Improving accuracy of myasthenia gravis autoantibody testing by reflex algorithm

Abstract

Objective:To improve myasthenia gravis (MG) autoantibody testing.Methods:MG serological tests with confirmatory or refuting clinical-electrodiagnostic (EDX) testing and cancer evaluations were reviewed over 4-years (2012-2015). All patients had acetylcholine-receptor-binding (AChR-Bi), modulating (AChR-Mo) and striational (STR) autoantibody testing, and negatives reflexed to muscle-specific-kinase (MuSK). Thymoma and cancer occurrences were correlated with STR and reflexed glutamic-acid-decarboxylase-65 (GAD65), ganglionic-acetylcholine-receptor (alpha-3), collapsin-response-mediating-protein-5 (CRMP5), and voltage-gated-potassium-channel-complex (VGKC) autoantibodies.Results:Of 433 tested, 133 (31%) met clinical-EDX criteria for MG. Best sensitivity (90%) occurred at AChR-Bi>0.02nmol/L, leaving 14 negative (6-ocular-MG, 7-generalized-MG, 1-MuSK-MG) with specificity 90% (31 false-positives). Using AChR-Mo antibodies (>20% loss) specificity was better (92%, 24 false-positives), however sensitivity dropped (85%). Specificity improved (95%) by testing AChR-Mo when AChR-Bi are positives, resulting in 45% reduction of false-positives (31 to 17), maintaining AChR-Bi 90% sensitivity. Cut-off values recommended by area-under-curve analysis did not outperform this approach. AChR-Bi and AChR-Mo values were significantly higher in true-positives. Computed tomography (CT) evaluations in 121 MG revealed 16 thymomas. Historical or subsequent cancers occurred in 22. STR and reflexed autoantibodies were not more common in MG with thymoma or other cancers. Full-body CT (n=34) was performed in those with STR and reflex autoantibody positivity, but without additional cancers found.Conclusion:Accuracy of MG serological testing is improved by reflexing AChR-Bi positive cases to AChR-Mo. STR and other reflexed cancer evaluation autoantibodies did not provide value beyond standard CT-chest imaging at the time of MG diagnosis. Diagnostic certainty is informed by AChR-Bi and AChR-Mo with higher values increasing specificity.

Positive acetylcholine receptor antibody in nonmyasthenic patients

“…These results are consistent with the recent publication of an improved accuracy of MG testing with increased specificity when both AChR binding and modulating antibody were positive. 6 However, AChR binding and modulating Abs of low concentration were also observed in MG, and, vice versa, highconcentration AChR Abs were infrequently seen in nonmyasthenic patients. These observations highlight foremost that an appropriate clinical presentation is equally important in the evaluation of patients for an MG diagnosis, and further emphasize that serologic results must be interpreted in the context of the history, physical examination, electrodiagnostic findings, and subsequent treatment response.…”

Consensus disease definitions for neurologic immune-related adverse events of immune checkpoint inhibitors

“…AChR binding with modulating antibodies has the highest specificity. 55 Rate of ACHR ab positivity in irMG has not been definitively established. Anti-straited muscle antibodies are frequently present in irMyopathy and/or irMG but are not diagnostic for irMG.…”

Diagnosis of Myasthenia Gravis

“…The observation that some MG patients have increased titer years before the clinical onset (as retrospectively found on preserved sera) may explain some of the apparent false-positive results [13].The RIPA for binding Ab is abnormal in up to 85% of adult patients with generalized MG, but only about 50% of patients with ocular MG [2,5,6,14]. Detection of modulating and blocking AChR-Ab through RIPA is commercially available but adds little diagnostic value [5], although others recently emphasized their significance [15]. In selected seronegative cases, the test may be repeated within 6-12 months, as delayed seroconversion is well-described, although rare [16].…”

“…The potential liability issues have limited the use of the study. It should be done by an expert [15] in a setting allowing to react to such effects, monitoring the heart rate and blood pressure [10,15]. A total of 0.6 mg atropine in a separate syringe should be available.…”

“…The patient should be referred for screening of the thymus and thyroid function tests to exclude comorbidities. However, authoritative sources recently report specificities of 90-95%, with dozens of false positives in large series of patients tested for MG [15]. Such results may relate to the use of antibody testing as a screening rather than as a confirmatory test.…”