Review

. 2025 May 13;148(5):1459-1478.

doi: 10.1093/brain/awae409.

De-escalating and discontinuing disease-modifying therapies in multiple sclerosis

Géraldine Androdias^{1

2}, Jan D Lünemann³, Elisabeth Maillart⁴, Maria Pia Amato^{5

6}, Bertrand Audoin^{7

8}, Arlette L Bruijstens⁹, Gabriel Bsteh^{10

11}, Helmut Butzkueven^{12

13}, Olga Ciccarelli^{14

15}, Alvaro Cobo-Calvo¹⁶, Tobias Derfuss^{17

18}, Franziska Di Pauli¹⁹, Gilles Edan^{20

21}, Christian Enzinger²², Ruth Geraldes^{23

24}, Cristina Granziera^{18

25

26}, Yael Hacohen^{27

28}, Hans-Peter Hartung^{29

30

31}, Sinéad Hynes³², Matilde Inglese^{33

34}, Ludwig Kappos^{18

35}, Hanna Kuusisto^{36

37}, Annette Langer-Gould³⁸, Melinda Magyari^{39

40

41}, Romain Marignier^{1

42}, Xavier Montalban^{16

43}, Marcin P Mycko⁴⁴, Bardia Nourbakhsh⁴⁵, Jiwon Oh⁴⁶, Celia Oreja-Guevara^{47

48}, Fredrik Piehl^{49

50}, Luca Prosperini⁵¹, Jaume Sastre-Garriga¹⁶, Finn Sellebjerg^{39

41}, Krzysztof Selmaj^{44

52}, Aksel Siva⁵³, Emma Tallantyre^{54

55}, Vincent van Pesch⁵⁶, Sandra Vukusic^{1

57

58

59}, Bianca Weinstock-Guttman⁶⁰, Frauke Zipp⁶¹, Mar Tintoré^{16

43}, Ellen Iacobaeus⁵⁰, Bruno Stankoff^{4

62}

Affiliations

¹ Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, Centre de Ressources, Recherche et Compétence sur la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69677 Lyon-Bron, France.
² Clinique de la Sauvegarde, Ramsay Santé, Lyon 69009, France.
³ Department of Neurology with Institute of Translational Neurology, University and University Hospital Münster, Münster 48149, Germany.
⁴ Department of Neurology, Multiple Sclerosis Center, Pitié-Salpêtrière Hospital, AP-HP, Paris 75013, France.
⁵ Departmente NEUROFARBA, University of Florence, Florence 50139, Italy.
⁶ IRCCS Fondazione Don Carlo Gnocchi, Florence 50143, Italy.
⁷ Department of Neurology, University Hospital of Marseille, Marseille 13005, France.
⁸ Centre de Résonance Magnétique Biologique et Médicale (CRMBM), CNRS, Aix Marseille University, Marseille Cedex 5 13385, France.
⁹ Department of Neurology, Erasmus Medical Center, Rotterdam 3015 GD, The Netherlands.
¹⁰ Department of Neurology, Medical University of Vienna, Vienna 1090, Austria.
¹¹ Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna 1090, Austria.
¹² Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne 3004, Australia.
¹³ Department of Neurology, Alfred Health, Melbourne 3004, Australia.
¹⁴ Queen Square MS Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
¹⁵ National Institute for Health and Care Research (NIHR), University College London Hospitals (UCLH) Biomedical Research Centre, London WC1B 5EH, UK.
¹⁶ Department of Neurology, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
¹⁷ Departments of Neurology and Biomedicine, University Hospital Basel, Basel 4031, Switzerland.
¹⁸ Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Basel, Basel 4031, Switzerland.
¹⁹ Department of Neurology, Medical University of Innsbruck, Innsbruck 6020, Austria.
²⁰ Department of Neurology, University Hospital of Rennes, Rennes 35033, France.
²¹ CIC-P 1414 INSERM, University Hospital of Rennes, Rennes 35033, France.
²² Department of Neurology, Medical University of Graz, Graz 8010, Austria.
²³ NMO service, Department of Neurology, Oxford University Hospitals, Oxford OX3 9DU, UK.
²⁴ Nuffield Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK.
²⁵ Neurology Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel 4031, Switzerland.
²⁶ Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, University Hospital Basel and University of Basel, Basel 4031, Switzerland.
²⁷ Queen Square MS Centre, Department of Neuroinflammation, Faculty of Brain Sciences, UCL Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK.
²⁸ Department of Neurology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
²⁹ Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany.
³⁰ Brain and Mind Center, Medical Faculty, University of Sydney, Sydney, NSW 2050, Australia.
³¹ Department of Neurology, Palacky University Olomouc, Olomouc 77900, Czech Republic.
³² School of Health Sciences, College of Medicine, Nursing and Health Sciences, University of Galway, Galway H91 TK33, UK.
³³ Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa 16132, Italy.
³⁴ MS Center, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy.
³⁵ Departments of Head Spine and Neuromedicine, Biomedicine, Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel 4031, Switzerland.
³⁶ Tampere University Hospital, Department of Neurology, Tampere 33520, Finland.
³⁷ University of Eastern Finland, Faculty of Social and Welfare Management, Kuopio 70211, Finland.
³⁸ Neurology Department, Los Angeles Medical Center, Southern California Permanente Medical Group, Kaiser Permanente, Los Angeles, CA 90027, USA.
³⁹ Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital-Rigshospitalet, Glostrup 2600, Denmark.
⁴⁰ Danish Multiple Sclerosis Registry, Copenhagen University Hospital-Rigshospitalet, Glostrup 2600, Denmark.
⁴¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
⁴² Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon-Bron 69677, France.
⁴³ Faculty of Medicine, UVIC-UCC Universitat Central de Catalunya, Vic 08500, Spain.
⁴⁴ Department of Neurology, University of Warmia and Mazury, Olsztyn 10719, Poland.
⁴⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USA.
⁴⁶ Division of Neurology, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto M5B1W8, Canada.
⁴⁷ Department of Neurology, Hospital Clinico San Carlos, IdISSC, Madrid 28040, Spain.
⁴⁸ Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.
⁴⁹ Department of Clinical Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden.
⁵⁰ Department of Neurology, Karolinska University Hospital, S171 76 Stockholm, Sweden.
⁵¹ MS Unit, S. Camillo-Forlanini Hospital, Rome 00152, Italy.
⁵² Center of Neurology, Lodz 90-324, Poland.
⁵³ Clinical Neuroimmunology Unit & MS Clinic, Department Of Neurology, Istanbul University Cerrahpasa School Of Medicine, Istanbul 34098, Turkey.
⁵⁴ Department of Neurology, University Hospital of Wales, Cardiff CF14 4XW, UK.
⁵⁵ Division of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff CF14 4XN, UK.
⁵⁶ Department of Neurology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels 1200, Belgium.
⁵⁷ Université de Lyon, Université Claude Bernard Lyon 1, Lyon-Villeurbanne 69100, France.
⁵⁸ Observatoire Français de la Sclérose en Plaques, Centre de Recherche en Neurosciences de Lyon, INSERM 1028 et CNRS UMR 5292, Lyon-Bron 69677, France.
⁵⁹ Eugène Devic EDMUS Foundation against multiple sclerosis, Bron 69500, France.
⁶⁰ Jacobs School of Medicine and Biomedical Sciences, SUNY University at Buffalo, UB Neurology, Buffalo 14203, NY, USA.
⁶¹ Department of Neurology, Focus Program Translational Neuroscience (FTN), and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany.
⁶² Sorbonne Université, Paris Brain Institute, ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière AP-HP, Paris 75013, France.

PMID: 39707906
PMCID: PMC12073975
DOI: 10.1093/brain/awae409

Review

De-escalating and discontinuing disease-modifying therapies in multiple sclerosis

Géraldine Androdias et al. Brain. 2025.

. 2025 May 13;148(5):1459-1478.

doi: 10.1093/brain/awae409.

Authors

Affiliations

¹ Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, Centre de Ressources, Recherche et Compétence sur la Sclérose en Plaques, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69677 Lyon-Bron, France.
² Clinique de la Sauvegarde, Ramsay Santé, Lyon 69009, France.
³ Department of Neurology with Institute of Translational Neurology, University and University Hospital Münster, Münster 48149, Germany.
⁴ Department of Neurology, Multiple Sclerosis Center, Pitié-Salpêtrière Hospital, AP-HP, Paris 75013, France.
⁵ Departmente NEUROFARBA, University of Florence, Florence 50139, Italy.
⁶ IRCCS Fondazione Don Carlo Gnocchi, Florence 50143, Italy.
⁷ Department of Neurology, University Hospital of Marseille, Marseille 13005, France.
⁸ Centre de Résonance Magnétique Biologique et Médicale (CRMBM), CNRS, Aix Marseille University, Marseille Cedex 5 13385, France.
⁹ Department of Neurology, Erasmus Medical Center, Rotterdam 3015 GD, The Netherlands.
¹⁰ Department of Neurology, Medical University of Vienna, Vienna 1090, Austria.
¹¹ Comprehensive Center for Clinical Neurosciences and Mental Health, Medical University of Vienna, Vienna 1090, Austria.
¹² Department of Neuroscience, School of Translational Medicine, Monash University, Melbourne 3004, Australia.
¹³ Department of Neurology, Alfred Health, Melbourne 3004, Australia.
¹⁴ Queen Square MS Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK.
¹⁵ National Institute for Health and Care Research (NIHR), University College London Hospitals (UCLH) Biomedical Research Centre, London WC1B 5EH, UK.
¹⁶ Department of Neurology, Multiple Sclerosis Centre of Catalonia (Cemcat), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona 08035, Spain.
¹⁷ Departments of Neurology and Biomedicine, University Hospital Basel, Basel 4031, Switzerland.
¹⁸ Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Basel, Basel 4031, Switzerland.
¹⁹ Department of Neurology, Medical University of Innsbruck, Innsbruck 6020, Austria.
²⁰ Department of Neurology, University Hospital of Rennes, Rennes 35033, France.
²¹ CIC-P 1414 INSERM, University Hospital of Rennes, Rennes 35033, France.
²² Department of Neurology, Medical University of Graz, Graz 8010, Austria.
²³ NMO service, Department of Neurology, Oxford University Hospitals, Oxford OX3 9DU, UK.
²⁴ Nuffield Department of Clinical Neurosciences, Oxford University, Oxford OX3 9DU, UK.
²⁵ Neurology Clinic and Policlinic, Departments of Medicine, Clinical Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel 4031, Switzerland.
²⁶ Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, University Hospital Basel and University of Basel, Basel 4031, Switzerland.
²⁷ Queen Square MS Centre, Department of Neuroinflammation, Faculty of Brain Sciences, UCL Queen Square Institute of Neurology, UCL, London WC1N 3BG, UK.
²⁸ Department of Neurology, Great Ormond Street Hospital for Children, London WC1N 3JH, UK.
²⁹ Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf 40225, Germany.
³⁰ Brain and Mind Center, Medical Faculty, University of Sydney, Sydney, NSW 2050, Australia.
³¹ Department of Neurology, Palacky University Olomouc, Olomouc 77900, Czech Republic.
³² School of Health Sciences, College of Medicine, Nursing and Health Sciences, University of Galway, Galway H91 TK33, UK.
³³ Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa 16132, Italy.
³⁴ MS Center, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy.
³⁵ Departments of Head Spine and Neuromedicine, Biomedicine, Research and Biomedical Engineering, University Hospital Basel and University of Basel, Basel 4031, Switzerland.
³⁶ Tampere University Hospital, Department of Neurology, Tampere 33520, Finland.
³⁷ University of Eastern Finland, Faculty of Social and Welfare Management, Kuopio 70211, Finland.
³⁸ Neurology Department, Los Angeles Medical Center, Southern California Permanente Medical Group, Kaiser Permanente, Los Angeles, CA 90027, USA.
³⁹ Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital-Rigshospitalet, Glostrup 2600, Denmark.
⁴⁰ Danish Multiple Sclerosis Registry, Copenhagen University Hospital-Rigshospitalet, Glostrup 2600, Denmark.
⁴¹ Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2100, Denmark.
⁴² Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon-Bron 69677, France.
⁴³ Faculty of Medicine, UVIC-UCC Universitat Central de Catalunya, Vic 08500, Spain.
⁴⁴ Department of Neurology, University of Warmia and Mazury, Olsztyn 10719, Poland.
⁴⁵ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore 21287, MD, USA.
⁴⁶ Division of Neurology, Department of Medicine, St. Michael's Hospital, University of Toronto, Toronto M5B1W8, Canada.
⁴⁷ Department of Neurology, Hospital Clinico San Carlos, IdISSC, Madrid 28040, Spain.
⁴⁸ Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.
⁴⁹ Department of Clinical Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden.
⁵⁰ Department of Neurology, Karolinska University Hospital, S171 76 Stockholm, Sweden.
⁵¹ MS Unit, S. Camillo-Forlanini Hospital, Rome 00152, Italy.
⁵² Center of Neurology, Lodz 90-324, Poland.
⁵³ Clinical Neuroimmunology Unit & MS Clinic, Department Of Neurology, Istanbul University Cerrahpasa School Of Medicine, Istanbul 34098, Turkey.
⁵⁴ Department of Neurology, University Hospital of Wales, Cardiff CF14 4XW, UK.
⁵⁵ Division of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff CF14 4XN, UK.
⁵⁶ Department of Neurology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels 1200, Belgium.
⁵⁷ Université de Lyon, Université Claude Bernard Lyon 1, Lyon-Villeurbanne 69100, France.
⁵⁸ Observatoire Français de la Sclérose en Plaques, Centre de Recherche en Neurosciences de Lyon, INSERM 1028 et CNRS UMR 5292, Lyon-Bron 69677, France.
⁵⁹ Eugène Devic EDMUS Foundation against multiple sclerosis, Bron 69500, France.
⁶⁰ Jacobs School of Medicine and Biomedical Sciences, SUNY University at Buffalo, UB Neurology, Buffalo 14203, NY, USA.
⁶¹ Department of Neurology, Focus Program Translational Neuroscience (FTN), and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany.
⁶² Sorbonne Université, Paris Brain Institute, ICM, Inserm, CNRS, Hôpital de la Pitié Salpêtrière AP-HP, Paris 75013, France.

PMID: 39707906
PMCID: PMC12073975
DOI: 10.1093/brain/awae409

Abstract

The development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has been highly successful in recent decades. It is now widely accepted that early initiation of DMTs after disease onset is associated with a better long-term prognosis. However, the question of when and how to de-escalate or discontinue DMTs remains open and critical. This topic was discussed during an international focused workshop organized by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in 2023. The aim was to review the current evidence on the rationale for, and the potential pitfalls of, treatment de-escalation in MS. Several clinical scenarios emerged, mainly driven by a change in the benefit-risk ratio of DMTs over the course of the disease and with ageing. The workshop also addressed the issue of de-escalation by the type of DMT used and in specific situations, including pregnancy and paediatric onset MS. Finally, we provide practical guidelines for selecting appropriate patients, defining de-escalation and monitoring modalities and outlining unmet needs in this field.

Keywords: ageing; de-escalation; discontinuation; disease-modifying therapy; multiple sclerosis; pregnancy.

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Conflict of interest statement

G.A. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Jannsen, Merck, Novartis, Roche and Sanofi-Genzyme. J.D.L. has received honoraria for acting as a member of Scientific Advisory Boards for Abbvie, Alexion, Argenx, Moderna, Sanofi and Takeda as well as speaker honoraria and travel support from Alexion, Argenx, Biogen, Roche Pharma AG, Merck, Moderna, Novartis, and Sanofi. His research is funded by the European Union, Deutsche Forschungsgesellschaft (DFG), Alexion, Argenx, Moderna, and Roche Pharma AG. E.M. reports research support from Biogen and ARSEP foundation and personal fees for lectures and advisory boards from Biogen, Janssen, Merck, Novartis, Roche, Sanofi, Teva. M.P.A. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Jannsen, Merck, Novartis, Roche, Sanofi-Genzyme, Sandoz and Celgene BMS, and research grants by Novartis, Merck and Roche. G.B. has participated in meetings sponsored by, received speaker honoraria or travel funding from Biogen, Celgene/BMS, Janssen, Lilly, Merck, Novartis, Roche, Sanofi-Genzyme and Teva, and received honoraria for consulting Biogen, Celgene/BMS, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. He has received unrestricted research grants from Celgene/BMS and Novartis. H.B. received institutional (Monash University) funding from Biogen, Hoffmann-La Roche Ltd, Merck, UCB, TEVA and Novartis for research projects, speaker honoraria and steering committee activities. He has received travel support from Novartis and Merck. O.C.: NIHR Research Professor (RP-2017-08-ST2-004); over the last 2 years, member of independent DSMB for Novartis; she gave a teaching talk in a Merck local symposium, and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium; she has received research grant support from the MS Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre, the Rosetree Trust, the National MS Society, and the NIHR-HTA. A.C.C. has received grant from Instituto de Salud Carlos III, Spain; JR19/00007. T.D. received speaker fees, research support, travel support, and/or served on Advisory Boards or Steering Committees of Alexion, Novartis, Merck, Biogen, GeNeuro, MedDay, Roche, and Sanofi Genzyme. F.D.P. has participated in meetings sponsored by, received honoraria (lectures, advisory boards, consultations) or travel funding from Amgen, Bayer, Biogen, Celgene, Horizon, Merck, Novartis, Sanofi-Genzyme, Roche and Teva. G.E. is the technical and scientific coordinator (RST) of the RHU Primus since 2021, having a partnership with the industrials Merck, Biogen, Pixyl for this research and economic program. C.E. has received personal compensation for consulting or speaking from Biogen-Idec, BMS, EMD-Serono, Novartis, Roche, and Sanofi-Genzyme. R.G. received support for scientific meetings and courses from Bayer, Biogen, Merck, Novartis, Jasen and honoraria for advisory work or talks from Biogen, Novartis, UCB, MIAC. C.G.: The University Hospital Basel (USB) and the Research Center for Clinical neuroimmunology and Neuroscience (RC2NB), as the employers of Cristina Granziera, have received the following fees which were used exclusively for (research support from Siemens, GeNeuro, Genzyme-Sanofi, Biogen, Roche. They also have received advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro, Merck, Biogen and Roche; as well as speaker fees from Genzyme-Sanofi, Novartis, GeNeuro, Merck, Biogen and Roche. H.P.H. received honoraria for serving on SC, DMC or speaking at symposia from Biogen, BMS Celgene, Merck, Novartis, Roche, Sanofi, TG Therapeutics; for work as section chief editor of Frontiers Neurology/Immunology. M.I. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, Biogen, Brystol Meyer Squibb, Janssen, Merck, Novartis, Roche and Sanofi-Genzyme. L.K.: Ludwig Kappos’ institutions (University Hospital Basel and RC2NB) have received compensation that was used exclusively to support research, for the following: consultancy fees from Bayer HealthCare, Biogen, Bristol Myers Squibb, Celltrion Inc., Eli Lilly SA, EMD Serono Research and Development, GlaxoSmithKline, Galapagos NV, Janssen, Japan Tobacco Inc., Kiniksa Pharmaceuticals, Merck Healthcare AG, Minoryx, Neurostatus UHB AG, Novartis, Roche, Sanofi, Santhera Pharmaceuticals, Shionogi BV, Wellmera AG, and Zai Lab; contracted research from the European Union, InnoSwiss, Merck Healthcare AG, Novartis, Neurostatus UHB AG, Sanofi, and Roche; speaker fees and support of educational activities from Bristol Myers Squibb, Janssen, Roche, Sanofi, Merck, and Novartis; serving on the steering committee or advisory board for Biogen, EMD Serono Research and Development, Genentech, Janssen, Novartis, Clene Nanomedicine Inc., and Sanofi. H.K. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or participated in clinical trials from Merck, Sanofi, Novartis, Roche, Celgene, Jansen Cilag, Biogen, Sandoz, Argenx and Alexion. Research funding from Academy of Finland Strategic Research Council (31213358415) and the State funding for university-level health research, Tampere University Hospital, Finland (9AC042). A.L.G. has received grant support and awards from the Patient-Centered Outcomes Research Institute, the National MS Society, and Atara Biotherapeutics. She currently serves as a voting member on the California Technology Assessment Forum, a core program of the Institute for Clinical and Economic Review (ICER). M.M. served on scientific advisory board, as consultant for, received support for congress participation or speaker honoraria from Biogen, Sanofi, Roche, Novartis, Merck, Alexion and Bristol Myers Squibb. The Danish MS Registry received research support from Biogen, Genzyme, Roche, Merck and Novartis. R.M. serves on scientific advisory boards for Amgen/Horizon Therapeutics, UCB and Roche; and has received funding for travel and fees from Amgen, Alexion, Biogen, Roche. X.M. has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic Therapeutics, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS. M.P.M. has received speaking fees from Sanofi, Biogen, Merck, Serono, Novartis, Roche, Boehringer Ingelheim, Bristol Myers Squibb and Teva. B.N. has received research funding from the US National Multiple Sclerosis Society, the US National Institutes of Health, the US Department of Defense, PCORI, Genentech, and Axsome Therapeutics. He has received consulting honoraria from TG Therapeutics and Alkermes. J.O. has received grant funding from Brain Canada, MS Canada, the National MS Society, Biogen-Idec, Roche, and EMD-Serono and has received personal compensation for consulting or speaking from: Biogen-Idec, BMS, EMD-Serono, Eli-Lilly, Horizon Therapeutics, Novartis, Roche, and Sanofi-Genzyme. C.O.G. has received speaking and/or consultancy fees from Alexion, Biogen, BMS, Jannsen, Merck, Novartis, Roche, Sanofi, and Teva. F.P. has received research grants from Janssen, Merck KGaA and UCB, and fees for serving on DMC in clinical trials with Chugai, Lundbeck and Roche, and preparation of expert witness statement for Novartis. L.P. has received personal fees and non-financial support from Biogen, Bristol-Myers Squibb, Merck, Novartis, Roche, Sanofi and Viatris. J.S.G. received compensation in the last 24 months for consulting services and speaking honoraria from BMS, Sanofi, Merck, Janssen, Novartis, and Roche, is scientific director of Revista de Neurología and member of the editorial committee of Multiple Sclerosis Journal, for which he receives an honorarium. He has received research support from Fondo de Investigación en Salud (PI19/00950 and PI22/00750) from Instituto de Salud Carlos III, Spain. F.S. has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Biogen, Bristol Myers Squibb, Lundbeck, Merck, Novartis, Roche and Sanofi Genzyme, and has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme for his laboratory. K.S. has received personal compensation for consulting from Biogen, Celgene, GeNeuro, Merck, Novartis, Polpharma, Sanofi, Roche, TG Therapeutics, and received research support from Merck and Roche. A.S. has received research grants from The Turkish Multiple Sclerosis Society; and research grants from The Scientific and Technological Research Council Of Turkey & Istanbul University-Cerrahpasa Research Support Funds and has received honoraria or consultancy fees for participating to advisory boards, giving educational lectures and/or travel and registration coverage for attending scientific congresses or symposia from F. Hoffmann-La Roche Ltd, Merck-Serono, Novartis, Teva, Biogen Idec/Gen Pharma of Turkey, Alexion, Abdi Ibrahim Ilaç and Ali Raif Ilaç. E.T. has received honorarium for consulting work from Biogen, Janssen, Merck, Novartis, and Roche in the last 5 years. She has received travel grants to attend or speak at educational meetings from Biogen, Merck, Roche, Takeda and Novartis. V.v.P. received travel grants from Merck Healthcare KGaA (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb, Almirall and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare KGaA (Darmstadt, Germany), Bristol Meyer Squibb, Janssen, Almirall, Novartis Pharma, and Alexion. S.V. has received non-personal consulting and lecturing fees, travel grants and unconditional research support from Biogen, Janssen, Merck, Novartis, Roche, Sandoz and Sanofi. B.W.G. served as a consultant for Biogen, EMD Serono, Novartis, Genentech, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, Bayer, Janssen, Labcorp, Horizon and SANA. She also has received grant/research support from Novartis, Biogen and Horizon/Amgen. She serves in the editorial board for Children, CNS Drugs, MS International, Journal of Neurology and Frontiers Epidemiology. F.Z. has recently received research grants and/or consultation funds from Biogen, German Ministry of Education and Research (BMBF), Bristol-Meyers-Squibb, Celgene, German Research Foundation (DFG), Janssen, Max-Planck-Society (MPG), Merck Serono, Novartis, Progressive MS Alliance (PMSA), Roche, Sanofi Genzyme and Sandoz. M.T. has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Immunic Therapeutics, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma, Relapse Adjudication Committee for IMCYSE SA. E.I. has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme, and Merck and speaker's fees from Biogen and Sanofi-Genzyme. She has received an unrestricted research grant from Sanofi-Genzyme and research funding from Region Stockholm Clinical Research Appointment, Neuro Sweden and the Lindholm Fredholms Foundation. B.S. has received lecturing fees from Biogen Idec, Merck-Serono, Novartis, Sanofi and Janssen, and unconditional research support (to the institution) from Merck-Serono, Novartis, and Roche. The other authors report no competing interests.

Figures

**Figure 1**
**Rationale for de-escalation in multiple sclerosis**. PIRA = progression independent of relapse activity. *The benefit-risk ratio may be influenced by individual factors (cf. Fig. 2).

**Figure 2**
**Main factors influencing the benefit-risk balance of long-term disease-modifying therapies.** COPD = chronic obstructive pulmonary disease; DMF = dimethylfumarate; DMTs = disease-modifying therapies; HPV = human papillomavirus; JCV = John Cunningham virus; NTZ = natalizumab; OCR = ocrelizumab; RTX = rituximab; S1PRM = sphingosine-1-phosphate-receptor modulators.

**Figure 3**
**Main de-escalation scenarios depending on disease-modifying therapy subtypes.** DMT = disease-modifying therapies; EDSS = Expanded Disability Status Scale; IRT = immune reconstitution therapy; R/B = risk-benefit; y = years. *Proposed cut-off, take also into account disease duration.

**Figure 4**
**De-escalation strategies in the context of pregnancy planning.** GA = glatiramer acetate; IRT = immune reconstitution therapy; S1PR = sphingosine-1-phosphate receptor.

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References

1. Tintore M, Vidal-Jordana A, Sastre-Garriga J. Treatment of multiple sclerosis—Success from bench to bedside. Nat Rev Neurol. 2019;15:53–58. - PubMed
1. Lünemann JD, Ruck T, Muraro PA, Bar-Or A, Wiendl H. Immune reconstitution therapies: Concepts for durable remission in multiple sclerosis. Nat Rev Neurol. 2020;16:56–62. - PubMed
1. Chalmer TA, Baggesen LM, Nørgaard M, et al. . Early versus later treatment start in multiple sclerosis: A register-based cohort study. Eur J Neurol. 2018;25:1262-e110. - PubMed
1. Cobo-Calvo A, Tur C, Otero-Romero S, et al. . Association of very early treatment initiation with the risk of long-term disability in patients with a first demyelinating event. Neurology. 2023;101:e1280–e1292. - PMC - PubMed
1. Edan G, Le Page E. Escalation versus induction/high-efficacy treatment strategies for relapsing multiple sclerosis: Which is best for patients? Drugs. 2023;83:1351–1363. - PMC - PubMed

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De-escalating and discontinuing disease-modifying therapies in multiple sclerosis

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De-escalating and discontinuing disease-modifying therapies in multiple sclerosis

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