Progress in the treatment of myasthenia gravis

Abstract

Substantial therapeutic progress has been made in myasthenia gravis (MG) even before the era of molecular medicine. Here we characterize modern treatment algorithms that are adapted to disease severity and introduce the principle of escalating treatment strategies for MG. In very mild cases and in some ocular forms of MG, treatment with acetylcholinesterase inhibitors may be sufficient, at least temporarily, but commonly some kind of immunologically active treatment is needed. In generalized MG, a wide array of immunosuppressive treatments has been established through observational studies, some prospective, but most of them have never been tested in a double-blind, prospective and randomized trial. Within the immunologically active drugs, glucocorticosteroids (GCS) and the immunosuppressive drug azathioprine (Aza) have been studied the longest. Aza is still the standard base-line treatment, in particular in cases where high doses of GCS would be needed to maintain remission. If Aza is not tolerated, several alternatives are available including cyclosporine A (Cic A), mycophenolate mofetil, cyclophosphamide, and methotrexate, all of them off-label in most western countries. Tacrolimus is under investigation. More severe cases may profit from drug combinations in which compounds with more rapidly acting drugs (GCS, Cic A) are combined with others showing a more delayed action (Aza). All such combination therapies need to be supervised by an experienced neuroimmunological center because of potentially serious adverse reactions. Serial measurements of anti-acetylcholine receptor antibodies, once these are elevated, is a useful adjunct for monitoring long-term treatment success and may help in weaning from higher to lower doses or to single drugs rather than combinations. For very severe and treatment-resistant cases, co-treatment with intravenous immunoglobulins or different modalities of plasmapheresis may be considered on the short term while the humanized monoclonal anti-CD 20 antibody (rituximab) is a candidate for the long term. In highly refractory cases also immuno-ablation via high-dose cyclophosphamide, followed by hematologic trophic factors such as G-CSF, has been tried successfully. Future developments may include other immunologically active monoclonal antibodies (e.g., anti-CD 52, Campath-1). Up to 10% of patients with MG are associated with a malignant thymoma, often referred to as paraneoplastic MG, as detected by CT scan or MRI, and these patients require thymomectomy and sometimes postsurgical chemotherapy and radiation treatment. In nonthymoma patients with generalised MG, including older children and adults up to the 5th decade, a complete transsternal thymectomy is recommended based on available open trials and expert opinion, preferentially during the first year of disease. Endoscopic surgery may also be effective. Before surgery, pretreatment with immunosuppressive medication or plasmapheresis is usually recommended to ameliorate MG and subsequently reduce perioperative morbidity and mortality which is now near zero in experienced centers. Myasthenic crisis is the life-threatening exacerbation of MG and is best treated by plasmapheresis, mostly combined with immunoadsorption techniques. Intravenous immunoglobulins are a reasonable alternative, but a shortage in supplies and high prices limit its use.

Keywords: acetylcholine receptor; immuno-adsorption; immunoglobulins; immunosuppression; muscle specific kinase; plasmapheresis; thymoma.

Figure 1.

Neuromuscular junction in myasthenia gravis and in the Lambert Eaton Myasthenic Syndrome: schematic drawing of a motor endplate and a nerve terminal. Acetylcholine (ACh) upon release into the synaptic cleft is rapidly degraded by the specific acetylcholinesterase located at the bottom of the postsynaptic fold and in the basement membrane; MuSK, muscle specific kinase [Hoch et al. 2001]; VGCaChannels, voltage-gated calcium channels; C1, first component of classical pathway the complement cascade binding to the Fc portion of the binding and cross-linking IgG antibodies. Adapted from Toyka and Gold, 2007.