Patients with myasthenia gravis (MG) who are triple seronegative for antibodies appear to have a milder course of the disease, but frequently have ocular manifestations of the autoimmune disorder, researchers said at the American Association of Neuromuscular & Electrodiagnostic Medicine annual meeting.
Jonathan Morena, DO, a neurology resident at the Ohio State University Wexner Medical Center in Columbus, retrospectively reviewed charts of 255 patients with myasthenia gravis, including 21 with triple negative pathology.
“Triple seronegative patients required significantly fewer immunosuppressive agents compared with patients who are acetylcholine receptor antibody-positive (p=0.0001), and they trended towards having a less frequent history of hospitalizations, myasthenic crises, and intubations compared to all antibody positive groups," Dr. Morena reported in his presentation.
The researchers reviewed the records at Ohio State University from 2009 to 2019. Triple seronegative MG was defined by a history and examination consistent with myasthenia gravis and positive single fiber electromyography, repetitive nerve stimulation or edrophonium testing, but negative serology for acetylcholine receptor antibody, anti-muscle-specific tyrosine kinase, and lipoprotein-related protein 4 antibodies.
They identified 210 patients who were acetylcholine receptor antibody-positive, nine patients who were muscle-specific tyrosine kinase-positive; six patients who exhibited lipoprotein-related protein 4 antibodies; nine patients had double seronegative MG, and 21 patients were triple seronegative patients.,
Dr. Moreno and his colleagues found that 33 percent of the patients who had triple seronegative myasthenia gravis had ocular disease, which was significantly higher compared with 13 percent of those who were acetylcholine receptor antibody-positive (p=0.0250). One triple and one double seronegative myasthenia gravis patient had thymic hyperplasia and improved after thymectomy. Eleven triple seronegative myasthenia gravis patients had negative genetic testing for congenital myasthenic syndrome.
“Although likely rare, investigation for thymic pathology should be a consideration even in seronegative myasthenia gravis, and thymectomy should be considered when there are thymic abnormalities on imaging," Dr. Morena said. “We did not find alternate diagnoses in seronegative myasthenia gravis patients. Thus ancillary testing should be considered in carefully selected patients for cost-effective care."
Commenting on the study, Robert Lisak, MD, FAAN, the Parker Webber Chair in Neurology, and professor of neurology, and professor of biochemistry, microbiology and immunology, at Wayne State University in Detroit, explained, “In myasthenia gravis, antibodies block, alter, or destroy the receptors for acetylcholine at the neuromuscular junction, which prevents the muscle from contracting. This is most often caused by antibodies to the acetylcholine receptor itself, but antibodies to other proteins, such as muscle-specific kinase protein, also can impair transmission at the neuromuscular junction.
“The findings of a recent multicenter study that a small percentage of those who are double seronegative have antibodies to lipoprotein-related protein 4 and seem not to differ from acetylcholine receptor antibody-positive patients, although still not completely worked out, is helpful, Dr. Lisak told Neurology Today At the Meetings. “The current study suggests triple negative patients have mild disease and often ocular, although 50 percent or so of ocular are acetylcholine receptor antibody-positive, so there is overlap."
“We should realize the triple negatives might have different antibodies among them, still to be discovered," he said.
“As of now," he said, “differences in response to some therapies are most notable between acetylcholine receptor antibody-positive patients and muscle-specific tyrosine kinase-positive patients. Therapies aimed at inhibiting complement activation wouldn't be expected to work in muscle-specific tyrosine kinase-positive myasthenia gravis since the antibodies are predominately IgG4 and don't fix or activate complement.
“Muscle-specific tyrosine kinase-positive patients often fail to respond to acetylcholine esterase inhibitors and sometime worsen. IVIG seems more effective in were acetylcholine receptor antibody-positive patients than muscle-specific tyrosine kinase-positive myasthenia gravis and rituximab is more effective in muscle-specific tyrosine kinase-positive patients."
Dr. Morena did not disclose any relationships with industry.
Dr. Lisak disclosed relationships with Argenx, Guidepoint, Clearview, Clarivate, and Guidepointe.
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AANEM Abstract 1: Morena J, Jiang B, Freimer M, et al. Characteristics of triple seronegative myasthenia gravis. A single center experience.