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. 2018 Nov 1;75(11):1355-1363.
doi: 10.1001/jamaneurol.2018.1814.

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

A Sebastian López-Chiriboga  1   2 , Masoud Majed  1   2 , James Fryer  2   3 , Divyanshu Dubey  1   2 , Andrew McKeon  1   2   3 , Eoin P Flanagan  1   2 , Jiraporn Jitprapaikulsan  2   3 , Naga Kothapalli  2   3 , Jan-Mendelt Tillema  1   2 , John Chen  2   4 , Brian Weinshenker  1   2 , Dean Wingerchuk  2   5 , Jessica Sagen  2 , Avi Gadoth  2   3 , Vanda A Lennon  1   2   3   6 , B Mark Keegan  1   2 , Claudia Lucchinetti  1   2 , Sean J Pittock  1   2   3
Affiliations

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

A Sebastian López-Chiriboga et al. JAMA Neurol. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McKeon has a patent pending for glial fibrillary acidic protein and microtubule-associated protein 1B as markers of neurological autoimmunity and paraneoplastic disorders; has consulted for Grifols, MedImmune, and Euroimmun; and has received research support from MedImmune and Euroimmun. Dr Flanagan has received research support from MedImmune. Dr Weinshenker has received royalties from RSR, Oxford University, Hospices Civils de Lyon, and MVZ Labor PD Dr. Volkmann und Kollegen GbR for a patent of NMO-IgG as a diagnostic test for neuromyelitis optica (NMO) and related disorders. Dr Weinshenker also serves as a member of an adjudication committee for clinical trials in NMO being conducted by MedImmune and Alexion; as a consultant for Caladrius Biosciences and Brainstorm Therapeutics regarding potential clinical trials for NMO; and as a member of a data safety monitoring committee for clinical trials conducted by Novartis. Dr Wingerchuk has received research support paid to Mayo Clinic by Alexion and Terumo BCT and serves as a consultant for MedImmune and Caladrius Biosciences. Dr Lennon has received royalties for technology relating to aquaporin 4 (AQP4) antibodies for diagnosis of NMO and its spectrum disorders, is a named inventor on filed patents that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker, and has a patent pending for glial fibrillary acidic protein and microtubule-associated protein 1B as markers of neurological autoimmunity and paraneoplastic disorders. Dr Pittock is a named inventor on filed patents that relate to functional AQP4/NMO-IgG assays and NMO-IgG as a cancer marker; has consulted for Alexion and MedImmune; and has received research support from Grifols, MedImmune, and Alexion. All compensation for consulting activities is paid directly to Mayo Clinic. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Design
ADEM indicates acute disseminated encephalomyelitis; AQP4, aquaporin 4; IDD, inflammatory demyelinating disorder; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorder.
Figure 2.
Figure 2.. Kaplan-Meier Curves Showing Cumulative Probability of Remaining Relapse Free Following Initial Event in Children and Adults
A, Log-rank test: P = .02. B, Log-rank rest: P = .11. Tick marks indicate censored patients.
Figure 3.
Figure 3.. Detailed Magnetic Resonance Imaging (MRI) Changes of Representative Adults With Persistent MOG-IgG1 Positivity at Onset and Follow-up
Axial fluid-attenuated inversion recovery (FLAIR) MRI, axial postgadolinium T1-weighted MRI, and sagittal T2-weighted cervical spine MRI at initial presentation are shown; T2-weighted hyperintensities were not associated with enhancement. These abnormalities improved after treatment. A, Patient A is a woman in her 20s. After 19 months of follow-up, she experienced 3 relapses as well as 2 episodes of left-sided optic neuritis 6 months and 11 months after ADEM onset with good recovery with rituximab therapy, with an Expanded Disability Status Scale score of 0. She developed left optic neuritis after prednisone dose reduction (arrowhead). B, Patient B is a man in his 40s. After 25 months of follow-up, he experienced 4 relapses after prednisone dose reduction, including bilateral optic neuritis 4 months, 7 months and 16 months and right-sided optic neuritis 24 months after ADEM onset with good recovery with azathioprine therapy, with an Expanded Disability Status Scale score of 1. He developed bilateral optic neuritis after prednisone dose reduction (arrowheads).
See this image and copyright information in PMC

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