With the treatment options available
With the treatment options available today including a combination of symptomatic treatments and general immunosuppression, many MG patients can lead productive lives , , . The frequency of death has decreased due to improved management and detection of milder cases. At present, the overall mortality rate is about 2 percent, and higher in MG crisis (about 5 percent) . Symptomatic therapy of MG with anticholinesterase drugs temporarily enhances neuromuscular transmission by increasing the concentration of available gamma-Glu-Cys (ACh) to compensate for loss of AChRs, but it fully relieves symptoms in only a few patients and does not alter the autoimmune response , . Most patients require additional immunosuppressive treatment. Thymectomy is usually performed early on young-onset patients with generalized MG. However, the clinical efficacy of thymectomy has been questioned . Results of a multicenter, randomized, controlled thymectomy trial are eagerly awaited . Nonspecific immunosuppressive drugs mainly suppress lymphocyte activation and proliferation with little effect on long-lived plasma cells that are terminally differentiated cells and continue producing pathogenic antibodies , . Hence, the use of these drugs is hampered by delayed clinical response and undesirable side effects. Rituximab, a chimeric murine-human monoclonal antibody (mAb) that depletes B cells by binding to their CD20 surface marker, has been recently employed for the treatment of patients with severe or refractory MG. Several studies suggest that rituximab is more effective in patients with MuSK antibody positive MG than in patients with AChR antibody positive MG , . In all cases rituximab was used in combination with conventional immunosuppressants , . To date, the experience of the use of rituximab in MG is mainly in the form of single case reports and small case series of patients . Yale University is sponsoring a multicenter clinical trial (NCT02110706) to determine whether rituximab is a safe and beneficial therapeutic for MG. Plasmapheresis and intravenous immunoglobulin produce striking, albeit temporary, improvement, and are used for acute management of MG crisis. Although current treatments can help many patients achieve clinical remission, most patients must take immunosuppressive medication for many years or indefinitely, despite the risk of associated adverse effects . A distinct subset of patients is refractory to the available treatments , . Thus, the ultimate goal for MG treatment is to eliminate the pathogenic autoimmune response to AChR specifically without affecting the other functions of the immune system or causing other adverse effects. Such antigen-specific immunosuppressive therapy is not available for MG , . Experimental autoimmune myasthenia gravis (EAMG), an animal model for MG, can be induced in rats, mice, monkeys, and other susceptible species by immunization with AChRs from fish electric organs, mammalian muscle, or recombinant proteins that preserve the native conformation of the MIR , , , , . EAMG shares many clinical and immunopathological features with those of human MG. Thus, EAMG provides an excellent model system for exploring the immunopathological mechanisms of MG and therapeutic strategies of possible use in humans. EAMG in mice has an advantage because of its potential for genetic manipulation. However, EAMG in mice is difficult to induce, and usually requires multiple immunizations with AChR. Only a fraction of the mice develop EAMG after immunizations . Lewis rats are more susceptible to EAMG than mice and some other rat strains. The incidence of clinical EAMG in Lewis rats is nearly 100%. With sufficiently intense adjuvants, rat EAMG exhibits both a transient acute phase that occurs 8–14 days after immunization and recovers after 3–4 days, and a progressive chronic phase starting at about 30 days , . In the acute phase, low but rapidly increasing concentrations of antibody provoke transient release of C3 fragments of complement that attract macrophages to phagocytose postsynaptic membrane , . The acute phase is useful in studies of EAMG therapy because it can show that control and treated animals were equally affected prior to treatment. A similar acute response can be produced by passive transfer of MG or EAMG antiserum or mAbs to the MIR , , , , . Chronic EAMG closely mimics human MG in many aspects. In both MG and chronic EAMG, autoantibodies to AChR impair transmission primarily by reducing the amount of muscle AChR due to complement-mediated focal lysis of the postsynaptic membrane and antigenic modulation. However, macrophages are not involved. In the chronic phase, weakness is progressive, often ending in death , .