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Background: Myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR). NonAChR muscle autoantibodies are present in many MG serum samples, mainly from patients with thymoma or lateonset MG. The exact relationship between MG severity and several non-AChR muscle antibodies is unknown. Objective: To study the correlation between the severity of MG and the concentration of antibodies against striated muscle tissue sections, titin, citric acid antigen, ryanodine receptor, and AChR. Setting: The severity of MG was graded in 146 consecutive patients with MG, and their serum samples were tested for the presence of autoantibodies. Ten patients who were titin antibody positive were observed in longitudinal follow-up. Results: No significant difference was found in MG severity between late-onset and thymoma MG. Titin, citric acid antigen, and ryanodine receptor antibodies occurred significantly more often among patients with severe MG than among patients with less severe disease. Changes in MG severity correlated with changes in titin antibody titer in the individual patient. Titin antibodies showed a better longitudinal correlation with disease severity than the AChR antibodies. Conclusions: Non-AChR muscle autoantibodies occurred more frequently in severe MG regardless of MG subgroup. Thymoma per se does not generate a more severe MG. It may well be the presence of a humoral immune response to non-AChR muscle antigens such as titin, citric acid antigen, and ryanodine receptor that leads to a severe disease, not the presence of thymoma or a late age of onset. These antibodies can serve as important prognostic markers in MG regardless of the presence of thymoma. Arch Neurol. 2000;57:1596-1600

Background Tumor necrosis factor (TNF) α and TNF-β are proinflammatory cytokines thought to be involved in the pathogenesis of myasthenia gravis (MG). Objective To examine whether TNF polymorphisms are associated with MG, MG subgroups, and the presence of titin and ryanodine-receptor antibodies. Patients and Methods We did genotyping on 30 patients with MG and 92 healthy blood donors for 2 biallelic TNFA polymorphisms (G to A at positions −238 and −308) and 1 TNFB polymorphism ( Nco I digestive site) using methods based on the polymerase chain reaction. Results Patients with thymoma were typically homozygous for both the TNFA*T1 and the TNFB*2 alleles, but patients having an early onset of MG without thymoma were carriers of the TNFA*T2 and TNFB*1 alleles. Patients without thymoma who had the titin antibody had the same high frequency of TNFA*T1 and TNFB*2 as patients with thymoma, whereas patients without the titin antibody carried the same allele, TNFA*T2 and TNFB*1 , regardless of age and thymic disease. No association was found with acetylcholine-receptor levels or disease severity for any of the TNFA or TNFB polymorphisms. Conclusion Patients having MG, including those with thymoma, who have the titin antibody are most often homozygous for the TNFA*T1 and TNFB*2 alleles, whereas the presence of the TNFA*T2 and TNFB*1 alleles correlates with early-onset MG and the absence of titin antibodies.

Myasthenia gravis is an autoimmune disease caused, in most cases, by antibodies attaching to the acetylcholine receptor. Some myasthenia gravis patients have antibodies that bind in a cross-striational pattern to skeletal and heart muscle tissue sections (striational antibodies). These antibodies react with epitopes on the muscle proteins titin and ryanodine receptor, are found mainly in sera of patients with thymoma and late-onset myasthenia gravis, and may correlate with myasthenia gravis severity. Their presence may predict an unsatisfactory outcome after thymectomy. The detection of titin and ryanodine receptor antibodies provides more specific clinical information than the immunofluorescent demonstration of striational antibodies.