Indications for Testing
Testing for MG should be considered for patients presenting with new-onset muscle weakness, particularly when this weakness is accompanied by ptosis or diplopia.
MG is a condition that fulfills all major criteria for a disorder mediated by autoantibodies against AChR. After establishing a clinical diagnosis of MG based on characteristic presentation (eg, ocular and bulbar muscle weakness), AChR serum antibody status should be determined. If AChR testing is negative, MuSK testing is advised. Serologic testing should be performed before beginning therapy to avoid false-negative results.
Acetylcholine Receptor Antibodies
Circulating AChR antibodies are present in ~85% of patients with MG. AChR antibodies are classified into three types: binding, blocking, and modulating. The AChR binding assay, the most clinically useful and frequently utilized test, is highly specific for MG. In general, a positive AChR binding test in a patient with a compatible clinical presentation is diagnostic for MG. AChR blocking antibodies are usually found in association with binding antibodies and have a higher prevalence in generalized MG than in ocular MG. Tests of modulating AChR antibodies are less clinically useful, but may be considered in the event of a negative binding test and high suspicion of MG. AChR testing sensitivity varies depending on the type of MG; in generalized MG, about 85% of patients have AChR antibodies, whereas these antibodies are present in roughly 40% of patients with ocular MG.
A large number of individuals with AChR antibody-positive MG have thymic abnormalities, including thymic hyperplasia (most common) and thymic tumors. The absence of AChR antibodies does not rule out the diagnosis of MG. False-negative results may occur in the setting of immunosuppression or in patients who have been administered antivenom therapy. There is no clear correlation between AChR antibody serum titers and MG disease severity, and the usefulness of following AChR antibody levels to monitor treatment response is unclear.
Muscle-Specific Tyrosine Kinase Antibodies
In cases of generalized MG, approximately half of individuals without AChR antibodies have MuSK antibodies. Therefore, MuSK antibody measurement is recommended if a patient is AChR negative. MuSK antibody-seropositive individuals with MG are more likely than those without these antibodies to have atypical clinical features (eg, selective muscle weakness that often spares the ocular muscles), onset at a younger age, and no thymic pathology; this presentation is more likely to occur in females. As with AChR antibodies, the absence of MuSK antibodies does not rule out the diagnosis of MG.
Decreasing antibody levels may be associated with therapeutic response, suggesting that MuSK antibody levels might serve as a valuable biomarker to follow. However, more studies are needed in this area.
Other Myasthenia Gravis-Associated Antibodies
Other antibodies have been detected in patients with MG, including lipoprotein-related protein 4 (LRP4) and striated muscle antibodies. The LRP4 protein activates MuSK activity and promotes the clustering of AChRs and their stabilization at the neuromuscular junction. Recent studies have found anti-LRP4 antibodies in 2% and 50% of patients with double-seronegative MG.
Striational antibodies are not specific for MG and may be seen in individuals with other autoimmune diseases and in cases of thymoma without MG. Striated muscle antibodies, when detected in the presence of AChR, are associated with late-onset MG; as a marker for thymoma, striational antibodies are most useful in AChR antibody-seropositive patients in early-stage MG. Titin is one of the major antigenic targets of striational antibodies, and antititin antibodies may be useful when first-line diagnostic tests are negative, or when screening for the presence of thymoma in patients with MG. Titin antibodies appear to correlate with disease severity and have been postulated for use as a marker to assess disease prognosis. However, more research is required in this area before these antibodies are recommended for use as disease biomarkers.