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Observational Study
. 2025 Apr;39(4):403-416.
doi: 10.1007/s40263-025-01164-w. Epub 2025 Feb 14.

Treatment De-escalation in Relapsing-Remitting Multiple Sclerosis: An Observational Study

Jannis Müller  1   2   3 , Sifat Sharmin  1   2 , Johannes Lorscheider  3 , Dana Horakova  4 , Eva Kubala Havrdova  4 , Sara Eichau  5 , Francesco Patti  6 , Pierre Grammond  7 , Katherine Buzzard  8 , Olga Skibina  9 , Alexandre Prat  10 , Marc Girard  10 , Francois Grand'Maison  11 , Raed Alroughani  12 , Jeannette Lechner-Scott  13 , Daniele Spitaleri  14 , Michael Barnett  15 , Elisabetta Cartechini  16 , Maria Jose Sa  17 , Oliver Gerlach  18   19 , Anneke van der Walt  20 , Helmut Butzkueven  20 , Julie Prevost  21 , Tamara Castillo-Triviño  22 , Bassem Yamout  23 , Samia J Khoury  24 , Özgür Yaldizli  3 , Tobias Derfuss  3 , Cristina Granziera  3 , Jens Kuhle  3 , Ludwig Kappos  3 , Izanne Roos #  1   2 , Tomas Kalincik #  25   26 ; MSBase Study Group
Affiliations
Observational Study

Treatment De-escalation in Relapsing-Remitting Multiple Sclerosis: An Observational Study

Jannis Müller et al. CNS Drugs. 2025 Apr.

Abstract

Background: In relapsing-remitting multiple sclerosis (RRMS), extended exposure to high-efficacy disease modifying therapy may increase the risk of side effects, compromise treatment adherence, and inflate medical costs. Treatment de-escalation, here defined as a switch to a lower efficacy therapy, is often considered by patients and physicians, but evidence to guide such decisions is scarce. In this study, we aimed to compare clinical outcomes between patients who de-escalated therapy versus those who continued their therapy.

Methods: In this retrospective analysis of data from an observational, longitudinal cohort of 87,239 patients with multiple sclerosis (MS) from 186 centers across 43 countries, we matched treatment episodes of adult patients with RRMS who underwent treatment de-escalation from either high- to medium-, high- to low-, or medium- to low-efficacy therapy with counterparts that continued their treatment, using propensity score matching and incorporating 11 variables. Relapses and 6-month confirmed disability worsening were assessed using proportional and cumulative hazard models.

Results: Matching resulted in 876 pairs (de-escalators: 73% females, median [interquartile range], age 40.2 years [33.6, 48.8], Expanded Disability Status Scale [EDSS] 2.5 [1.5, 4.0]; non-de-escalators: 73% females, age 40.8 years [35.5, 47.9], and EDSS 2.5 [1.5, 4.0]), with a median follow-up of 4.8 years (IQR 3.0, 6.8). Patients who underwent de-escalation faced an increased hazard of future relapses (hazard ratio 2.36 and 95% confidence intervals [CI] [1.79-3.11], p < 0.001), which was confirmed when considering recurrent relapses (2.43 [1.97-3.00], p < 0.001). It was also consistent across subgroups stratified by age, sex, disability, disease duration, and time since last relapse.

Conclusions: On the basis of this observational analysis, de-escalation may not be recommended as a universal treatment strategy in RRMS. The decision to de-escalate should be considered on an individual basis, as its safety is not clearly guided by specific patient or disease characteristics evaluated in this study.

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Conflict of interest statement

Declarations. Funding: Open Access funding enabled and organized by CAUL and its Member Institutions. The work was supported by grants by the Swiss Science Foundation to J.M. [P500PM_214230 and P5R5PM_225288], and by NHMRC Investigator Grants to T.K. [2026836]. I.R. is supported by a MS Australia postdoctoral fellowship grant. The MSBase Foundation is a not-for-profit organization that receives support from Biogen, Novartis, Merck, Roche, Teva, and Sanofi Genzyme. Design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication were conducted separately and apart from the guidance of the sponsors. Conflicts of interest: Jannis Müller received funding from the Swiss National Science Foundation (grant no. P500PM_214230 and P5R5PM_225288). Sifat Sharmin receives research support from MS Australia. Johannes Lorscheider received research support from Innosuisse—Swiss Innovation Agency, the University of Basel, Biogen, and Novartis; received speaker fees, travel support, and/or compensation for advisory boards from Bristol Myers Squibb, Novartis, Roche, and Teva. Dana Horakova was supported by the Charles University: Cooperatio Program in Neuroscience; by the project National Institute for Neurological Research (Program EXCELES, ID project no. LX22NPO5107)—funded by the European Union—Next Generation EU; and by General University Hospital in Prague project MH CZ-DRO-VFN64165. She also received compensation for travel, speaker honoraria, and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva, as well as support for research activities from Biogen Idec. Eva Kubala Havrdova received honoraria/research support from Biogen, Merck Serono, Novars, Roche, and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars, and Sanofi Genzyme; received honoraria/research support from Biogen, Merck Serono, Novars, Roche, and Teva; has been a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars, and Sanofi Genzyme; and has been supported by the Czech Ministry of Education—project Cooperatio LF1, research area Neuroscience, and the project National Institute for Neurological Research (Program EXCELES, ID project no. LX22NPO5107)—funded by the European Union—Next Generation EU. Sara Eichau has received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Janssen, Bristol-Meyers, Bayer, Sanofi Genzyme, Roche, and Teva. Francesco Patti received personal compensation for serving on advisory boards by Almirall, Alexion, Biogen, Bristol, Janssen, Merck, Novartis, and Roche. He further received research grants from Alexion, Almirall, Biogen, Bristol, Merck, Novartis, and Roche, and from FISM, Reload Association (Onlus), Italian Health Minister, and the University of Catania. Pierre Grammond has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, and Pendopharm, and he has received grant support from Genzyme and Roche. He has received research grants for his institution from Biogen idec, Sanofi Genzyme, and EMD Serono. Katherine Buzzard received speaker honoraria and/or education support from Biogen, Teva, Novartis, Genzyme-Sanofi, Roche, Merck, and Alexion and has been a member of advisory boards for Merck and Biogen. Olga Skibina received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen, and Genzyme. Alexandre Prat has no disclosures to declare. Marc Girard has no disclosures to declare. Francois Grand’Maison received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, and ATARA Pharmaceuticals. Raed Alroughani received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi-Genzyme. Jeannette Lechner-Scott 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. Daniele Spitaleri received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis, and Sanofi-Aventis, and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva, and Merck. Michael Barnett served on scientific advisory boards for Biogen, Novartis, and Genzyme and has received conference travel support from Biogen and Novartis. He serves on steering committees for trials conducted by Novartis. His institution has received research support from Biogen, Merck and Novartis. Elisabetta Cartechini has no disclosures to declare. Maria Jose Sa received consulting fees, speaker honoraria, and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck-Serono, Novartis, Roche, Sanofi, and Teva. Oliver Gerlach has nothing to disclose. Anneke van der Walt served on advisory boards and receives unrestricted research grants from Novartis, Biogen, Merck, and Roche She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck. She receives grant support from the National Health and Medical Research Council of Australia and MS Research Australia. Helmut Butzkueven has received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL, and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd., and Merck; and has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee. Julie Prevost accepted travel compensation from Novartis, Biogen, Genzyme, and Teva and speaking honoraria from Biogen, Novartis, Genzyme, and Teva. Tamara Castillo-Triviño received speaking/consulting fees and/or travel funding from Almirall, Biogen, Bristol Myers Squibb, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, and Teva. Bassem Yamout received honoraria as a speaker and member of scientific advisory boards from Sanofi, Bayer, Biogen, Merck, Janssen, Novartis, Roche, and Aspen. Samia J. Khoury received compensation for scientific advisory board activity from Merck and Roche and received compensation for serving on the IDMC for Biogen. Özgür Yaldizli received grants from Swiss National Science Foundation, ECTRIMS/MAGNIMS, University of Basel, Pro Patient Stiftung University Hospital Basel, Free Academy Basel, and the Swiss Multiple Sclerosis Society and received advisory board, lecture, and consultancy fees from Roche, Sanofi Genzyme, Allmirall, Biogen, and Novartis. Tobias Derfuss 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. Cristina Granziera’s employer, the University Hospital Basel (USB), has received the following fees which were used exclusively for research support: (i) advisory board and consultancy fees from Actelion, Genzyme-Sanofi, Novartis, GeNeuro, and Roche; (ii) speaker fees from Genzyme-Sanofi, Novartis, GeNeuro, and Roche; and (iii) research support from Siemens, GeNeuro, and Roche. Cristina Granziera is supported by the Swiss National Science Foundation (SNSF) grant PP00P3_176984, the Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung, and the EUROSTAR E!113682 HORIZON2020. Jens Kuhle received speaker fees, research support, travel support, and/or served on advisory boards by the Swiss MS Society, Swiss National Research Foundation (320030_189140/1), University of Basel, Progressive MS Alliance, Alnylam, Bayer, Biogen, Bristol Myers Squibb, Celgene, Immunic, Merck, Neurogenesis, Novartis, Octave Bioscience, Quanterix, Roche, Sanofi, and Stata DX. Ludwig Kappos’ institution (University Hospital Basel) received grants, contracts, or payments from Novartis, Roche, and Innosuisse; consulting fees from AurigaVision, Bayer AG, df-mp Molnia&Pohlman, Genentech, Glaxo Smith Kline, Janssen LLC, Japan Tobacco Inc, Merck, Novartis, Roche, Senda Biosciences Inc, Shionogi BV, and Wellmera AG; payment or honoraria for lectures, presentations, or speaker bureaus from BMS, Celgene, Janssen, Merck, Novartis, and Roche; support for attending meetings and/or travel from MH Consulting, Österreichische Gesellschaft für Neurologie, Novartis Biociencias S.A., and Eli Lilly; payments for advisory boards of Actelion, Merck Healtchcare KGgA, Novartis, Roche, Sanofi, and TG Therapeutics; and payments for participation on data safety monitoring boards of Minoryx Therapeutics S.L. and Santhera Pharmaceuticals. L.K. is an unpaid member of the supervisory board of Neurostatus UHB AG, CEO of the Foundation of Clinical Neuroimmunology and Neuroscience (“RC2N”), MAGNIMS Steering Committee, and board member of the European Charcot Foundation. Izanne Roos has served on scientific advisory boards, received conference travel support and/or speaker honoraria from Roche, Novartis, Merck, and Biogen. Izanne Roos is supported by a MS Australia and the Trish Multiple Sclerosis Research Foundation. Tomas Kalincik served on scientific advisory boards for MS International Federation and World Health Organization, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck, and Biogen; served on the steering committee for the 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. Tomas Kalincik is an editorial board member of CNS Drugs. Tomas Kalincik was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Ethics approval: This study received ethics approval from the Melbourne Health Human Research Ethics Committee and the local institutional review boards in all centers. Consent to participate: Written informed consent was obtained from all patients. Consent for publication: Not applicable. Availability of data and material: The MSBase registry is a data processor and warehouses data from individual principal investigators who agree to share their datasets on a project-by-project basis. Data access to external parties can be granted on reasonable request at the sole discretion of the principal investigators, who will need to be approached individually for permission. Code availability: The R package MSoutcomes, which was used for the analyses in this study, is openly available on the Comprehensive R Archive Network (CRAN). Authors’ contributions: Conception and design of the study: J.M., S.S., J.L., Ö.Y., C.G., T.D., J.K., L.K., I.R., and T.K. Acquisition and analysis of data: J.M., S.S., D.H., E.K.H., S.E., F.P., P.G., K.B., O.S., A.P., M.G., F.G., R.A., J.L.S., D.S., M.B., E.C., M.J.S., O.G., A.V.W., H.B., J.P., T.C.T., B.Y., S.J.K., I.R., and T.K. Drafting a significant portion of the manuscript or figures: J.M., S.S., J.L., D.H., E.K.H., S.E., F.P., P.G., K.B., O.S., A.P., M.G., F.G., R.A., J.L.S., D.S., M.B., E.C., M.J.S., O.G., A.V.W., H.B., J.P., T.C.T., B.Y., S.J.K., Ö.Y., T.D., C.G., J.K., L.K., I.R., and T.K. All authors have read and approved the final submitted manuscript and agree to be accountable for the work.

Figures

Fig. 1
Fig. 1
Matching procedure of three exemplary de-escalating patients (De-escalator A, De-escalator B, and De-escalator C). Sex, EDSS, age, and last relapse represent 4 examples of the 11 matching variables, given for multiple visits over time. For de-escalating patients, baseline was defined as the date of treatment switch. For non-de-escalating patients, baseline was determined through propensity score matching, selecting the visit that most closely matched the baseline of the de-escalating patients (green line, upper panel) out of all available visits (green dashed lines, upper panel) of all patients. Matched baselines are indicated by matching color-coded boxes. In the lower panel, note that one non-de-escalating patient (Non-de-escalator Y) was matched to two separate de-escalating patients (De-escalator B and De-escalator C, respectively) at two different timepoints. EDSS Expanded Disability Status Scale
Fig. 2
Fig. 2
Risk of being free from (A) relapses, and (B) 6-month confirmed EDSS worsening. Kaplan–Meier curves and numbers at risk. HR hazard risk, 95% CI 95% confidence interval
Fig. 3
Fig. 3
Subgroups stratified by age, time since last relapse, gender, disease duration and EDSS. Forrest plot displaying hazard ratios and 95% confidence intervals. EDSS Expanded Disability Status Scale, HR hazard ratio
Fig. 4
Fig. 4
The risk of relapses among patients stratified by age and time since last relapse. HR and confidence intervals derive from conditional hazard models capturing recurring outcome events during the entire follow-up period. Results from the Cox proportional hazards model are given in Supplementary Fig. 4. (A) The data is stratified into nine separately matched groups, providing higher granularity, while acknowledging the limitation of small sample sizes and numbers of outcome events, and (B) stratification is performed for four separately matched groups, enhancing statistical power and sample size, sacrificing granularity. Stratified groups with HR confidence intervals crossing the threshold “1” are highlighted in blue. HR hazard ratio
Fig. 5
Fig. 5
Subgroup analyses stratified for DMT groups: patients switching from high- to medium- (left panel), high- to low- (middle panel), and medium- to low-efficacy DMTs (right panel). Top panels show DMTs as bar charts of non-de-escalators (left bar), de-escalators prior to de-escalation (middle bar), and de-escalators after de-escalation (right bar). Lower panels show Kaplan–Meier curves of the groups under consideration (non-de-escalators versus de-escalators). CD20 anti CD20-antibodies (encompassing rituximab and ocrelizumab), DMF dimethyl fumarate, DMTs disease modifying therapies, GA glatiramer acetate, HR hazard ratio, INF interferon (encompassing interferon beta-1a, interferon beta-1b, and peginterferon beta-1a), NTZ natalizumab, OZA ozanimod, S1P S1P-modulators (encompassing fingolimod, ozanimod, and siponimod), TFL teriflunomide, 95% CI 95% confidence interval
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