The current management of MG includes the use of anticholinesterase drugs for temporary improvement of neuromuscular transmission, removal of anti-AChR Abs by plasma exchange or specific immunoadsorption procedures, use of nonspecific immunosuppressants or immunomodulators to curb the anti-AChR response, and thymectomy (Table ). No current treatment targets the autoimmune defect of MG selectively. However, the advances in understanding the pathogenesis of autoimmunity and MG suggest that new approaches that will curb or even eliminate the anti-AChR response specifically will be forthcoming (see Table and “The future”).
Current and potential therapies for MG management
Anticholinesterase drugs improve myasthenic symptoms in nearly all patients, but they fully relieve the symptoms in only a few. Thus, most patients require additional immunosuppressive treatment (see below). A novel approach to long-term therapeutic inhibition of AChE activity in MG patients is based on the observation that in the NMJ of both MG patients and EAMG animals, there is enhanced transcription and altered splicing of AChE pre-mRNA, with accumulation of a normally rare readthrough AChE-R variant (89
). The commonly occurring synaptic AChE-S variant forms membrane multimers. In contrast, AChE-R exists as soluble monomers that lack the carboxyterminal cysteine needed for membrane attachment. Thus, AChE-R permeates the synaptic space and degrades ACh before it reaches the postsynaptic membrane, thereby compromising AChR activation. These observations prompted the design and use of EN101, an antisense oligonucleotide that suppresses the expression of AChE-R. EN101 normalizes neuromuscular transmission in EAMG by modulating the synthesis of AChE variants, thereby affecting the rate of ACh hydrolysis and the efficacy of AChR activation (90
). EN101 is undergoing human trials.
Despite the lack of large controlled trials, corticosteroids are the immunosuppressive agent most frequently used for the treatment of MG and the most consistently effective (91
). They are administered at high doses for several months and at low doses for years. Anti-AChR Ab levels decrease in the first months of therapy. Most patients obtain a clinical benefit, which may be related to reduction of lymphocyte differentiation and proliferation, redistribution of lymphocytes into tissues that are not sites of immunoreactivity, changes in cytokine expression (primarily of TNF, IL-1, and IL-2), inhibition of macrophage function and of antigen processing and presentation, or a possible increase in muscle AChR synthesis. The shortcoming of corticosteroid treatment is the frequent steroid-related complications. This has motivated the use of other immunosuppressants, either as “steroid-sparing” agents or as a substitute for corticosteroids; a proportion of MG patients can be treated successfully without corticosteroids.
Azathioprine, a purine analog, reduces nucleic acid synthesis, thereby interfering with T and B cell proliferation. It has been utilized as a single immunosuppressant agent in MG since the 1970s, and large, retrospective reports support its efficacy (92
). A randomized, double-blind trial demonstrated its efficacy also as a steroid-sparing agent. Its major disadvantage is the delayed clinical response, which may take up to 15 months (93
Cyclophosphamide administered intravenously and orally is an effective treatment for MG (94
); more than half of the patients became asymptomatic after 1 year of treatment. Its delayed effect and undesirable side effects (hair loss, and less frequently, nausea, vomiting, anorexia, and skin discoloration) limits its use to the management of patients who do not respond to other immunosuppressive treatments.
Cyclosporine is a cyclic undecapeptide that blocks the synthesis of cytokines (and especially IL-2), IL-2 receptors, and other proteins critical in the function of CD4+
T cells. Its efficacy in MG was first suggested by a small, randomized, placebo-controlled study, which has not been followed by similar studies on larger groups of patients (95
). However, larger retrospective studies have supported its use as a steroid-sparing agent (96
Tacrolimus, a macrolide antibiotic, is similar to cyclosporine in its biological activity. No large controlled studies on the efficacy of tacrolimus in MG are available. However, a large retrospective study of treatment-resistant patients supports its use as a steroid-sparing agent (97
In the US, mycophenolate mofetil is increasingly used both as a steroid-sparing agent and as a stand-alone immunosuppressant. Unfortunately, the investigations that support its use studied small patient groups or were of a retrospective nature; therefore the value of their conclusions is limited (98
). Those studies suggest that mycophenolate has limited toxicity, consistent with its selective inhibitory activity of guanosine nucleotide synthesis in activated T and B cells, which should limit its effects on other cell types (99
). Randomized, controlled trials to evaluate mycophenolate mofetil usefulness in MG treatment are under way.
For some MG patients, symptoms do not improve with the use of corticosteroids or one of the immunosuppressive agents described above, alone or in combination, and they may develop intolerable side effects prompting consideration of other therapeutic options. MG patients resistant to therapy have been successfully treated with cyclophosphamide in combination with bone marrow transplant (100
) or with rituximab, a monoclonal Ab against the B cell surface marker CD20 (101
). Etanercept, a soluble, recombinant TNF receptor that competitively blocks the action of TNF-α, has been shown to have a steroid-sparing effects in studies on small groups of patients (102
). Plasma exchange and i.v. Ig (IVIg) (discussed below) can be used as chronic therapy although their benefit has not been documented in rigorously designed studies.
Plasma exchange (plasmapheresis) and IVIg are used for acute management of severe muscular weakness. Plasmapheresis involves replacing 1–1.5 times the plasma volume with saline, albumin, or plasma protein fraction, leading to a reduction of serum AChR Ab levels (103
). For IVIg therapy, Ig isolated from pooled human plasma by ethanol cryoprecipitation is administered for 5 days (0.4 g/kg/day). Fewer infusions at higher doses are also used. The mechanism of action of IVIg is complex and likely includes inhibition of cytokines, competition with autoantibodies, inhibition of complement deposition, interference with binding of Fc receptor on macrophages and Ig receptor on B cells, and interference with antigen recognition by sensitized T cells (104
). More specific techniques to remove pathogenic anti-AChR Abs utilizing immunoadsorption have been developed recently, which offer a more targeted approach to MG treatment (105
The observations that lead to therapeutic ablation of the thymus in MG have been mentioned above. However, the clinical efficacy of thymectomy has been questioned because the evidence supporting its use is not solid (106
). Retrospective studies yielded widely different conclusions, but they included patients whose thymi were removed by different surgical approaches, and they used different definitions of remission and limited statistical analysis (107
). Moreover, corticosteroids and other immunosuppressive agents are commonly used by MG patients undergoing thymectomy, making it difficult to ascertain whether thymectomy provides additional benefits. Usually, thymectomy is performed on patients early in the course of their disease and restricted to patients younger than 60. A review by the American Academy of Neurology concluded that, while thymectomy should be considered a treatment option
, its benefits in nonthymomatous MG have not been firmly established (106
) and that a prospective, controlled, randomized study with standardized medical therapy for all patients is needed. Also, the NIH is sponsoring a clinical trial to determine whether the extended transsternal thymectomy reduces corticosteroid requirements for patients with AChR Ab–positive nonthymomatous gMG (108
Thymectomy may not be a viable therapeutic approach for anti-MuSK Ab–positive patients because their thymi lack the germinal centers and the infiltrates of lymphocytes that characterize thymi from patients who have anti-AChR Abs. This suggests that a different pathologic mechanism occurs in anti-MuSK Ab–positive and anti-AChR Ab–positive MG.
Lack of well-designed investigations with appropriate statistical power undermines the rationale for use of the current immunotherapies for MG. Moreover, there are no rigorous trials that compare the efficacy of the various immunosuppressive approaches. Different factors contribute to this situation, including the variable clinical presentations and time course of MG and its low incidence; a lack of agreed-upon clinical scales to measure the outcome of the treatment; and a suboptimal cooperation among the major centers that care for MG patients during clinical trials (109