The prognosis for patients with
myasthenia gravis (MG) has improved significantly over the past half century, including substantial reductions in mortality and morbidity. However, approximately 10% of patients fails to respond adequately to current
therapies and are considered treatment refractory, or treatment intolerant, and up to 80% have disease that fails to achieve complete stable remission. Although patients with
autoantibodies to muscle-specific
tyrosine kinase (anti-
MuSK positive) are more likely to become treatment refractory than those with
autoantibodies to the
acetylcholine receptor (anti-AChR positive), each of these serotypes is substantially represented in the refractory MG population. Other risk factors for becoming treatment refractory include history of
thymoma or
thymectomy and female sex. A modified treatment algorithm for MG is proposed: patients who have disease that fails to respond to the stepwise approach to
therapy, are treatment intolerant, or who require chronic rescue measures despite ongoing
therapy, should be considered treatment refractory and emerging
therapies should be considered. Three emerging
monoclonal antibody-based
therapies are discussed: the anti-B-cell agent
rituximab; the terminal complement activation inhibitor
eculizumab; and
belimumab, which targets
B-cell activating factor. Increased understanding of molecular pathophysiology and accurate antibody subtyping in MG should lead to the use of new therapeutic agents and successful management of treatment-refractory patients.