Myasthenic Antibodies and Disease Phenotype

Abstract & Commentary

By Michael Rubin, MD, Professor of Clinical Neurology, Weill Cornell Medical Center

Dr. Rubin reports no financial relationships relevant to this field of study.

Synopsis: There are clinical differences in patients with myasthenia gravis, based on which antibody type is present in the serum — acetylcholine receptor antibodies, muscle-specific kinase antibodies, clustered-receptor antibodies, or seronegative patients.

Source: Oh SJ, et al. Different characteristic phenotypes according to antibody in myasthenia gravis. J Clin Neuromusc Dis 2012;14:57-65.

Do the presence or absence of acetylcholine receptor (AchR)-binding antibodies (Abs) and muscle-specific kinase (MuSK) Abs correlate with disease phenotype in myasthenia gravis (MG)? To address this question, retrospective review was undertaken of the clinical, laboratory, and electrodiagnostic data of 235 MG patients seen between May 1, 2003, and January 1, 2008, at the University of Alabama Neuromuscular Disease Clinic, in Birmingham, Alabama. Patients were divided into those positive for AchR Abs, those positive for MuSK Abs, and those seronegative for both AchR and MuSK Abs. Diagnosis of MG was based on the presence of fluctuating muscle weakness, in conjunction with either positive AChR binding Abs, positive MuSK Abs, abnormal decrement on repetitive nerve stimulation testing performed on four muscles (abductor digiti minimi, flexor carpi ulnaris, orbicularis oris, and trapezius), abnormal jitter on single-fiber electromyography of the extensor digitorum communis (EDC) muscle, or frontalis muscle if the former was normal. Ocular MG was diagnosed when this was the solitary finding and persisted for 2 or more years, bulbar MG when respiratory or pharyngeal muscle involvement was evident, and severity of disease was determined using the MG Foundation of America classification. Statistical analyses included the unpaired t test and Pearson X2 test, with P values < 0.05 considered statistically significant.

AChR Ab-positive MG peaked at 20-29 years of age, mostly in women, and again at 60-69 years of age, mostly in men, whereas MuSK Ab-positive MG plateaued over 3 decades, from 10-39 years of age, with a mean age of onset of 32.6 years. Seronegative MG plateaued over 4 decades, from 30-69 years of age. AChR Abs were positive in 68.5% (161 cases) and MuSK Abs in 6.4% (15 cases), the latter more commonly in African Americans (7 of 49, 14%) than whites (8 of 186, 4%). African Americans were also over-represented in the AChR Ab-negative generalized MG group, 50% vs 17%, whereas they were under-represented in AChR Ab-positive ocular MG, (25%, vs 68.4% white patients). Hence, African Americans are more commonly MuSK positive, as are women compared to men, whereas whites are more commonly ocular with AChR Ab positivity. Purely ocular MG, which comprised 11.5% of all MG, was always MuSK-negative, and comprised 20.3% of those seronegative. Of those presenting with ocular MG, 54% remained so at 2 years, and those positive for AchR Abs were more likely to generalize. Seronegative MG tended to have a milder form at presentation, and rarely experienced respiratory difficulty or myasthenic crisis. Those with MuSK Abs tended to be predominantly faciobulbar, and never harbored a thymoma, which was found predominantly in AchR Ab-positive MG. Response to edrophonium, anticholinesterase, and intravenous immunoglobulin was poor in MuSK-positive MG, but long-term outcome was similar in all three groups.

Commentary

Among patients with generalized MG, 80-85% demonstrate antibodies directed against the acetylcholine receptor (AchR-Abs), 5-8% have antibodies against muscle-specific kinase, and 10% are said to be seronegative. Clustered AChR-Abs, initially termed low-affinity AchR-Abs, are present in approximately 60% of patients with seronegative generalized myasthenia, and are detected by immunofluorescence assay, based on binding of IgG1 to AChRs expressed in a cell line and clustered by rapsyn, the intracellular scaffolding protein.1 Among patients with seronegative ocular myasthenia, up to 50% appear to have clustered AChR-Abs which, when injected intraperitoneally into mice, can passively transfer disease and hence appear to be pathogenic, with mechanisms similar to those seen with typical AChRs.2 It appears that even seronegative myasthenia is, in the majority of cases, autoimmune in nature.

References

  1. Leite MI, et al. IgG1 antibodies to acetylcholine receptors in “seronegative” myasthenia gravis. Brain 2008;131(Pt 7):1940-1952.
  2. Jacob S, et al. Presence and pathogenic relevance of antibodies to clustered acetylcholine receptor in ocular and generalized myasthenia gravis. Arch Neurol 2012;69:994-1001.