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. 2024 May 14;95(6):544-553.
doi: 10.1136/jnnp-2023-332851.

The MOG antibody non-P42 epitope is predictive of a relapsing course in MOG antibody-associated disease

Ganesha Liyanage  1   2 , Benjamin P Trewin  3   4 , Joseph A Lopez  1 , Jane Andersen  1   4 , Fiona Tea  1 , Vera Merheb  1 , Kristy Nguyen  1 , Fiona X Z Lee  1 , Marzena J Fabis-Pedrini  5   6 , Alicia Zou  1 , Ali Buckland  5 , Anthony Fok  7 , Michael H Barnett  8 , Stephen W Reddel  8   9 , Romain Marignier  10   11 , Aseel El Hajj  10   11 , Mastura Monif  12 , Anneke van der Walt  12 , Jeannette Lechner-Scott  13   14   15 , Allan G Kermode  5   16 , Tomas Kalincik  17   18 , Simon A Broadley  19   20 , Russell C Dale  4   21 , Sudarshini Ramanathan  3   4   8   9 , Fabienne Brilot  22   2   8 ; on behalf the Australasian MOGAD Study Group
Collaborators, Affiliations

The MOG antibody non-P42 epitope is predictive of a relapsing course in MOG antibody-associated disease

Ganesha Liyanage et al. J Neurol Neurosurg Psychiatry. .

Abstract

Background: Myelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients.

Methods: MOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated.

Results: Of 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%).

Conclusions: Non-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes.

Keywords: IMMUNOLOGY; MULTIPLE SCLEROSIS; NEUROIMMUNOLOGY.

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Conflict of interest statement

Competing interests: MF-P has received research grant from MS Australia and travel compensation from Merck. MB reports research grants from Genzyme-Sanofi, Novartis, Biogen, Merck and BMS; and is a Research Consultant for RxMx and Research Director for the Sydney Neuroimaging Analysis Centre. SWR has received funds over the last 5 years including but not limited to travel support, honoraria, trial payments, research and clinical support to the neurology department or academic projects of which he is a member has been received from bodies and charities: NHMRC, NBA, MAA, Lambert Initiative, Beeren foundation, anonymous donors; and from pharmaceutical/biological companies: Alexion, Biogen, CSL, Genzyme, Grifols, Merck, Novartis, Roche, Sanofi. MM has served on scientific and commercial advisory boards for Merck Serono. AvdW has received travel support from Merck Serono, Novartis, Biogen, Roche and Sanofi. She has served on scientific and commercial advisory boards for Merck, Novartis, Sanofi and Roche, and has received unencumbered research grants from Novartis, Biogen, Merck and Roche. JLS has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Bayer Health Care, Biogen, Genzyme Sanofi, Merck, Novartis and TEVA. AGK has in recent times received speaker honoraria and Scientific Advisory Board fees from Bayer, BioCSL, Biogen-Idec, Lgpharma, Merck, Novartis, Roche, Sanofi-Aventis, Sanofi-Genzyme, Teva, NeuroScientific Biopharmaceuticals, Innate Immunotherapeutics, and Mitsubishi Tanabe Pharma. His work has received grant funding from the Eyewall Foundation, Trish MS Foundation, MS Australia, MS Western Australia, the MS Base Foundation, the National Health and Medical Research Council of Australia, and the National Multiple Sclerosis Society, USA. He is an investigator in clinical trials sponsored by Biogen Idec and Novartis. TK served on scientific advisory boards for BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis and Sanofi-Genzyme, has received speakers honoraria from Biogen-Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis and Genzyme, and was the recipient of an unencumbered research grant from Biogen-Idec. RCD received research funding from the Petre Foundation and National Health and Medical Research Council (Australia). He has received honoraria form Biogen Idec and Merck Serono as invited speaker. SR received research funding from the National Health and Medical Research Council (Australia), the Royal Australasian College of Physicians, and the University of Sydney. She serves as a consultant on an advisory board for UCB and Limbic Neurology, The MOG Project and the Sumaira Foundation, and has been an invited speaker for Biogen, Excemed, Alexxion, Limbic Neurology, and Novartis. FB has received research funding from NSW Health, MS Australia, the National Health Medical Research Council (Australia), the Medical Research Future Fund (Australia) and investigator-initiated research grant from Novartis. She was on an advisory boards for Novartis, Merck and The MOG Project and the Sumaira Foundation, and has been an invited speaker for Biogen, Novartis and Limbic Neurology.

Figures

Figure 1
Figure 1
P42 and H103/S104 epitopes were the key MOG-IgG epitopes in adults. (A) MOG-IgG was assessed in 202 patient sera, and P42 and H103/S104 epitope statuses were determined. (B) Sera with MOG-IgG recognise one, both or neither of the two immunodominant epitopes. (C) EDSS and (D) VFSS scores were compared between MOG-IgG epitopes, and between disease onset and last follow-up date. EDSS, Expanded Disability Status Scale; MOG, myelin oligodendrocyte glycoprotein; VFSS, Visual Functional Systems Score.
Figure 2
Figure 2
Non-P42 MOG-IgG was associated with a relapsing disease course. Alluvial plots demonstrating the proportion of MOGAD patients (n=202) with monophasic and relapsing disease course and their (A) P42 MOG-IgG and (B) H103/S104 MOG-IgG status. (C) Univariate Cox proportional hazard model illustrating the HR of a relapsing course in each epitope group compared with the corresponding reference group as follows: patients with MOG-IgG binding to a P42 epitope (top row), H103/S104 epitope (second row) and P42 and non-H103/S104 epitope (last three rows). (D) Kaplan-Meier curve showing the relapse-freedom period of patients with P42 MOG-IgG compared with non-P42 MOG-IgG (number of censored observations and number at risk are shown below the curve). 95% CIs are shown in shaded areas on both sides of the survival curves. MOGAD, myelin oligodendrocyte glycoprotein antibody-associated disease.
Figure 3
Figure 3
Non-P42 MOG-IgG was the strongest predictor of a relapsing course in patients with UON at onset. (A) Alluvial plots representing the distribution of MOG-IgG epitope status across MOGAD clinical phenotypes including ON, TM, ON/TM, mixed and brain. Patients with ON included UON and BON. (B) Univariate Cox proportional hazard model showing the risk of a relapsing course in patients with non-42 MOG-IgG within each phenotype category compared with the reference group (patients with P42 MOG-IgG within that phenotype category). (C) Multivariable Cox proportional hazard model showing the risk of a relapsing course in patients with UON, BON, TM and brain phenotypes at onset and whose non-P42 MOG-IgG were tested before the first relapse. The reference patients were patients with BON and non-P42 MOG-IgG. (D) Longitudinal serial samples from relapsing (top; purple background) and monophasic patients (bottom; green background) showing that MOG-IgG epitopes remain highly stable over time irrespective of treatment. Patient sera were assessed from the first sample to the last sample collected for a median duration of 126 days in relapsing patients and 160 days in monophasic patients. Basic information on treatment or lack thereof at time of blood collection were available for 10 patients and treatments included corticosteroids, rituximab, mycophenolate or untreated. Samples collected at onset or during the first clinical episode (within 30 days of the onset, shown by the dotted line) were defined as ‘sample collected at onset or the first episode’, and diamonds were used to represent these blood collections. Inverted triangles show clinical relapses. BON, bilateral optic neuritis; ON, optic neuritis; TM, transverse myelitis; UON, unilateral optic neuritis.
Figure 4
Figure 4
Distribution of non-P42 MOG-IgG in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) at onset. Patients with different MOGAD phenotypes at onset were stratified into their P42 epitope status and subsequently their disease course. Age at onset and time to first relapse are shown (median and IQR). There was no statistical difference between epitope groups for age at onset and time to first relapse. Sensitivity, specificity and PPV could not be determined in some groups due to the absence of patients with MOG-IgG non-P42 epitope in the ON/TM and Mixed groups, and the absence of patients with a monophasic course in the ON (NOS) group. BON, bilateral optic neuritis; NOS, not otherwise specified; PPV, positive predictive value, TM, transverse myelitis; UON, unilateral optic neuritis.
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