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.

Brain and Mind Center Medical Faculty University of Sydney Sydney NSW 2050 Australia

Center of Neurology Lodz 90 324 Poland

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

Centre de Résonance Magnétique Biologique et Médicale CNRS Aix Marseille University Marseille Cedex 5 13385 France

CIC P 1414 INSERM University Hospital of Rennes Rennes 35033 France

Clinical Neuroimmunology Unit and MS Clinic Department Of Neurology Istanbul University Cerrahpasa School Of Medicine Istanbul 34098 Turkey

Clinique de la Sauvegarde Ramsay Santé Lyon 69009 France

Comprehensive Center for Clinical Neurosciences and Mental Health Medical University of Vienna Vienna 1090 Austria

Danish Multiple Sclerosis Center Department of Neurology Copenhagen University Hospital Rigshospitalet Glostrup 2600 Denmark

Danish Multiple Sclerosis Registry Copenhagen University Hospital Rigshospitalet Glostrup 2600 Denmark

Departamento de Medicina Facultad de Medicina Universidad Complutense de Madrid 28040 Madrid Spain

Department of Clinical Medicine Faculty of Health and Medical Sciences University of Copenhagen Copenhagen 2100 Denmark

Department of Clinical Neuroscience Karolinska Institute 171 77 Stockholm Sweden

Department of Neurology Alfred Health Melbourne 3004 Australia

Department of Neurology Cliniques Universitaires Saint Luc UCLouvain Brussels 1200 Belgium

Department of Neurology Erasmus Medical Center Rotterdam 3015 GD The Netherlands

Department of Neurology Focus Program Translational Neuroscience University Medical Center of the Johannes Gutenberg University Mainz 55131 Germany

Department of Neurology Great Ormond Street Hospital for Children London WC1N 3JH UK

Department of Neurology Hospital Clinico San Carlos IdISSC Madrid 28040 Spain

Department of Neurology Johns Hopkins University School of Medicine Baltimore 21287 MD USA

Department of Neurology Karolinska University Hospital S171 76 Stockholm Sweden

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf 40225 Germany

Department of Neurology Medical University of Graz Graz 8010 Austria

Department of Neurology Medical University of Innsbruck Innsbruck 6020 Austria

Department of Neurology Medical University of Vienna Vienna 1090 Austria

Department of Neurology Multiple Sclerosis Center Pitié Salpêtrière Hospital AP HP Paris 75013 France

Department of Neurology Multiple Sclerosis Centre of Catalonia Hospital Universitari Vall d'Hebron Universitat Autònoma de Barcelona Barcelona 08035 Spain

Department of Neurology Palacky University Olomouc Olomouc 77900 Czech Republic

Department of Neurology University Hospital of Marseille Marseille 13005 France

Department of Neurology University Hospital of Rennes Rennes 35033 France

Department of Neurology University Hospital of Wales Cardiff CF14 4XW UK

Department of Neurology University of Warmia and Mazury Olsztyn 10719 Poland

Department of Neurology with Institute of Translational Neurology University and University Hospital Münster Münster 48149 Germany

Department of Neuroscience Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genoa Genoa 16132 Italy

Department of Neuroscience School of Translational Medicine Monash University Melbourne 3004 Australia

Departmente NEUROFARBA University of Florence Florence 50139 Italy

Departments of Head Spine and Neuromedicine Biomedicine Research and Biomedical Engineering University Hospital Basel and University of Basel Basel 4031 Switzerland

Departments of Neurology and Biomedicine University Hospital Basel Basel 4031 Switzerland

Division of Neurology Department of Medicine St Michael's Hospital University of Toronto Toronto M5B1W8 Canada

Division of Psychological Medicine and Clinical Neuroscience Cardiff University Cardiff CF14 4XN UK

Eugène Devic EDMUS Foundation against multiple sclerosis Bron 69500 France

Faculty of Medicine UVIC UCC Universitat Central de Catalunya Vic 08500 Spain

IRCCS Fondazione Don Carlo Gnocchi Florence 50143 Italy

Jacobs School of Medicine and Biomedical Sciences SUNY University at Buffalo UB Neurology Buffalo 14203 NY USA

MS Center IRCCS Ospedale Policlinico San Martino Genoa 16132 Italy

MS Unit S Camillo Forlanini Hospital Rome 00152 Italy

National Institute for Health and Care Research Biomedical Research Centre London WC1B 5EH UK

Neurology Clinic and Policlinic Departments of Medicine Clinical Research and Biomedical Engineering University Hospital Basel and University of Basel Basel 4031 Switzerland

Neurology Department Los Angeles Medical Center Southern California Permanente Medical Group Kaiser Permanente Los Angeles CA 90027 USA

NMO service Department of Neurology Oxford University Hospitals Oxford OX3 9DU UK

Nuffield Department of Clinical Neurosciences Oxford University Oxford OX3 9DU UK

Observatoire Français de la Sclérose en Plaques Centre de Recherche en Neurosciences de Lyon INSERM 1028 et CNRS UMR 5292 Lyon Bron 69677 France

Queen Square MS Centre Department of Neuroinflammation Faculty of Brain Sciences UCL Queen Square Institute of Neurology UCL London WC1N 3BG UK

Queen Square MS Centre Department of Neuroinflammation UCL Queen Square Institute of Neurology London WC1N 3BG UK

Research Center for Clinical Neuroimmunology and Neuroscience Basel University Basel Basel 4031 Switzerland

School of Health Sciences College of Medicine Nursing and Health Sciences University of Galway Galway H91 TK33 UK

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

Sorbonne Université Paris Brain Institute ICM Inserm CNRS Hôpital de la Pitié Salpêtrière AP HP Paris 75013 France

Tampere University Hospital Department of Neurology Tampere 33520 Finland

Translational Imaging in Neurology Basel Department of Biomedical Engineering University Hospital Basel and University of Basel Basel 4031 Switzerland

Université de Lyon Université Claude Bernard Lyon 1 Lyon Villeurbanne 69100 France

University of Eastern Finland Faculty of Social and Welfare Management Kuopio 70211 Finland

Zobrazit více v PubMed

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

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

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

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. PubMed PMC

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. PubMed PMC

Prosperini L, Mancinelli CR, Solaro CM, et al. . Induction versus escalation in multiple sclerosis: A 10-year real world study. Neurotherapeutics. 2020;17:994–1004. PubMed PMC

Edan G, Comi G, Le Page E, et al. . Mitoxantrone prior to interferon beta-1b in aggressive relapsing multiple sclerosis: A 3-year randomised trial. J Neurol Neurosurg Psychiatry. 2011;82:1344–1350. PubMed

Muraro PA, Martin R, Mancardi GL, Nicholas R, Sormani MP, Saccardi R. Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis. Nat Rev Neurol. 2017;13:391–405. PubMed

Giovannoni G, Singer BA, Issard D, Jack D, Vermersch P. Durability of no evidence of disease activity-3 (NEDA-3) in patients receiving cladribine tablets: The CLARITY extension study. Mult Scler. 2022;28:1219–1228. PubMed PMC

Coles AJ, Jones JL, Vermersch P, et al. . Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data. Mult Scler. 2022;28:842–846. PubMed PMC

Hartung HP, Meuth SG, Miller DM, Comi G. Stopping disease-modifying therapy in relapsing and progressive multiple sclerosis. Curr Opin Neurol. 2021;34:598–603. PubMed

Pérez-García JM, Cortés J, Ruiz-Borrego M, et al. . 3-year invasive disease-free survival with chemotherapy de-escalation using an 18F-FDG-PET-based, pathological complete response-adapted strategy in HER2-positive early breast cancer (PHERGain): A randomised, open-label, phase 2 trial. Lancet. 2024;403:1649–1659. PubMed

Tanaka Y, Yamaguchi A, Miyamoto T, et al. . Selection of treatment regimens based on shared decision-making in patients with rheumatoid arthritis on remission in the FREE-J study. Rheumatology (Oxford). 2022;61:4273–4285. PubMed PMC

Perdaens O, van Pesch V. Molecular mechanisms of immunosenescene and inflammaging: Relevance to the immunopathogenesis and treatment of multiple sclerosis. Front Neurol. 2021;12:811518. PubMed PMC

Olsson J, Wikby A, Johansson B, Löfgren S, Nilsson BO, Ferguson FG. Age-related change in peripheral blood T-lymphocyte subpopulations and cytomegalovirus infection in the very old: The Swedish longitudinal OCTO immune study. Mech Ageing Dev. 2000;121:187–201. PubMed

Scholz JL, Diaz A, Riley RL, Cancro MP, Frasca D. A comparative review of aging and B cell function in mice and humans. Curr Opin Immunol. 2013;25:504–510. PubMed PMC

Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T. Innate immunosenescence: Effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol. 2012;24:331–341. PubMed

Franceschi C, Bonafè M, Valensin S, et al. . Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–254. PubMed

Lassmann H. Pathogenic mechanisms associated with different clinical courses of multiple sclerosis. Front Immunol. 2018;9:3116. PubMed PMC

Kuhlmann T, Moccia M, Coetzee T, et al. . Multiple sclerosis progression: Time for a new mechanism-driven framework. Lancet Neurol. 2023;22:78–88. PubMed PMC

Kutzelnigg A, Lucchinetti CF, Stadelmann C, et al. . Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005;128(Pt 11):2705–2712. PubMed

Androdias G, Reynolds R, Chanal M, Ritleng C, Confavreux C, Nataf S. Meningeal T cells associate with diffuse axonal loss in multiple sclerosis spinal cords. Ann Neurol. 2010;68:465–476. PubMed

Tallantyre EC, Bø L, Al-Rawashdeh O, et al. . Clinico-pathological evidence that axonal loss underlies disability in progressive multiple sclerosis. Mult Scler. 2010;16:406–411. PubMed

Lublin FD, Häring DA, Ganjgahi H, et al. . How patients with multiple sclerosis acquire disability. Brain. 2022;145:3147–3161. PubMed PMC

Tur C, Carbonell-Mirabent P, Cobo-Calvo Á, et al. . Association of early progression independent of relapse activity with long-term disability after a first demyelinating event in multiple sclerosis. JAMA Neurol. 2023;80:151–160. PubMed PMC

Confavreux C, Vukusic S. Natural history of multiple sclerosis: A unifying concept. Brain. 2006;129(Pt 3):606–616. PubMed

Tutuncu M, Tang J, Zeid NA, et al. . Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler. 2013;19:188–198. PubMed PMC

Vaughn CB, Jakimovski D, Kavak KS, et al. . Epidemiology and treatment of multiple sclerosis in elderly populations. Nat Rev Neurol. 2019;15:329–342. PubMed

Tremlett H, Zhao Y, Joseph J, Devonshire V. UBCMS clinic neurologists. Relapses in multiple sclerosis are age- and time-dependent. J Neurol Neurosurg Psychiatry. 2008;79:1368–1374. PubMed

Koch MW, Mostert J, Zhang Y, et al. . Association of age with contrast-enhancing lesions across the multiple sclerosis disease Spectrum. Neurology. 2021;97:e1334–e1342. PubMed PMC

Schweitzer F, Laurent S, Fink GR, et al. . Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Curr Opin Neurol. 2019;32:305–312. PubMed

Mouresan EF, Mentesidou E, Berglund A, McKay KA, Hillert J, Iacobaeus E. Clinical characteristics and long-term outcomes of late-onset multiple sclerosis: A Swedish nationwide study. Neurology. 2024;102:e208051. PubMed PMC

Foong YC, Merlo D, Gresle M, et al. . Comparing ocrelizumab to interferon/glatiramer acetate in people with multiple sclerosis over age 60. J Neurol Neurosurg Psychiatry. 2024;95:767–774. PubMed

Brown JWL, Coles A, Horakova D, et al. . Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis. JAMA. 2019;321:175–187. PubMed PMC

Kapoor R, Ho PR, Campbell N, et al. . Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): A phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension. Lancet Neurol. 2018;17:405–415. PubMed

Kappos L, Bar-Or A, Cree BAC, et al. . Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): A double-blind, randomised, phase 3 study. Lancet. 2018;391:1263–1273. PubMed

Montalban X, Hauser SL, Kappos L, et al. . Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376:209–220. PubMed

Luna G, Alping P, Burman J, et al. . Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol. 2020;77:184–191. PubMed PMC

Alping P, Burman J, Lycke J, Frisell T, Piehl F. Safety of alemtuzumab and autologous hematopoietic stem cell transplantation compared to noninduction therapies for multiple sclerosis. Neurology. 2021;96:e1574–e1584. PubMed PMC

Langer-Gould A, Li BH, Smith JB, Xu S. Multiple sclerosis, rituximab, hypogammaglobulinemia, and risk of infections. Neurol Neuroimmunol Neuroinflamm. 2024;11:e200211. PubMed PMC

Vollmer BL, Wallach AI, Corboy JR, Dubovskaya K, Alvarez E, Kister I. Serious safety events in rituximab-treated multiple sclerosis and related disorders. Ann Clin Transl Neurol. 2020;7:1477–1487. PubMed PMC

Virtanen S, Piehl F, Frisell T. Impact of previous treatment history and B-cell depletion treatment duration on infection risk in relapsing-remitting multiple sclerosis: A nationwide cohort study. J Neurol Neurosurg Psychiatry. 2024;95:1150–1157. PubMed PMC

Hauser SL, Kappos L, Montalban X, et al. . Safety of ocrelizumab in patients with relapsing and primary progressive multiple sclerosis. Neurology. 2021;97:e1546–e1559. PubMed PMC

Berger JR, Cree BA, Greenberg B, et al. . Progressive multifocal leukoencephalopathy after fingolimod treatment. Neurology. 2018;90:e1815–e1821. PubMed PMC

Prosperini L, Scarpazza C, Imberti L, Cordioli C, De Rossi N, Capra R. Age as a risk factor for early onset of natalizumab-related progressive multifocal leukoencephalopathy. J Neurovirol. 2017;23:742–749. PubMed

Jordan AL, Yang J, Fisher CJ, Racke MK, Mao-Draayer Y. Progressive multifocal leukoencephalopathy in dimethyl fumarate-treated multiple sclerosis patients. Mult Scler. 2022;28:7–15. PubMed PMC

Bloomgren G, Richman S, Hotermans C, et al. . Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870–1880. PubMed

Grebenciucova E, Reder AT, Bernard JT. Immunologic mechanisms of fingolimod and the role of immunosenescence in the risk of cryptococcal infection: A case report and review of literature. Mult Scler Relat Disord. 2016;9:158–162. PubMed

Briner M, Bagnoud M, Miclea A, et al. . Time course of lymphocyte repopulation after dimethyl fumarate-induced grade 3 lymphopenia: Contribution of patient age. Ther Adv Neurol Disord. 2019;12:1756286419843450. PubMed PMC

Bar-Or A, Calkwood JC, Chognot C, et al. . Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study. Neurology. 2020;95:e1999–e2008. PubMed PMC

Tallantyre EC, Vickaryous N, Anderson V, et al. . COVID-19 Vaccine response in people with multiple sclerosis. Ann Neurol. 2022;91:89–100. PubMed PMC

Lebrun C, Rocher F. Cancer risk in patients with multiple sclerosis: Potential impact of disease-modifying drugs. CNS Drugs. 2018;32:939–949. PubMed

Confavreux C, Saddier P, Grimaud J, Moreau T, Adeleine P, Aimard G. Risk of cancer from azathioprine therapy in multiple sclerosis: A case-control study. Neurology. 1996;46:1607–1612. PubMed

Alping P, Askling J, Burman J, et al. . Cancer risk for fingolimod, natalizumab, and rituximab in multiple sclerosis patients. Ann Neurol. 2020;87:688–699. PubMed

Stamatellos VP, Rigas A, Stamoula E, Lallas A, Papadopoulou A, Papazisis G. S1p receptor modulators in multiple sclerosis: Detecting a potential skin cancer safety signal. Mult Scler Relat Disord. 2022;59:103681. PubMed

Prosperini L, Haggiag S, Tortorella C, Galgani S, Gasperini C. Age-related adverse events of disease-modifying treatments for multiple sclerosis: A meta-regression. Mult Scler. 2021;27:1391–1402. PubMed

Marrie RA, Fisk JD, Fitzgerald K, et al. . Etiology, effects and management of comorbidities in multiple sclerosis: Recent advances. Front Immunol. 2023;14:1197195. PubMed PMC

Hua LH, Harris H, Conway D, Thompson NR. Changes in patient-reported outcomes between continuers and discontinuers of disease modifying therapy in patients with multiple sclerosis over age 60. Mult Scler Relat Disord. 2019;30:252–256. PubMed

Tallantyre EC, Dobson R, Froud JLJ, et al. . Real-world persistence of multiple sclerosis disease-modifying therapies. Eur J Neurol. 2024;31:e16289. PubMed PMC

Alping P, Neovius M, Piehl F, Frisell T. Real-World healthcare cost savings and reduced relapse rate with off-label rituximab versus disease-modifying treatments approved for relapsing-remitting multiple sclerosis: A nationwide cost-effectiveness study. Ann Neurol. 2024;95:1099–1111. PubMed

Khakban A, Rodriguez Llorian E, Michaux KD, et al. . Direct health care costs associated with multiple sclerosis: A population-based cohort study in British Columbia, Canada, 2001–2020. Neurology. 2023;100:e899–e910. PubMed PMC

Simoens S. Societal economic burden of multiple sclerosis and cost-effectiveness of disease-modifying therapies. Front Neurol. 2022;13:1015256. PubMed PMC

Lublin FD, Reingold SC, Cohen JA, et al. . Defining the clinical course of multiple sclerosis: The 2013 revisions. Neurology. 2014;83:278–286. PubMed PMC

Jouvenot G, Courbon G, Lefort M, et al. . High-Efficacy therapy discontinuation vs continuation in patients 50 years and older with nonactive MS. JAMA Neurol. 2024;81:490–498. PubMed PMC

Chappuis M, Rousseau C, Bajeux E, et al. . Discontinuation of second- versus first-line disease-modifying treatment in middle-aged patients with multiple sclerosis. J Neurol. 2023;270:413–422. PubMed

Corboy JR, Fox RJ, Kister I, et al. . Risk of new disease activity in patients with multiple sclerosis who continue or discontinue disease-modifying therapies (DISCOMS): A multicentre, randomised, single-blind, phase 4, non-inferiority trial. Lancet Neurol. 2023;22:568–577. PubMed

Gisela Z, Carla P, Josefina B, et al. . Disease activity after discontinuation of disease-modifying therapies in patients with multiple sclerosis in Argentina: Data from the nationwide registry RelevarEM. Neurol Res. 2023;45:112–117. PubMed

Jakimovski D, Kavak KS, Vaughn CB, et al. . Discontinuation of disease modifying therapies is associated with disability progression regardless of prior stable disease and age. Mult Scler Relat Disord. 2022;57:103406. PubMed

Roos I, Malpas C, Leray E, et al. . Disease reactivation after cessation of disease-modifying therapy in patients with relapsing-remitting multiple sclerosis. Neurology. 2022;99:e1926–e1944. PubMed PMC

Bsteh G, Hegen H, Riedl K, et al. . Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: The VIAADISC score. Eur J Neurol. 2021;28:1609–1616. PubMed PMC

McFaul D, Hakopian NN, Smith JB, Nielsen AS, Langer-Gould A. Defining benign/burnt-out MS and discontinuing disease-modifying therapies. Neurol Neuroimmunol Neuroinflamm. 2021;8:e960. PubMed PMC

Pasca M, Forci B, Mariottini A, et al. . Sustained disease remission after discontinuation of disease modifying treatments in relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2021;47:102591. PubMed

Kaminsky AL, Omorou AY, Soudant M, et al. . Discontinuation of disease-modifying treatments for multiple sclerosis in patients aged over 50 with disease inactivity. J Neurol. 2020;267:3518–3527. PubMed

Yano H, Gonzalez C, Healy BC, Glanz BI, Weiner HL, Chitnis T. Discontinuation of disease-modifying therapy for patients with relapsing-remitting multiple sclerosis: Effect on clinical and MRI outcomes. Mult Scler Relat Disord. 2019;35:119–127. PubMed

Prosperini L, Kinkel RP, Miravalle AA, Iaffaldano P, Fantaccini S. Post-natalizumab disease reactivation in multiple sclerosis: Systematic review and meta-analysis. Ther Adv Neurol Disord. 2019;12:1756286419837809. PubMed PMC

Lo Re M, Capobianco M, Ragonese P, et al. . Natalizumab discontinuation and treatment strategies in patients with multiple sclerosis (MS): A retrospective study from two Italian MS centers. Neurol Ther. 2015;4:147–157. PubMed PMC

Hatcher SE, Waubant E, Nourbakhsh B, Crabtree-Hartman E, Graves JS. Rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment. JAMA Neurol. 2016;73:790–794. PubMed

Vidal-Jordana A, Tintoré M, Tur C, et al. . Significant clinical worsening after natalizumab withdrawal: Predictive factors. Mult Scler. 2015;21:780–785. PubMed

Litwin T, Smoliński Ł, Członkowka A. Substantial disease exacerbation in a patient with relapsing-remitting multiple sclerosis after withdrawal from siponimod. Neurol Neurochir Pol. 2018;52:98–101. PubMed

Juto A, Fink K, Al Nimer F, Piehl F. Interrupting rituximab treatment in relapsing-remitting multiple sclerosis; no evidence of rebound disease activity. Mult Scler Relat Disord. 2020;37:101468. PubMed

Mustonen T, Rauma I, Hartikainen P, et al. . Risk factors for reactivation of clinical disease activity in multiple sclerosis after natalizumab cessation. Mult Scler Relat Disord. 2020;38:101498. PubMed

Barry B, Erwin AA, Stevens J, Tornatore C. Fingolimod rebound: A review of the clinical experience and management considerations. Neurol Ther. 2019;8:241–250. PubMed PMC

Landi D, Signori A, Cellerino M, et al. . What happens after fingolimod discontinuation? A multicentre real-life experience. J Neurol. 2022;269:796–804. PubMed

Wandall-Holm MF, Holm RP, Heick A, Langkilde AR, Magyari M. Risk of T2 lesions when discontinuing fingolimod: A nationwide predictive and comparative study. Brain Commun. 2024;6:fcad358. PubMed PMC

Malpas CB, Roos I, Sharmin S, et al. . Multiple sclerosis relapses following cessation of fingolimod. Clin Drug Investig. 2022;42:355–364. PubMed PMC

Framke E, Pontieri L, Bramow S, Sellebjerg F, Magyari M. Rebound of clinical disease activity after fingolimod discontinuation? A nationwide cohort study of patients in Denmark. J Neurol Neurosurg Psychiatry. 2022;93:1317–1321. PubMed

Kister I, Spelman T, Alroughani R, et al. . Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: A propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016;87:1133–1137. PubMed

Bonenfant J, Bajeux E, Deburghgraeve V, Le Page E, Edan G, Kerbrat A. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. 2017;24:237–244. PubMed

Kappos L, Wolinsky JS, Giovannoni G, et al. . Contribution of relapse-independent progression vs relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials. JAMA Neurol. 2020;77:1132–1140. PubMed PMC

Gärtner J, Hauser SL, Bar-Or A, et al. . Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II. Mult Scler. 2022;28:1562–1575. PubMed PMC

Conway BL, Zeydan B, Uygunoğlu U, et al. . Age is a critical determinant in recovery from multiple sclerosis relapses. Mult Scler. 2019;25:1754–1763. PubMed

Hosny HS, Shehata HS, Ahmed S, Ramadan I, Abdo SS, Fouad AM. Predictors of severity and outcome of multiple sclerosis relapses. BMC Neurol. 2023;23:67. PubMed PMC

Sim FJ, Zhao C, Penderis J, Franklin RJM. The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J Neurosci. 2002;22:2451–2459. PubMed PMC

McGinley MP, Cola PA, Fox RJ, Cohen JA, Corboy JJ, Miller D. Perspectives of individuals with multiple sclerosis on discontinuation of disease-modifying therapies. Mult Scler. 2020;26:1581–1589. PubMed

Tallantyre EC, Major PC, Atherton MJ, et al. . How common is truly benign MS in a UK population? J Neurol Neurosurg Psychiatry. 2019;90:522–528. PubMed PMC

Freedman MS, Devonshire V, Duquette P, et al. . Treatment optimization in multiple sclerosis: Canadian MS working group recommendations. Can J Neurol Sci. 2020;47:437–455. PubMed

Rae-Grant A, Day GS, Marrie RA, et al. . Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the guideline development, dissemination, and implementation subcommittee of the American academy of neurology. Neurology. 2018;90:777–788. PubMed

Vollmer BL, Wolf AB, Sillau S, Corboy JR, Alvarez E. Evolution of disease modifying therapy benefits and risks: An argument for De-escalation as a treatment paradigm for patients with multiple sclerosis. Front Neurol. 2021;12:799138. PubMed PMC

Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in multiple sclerosis group. N Engl J Med. 1998;339:285–291. PubMed

Hellwig K, Tokic M, Thiel S, et al. . Multiple sclerosis disease activity and disability following discontinuation of natalizumab for pregnancy. JAMA Netw Open. 2022;5:e2144750. PubMed PMC

Krysko KM, Dobson R, Alroughani R, et al. . Family planning considerations in people with multiple sclerosis. Lancet Neurol. 2023;22:350–366. PubMed

Yeh WZ, Widyastuti PA, Van der Walt A, et al. . Natalizumab, fingolimod and dimethyl fumarate use and pregnancy-related relapse and disability in women with multiple sclerosis. Neurology. 2021;96:e2989–e3002. PubMed PMC

Bsteh G, Algrang L, Hegen H, et al. . Pregnancy and multiple sclerosis in the DMT era: A cohort study in western Austria. Mult Scler. 2020;26:69–78. PubMed

Razaz N, Piehl F, Frisell T, Langer-Gould AM, McKay KA, Fink K. Disease activity in pregnancy and postpartum in women with MS who suspended rituximab and natalizumab. Neurol Neuroimmunol Neuroinflamm. 2020;7:e903. PubMed PMC

Zhu C, Zhou Z, Roos I, et al. . Comparing switch to ocrelizumab, cladribine or natalizumab after fingolimod treatment cessation in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022;93:1330–1337. PubMed

Fragoso YD, Adoni T, Gomes S, et al. . Severe exacerbation of multiple sclerosis following withdrawal of fingolimod. Clin Drug Investig. 2019;39:909–913. PubMed

Foley JF, Defer G, Ryerson LZ, et al. . Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): A randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022;21:608–619. PubMed

Ryerson LZ, Foley J, Chang I, et al. . Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology. 2019;93:e1452–e1462. PubMed PMC

Sellner J, Rommer PS. A review of the evidence for a natalizumab exit strategy for patients with multiple sclerosis. Autoimmun Rev. 2019;18:255–261. PubMed

Cohan SL, Moses H, Calkwood J, et al. . Clinical outcomes in patients with relapsing-remitting multiple sclerosis who switch from natalizumab to delayed-release dimethyl fumarate: A multicenter retrospective observational study (STRATEGY). Mult Scler Relat Disord. 2018;22:27–34. PubMed

Cohan S, Gervasi-Follmar T, Kamath A, et al. . The results of a 24-month controlled, prospective study of relapsing multiple sclerosis patients at risk for progressive multifocal encephalopathy, who switched from prolonged use of natalizumab to teriflunomide. Mult Scler J Exp Transl Clin. 2021;7:20552173211066588. PubMed PMC

Iaffaldano P, Lucisano G, Pozzilli C, et al. . Fingolimod versus interferon beta/glatiramer acetate after natalizumab suspension in multiple sclerosis. Brain. 2015;138(Pt 11):3275–3286. PubMed

Alping P, Frisell T, Novakova L, et al. . Rituximab versus fingolimod after natalizumab in multiple sclerosis patients. Ann Neurol. 2016;79:950–958. PubMed

Bigaut K, Kremer L, Fabacher T, et al. . Ocrelizumab versus fingolimod after natalizumab cessation in multiple sclerosis: An observational study. J Neurol. 2022;269:3295–3300. PubMed PMC

Zhong M, van der Walt A, Monif M, et al. . Prediction of relapse activity when switching to cladribine for multiple sclerosis. Mult Scler. 2023;29:119–129. PubMed

Zanghì A, Gallo A, Avolio C, et al. . Exit strategies in natalizumab-treated RRMS at high risk of progressive multifocal leukoencephalopathy: A multicentre comparison study. Neurotherapeutics. 2021;18:1166–1174. PubMed PMC

Fox RJ, Cree BAC, De Sèze J, et al. . MS disease activity in RESTORE: A randomized 24-week natalizumab treatment interruption study. Neurology. 2014;82:1491–1498. PubMed PMC

Fragoso YD, Adoni T, Alves-Leon SV, et al. . Alternatives for reducing relapse rate when switching from natalizumab to fingolimod in multiple sclerosis. Expert Rev Clin Pharmacol. 2016;9:541–546. PubMed

Cohen M, Maillart E, Tourbah A, et al. . Switching from natalizumab to fingolimod in multiple sclerosis: A French prospective study. JAMA Neurol. 2014;71:436–441. PubMed

Verkkoniemi-Ahola A, Hartikainen P, Hassi K, et al. . Real-world treatment outcomes and safety of natalizumab in Finnish multiple sclerosis patients. Mult Scler J Exp Transl Clin. 2023;9:20552173231204466. PubMed PMC

Weinstock-Guttman B, Hagemeier J, Kavak KS, et al. . Randomised natalizumab discontinuation study: Taper protocol may prevent disease reactivation. J Neurol Neurosurg Psychiatry. 2016;87:937–943. PubMed

Toorop AA, van Lierop ZYG, Strijbis EEM, et al. . Mild progressive multifocal leukoencephalopathy after switching from natalizumab to ocrelizumab. Neurol Neuroimmunol Neuroinflamm. 2021;8:e904. PubMed PMC

Honce JM, Nair KV, Sillau S, et al. . Rituximab vs placebo induction prior to glatiramer acetate monotherapy in multiple sclerosis. Neurology. 2019;92:e723–e732. PubMed PMC

Baker D, Pryce G, James LK, Marta M, Schmierer K. The ocrelizumab phase II extension trial suggests the potential to improve the risk: Benefit balance in multiple sclerosis. Mult Scler Relat Disord. 2020;44:102279. PubMed

Starvaggi Cucuzza C, Longinetti E, Ruffin N, et al. . Sustained low relapse rate with highly Variable B-cell repopulation dynamics with extended rituximab dosing intervals in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2023;10:e200056. PubMed PMC

Claverie R, Perriguey M, Rico A, et al. . Efficacy of rituximab outlasts B-cell repopulation in multiple sclerosis: Time to rethink dosing? Neurol Neuroimmunol Neuroinflamm. 2023;10:e200152. PubMed PMC

Novak F, Bajwa HM, Østergaard K, et al. . Extended interval dosing with ocrelizumab in multiple sclerosis. Mult Scler. 2024;30:847–856. PubMed

Louapre C, Ibrahim M, Maillart E, et al. . Anti-CD20 therapies decrease humoral immune response to SARS-CoV-2 in patients with multiple sclerosis or neuromyelitis optica spectrum disorders. J Neurol Neurosurg Psychiatry. 2022;93:24–31. PubMed

Januel E, Hajage D, Labauge P, et al. . Association between anti-CD20 therapies and COVID-19 severity among patients with relapsing-remitting and progressive multiple sclerosis. JAMA Netw Open. 2023;6:e2319766. PubMed PMC

Maarouf A, Rico A, Boutiere C, et al. . Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond? Neurol Neuroimmunol Neuroinflamm. 2020;7:e825. PubMed PMC

Rico A, Ninove L, Maarouf A, et al. . Determining the best window for BNT162b2 mRNA vaccination for SARS-CoV-2 in patients with multiple sclerosis receiving anti-CD20 therapy. Mult Scler J Exp Transl Clin. 2021;7:20552173211062142. PubMed PMC

Asplund Högelin K, Ruffin N, Pin E, et al. . B-cell repopulation dynamics and drug pharmacokinetics impact SARS-CoV-2 vaccine efficacy in anti-CD20-treated multiple sclerosis patients. Eur J Neurol. 2022;29:3317–3328. PubMed PMC

Schuckmann A, Steffen F, Zipp F, Bittner S, Pape K. Impact of extended interval dosing of ocrelizumab on immunoglobulin levels in multiple sclerosis. Med. 2023;4:361–372.e3. PubMed

Hauser SL, Bar-Or A, Weber MS, et al. . Association of higher ocrelizumab exposure with reduced disability progression in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2023;10:e200094. PubMed PMC

Mariottini A, Muraro PA, Lünemann JD. Antibody-mediated cell depletion therapies in multiple sclerosis. Front Immunol. 2022;13:953649. PubMed PMC

Silfverberg T, Zjukovskaja C, Ljungman P, et al. . Haematopoietic stem cell transplantation for treatment of relapsing-remitting multiple sclerosis in Sweden: An observational cohort study. J Neurol Neurosurg Psychiatry. 2024;95:125–133. PubMed PMC

Kalincik T, Sharmin S, Roos I, et al. . Comparative effectiveness of autologous hematopoietic stem cell transplant vs fingolimod, natalizumab, and ocrelizumab in highly active relapsing-remitting multiple sclerosis. JAMA Neurol. 2023;80:702–713. PubMed PMC

Kalincik T, Sharmin S, Roos I, et al. . Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis. J Neurol Neurosurg Psychiatry. 2024;95:775–783 PubMed

Cohen JA, Coles AJ, Arnold DL, et al. . Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet. 2012;380:1819–1828. PubMed

Coles AJ, Twyman CL, Arnold DL, et al. . Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet. 2012;380:1829–1839. PubMed

Giovannoni G, Comi G, Cook S, et al. . A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362:416–426. PubMed

Coles AJ, Cohen JA, Fox EJ, et al. . Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings. Neurology. 2017;89:1117–1126. PubMed PMC

Atkins HL, Bowman M, Allan D, et al. . Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: A multicentre single-group phase 2 trial. Lancet. 2016;388:576–585. PubMed

Boffa G, Massacesi L, Inglese M, et al. . Long-term clinical outcomes of hematopoietic stem cell transplantation in multiple sclerosis. Neurology. 2021;96:e1215–e1226. PubMed

Burman J, Iacobaeus E, Svenningsson A, et al. . Autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: The Swedish experience. J Neurol Neurosurg Psychiatry. 2014;85:1116–1121. PubMed

Burt RK, Balabanov R, Burman J, et al. . Effect of nonmyeloablative hematopoietic stem cell transplantation vs continued disease-modifying therapy on disease progression in patients with relapsing-remitting multiple sclerosis: A randomized clinical trial. JAMA. 2019;321:165–174. PubMed PMC

Oreja-Guevara C, Brownlee W, Celius EG, et al. . Expert opinion on the long-term use of cladribine tablets for multiple sclerosis: Systematic literature review of real-world evidence. Mult Scler Relat Disord. 2023;69:104459. PubMed

Meuth SG, Bayas A, Kallmann B, et al. . Long-term management of multiple sclerosis patients treated with cladribine tablets beyond year 4. Expert Opin Pharmacother. 2022;23:1503–1510. PubMed

Vukusic S, Carra-Dalliere C, Ciron J, et al. . Pregnancy and multiple sclerosis: 2022 recommendations from the French multiple sclerosis society. Mult Scler. 2023;29:11–36. PubMed

Rød BE, Torkildsen Ø, Myhr KM, Bø L, Wergeland S. Safety of breast feeding during rituximab treatment in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2022;94:38–41. PubMed PMC

Chitnis T, Aaen G, Belman A, et al. . Improved relapse recovery in paediatric compared to adult multiple sclerosis. Brain. 2020;143:2733–2741. PubMed

Hacohen Y, Banwell B, Ciccarelli O. What does first-line therapy mean for paediatric multiple sclerosis in the current era? Mult Scler. 2021;27:1970–1976. PubMed

Renoux C, Vukusic S, Mikaeloff Y, et al. . Natural history of multiple sclerosis with childhood onset. N Engl J Med. 2007;356:2603–2613. PubMed

Kopp TI, Blinkenberg M, Petersen T, Sorensen PS, Magyari M. Long term effect of delayed treatment on disability in patients with paediatric onset multiple sclerosis: A prospective danish cohort study. Mult Scler Relat Disord. 2020;40:101956. PubMed

Benallegue N, Rollot F, Wiertlewski S, et al. . Highly effective therapies as first-line treatment for pediatric-onset multiple sclerosis. JAMA Neurol. 2024;81:273–282. PubMed PMC

Venet M, Lepine A, Maarouf A, et al. . Control of disease activity with large extended-interval dosing of rituximab/ocrelizumab in highly active pediatric multiple sclerosis. Mult Scler. 2024;30:261–265. PubMed

D’Souza M, Papadopoulou A, Girardey C, Kappos L. Standardization and digitization of clinical data in multiple sclerosis. Nat Rev Neurol. 2021;17:119–125. PubMed

Kuhle J, Kropshofer H, Haering DA, et al. . Blood neurofilament light chain as a biomarker of MS disease activity and treatment response. Neurology. 2019;92:e1007–e1015. PubMed PMC

Benkert P, Meier S, Schaedelin S, et al. . Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: A retrospective modelling and validation study. Lancet Neurol. 2022;21:246–257. PubMed

Axelsson M, Malmeström C, Nilsson S, Haghighi S, Rosengren L, Lycke J. Glial fibrillary acidic protein: A potential biomarker for progression in multiple sclerosis. J Neurol. 2011;258:882–888. PubMed

Meier S, Willemse EAJ, Schaedelin S, et al. . Serum glial fibrillary acidic protein compared with neurofilament light chain as a biomarker for disease progression in multiple sclerosis. JAMA Neurol. 2023;80:287–297. PubMed PMC

Bose G, Healy BC, Saxena S, et al. . Increasing neurofilament and glial fibrillary acidic protein after treatment discontinuation predicts multiple sclerosis disease activity. Neurol Neuroimmunol Neuroinflamm. 2023;10:e200167. PubMed PMC

Personalized treatment decision algorithms for the clinical application of serum neurofilament light chain in multiple sclerosis: A modified Delphi Study