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  • Predictors of relapse risk and treatment response in AQP4-IgG positive and seronegative NMOSD: A multicentre study

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Neuro-inflammation
Original research
Predictors of relapse risk and treatment response in AQP4-IgG positive and seronegative NMOSD: A multicentre study
  1. Pakeeran Siriratnam1,2,3,
  2. Paul Sanfilippo1,2,
  3. Anneke van der Walt1,2,
  4. Sifat Sharmin4,
  5. Yi Chao Foong1,5,
  6. Wei Zhen Yeh1,2,
  7. Chao Zhu1,
  8. Samia Joseph Khoury6,7,
  9. Tunde Csepany8,
  10. Barbara Willekens9,10,
  11. Masoud Etemadifar11,12,
  12. Serkan Ozakbas,13,14,
  13. Petra Nytrova15,
  14. Ayse Altintas16,
  15. Abdullah Al-Asmi17,
  16. Bassem Yamout6,18,
  17. Guy Laureys19,
  18. Francesco Patti20,21,
  19. Magdolna Simo22,
  20. Andrea Surcinelli23,
  21. Matteo Foschi24,25,
  22. Pamela A McCombe26,27,
  23. Raed Alroughani28,
  24. José Luis Sánchez-Menoyo29,30,
  25. Recai Turkoglu31,
  26. Aysun Soysal32,
  27. Jeanette Lechner Scott33,34,
  28. Tomas Kalincik4,35,
  29. Helmut Butzkueven1,2,
  30. Vilija Jokubaitis1,
  31. Saif Huda3,
  32. Mastura Monif1,2
  33. MSBASE study group
    1. 1Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne, Victoria, Australia
    2. 2Alfred Health, Department of Neurology, Melbourne, Victoria, Australia
    3. 3Neurology, Walton Centre for Neurology and Neurosurgery, Liverpool, UK
    4. 4Department of Medicine, CORe, University of Melbourne, Melbourne, Victoria, Australia
    5. 5Neurology, Royal Hobart Hospital, Hobart, Tasmania, Australia
    6. 6Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon
    7. 7American University of Beirut, Beirut, Lebanon
    8. 8Department of Neurology, University of Debrecen, Debrecen, Hungary
    9. 9Neurology, Universitair Ziekenhuis Antwerpen, Edegem, Belgium
    10. 10Faculty of Medicine and Health Sciences, Translational Neurosciences Research Group, University of Antwerp, Wilrijk, Belgium
    11. 11Faculty of Medicine, Isfahan University of Medical sciences, Isfahan, Iran (the Islamic Republic of)
    12. 12Neurology, Dr. Etemadifar MS Institute, Isfahan, Iran (the Islamic Republic of)
    13. 13Izmir University of Economics, Medical Point Hospital, İzmir, Turkey
    14. 14Multiple Sclerosis Research Association, Izmir, Turkey
    15. 15Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic
    16. 16Department of Neurology, School of Medicine and Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey
    17. 17College of Medicine & Health Sciences and Sultan Qaboos University Hospital, Sultan Qaboos University, Al-Khodh, Oman
    18. 18Neurology Department, Harley Street Medical Centre, Abu Dhabi, UAE
    19. 19Department of Neurology, Universitair Ziekenhuis Gent, Gent, Belgium
    20. 20Neuroscience, Department of Surgical and Medical Sciences and Advanced Technologies 'G.F. Ingrassia', University of Catania, Catania, Italy
    21. 21Multiple Sclerosis Unit, AOU Policlinico G Rodolico-San Marco, University of Catania, Catania, Italy
    22. 22Department of Neurology, Semmelweis University, Budapest, Hungary
    23. 23Department of Neuroscience, S Maria delle Croci Hospital, Ravenna, Italy
    24. 24Department of Neuroscience, MS Center, Neurology Unit, S. Maria delle Croci Hospital, Ravenna, Italy
    25. 25Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
    26. 26The University of Queensland, Brisbane, Queensland, Australia
    27. 27Department of Neurology, Royal Brisbane Hospital, Brisbane, Queensland, Australia
    28. 28Division of Neurology, Department of Medicine, Amiri Hospital, Kuwait City, Kuwait
    29. 29Neurology, Galdakao-Usanosolo University Hospital, Osakidetza-Basque Health Service, Galdakao, Spain
    30. 30Biocruces-Bizkaia Health Research Institute, Barakaldo, Spain
    31. 31Department of Neurology, Haydarpasa Numune Training and Research Hospital, Istanbul, Turkey
    32. 32Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey
    33. 33Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia
    34. 34Hunter New England Health, John Hunter Hospital, New Lambton Heights, New South Wales, Australia
    35. 35Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
    1. Correspondence to Dr Mastura Monif; mastura.monif{at}monash.edu

    Abstract

    Background Neuromyelitis optica spectrum disorder (NMOSD) can be categorised into aquaporin-4 antibody (AQP4-IgG) NMOSD or seronegative NMOSD. While our knowledge of AQP4-IgG NMOSD has evolved significantly in the past decade, seronegative NMOSD remains less understood. This study aimed to evaluate the predictors of relapses and treatment responses in AQP4-IgG NMOSD and seronegative NMOSD.

    Methods This was a multicentre, international, retrospective cohort study using the MSBase registry. Recurrent relapse risk was assessed using an Andersen-Gill model and risk of first relapse was evaluated using a Cox proportional hazards model. Covariates that putatively influence relapse risk included demographic factors, clinical characteristics and immunosuppressive therapies; the latter was assessed as a time-varying covariate.

    Results A total of 398 patients (246 AQP4-IgG NMOSD and 152 seronegative NMOSD) were included. The AQP4-IgG NMOSD and seronegative NMOSD patients did not significantly differ by age at disease onset, ethnicity or annualised relapse rate. Both low-efficacy and high-efficacy immunosuppressive therapies were associated with significant reductions in recurrent relapse risk, with notably greater protection conferred by high-efficacy therapies in both AQP4-IgG NMOSD (HR 0.27, 95% CI 0.15 to 0.49, p<0.001) and seronegative NMOSD (HR 0.21, 95% CI 0.08 to 0.51, p<0.001). Longer disease duration (HR 0.97, 95% CI 0.95 to 0.99, p<0.001) and male sex (HR 0.52, 95% CI 0.34 to 0.84, p=0.007) were additional protective variables in reducing the recurrent relapse risk for the AQP4-IgG NMOSD group.

    Conclusion Although further studies are needed to improve our understanding of seronegative NMOSD, our findings underscore the importance of aggressive treatment with high-efficacy immunotherapies in both NMOSD subtypes, regardless of serostatus.

    • MULTIPLE SCLEROSIS
    • NEUROIMMUNOLOGY
    • IMMUNOLOGY
    • MEDICINE
    • HEALTH ECONOMICS

    Data availability statement

    Data are available on reasonable request.

    https://doi.org/10.1136/jnnp-2024-334090

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      Data availability statement

      Data are available on reasonable request.

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      Footnotes

      • X @mattfos89, @https://x.com/masturamonif

      • Collaborators Dana Horakova, Liesbeth Van Hijfte, Cavit Boz, Nevin Shalaby, Francois Grand'Maison, Mario, Habek, Bhim Singhal, Suzanne Hodgkinson, Katherine Buzzard, Olga Skibina, Mark Slee, Jabir Alkhaboori, Jihad Inshasi, Emmanuelle Lapointe, Mike Boggild, Steve Vucic, Orla Gray, Dheeraj Khurana, Maria Pia Amato, Edgardo Cristiano, Yaou Liu, Elisabetta Cartechini, Talal Al-Harbi,Todd Hardy.

      • Contributors PSiriratnam performed the statistical analyses, interpreted the results, drafted and revised the manuscript. PS contributed to the statistical analysis, interpreted the results and edited the manuscript. MM, SH, VJ, HB and AvdW contributed to study design, data collection, designed the statistical analyses, interpreted the results, edited and reviewed the manuscript. MM is the guarantor. SS, YCF, WZY and CZ interpreted the results and edited and reviewed the manuscript. SJK, TC, BW, ME, SO, PN, AA, A-AA, BY, GL, FP, MS, ASurcinelli, MF, PAM, RA, JLS-M, RT, ASoysal, JLS and TK contributed data, interpreted the results and edited and reviewed the manuscript.

      • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

      • Competing interests The author(s) would like to disclose the following. PSiriratnam has received travel support from Novartis and Biogen; AvdW has received travel support and served on advisory boards for Novartis, Biogen, Merck Serono, Roche and Teva, she receives grant support from the National Health and Medical Research Council of Australia; HB served on scientific advisory boards for Biogen, Novartis and Sanofi-Aventis and received conference travel support from Novartis, Biogen and Sanofi Aventis, he serves on steering committees for trials conducted by Biogen and Novartis and received research support from Merck, Novartis and Biogen, Medical Research Council and MS Research Australia; YCF has received travel support from Roche and Biogen, he receives grant support from Australian National Health Medical Research Council, Australia and New Zealand Association of Neurologists, AVANT foundation and MS Research Australia; WZY has received speaker honoraria from Merck and Novartis; CZ receives fellowship from the Trish Multiple Sclerosis Research Foundation; VJ receives fellowship and research support from the National Health and Medical Research Council of Australia, she also receives research grant support form F.Hoffmann La-Roche and the International Progressive MS Alliance; SH receives research support from academic entity - National Institute for Health Research (NIHR304529): Research funding; MM has served on advisory board for Merck, and Novartis and has received speaker honoraria from Merck, Biogen and Novartis, her institution receives funding from Merck, Australian National Health; TK served on scientific advisory boards for MS International Federation and WHO, 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, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck; SJK received compensation for scientific advisory board activity from Merck and Roche, and received compensation for serving on the IDMC for Biogen; TC received speaker honoraria/conference travel support from Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva; BW received honoraria for acting as a member of Scientific Advisory Boards/Consultancy for Alexion, Almirall, Biogen, Celgene/BMS, Merck, Janssen, Novartis, Roche, Sandoz, Sanofi-Genzyme and speaker honoraria and travel support from Biogen, Celgene/BMS, Merck, Novartis, Roche, Sanofi-Genzyme, research and/or patient support grants from Biogen, Janssen, Merck, Sanofi-Genzyme, Roche, Honoraria and grants were paid to UZA/UZA Foundation, further, B.W. received research funding from FWO-TBM, Belgian Charcot Foundation, Start2Cure Foundation, Queen Elisabeth Medical Foundation for Neurosciences and the National MS Society USA; PN received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Roche, Jannsen, Astra Zeneca and financial support for research activities from Roche and Merck, the work of PN was supported by Ministry of Health of the Czech Republic, grant nr. NU23-05-00462; AA received speaker honoraria from Novartis and Alexion; AA-A received personal compensation for serving as a Scientific Advisory or speaker/moderator for Novartis, Biogen, Roche, Sanofi-Genzyme, and Merck; BY received honoraria as a speaker and member of scientific advisory boards from Sanofi, Bayer, Biogen, Merck, Janssen, Novartis, Roche and Aspen; GL received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen; FP received personal compensation for serving on advisory board by Almirall, Alexion, Biogen, Bristol, Janssen, Merck, Novartis and Roche, he further received research grant by Alexion, Almirall, Biogen, Bristol, Merck, Novartis and Roche and by FISM, Reload Association (Onlus), Italian Health Minister and University of Catania. Magdolna Simo received speaker honoraria from Novartis, Biogen, Bayer Schering, Sanofi, Merck, Roche, congress/travel compensation from Teva, Biogen, Merck, Bayer Schering Novartis, Roche; MF received travel and meeting attendance support from Novartis, Biogen, Roche, Sanofi-Genzyme and Merck; ASoysal received travel and meeting attendance support from Novartis, Biogen, Roche, Merck, Bristol, Sanofi-Genzyme, Almirall, Piam; PAM received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi and travel grants from Novartis, Biogen and Bayer Schering; RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme; JLS-M, accepted travel compensation from Novartis, Merck and Biogen, speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche; JLS received travel compensation from Novartis, Biogen, Roche and Merck, her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis.

      • Provenance and peer review Not commissioned; externally peer reviewed.

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