Treatment of myasthenia gravis

Abstract

Myasthenia gravis is a prototypic antibody-mediated neurological autoimmune disorder. Its pathogenesis is much better understood than that of multiple sclerosis or immune neuropathies. Currently two targets in the endplate membrane are considered as autoantigens, the acetylcholine receptor (in up to 90%) and the muscle-specific kinase (MuSK, in about 5%). Fortunately, substantial therapeutic progress has been made even before the era of molecular and translational medicine. In this review we characterise modern treatment algorithms that are adapted to disease severity and introduce the principle of escalating treatment strategies for myasthenia gravis. In mild cases and ocular forms of myasthenia gravis treatment with acetylcholine esterase inhibitors may be sufficient, at least temporarily. In generalised myasthenia gravis a wide array of immunosuppressive treatments have been established but most have never been tested in a full-size prospective randomised trial. Up to 10% of patients with myasthenia gravis are associated with a thymoma, i.e. of paraneoplastic origin, and this has to be looked for by CAT scan or MRI. In non-thymoma patients younger than about 50 years of age and with generalised weakness a complete early (but not urgent) thymectomy is considered as state of the art based on circumstantial evidence and expert opinion; the best type of procedure is still under debate. Usually, pretreatment with immunosuppressive medication or plasma-pheresis is recommended. Myasthenic crisis is best treated by plasma-pheresis, mostly combined with immunoadsorption techniques. Intravenous immunoglobulins are a reasonable therapeutic alternative, but a shortage in supply and high prices limit its use. With regard to immunosuppression azathioprine is still the standard base-line treatment, often combined with initial corticosteroids. In rare patients with inborn hepatic enzyme deficiency of thiomethylation azathioprine it is not well tolerated and may be substituted by mycophenolate mofetil. Severe cases may profit from combined immunosuppression with corticosteroids, cyclosporine A and even moderate doses of methotrexate or cyclophosphamide. Tacrolimus is under investigation. All such combination therapies need to be supervised by an experienced academic neuroimmunological centre. Serial measurements of anti-acetylcholine receptor antibodies, once these are elevated, or MuSK antibodies are a useful adjunct for monitoring treatment success. In escalating therapy for very severe cases one may employ monoclonal anti-CD 20 antibodies (rituximab). In highly refractory cases also immunoablation via high-dose cyclophosphamide, followed by trophic factors such as G-CSF has been suggested.