How Should We Manage False-Positive Myasthenia Gravis Antibody Studies?

By Michael Rubin, MD

Professor of Clinical Neurology, Weill Cornell Medical College

SYNOPSIS: False-positive autoantibody tests for myasthenia gravis occur in a small number of patients who undergo broad screening for autoimmune disorders affecting the peripheral and central nervous system. Careful investigation of clinical and electrophysiological features of each patient will determine the validity of these tests.

SOURCE: Sun F, Tavella-Burka S, Li J, Li Y. Positive acetylcholine receptor antibody in nonmyasthenic patients. Muscle Nerve 2022;65:508-512.

After single-fiber electromyography, serologic tests using radioimmunoprecipitation assays for autoantibodies are the most reliable laboratory test to confirm a diagnosis of myasthenia gravis (MG) with acetylcholine receptor antibodies (AChR-Ab) present in 80% to 90% of generalized MG, and 40% to 55% of ocular MG. Studies from the 1970s and 1980s indicate that AChR-binding Ab are virtually never seen in healthy persons and AChR-blocking Ab have no significant false-positives, whereas false-positive modulating AChR-Ab may be problematic. Paraneoplastic autoantibody profiles, currently performed for a variety of circumstances, offer a fresh look at the incidence of unexpected AChR-Ab positivity in nonmyasthenic patients.

Between Jan. 1, 2010, and Dec. 31, 2018, all patients who had paraneoplastic autoantibody profile studies performed at the Cleveland Clinic, Cleveland, OH, were included for study. Patients positive for AChR-binding Ab were identified; underwent retrospective chart review encompassing age, gender, initial clinical presentation, laboratory testing, electrodiagnostic studies, final diagnosis, and follow-up; and were divided into those with and without suspected MG. Statistical analysis comprised Wilcox testing, and chi-square or Fisher exact testing, with P < 0.05 considered statistically significant. Among 10,855 patients who underwent paraneoplastic autoantibody studies during the study period, 224 (2.1%) were positive for AChR-binding Ab, 58 with a known history of MG and 166 without a known history of MG, the latter group comprising 30 patients with newly diagnosed MG, 125 without MG, and 11 with incomplete workup. Compared to nonmyasthenic patients, MG patients were more likely to have raised a clinical suspicion of MG on presentation, possess higher AChR-binding antibody titers, and have higher frequency of AChR-modulating AChR-Ab. AChR-binding Ab > 0.5 nmol/L, with modulating Ab > 20%, was diagnostic of MG in the appropriate clinical setting.

Among the nonmyasthenic group, both peripheral nervous system (PNS) and central nervous system (CNS) disorders were diagnosed. PNS disorders included chronic inflammatory demyelinating neuropathy, large or small fiber neuropathy, dysautonomia, fibromyalgia, myopathy, and amyotrophic lateral sclerosis. CNS disorders encompassed dementia, myelitis, epilepsy, stroke, multiple sclerosis, stiff-person syndrome, and CNS encephalitis or vasculitis. Non-neurologic disorders that were diagnosed included hypothyroidism, Sjögren’s syndrome, and thymoma. AChR-binding antibodies may be found in nonmyasthenic patients, but analysis of clinical findings and AChR-binding and -modulating Ab results will permit confirmation of a diagnosis of MG. Having one confirmed autoimmune disease increases the probability of having other autoimmune diseases, and we must carefully investigate each patient.

Commentary

Might the autoantibody profile in MG patients predict those who may be refractory to therapy? Among 113 MG patients followed at the Neuromuscular Center, Department of Neurology, University of Patras, Patras, Greece, 15 patients (13.3%) were refractory to treatment, based on Rath criteria. Rath criteria comprise any of the following: Myasthenia Gravis Foundation of America (MGFA) class III for at least 12 months, MGFA less than class III but with at least two severe relapses requiring intravenous immunoglobulin or plasma exchange, or MGFA less than class III without exacerbations but immunosuppressant-dependent. Six refractory patients were double seronegative, AChR-Ab or muscle-specific tyrosine kinase (MuSK) antibodies (P = 0.031). MuSK antibodies were not found in any refractory patient, who more frequently had earlier onset and thymic pathology. Refractory patients may require individualized, targeted treatment.¹

Reference

1. Veltsista D, Kefalopoulou Z, Tzartos J, Chroni E. Autoantibody profile in myasthenia gravis patients with a refractory phase. Muscle Nerve 2022;65:607-611.