Association of MOG-IgG Serostatus with Relapse after Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG-Associated Disorders

A. Sebastian López-Chiriboga, Masoud Majed, James Fryer, Divyanshu Dubey, Andrew McKeon, Eoin Flanagan, Jiraporn Jitprapaikulsan, Naga Kothapalli, Jan-Mendelt Tillema, John Chen, Brian G Weinshenker, Dean Marko Wingerchuk, Jessica Sagen, Avi Gadoth, Vanda A Lennon, B Mark Keegan, Claudia F Lucchinetti, Sean J Pittock

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Abstract

Importance: Recent studies have reported a higher relapse rate following an initial inflammatory demyelinating disorder in pediatric patients with persistent seropositivity of antibodies targeting myelin oligodendrocyte glycoprotein (MOG-IgG1). To date, the clinical implications of longitudinal MOG-IgG1 seropositivity using live cell assays with IgG1 secondary antibodies in adults after acute disseminated encephalomyelitis (ADEM) are unknown. Objective: To determine whether MOG-IgG1 serostatus (transient vs persistent) and titer change over time provide clinical utility in predicting the likelihood of relapse after ADEM. Design, Setting, and Participants: This cohort study identified patients with an initial diagnosis of ADEM evaluated at a single referral center between January 1, 1990, and October 1, 2017. Fifty-one patients were included, including 31 children and 20 adults. Longitudinal serologic testing was performed detecting autoantibodies targeting aquaporin 4 (AQP4-IgG) and MOG-IgG1 with clinically validated fluorescence-activated cell sorting assays. Patients were divided into 3 cohorts: persistent seropositivity, transient seropositivity, and seronegativity. Main Outcomes and Measures: Clinical demographic characteristics, longitudinal AQP4-IgG and MOG-IgG1 serostatus, titers, relapses, use of immunotherapy, and Expanded Disability Status Scale score at follow-up. Results: Of 51 patients presenting with an initial diagnosis of ADEM, 20 (39%) were adult, 24 (47%) were female, and ages ranged from 12 months to 57 years. Seventeen patients fulfilled criteria for persistent seropositivity; of those, 8 of 9 children (89%) and 7 of 8 adults (88%) had at least 1 relapse after median (range) follow-up periods of 75 (15-236) months and 39 (9-161) months, respectively. Eight patients (16%), including 4 adults, fulfilled criteria for transient seropositivity; of those, no children and 1 of 4 adults (25%) relapsed after median (range) follow-up periods of 32 (24-114) months and 16 (13-27) months, respectively. Of 24 patients with AQP4-IgG and MOG-IgG seronegativity, 6 of 17 children (35%) and 2 of 7 adults (29%) had at least 1 relapse after median (range) follow-up periods of 36 (3-203) months and 34 (15-217) months, respectively. There were only 2 patients, including 1 adult, with AQP4-IgG seropositivity, and both relapsed. The hazard ratio for relapses in those with persistent MOG-IgG1 positivity compared with AQP4-IgG and MOG-IgG1 seronegativity was 3.1 (95% CI, 1.1-8.9; P =.04) in children and 5.5 (95% CI, 1.4-22.5; P =.02) in adults. Immunotherapy was used in 5 of 9 children (56%) and 6 of 8 adults (75%) with persistent seropositivity and in 3 of 17 children (18%) and 1 of 7 adults (14%) with AQP4-IgG and MOG-IgG seronegativity. Conclusions and Relevance: Relapse occurred in 15 of 17 patients (88%) with persistent MOG-IgG1 seropositivity after ADEM; only 1 patient with transient seropositivity experienced relapse. Our data extend the clinical utility of MOG-IgG1 serological testing to adult patients and highlights that longitudinal serologic evaluation of MOG-IgG1 could help predict disease course and consideration of immunotherapy.

Original languageEnglish (US)
Pages (from-to)1355-1363
Number of pages9
JournalJAMA Neurology
Volume75
Issue number11
DOIs
StatePublished - Nov 1 2018

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Acute Disseminated Encephalomyelitis
Immunoglobulin G
Recurrence
Immunotherapy
Myelin-Oligodendrocyte Glycoprotein
Aquaporin 4

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

@article{7de3988c56fb4c72b8be4852be2acedb,
title = "Association of MOG-IgG Serostatus with Relapse after Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG-Associated Disorders",
abstract = "Importance: Recent studies have reported a higher relapse rate following an initial inflammatory demyelinating disorder in pediatric patients with persistent seropositivity of antibodies targeting myelin oligodendrocyte glycoprotein (MOG-IgG1). To date, the clinical implications of longitudinal MOG-IgG1 seropositivity using live cell assays with IgG1 secondary antibodies in adults after acute disseminated encephalomyelitis (ADEM) are unknown. Objective: To determine whether MOG-IgG1 serostatus (transient vs persistent) and titer change over time provide clinical utility in predicting the likelihood of relapse after ADEM. Design, Setting, and Participants: This cohort study identified patients with an initial diagnosis of ADEM evaluated at a single referral center between January 1, 1990, and October 1, 2017. Fifty-one patients were included, including 31 children and 20 adults. Longitudinal serologic testing was performed detecting autoantibodies targeting aquaporin 4 (AQP4-IgG) and MOG-IgG1 with clinically validated fluorescence-activated cell sorting assays. Patients were divided into 3 cohorts: persistent seropositivity, transient seropositivity, and seronegativity. Main Outcomes and Measures: Clinical demographic characteristics, longitudinal AQP4-IgG and MOG-IgG1 serostatus, titers, relapses, use of immunotherapy, and Expanded Disability Status Scale score at follow-up. Results: Of 51 patients presenting with an initial diagnosis of ADEM, 20 (39{\%}) were adult, 24 (47{\%}) were female, and ages ranged from 12 months to 57 years. Seventeen patients fulfilled criteria for persistent seropositivity; of those, 8 of 9 children (89{\%}) and 7 of 8 adults (88{\%}) had at least 1 relapse after median (range) follow-up periods of 75 (15-236) months and 39 (9-161) months, respectively. Eight patients (16{\%}), including 4 adults, fulfilled criteria for transient seropositivity; of those, no children and 1 of 4 adults (25{\%}) relapsed after median (range) follow-up periods of 32 (24-114) months and 16 (13-27) months, respectively. Of 24 patients with AQP4-IgG and MOG-IgG seronegativity, 6 of 17 children (35{\%}) and 2 of 7 adults (29{\%}) had at least 1 relapse after median (range) follow-up periods of 36 (3-203) months and 34 (15-217) months, respectively. There were only 2 patients, including 1 adult, with AQP4-IgG seropositivity, and both relapsed. The hazard ratio for relapses in those with persistent MOG-IgG1 positivity compared with AQP4-IgG and MOG-IgG1 seronegativity was 3.1 (95{\%} CI, 1.1-8.9; P =.04) in children and 5.5 (95{\%} CI, 1.4-22.5; P =.02) in adults. Immunotherapy was used in 5 of 9 children (56{\%}) and 6 of 8 adults (75{\%}) with persistent seropositivity and in 3 of 17 children (18{\%}) and 1 of 7 adults (14{\%}) with AQP4-IgG and MOG-IgG seronegativity. Conclusions and Relevance: Relapse occurred in 15 of 17 patients (88{\%}) with persistent MOG-IgG1 seropositivity after ADEM; only 1 patient with transient seropositivity experienced relapse. Our data extend the clinical utility of MOG-IgG1 serological testing to adult patients and highlights that longitudinal serologic evaluation of MOG-IgG1 could help predict disease course and consideration of immunotherapy.",
author = "L{\'o}pez-Chiriboga, {A. Sebastian} and Masoud Majed and James Fryer and Divyanshu Dubey and Andrew McKeon and Eoin Flanagan and Jiraporn Jitprapaikulsan and Naga Kothapalli and Jan-Mendelt Tillema and John Chen and Weinshenker, {Brian G} and Wingerchuk, {Dean Marko} and Jessica Sagen and Avi Gadoth and Lennon, {Vanda A} and Keegan, {B Mark} and Lucchinetti, {Claudia F} and Pittock, {Sean J}",
year = "2018",
month = "11",
day = "1",
doi = "10.1001/jamaneurol.2018.1814",
language = "English (US)",
volume = "75",
pages = "1355--1363",
journal = "JAMA Neurology",
issn = "2168-6149",
publisher = "American Medical Association",
number = "11",

}

TY - JOUR

T1 - Association of MOG-IgG Serostatus with Relapse after Acute Disseminated Encephalomyelitis and Proposed Diagnostic Criteria for MOG-IgG-Associated Disorders

AU - López-Chiriboga, A. Sebastian

AU - Majed, Masoud

AU - Fryer, James

AU - Dubey, Divyanshu

AU - McKeon, Andrew

AU - Flanagan, Eoin

AU - Jitprapaikulsan, Jiraporn

AU - Kothapalli, Naga

AU - Tillema, Jan-Mendelt

AU - Chen, John

AU - Weinshenker, Brian G

AU - Wingerchuk, Dean Marko

AU - Sagen, Jessica

AU - Gadoth, Avi

AU - Lennon, Vanda A

AU - Keegan, B Mark

AU - Lucchinetti, Claudia F

AU - Pittock, Sean J

PY - 2018/11/1

Y1 - 2018/11/1

N2 - Importance: Recent studies have reported a higher relapse rate following an initial inflammatory demyelinating disorder in pediatric patients with persistent seropositivity of antibodies targeting myelin oligodendrocyte glycoprotein (MOG-IgG1). To date, the clinical implications of longitudinal MOG-IgG1 seropositivity using live cell assays with IgG1 secondary antibodies in adults after acute disseminated encephalomyelitis (ADEM) are unknown. Objective: To determine whether MOG-IgG1 serostatus (transient vs persistent) and titer change over time provide clinical utility in predicting the likelihood of relapse after ADEM. Design, Setting, and Participants: This cohort study identified patients with an initial diagnosis of ADEM evaluated at a single referral center between January 1, 1990, and October 1, 2017. Fifty-one patients were included, including 31 children and 20 adults. Longitudinal serologic testing was performed detecting autoantibodies targeting aquaporin 4 (AQP4-IgG) and MOG-IgG1 with clinically validated fluorescence-activated cell sorting assays. Patients were divided into 3 cohorts: persistent seropositivity, transient seropositivity, and seronegativity. Main Outcomes and Measures: Clinical demographic characteristics, longitudinal AQP4-IgG and MOG-IgG1 serostatus, titers, relapses, use of immunotherapy, and Expanded Disability Status Scale score at follow-up. Results: Of 51 patients presenting with an initial diagnosis of ADEM, 20 (39%) were adult, 24 (47%) were female, and ages ranged from 12 months to 57 years. Seventeen patients fulfilled criteria for persistent seropositivity; of those, 8 of 9 children (89%) and 7 of 8 adults (88%) had at least 1 relapse after median (range) follow-up periods of 75 (15-236) months and 39 (9-161) months, respectively. Eight patients (16%), including 4 adults, fulfilled criteria for transient seropositivity; of those, no children and 1 of 4 adults (25%) relapsed after median (range) follow-up periods of 32 (24-114) months and 16 (13-27) months, respectively. Of 24 patients with AQP4-IgG and MOG-IgG seronegativity, 6 of 17 children (35%) and 2 of 7 adults (29%) had at least 1 relapse after median (range) follow-up periods of 36 (3-203) months and 34 (15-217) months, respectively. There were only 2 patients, including 1 adult, with AQP4-IgG seropositivity, and both relapsed. The hazard ratio for relapses in those with persistent MOG-IgG1 positivity compared with AQP4-IgG and MOG-IgG1 seronegativity was 3.1 (95% CI, 1.1-8.9; P =.04) in children and 5.5 (95% CI, 1.4-22.5; P =.02) in adults. Immunotherapy was used in 5 of 9 children (56%) and 6 of 8 adults (75%) with persistent seropositivity and in 3 of 17 children (18%) and 1 of 7 adults (14%) with AQP4-IgG and MOG-IgG seronegativity. Conclusions and Relevance: Relapse occurred in 15 of 17 patients (88%) with persistent MOG-IgG1 seropositivity after ADEM; only 1 patient with transient seropositivity experienced relapse. Our data extend the clinical utility of MOG-IgG1 serological testing to adult patients and highlights that longitudinal serologic evaluation of MOG-IgG1 could help predict disease course and consideration of immunotherapy.

AB - Importance: Recent studies have reported a higher relapse rate following an initial inflammatory demyelinating disorder in pediatric patients with persistent seropositivity of antibodies targeting myelin oligodendrocyte glycoprotein (MOG-IgG1). To date, the clinical implications of longitudinal MOG-IgG1 seropositivity using live cell assays with IgG1 secondary antibodies in adults after acute disseminated encephalomyelitis (ADEM) are unknown. Objective: To determine whether MOG-IgG1 serostatus (transient vs persistent) and titer change over time provide clinical utility in predicting the likelihood of relapse after ADEM. Design, Setting, and Participants: This cohort study identified patients with an initial diagnosis of ADEM evaluated at a single referral center between January 1, 1990, and October 1, 2017. Fifty-one patients were included, including 31 children and 20 adults. Longitudinal serologic testing was performed detecting autoantibodies targeting aquaporin 4 (AQP4-IgG) and MOG-IgG1 with clinically validated fluorescence-activated cell sorting assays. Patients were divided into 3 cohorts: persistent seropositivity, transient seropositivity, and seronegativity. Main Outcomes and Measures: Clinical demographic characteristics, longitudinal AQP4-IgG and MOG-IgG1 serostatus, titers, relapses, use of immunotherapy, and Expanded Disability Status Scale score at follow-up. Results: Of 51 patients presenting with an initial diagnosis of ADEM, 20 (39%) were adult, 24 (47%) were female, and ages ranged from 12 months to 57 years. Seventeen patients fulfilled criteria for persistent seropositivity; of those, 8 of 9 children (89%) and 7 of 8 adults (88%) had at least 1 relapse after median (range) follow-up periods of 75 (15-236) months and 39 (9-161) months, respectively. Eight patients (16%), including 4 adults, fulfilled criteria for transient seropositivity; of those, no children and 1 of 4 adults (25%) relapsed after median (range) follow-up periods of 32 (24-114) months and 16 (13-27) months, respectively. Of 24 patients with AQP4-IgG and MOG-IgG seronegativity, 6 of 17 children (35%) and 2 of 7 adults (29%) had at least 1 relapse after median (range) follow-up periods of 36 (3-203) months and 34 (15-217) months, respectively. There were only 2 patients, including 1 adult, with AQP4-IgG seropositivity, and both relapsed. The hazard ratio for relapses in those with persistent MOG-IgG1 positivity compared with AQP4-IgG and MOG-IgG1 seronegativity was 3.1 (95% CI, 1.1-8.9; P =.04) in children and 5.5 (95% CI, 1.4-22.5; P =.02) in adults. Immunotherapy was used in 5 of 9 children (56%) and 6 of 8 adults (75%) with persistent seropositivity and in 3 of 17 children (18%) and 1 of 7 adults (14%) with AQP4-IgG and MOG-IgG seronegativity. Conclusions and Relevance: Relapse occurred in 15 of 17 patients (88%) with persistent MOG-IgG1 seropositivity after ADEM; only 1 patient with transient seropositivity experienced relapse. Our data extend the clinical utility of MOG-IgG1 serological testing to adult patients and highlights that longitudinal serologic evaluation of MOG-IgG1 could help predict disease course and consideration of immunotherapy.

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