given by subcutaneous injection.
Pediatric. Safety and efficacy in individuals under 18 years of age has not been established.
Geriatric. There are no studies on this drug in the elderly.
Pregnancy. No adverse effects on fetal development have been observed in experimental animals. With regard to use by pregnant women with multiple sclerosis, it is an FDA category B drug. Although a retrospective study showed no deleterious effects from glatiramer acetate in pregnant women with multiple sclerosis or in their offspring, use of glatiramer acetate during pregnancy should be restricted to the most difficult cases where the benefits clearly outweigh the risks (11). A prospective, observational, multicenter study showed that a mother’s exposure to glatiramer is not associated with a higher frequency of spontaneous abortion, or other negative pregnancy and fetal outcomes, implying that it can be used safely during pregnancy (12).
It is not known if glatiramer is excreted in human milk. Caution should, therefore, be exercised when the drug is used by nursing mothers.
No interactions have been identified with glatiramer acetate and drugs used in the management of multiple sclerosis, eg, corticosteroids and interferon beta.
Relapsing-remitting multiple sclerosis patients taking glatiramer acetate continuously for up to 22 years as disease-modifying monotherapy experience minimal disability progression, and this experience attests to its safety and tolerability (15). Lipoatrophy is reported as an adverse effect. The patients should be made aware of this adverse reaction. They should be able to recognize it and discontinue injecting in areas where it is identified. Adverse effects of glatiramer acetate include increased risk of coronary artery disease. Genome-wide association studies of genes known to interact with glatiramer acetate have identified three CAD risk alleles within the transforming growth factor B1 (TGFB1) gene on chromosome 19 (06).
No special treatment is required for adverse effects.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.See Profile
Nearly 3,000 illustrations, including video clips of neurologic disorders.
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
Full spectrum of neurology in 1,200 comprehensive articles.
Listen to MedLink on the go with Audio versions of each article.
Jan. 23, 2023
Jan. 05, 2023
Jan. 04, 2023
Jan. 01, 2023
Dec. 30, 2022
Neuropharmacology & Neurotherapeutics
Dec. 27, 2022
Dec. 25, 2022
Behavioral & Cognitive Disorders
Dec. 22, 2022