MOG and Aquaporin-4 Antibody Frequency, Clinical and MRI Characteristics, and Disease Course Among Children Diagnosed with MS and Controls

Background: There are limited data on the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among pediatric-onset MS (POMS) patients and healthy controls. Using a prospective cohort of POMS patients and healthy controls, we aimed to determine the frequency of MOG-IgG and AQP4-IgG in both groups, compare clinical characteristics and outcomes in seronegative vs seropositive children, and identify predictors of final diagnosis. Methods: POMS patients and controls were enrolled at 14 US sites through a case-control study on POMS risk factors. Follow-up data were prospectively collected. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays. Medical records were re-reviewed in seropositive cases to confirm final diagnosis. Findings: We included 1196 participants, 493 POMS and 703 controls. AQP4-IgG was negative in all participants. MOG-IgG was positive in 30/493 cases (6%) and 0/703 (0%) controls. Twenty-five of 30 MOG-IgG positives (83%) were determined to have MOG-IgG-associated disease (MOGAD) while 5/30 (17%) maintained a diagnosis of MS. The MOG-IgG false-positive rate was 1%. MOGAD cases, compared with MS, were more commonly female (84% vs 64%; p=0.044), presented at younger age (mean 8∙2±4∙2 vs 14∙7±2∙6 years; p<0.001), more commonly had initial optic nerve symptoms (64% vs 33%; p=0∙002) or ADEM (32% vs 2%; p<0∙001), and less commonly had initial spinal cord symptoms (15% vs 51%; p=0∙002), serum Epstein-Barr virus (EBV) positivity (44% vs 95%; p<0∙001), or CSF oligoclonal bands (20% vs 69%; p<0∙001). Interpretation: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric CNS demyelinating disease. Only 5% of those with prior POMS diagnoses ultimately had MOGAD; none had AQP4-IgG positivity. False-positive MOG-IgG was rare. Predictors of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and EBV exposure. Funding: National Multiple Sclerosis Society and National Institute of Neurological Disorders and Stroke (R01NS113828, 1R01NS071463, S1-1808-32326). Declaration of Interest: CMG reports grants or contracts from NMSS. TCC reports support for present manuscript from NMSS; grants or contracts from F Hoffman-La Roche Ltd. LB reports grants or contracts from Biogen, Shore Foundation, ROHHAD Fight, Alexion, NIH; consulting fees from MA Department of Public Health, Vaccine Injury Compensation Program; support from NMSS, CDC. TC reports grants or contracts from NIH, NMSS, US Department of Defense, Sumaira Foundation, Brainstorm Cell Therapeutics, Octave Bioscience, Roche Genentech, Tiziana Life Sciences; consulting fees from Biogen, Novartis, Roche Genentech, Sanofi Genzyme; participation on a data safety monitoring board or advisory board for Novartis. MPG reports support for present manuscript from NMSS, NINDS; grants or contracts from Novartis/Genentech. MSG reports grants or contracts from NIA/NIH, NIAID; support from Capital Medical University Beijing, Shandon Madic Technologies Co Ltd, Tacheng Talent Office; stock or stock options with Moderna, BioNTech. JG reports grants or contracts from Biogen, Octave, NMSS, ABM; consulting fees from Novartis; payment or honoraria from Alexion, BMS, Genentech. BMG reports grants or contracts from Clene Nanomedicine, Chugai, Medimmune, PCORI, Guthy Jackson Foundation, NMSS, NIH, Siegel Rare Neuroimmune Association; royalties or licenses from UpToDate; consulting fees from Alexion, Novartis, EMD Serono, Genentech, Horizon, Signant, Sandoz, Immunovant, Greenwich Bio, IQVIA, Druggability Tech, PRIME education; payment or honoraria from Texas Neurological Society, CMSC, AAN; payment from Rubin Anders; support from Greenwich Bio, Novartis; a patent; leadership or fiduciary role in Siegel Rare Neuroimmune Association. LK reports grants or contracts from Biogen, University of Utah, NMSS; royalties or licenses from various pharmaceuticals; consulting fees from Biogen, Everyday Health, Genentech, Gerson Lehman, Novartis, Sanofi, Eisai, Roche, Janssen, Cambridge Medical Technologies, Medergy, Celegene; payment or honoraria from At the Limits; support from Sanofi; participation on a data safety monitoring board or advisory board for Biogen. TL reports grants or contracts from NMSS and National Institute of Neurological Disorders and Stroke. SJP reports grants or contracts from Alexion, NIH, MedImmune/Viela Bio, Grifols, Guthy Jackson, AEA; consulting fees from Alexion, MedImmune/Viela Bio, Euroimmun, Roche/Genentech, Sage Therapeutics, Prime Therapeutics, UCB, Astellas; issued patents # 8,889,102 and 9,891,219B2 as well as pending patents for GFAP-IgG, Septin-5-1gG, MAP1B-IgG, Kelch-like protein 11, PDE10A; participation on a data safety monitoring board or advisory board for UCB Inc, Hoffman/LaRoche AG, Alexion, Genentech. MRR reports leadership or fiduciary role for Ad Board for PPD and PI in Medimmune trial. TS reports support from the Network of Pediatric MS Centers; participation on a data safety monitoring board or advisory board for Biogen. BW reports grants or contracts from Biogen, Novartis, Genentech; consulting fees from Biogen, Novartis, Genentech, Genzyme, Sanofi, Horizon, Janssen, Bayer; payment or honoraria from Biogen, Janssen, Genentech; leadership or fiduciary role for ACTRIMS. EW reports grants or contracts from NIH, NMSS, Race to Erase MS, PCORI; consulting fees from Jazz Pharma, Emerald, DBV; participation on a data safety monitoring board or advisory board for Novartis; other financial or non-financial interests with Roche, Biogen, Alexion. EPF reports grants or contracts from NIH; consulting fees from Alexion, Genentech, Horizon Therapeutics; payment or honoraria from Pharmacy Times; other financial or non-financial interests with Medimmune/Viela-Bio/Horizon Therapeutics. Ethical Approval: The study was approved by the Institutional Review Board at each participating institution and consent was obtained as per individual institutional guidelines