Myasthenia Gravis: Do the Subtypes Matter?

Acquired myasthenia gravis (MG) is a group of neuromuscular junction (NMJ) disorders caused by autoantibodies against components of postsynaptic muscle endplate. Autoantibodies target the acetylcholine receptor (AChR), muscle-specific kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4) and agrin. Clinically, MG is characterised by fluctuant muscle weakness.[1]

MG is classified into subtypes based on serum antibodies and clinical features. Identification of the specific subtype dictates the therapeutic approach and also prognosis.[12] Clinical subtypes include ocular MG, early-onset generalised MG and late-onset MG. The subtypes by antibodies include MG with AChR antibodies, MG with anti-MuSK antibodies, MG with anti-LRP4 antibodies, seronegative myasthenia and myasthenia with coexisting autoimmune diseases.[12] The other subtype is adult-onset MG with thymoma with titin and ryanodine receptor antibodies.[3] The relative prevalence of subtypes by antibodies is: MG with AChR antibodies 80%, MG with MuSK antibodies 4%, MG with LRP4 antibodies 2% and seronegative myasthenia.[1]

In this issue of Annals of India Academy of Neurology, Samal and colleagues compared the demographic and clinical characteristics, treatment response, and outcome of MG with MuSK antibodies, MG with AChR antibodies and seronegative MG.[4] They did not find any difference among all the three subtypes in all the parameters studied including long-term prognosis and quality of life. The authors concluded that clinical features and response to therapy in addition to antibody status must be considered before planning a therapy. These observations are at variance from the published studies. The major limitations of the study are retrospective nature of the study, small sample size in the MuSK positive and seronegative groups and different treatment protocols.

There are distinct differences between late-onset MG with AChR antibodies and MG with MuSK antibodies. MuSK antibodies are mainly IgG4, unlike the IgG1 and IgG3 anti-AChR antibodies, and are not complement activating.[5] MG with MuSK antibodies is seen predominantly in females, commonly has atypical clinical features such as the selective facial, bulbar, neck, and respiratory muscle weakness and marked muscle atrophy, occasionally with relative sparing of ocular muscles.[67] Respiratory crises are more common. Weakness can involve muscles that are not usually symptomatic in MG such as paraspinal and upper oesophageal muscles.[8] Anticholinesterase agents are less effective and induce frequent side effects.[9] Thymus histology is usually normal.[9] MG with MuSK antibodies has lower response with immunosuppressive treatment, and rituximab has a favourable response.[1] Thymectomy may not be associated with clinical improvement in MG with MuSK antibodies.[1011]

Accumulating evidence suggests that clinical MG subtypes might respond differently to treatments. However, treatment is far from antibody specific. The future research approach should be towards an individually adapted treatment based on biomarker (autoantibody) assessment and monitoring.[1]

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