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. 2025 Jun;32(6):e70214.
doi: 10.1111/ene.70214.

Comorbidities Are Associated With Unfavorable Outcome in Aquaporin-4 Antibody Positive Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: Exploratory Study From the CROCTINO Cohort

Sara Samadzadeh  1   2   3   4   5 , Frederike Cosima Oertel  3   4   5 , Hadi Salih  3   4   5 , Ting-Yi Lin  3   4   5   6 , Seyedamirhosein Motamedi  3   4   5 , Claudia Chien  3   5   7 , Lawrence J Cook  8 , Marco Aurélio Lana-Peixoto  9 , Mariana Andrade Fontenelle  10 , Ho Jin Kim  11 , Jae-Won Hyun  11 , Su-Kyung Jung  11 , Jaqueline Palace  12 , Adriana Roca-Fernandez  12 , Maria Isabel Leite  12 , Srilakshmi M Sharma  13 , Fereshteh Ashtari  14 , Rahele Kafieh  15 , Alireza Dehghani  16 , Mohsen Pourazizi  16 , Lekha Pandit  17 , Anitha Dcunha  17 , Orhan Aktas  18 , Marius Ringelstein  18   19 , Philipp Albrecht  18   20 , Eugene F May  21 , Caryl Tongco  22 , Letizia Leocani  23   24   25 , Marco Pisa  26 , Marta Radaelli  27 , Bernardo Sánchez-Dalmau  28 , Elena H Martinez-Lapiscina  29 , Hadas Stiebel-Kalish  30   31   32 , Mark A Hellmann  33 , Itay Lotan  33 , Sasitorn Siritho  34 , Jérôme de Seze  35 , Thomas Senger  36 , Joachim Havla  36 , Romain Marignier  37 , Caroline Froment Tilikete  38 , Alvaro Cobo-Calvo  39 , Denis Bichuetti  40 , Ivan Maynart Tavares  41 , Kerstin Soelberg  42 , Ayse Altintas  43   44 , Rengin Yildirim  45 , Uygur Tanriverdi  44 , Anu Jacob  46   47 , Saif Huda  46 , Zoe Rimler  48 , Allyson Reid  48 , Yang Mao-Draayer  49 , Pablo Villoslada  50 , Ibis Soto de Castillo  51 , Ari Green  52 , Axel Petzold  53   54   55   56 , Michael R Yeaman  22   57 , Terry J Smith  58   59 , Alexander U Brandt  3   4   5 , Hanna G Zimmermann  3   4   5 , Friedemann Paul  3   4   5   60 , Nasrin Asgari  1   2 ; Guthy Jackson Charitable Foundation – International Clinical Consortium and CROCTINO Collaborators
Affiliations

Comorbidities Are Associated With Unfavorable Outcome in Aquaporin-4 Antibody Positive Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease: Exploratory Study From the CROCTINO Cohort

Sara Samadzadeh et al. Eur J Neurol. 2025 Jun.

Abstract

Background: Comorbidities occur in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and double seronegative NMOSD (DN-NMOSD), potentially contributing to a less favorable disease course.

Objectives: To characterize comorbidities in AQP4-NMOSD, MOGAD, and DN-NMOSD and assess their association with optic neuritis (ON) outcomes by optical coherence tomography (OCT) in AQP4-NMOSD.

Methods: Four hundred and forty-two participants from the CROCTINO cohort were evaluated for comorbidities.

Results: In AQP4-NMOSD patients (n = 360), 43.5% (n = 161) had comorbidities, equally divided between single and multiple. In MOGAD (n = 49), 40.8% had comorbidities, with 75% (n = 15) single and 25% (n = 5) multiple. In DN-NMOSD (n = 33), 36.4% (n = 12) had comorbidities equally split. AQP4-NMOSD patients had more multiple comorbidities (50%, n = 81/161) than MOGAD (25%, n = 5/20, p = 0.03) and more autoimmune disorders (AID) (40.4%, n = 65) than MOGAD (20%, n = 4, p = 0.09) and DN-NMOSD (none, p = 0.004). Cardiovascular comorbidities and related risk factors (CVC/RF) occurred in 34.8% (n = 56) of AQP4-NMOSD, 50% (n = 10) of MOGAD, and 33.3% (n = 4) of DN-NMOSD. Expanded Disability Status Scale was higher in MOGAD (3.0 vs. 2.0, p = 0.006) and DN-NMOSD (5.0 vs. 2.0, p = 0.008) with comorbidities. AQP4-NMOSD patients with CVC/RF had higher ON relapse rates than those with AID (1.06 ± 3.33 vs. 0.49 ± 0.98, p < 0.001). OCT revealed reduced inner nuclear layer thickness in AQP4-NMOSD with comorbidities compared to non-comorbidity (B = -1.52, p = 0.047), more pronounced with CVC/RF (B = -2.96, p = 0.009).

Conclusion: Comorbidities are frequent in AQP4-NMOSD and MOGAD and are associated with ON frequency and disability. These findings highlight the need for proactive comorbidity management to improve patient care.

Keywords: anti‐aquaporin‐4 (AQP4); anti‐myelin oligodendrocyte glycoprotein antibody‐associated disease; comorbidity; double‐seronegative NMOSD; neuromyelitis optica spectrum disorder; optical coherence tomography.

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Conflict of interest statement

F.C.O. currently receives research support from the Hertie foundation, the Deutsche Forschungsgemeinschaft (DFG) and Novartis, all unrelated to this study. She received fellowship support from the American Academy of Neurology, National MS Society until 2023. She is a member of the working committee of the International Multiple Sclerosis Visual System (IMSVISUAL) Consortium. H.G.Z. reports grants from Novartis, unrelated to this study H.J.K. has received a grant from the National Research Foundation of Korea and research support from AprilBio, Eisai, and UCB; received consultancy/speaker fees from Alexion, Altos Biologics, AstraZeneca, Biogen, Daewoong Pharmaceutical, Eisai, GC Pharma, Handok Pharmaceutical, Kaigene, Kolon Life Science, MDimune, Merck Serono, Mitsubishi Tanabe Pharma, Roche, and Sanofi Genzyme; is a co‐editor for the Multiple Sclerosis Journal; and an associated editor for the Journal of Clinical Neurology. J.P. has received support for scientific meetings and honorariums for advisory work from Merck Serono, Novartis, Chugai, Alexion, Roche, Medimmune, Amgen, Vitaccess, UCB, Mitsubishi, Amplo, and Janssen, grants from Alexion, Argenx, Clene, Roche, Medimmune, and Amplo biotechnology, patent ref P37347WO and license agreement Numares multimarker MS diagnostics, and shares in AstraZeneca. Her group has been awarded an ECTRIMS fellowship and a Sumaira Foundation grant to start later this year. A Charcot fellow worked in Oxford 2019–2021. She acknowledges partial funding to the trust by National Health Service (NHS) Highly Specialised Services England. She is on the medical advisory boards of the Sumaira Foundation and MOG project charities, is a member of the Guthy Jackson Foundation Charity, and is on the Board of the European Charcot Foundation and the steering committee of MAGNIMS and the UK NHSE IVIG Committee, and chairman of the NHSE neuroimmunology patient pathway, and ECTRIMS Council member on the educational committee since June 2023. On the ABN advisory groups for MS and neuroinflammation and neuromuscular diseases, A.R.‐F. is sponsored by Abide Therapeutic outside of the submitted work and reports no potential conflicts of interest. P.A. received, with approval of the Rector of Heinrich‐Heine University and the CEO of University of Düsseldorf Hospital, personal fees, research grants, and non‐financial support from Allergan, Biogen, Celgene, Janssen Cilag, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche; personal fees and non‐financial support from Bayer Healthcare, Teva, and Sanofi‐Aventis/Genzyme; and grants from the German Research Foundation (DFG), all outside the submitted work. M.R. received speaker honoraria from Novartis, Bayer Vital GmbH, Roche, Alexion, and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, and Merck, none related to this study. H.S.‐K. has received support for scientific meetings from Roche. A.U.B. is co‐founder and shareholder of Motognosis GmbH and Nocturne GmbH. He is named as inventor on several patent applications regarding MS serum biomarkers, OCT image analysis, and perceptive visual computing. A.U.B. is now a full‐time employee and holds stocks of Eli Lilly and Corporation. His contribution to this work is his own and does not reflect Eli Lilly and Corporation. F.P. reports research grants and speaker honoraria from Bayer, Teva, Genzyme, Merck, Novartis, MedImmune, and is a member of the steering committee of the OCTIMS study (Novartis), all unrelated to this work. E.H.M.‐L. received funding from the Instituto de Salud Carlos III (Spain) and Fondo Europeo de Desarrollo Regional (FEDER—JR16/00006), Grant for MS Innovation, Fundació Privada Cellex, and Marató TV3 Charitable Foundation, and is a researcher in the OCTIMS study, an observational study (that involves no specific drugs) to validate SD‐OCT as a biomarker for MS, sponsored by Novartis, and has received honoraria and travel support for international and national meetings over the last 3 years from Biogen, Novartis, Roche, and Genzyme. She is a member of the working committee of the International Multiple Sclerosis Visual System (IMSVISUAL) Consortium. M.A.L.‐P. has received funding for travel and speaker honoraria from Novartis, Horizon Therapeutics, and Roche. M.I.L. reported being involved in aquaporin 4 testing, receiving salary from the NHS National Highly Specialised Commissioning Group for Neuromyelitis Optica, UK, being supported by the National Institute for Health Research Oxford Biomedical Research Centre, UK, and receiving speaking honoraria and travel grants from Biogen Idec, and a travel grant from Novartis. S.S.I. received funding for travel and speaker honoraria from Merck Serono (Thailand), Roche (Thailand), DKSH (Thailand), Pacific Healthcare (Thailand), Eisai (Thailand), Biogen Idec, UCB (Thailand), and Novartis. A.A. reports personal fees from received honoraria for giving educational presentations on multiple sclerosis, NMOSD, and neuroimmunology from Novartis and Alexion. Dr. Altintas has received travel and registration coverage for attending several national and international meetings from Merck‐Serono. A.J. has received compensation for advisory board, consulting, meeting attendance, and speaking from Biogen, Terumo‐BCT, Genentech, Shire, and Chugai Pharmaceuticals. S.H. is partly funded by NHS Highly Specialised Services England to run an NMO UK service. S.H. has received research funding from the NIHR. R.M. serves on the scientific advisory board for MedImmune and has received funding for travel and honoraria from Biogen, Merck Serono, Novartis, Sanofi‐Genzyme, Roche, and Teva. D.B. has received speaking/consulting honoraria from Bayer Health Care, Biogen Idec, Merck, Sanofi‐Genzyme, TEVA, and Roche, and had travel expenses to scientific meetings sponsored by Bayer Health Care, Merck Serono, TEVA, and Roche. J.H. reports a grant for OCT research from the Friedrich‐Baur‐Stiftung and Merck, personal fees and non‐financial support from Merck, Alexion, Novartis, Roche, Celgene, Biogen, Bayer, and Horizon, and non‐financial support from the Sumaira Foundation and Guthy‐Jackson Charitable Foundation, all outside the submitted work. L.L. received honoraria for consulting services from Merck, Roche, Biogen, and for speaking activities from Teva; research support from Merck, Biogen, Novartis; travel support from Merck, Roche, Biogen, and Almirall. O.A. has received honoraria for speaking/consultation and travel grants from Bayer Healthcare, Biogen Idec, Chugai, Novartis, Medimmune, Merck Serono, and Teva, and research grants from Bayer Healthcare, Biogen Idec, Novartis, and Teva. M.R. received speaker honoraria from Novartis, Bayer Vital GmbH, and Ipsen, and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, and Merck, none related to this study. P.V. has received consultancy fees and holds stocks in Bionure investments, Accure Therapeutics, Attune Neurosciences, Adhera Health, Clight, QMENTA, and NeuroPrex. J.‐W.H. has received a grant from the National Research Foundation of Korea. A.P. received salary support—grant to Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology. Y.M.‐D. has served as a consultant and/or received grant support from: Acorda, Bayer Pharmaceutical, Biogen Idec, Celgene, EMD Serono, Genzyme, Novartis, Questor, Chugai, and Teva Neuroscience, and is currently supported by grants from NIH NIAID Autoimmune Center of Excellence: UM1‐AI110557; NIH NINDS R01‐NS 080821. M.R.Y. is founder of NovaDigm Therapeutics, Inc., ImmunoTx, LLC, Tegos Therapeutics, LLC, and Metacin, Inc. He is the principal inventor on United States and international patents regarding anti‐infectives, immunotherapeutics, and vaccines. He has received research funding from the National Institutes of Health (NIH), National Institute of Allergy & Infectious Diseases (NIAID) and Department of Defense (DOD), United States of America. He has received speaker or advisory honoraria from Alexion/AstraZeneca, Horizon/Amgen, and Genentech/Roche. He serves as Chair Advisor to the Guthy‐Jackson Charitable Foundation. J.S. has nothing to disclose. The remaining co‐authors have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Distribution of comorbidity, cardiovascular comorbidities and risk factors, and autoimmune comorbidities among AQP4‐IgG seropositive neuromyelitis optica spectrum disorder (AQP4‐NMOSD), myelin oligodendrocyte glycoprotein antibody disease (MOGAD), and double seronegative with NMOSD phenotype (DN‐NMOSD). RF: risk factors.
FIGURE 2
FIGURE 2
(A) Violin plot of age distribution by comorbidity in AQP4‐NMOSD. No: No comorbidity, Single: Single Comorbidity, Multiple: Multiple comorbidities. *Statistical significance is indicated where p < 0.05. (B) ROC Curve depicting the logistic regression model's performance in comorbidity prediction by age for AQP4‐NMOSD, with an AUC of 0.67. The optimal age cutoff is approximately 48.5 years, maximizing the sum of sensitivity and specificity at the given points of 0.55 and 0.71, respectively.
FIGURE 3
FIGURE 3
Boxplot of OCT parameters in the AQP‐NMOSD group. (A) Peripapillary Retinal nerve fiber layer (pRNFL) thickness, (B) ganglion cell‐inner plexiform layer (GCIPL) thickness, and (C) inner nuclear layer (INL) thickness comparing patients with and without a history of optic neuritis (ON). Number of ON eyes: No comorbidity n = 108; at least one comorbidity: N = 43; at least one autoimmune comorbidity: N = 21; at least one cardiovascular comorbidities & risk factors: N = 19. Statistics: Linear mixed‐effects modeling was applied separately to two subsets of eyes—those with ON and those without. This analysis included random effects to account for inter‐eye within‐subject variations and fixed effects for comorbidity, AID, and CVC/RF separately. *Statistical significance is indicated where p < 0.05. Abbreviations: Com−NON: Patients without comorbidities and without a history of ON; Com+NON: Patients with comorbidities but without a history of ON; AID+NON: Patients with autoimmune comorbidities but without a history of ON; CVC/RF+NON: Patients with cardiovascular comorbidities & risk factors but without a history of ON; Com−ON: Patients without comorbidities and without a history of ON; Com+ON: Patients with comorbidities and with a history of ON; AID+ON: Patients with autoimmune comorbidities and with a history of ON; CVC/RF+ON: Patients with cardiovascular comorbidities & risk factors and with a history of ON. Statistics: Linear mixed‐effects modeling was applied separately to two subsets of eyes—those with ON and those without. This analysis included random effects to account for inter‐eye within‐subject variations and fixed effects for comorbidity, AID, and CVC/RF separately. *Statistical significance is indicated where p < 0.05.
See this image and copyright information in PMC

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