Abstract:The neuromuscular junction (NMJ) is a prototypic synapse although its structure is rather different from those of the central nervous system (CNS). The unmyelinated motor nerve terminals are separated from the postsynaptic membrane by a cleft that contains a basal lamina. This includes many proteins such as collagens, laminins, fibronectin and perlecan which help anchor some of the key elements involved in NMJ The neuromuscular junction (NMJ) is a specialized synapse with a complex structural and functional or… Show more
“…It is mainly caused by an autoimmune response to the nicotinic acetylcholine receptor (AChR) and less frequently to muscle-specific tyrosine kinase in a subset of anti-AChR-negative MG 1. In Japan, the estimated number of MG patients is 15 000 to 20 000 according to an epidemiological study conducted in 2006 2.…”
Objectives To evaluate the ability of tacrolimus to reduce the corticosteroid dose in patients with myasthenia gravis (MG) and the drug's safety in a double-blind, placebo-controlled, parallel group study. Methods Patients being treated with oral prednisolone at doses equivalent to 10e20 mg/day, and with stable symptoms, were randomised to tacrolimus or placebo in a 28-week double-blind study. The dose of corticosteroid was tapered with the procedures specified in the protocol. The primary efficacy endpoint was the mean daily prednisolone dose given in the last 12 weeks of the study.Results Eighty patients received the study drug (40 patients in each group) and were included in the full analysis set. In the full analysis set, there was no significant difference in the primary efficacy endpoint between the two groups (p¼0.078). However, some secondary analyses suggested the steroid-sparing effect of tacrolimus. Tacrolimus was well tolerated, and no safety concerns were noted. Conclusions This study suggests that tacrolimus has a potential advantage as a steroid-sparing agent in the treatment of MG patients. Clinical trial registration number NCT00309088. Name of the trial registry: FK506 Phase 3 Study: A Study for Steroid Non-Resistant MG Patients.
“…It is mainly caused by an autoimmune response to the nicotinic acetylcholine receptor (AChR) and less frequently to muscle-specific tyrosine kinase in a subset of anti-AChR-negative MG 1. In Japan, the estimated number of MG patients is 15 000 to 20 000 according to an epidemiological study conducted in 2006 2.…”
Objectives To evaluate the ability of tacrolimus to reduce the corticosteroid dose in patients with myasthenia gravis (MG) and the drug's safety in a double-blind, placebo-controlled, parallel group study. Methods Patients being treated with oral prednisolone at doses equivalent to 10e20 mg/day, and with stable symptoms, were randomised to tacrolimus or placebo in a 28-week double-blind study. The dose of corticosteroid was tapered with the procedures specified in the protocol. The primary efficacy endpoint was the mean daily prednisolone dose given in the last 12 weeks of the study.Results Eighty patients received the study drug (40 patients in each group) and were included in the full analysis set. In the full analysis set, there was no significant difference in the primary efficacy endpoint between the two groups (p¼0.078). However, some secondary analyses suggested the steroid-sparing effect of tacrolimus. Tacrolimus was well tolerated, and no safety concerns were noted. Conclusions This study suggests that tacrolimus has a potential advantage as a steroid-sparing agent in the treatment of MG patients. Clinical trial registration number NCT00309088. Name of the trial registry: FK506 Phase 3 Study: A Study for Steroid Non-Resistant MG Patients.
“…Patients with a history of smoking or cerebellar dysfunction and older patients with rapid progression of symptoms, are more likely to have an underlying malignancy 76. The prognosis in patients with both LEMS and SCLC is poor, with a 2-year survival of less than 10%, albeit better than in patients without LEMS, suggesting a possible antitumour effect of the antibodies.…”
“…MG is among the best characterized antibody-mediated diseases with the primary antigenic targets being neuromuscular junction (NMJ) proteins, primarily the nicotinic acetylcholine receptor (AChR) [1], [24]. The antibodies produce a reduction of AChR number and damage the muscle endplate, leading to a failure of neuromuscular transmission with resulting muscle weakness.…”
The mechanisms that underlie the development and maintenance of autoimmunity in myasthenia gravis are poorly understood. In this investigation, we evaluate the role of survivin, a member of the inhibitor of apoptosis protein family, in humans and in two animal models. We identified survivin expression in cells with B lymphocyte and plasma cells markers, and in the thymuses of patients with myasthenia gravis. A portion of survivin-expressing cells specifically bound a peptide derived from the alpha subunit of acetylcholine receptor indicating that they recognize the peptide. Thymuses of patients with myasthenia gravis had large numbers of survivin-positive cells with fewer cells in the thymuses of corticosteroid-treated patients. Application of a survivin vaccination strategy in mouse and rat models of myasthenia gravis demonstrated improved motor assessment, a reduction in acetylcholine receptor specific autoantibodies, and a retention of acetylcholine receptor at the neuromuscular junction, associated with marked reduction of survivin-expressing circulating CD20+ cells. These data strongly suggest that survivin expression in cells with lymphocyte and plasma cell markers occurs in patients with myasthenia gravis and in two animal models of myasthenia gravis. Survivin expression may be part of a mechanism that inhibits the apoptosis of autoreactive B cells in myasthenia gravis and other autoimmune disorders.
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