TY - JOUR
T1 - Improving accuracy of myasthenia gravis autoantibody testing by reflex algorithm
AU - Shelly, Shahar
AU - Paul, Pritikanta
AU - Bi, Hongyan
AU - Dubey, Divyanshu
AU - Milone, Margherita
AU - Sorenson, Eric J.
AU - Crum, Brian A.
AU - Laughlin, Ruple S.
AU - Liewluck, Teerin
AU - Mandrekar, Jay
AU - Pittock, Sean J.
AU - Zekeridou, Anastasia
AU - McKeon, Andrew
AU - Harper, Michael C.
AU - Mills, John R.
AU - Klein, Christopher J.
N1 - Funding Information:
S. Shelly, P. Paul, and H. Bi report no disclosures. D. Dubey reports research support from Center of Multiple Sclerosis and Autoimmune Neurology and Grifols Pharmaceuticals and has consulted for UCB Pharmaceuticals. All compensation for consulting activities is paid directly to Mayo Clinic. M. Milone reports research funding from a Mayo Clinic benefactor (John Lawyer) and honorarium to serve as associate editor for Neurology Genetics. E.J. Sorenson, B.A. Crum, R.S. Laughlin, T. Liewluck, and J. Mandrekar report no disclosures. S.J. Pittock reports grants, personal fees, and nonfinancial support from Alexion Pharmaceuticals, Inc.; grants from Grifols and Autoimmune Encephalitis Alliance; grants, personal fees, nonfinancial support, and other from MedImmune, Inc.; other support from Astellas; and personal fees from UCB. S.J. Pittock has patent 8,889,102 (application 12-678350): Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia: issued; patent 9,891,219B2 (application 12-573942): Methods for Treating Neuromyelitis Optica (NMO) by Administration of Eculizumab to an individual that is Aquaporin-4 (AQP4)-IgG Autoantibody positive: issued; a patent on GFAP-IgG pending, a patent on Septin-5-IgG pending, a patent on MAP1B-IgG pending, and a patent on KLHL11 pending. A. Zekeridou reports a patent pending for PDE10A-IgG as a biomarker of neurological autoimmunity. A. McKeon reports he has a patent pending for MAP1B as a marker of neurological autoimmunity and paraneoplastic disorders; consulted for Grifols, Medimmune, and Euroimmun without personal compensation; and received research support from Medimmune and Euroimmun. M.C. Harper and J.R. Mills report no disclosures. C.J. Klein reports he is on the therapeutic CMTA advisory board; has received teaching honorarium from Ackea Pharmaceuticals for lectures on hereditary TTR amyloidosis and Fabry disease; is a paid consultant to Pfizer regarding tafamidis but has received no personal compensation; and has participated in clinical trials for inotersen and patisiran but received no personal compensation for his participation. Go to Neurology.org/N for full disclosures.
Funding Information:
This work was supported by the Mayo Clinic Foundation and the Department of Laboratory Medicine and Pathology, The Center of Individualized Medicine, and The Center for MS and Autoimmune Neurology.
Publisher Copyright:
© American Academy of Neurology.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - ObjectiveTo improve myasthenia gravis (MG) autoantibody testing.MethodsMG serologic 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 (α3), collapsin response mediating protein-5, and voltage-gated potassium channel complex autoantibodies.ResultsOf 433 samples tested, 133 (31%) met clinical-EDX criteria for MG. Best sensitivity (90%) occurred at AChR-Bi >0.02 nmol/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), but sensitivity dropped (85%). Specificity improved (95%) by testing AChR-Mo when AChR-Bi are positive, resulting in 45% reduction of false-positives (31-17), maintaining AChR-Bi 90% sensitivity. Cutoff values recommended by area under the curve analysis did not outperform this approach. AChR-Bi and AChR-Mo values were significantly higher in true-positives. CT evaluations in 121 MG samples 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.ConclusionAccuracy of MG serologic 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.
AB - ObjectiveTo improve myasthenia gravis (MG) autoantibody testing.MethodsMG serologic 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 (α3), collapsin response mediating protein-5, and voltage-gated potassium channel complex autoantibodies.ResultsOf 433 samples tested, 133 (31%) met clinical-EDX criteria for MG. Best sensitivity (90%) occurred at AChR-Bi >0.02 nmol/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), but sensitivity dropped (85%). Specificity improved (95%) by testing AChR-Mo when AChR-Bi are positive, resulting in 45% reduction of false-positives (31-17), maintaining AChR-Bi 90% sensitivity. Cutoff values recommended by area under the curve analysis did not outperform this approach. AChR-Bi and AChR-Mo values were significantly higher in true-positives. CT evaluations in 121 MG samples 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.ConclusionAccuracy of MG serologic 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.
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U2 - 10.1212/WNL.0000000000010910
DO - 10.1212/WNL.0000000000010910
M3 - Article
C2 - 32938782
AN - SCOPUS:85097003511
SN - 0028-3878
VL - 95
SP - E3002-E3011
JO - Neurology
JF - Neurology
IS - 22
ER -