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

Özgür Yaldizli^{1

2

3

4}, Pascal Benkert¹, Lutz Achtnichts⁵, Amit Bar-Or⁶, Viviane Bohner-Lang⁷, Claire Bridel⁸, Manuel Comabella⁹, Oliver Findling¹⁰, Giulio Disanto¹¹, Sebastian Finkener¹⁰, Claudio Gobbi¹¹, Cristina Granziera^{2

3

4}, Marina Herwerth^{12

13

14}, Robert Hoepner¹⁵, Dana Horakova¹⁶, Nicole Kamber¹⁷, Michael Khalil¹⁸, Philipp Kunz⁷, Patrice Lalive¹⁹, Ralf Linker²⁰, Johannes Lorscheider^{2

3}, Stefanie Müller²¹, Johanna Oechtering^{2

3}, Victoria Pettypool⁷, Fredrik Piehl^{22

23}, Caroline Pot²⁴, Patrick Roth²⁵, Marie Théaudin²⁴, Mar Tintore⁹, Carmen Tur⁹, Denis Uffer²¹, Marjolaine Uginet¹⁹, Jochen Vehoff²¹, Heinz Wiendl²⁶, Tjalf Ziemssen²⁷, Chiara Zecca^{11

28}, Anke Salmen²⁹, David Leppert², Tobias Derfuss^{2

3}, Ludwig Kappos², Lars G Hemkens^{1

2}, Perrine Janiaud², Jens Kuhle^{2

30

31

32}

Affiliations

¹ Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
² Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.
³ Neurologic Clinic and Policlinic, MS Centre, University Hospital Basel, Basel, Switzerland.
⁴ Translational Imaging in Neurology Basel, Department of Medicine and Biomedical Engineering, University Hospital Basel, University of Basel, Basel, Switzerland.
⁵ Neurozentrum Oberaargau, Langenthal, Switzerland.
⁶ Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Patient Consultant, Basel, Switzerland.
⁸ Translational Biomarker Research Group, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁹ Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron Barcelona Hospital, Barcelona, Spain.
¹⁰ Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
¹¹ Multiple Sclerosis Center, Neurocenter of Southern Switzerland, Ospedale Regionale di Lugano (EOC), Lugano, Switzerland.
¹² Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
¹³ Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
¹⁴ Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
¹⁵ Department of Neurology, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁶ Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic.
¹⁷ Division of Neurology, Department of Internal Medicine, Bürgerspital Solothurn, Solothurn, Switzerland.
¹⁸ Department of Neurology, Medical University of Graz, Graz, Austria.
¹⁹ Division of Neurology, Department of Clinical Neurosciences, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
²⁰ Department of Neurology, University of Regensburg, Regensburg, Germany.
²¹ Department of Neurology, University Teaching and Research Hospital St. Gallen, St. Gallen, Switzerland.
²² Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
²³ Neuroimmunology Unit, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
²⁴ Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.
²⁵ Department of Neurology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
²⁶ Department of Neurology, Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
²⁷ Center of Clinical Neuroscience, Neurological Clinic, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
²⁸ Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Lugano, Switzerland.
²⁹ Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Bochum, Germany.
³⁰ Departments of Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
³¹ Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.
³² Multiple Sclerosis Centre, University Hospital Basel, Basel, Switzerland.

PMID: 40296363
PMCID: PMC12228887
DOI: 10.1177/13524585251335466

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

Özgür Yaldizli et al. Mult Scler. 2025 Jul.

. 2025 Jul;31(8):932-943.

doi: 10.1177/13524585251335466. Epub 2025 Apr 28.

Authors

Affiliations

¹ Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
² Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.
³ Neurologic Clinic and Policlinic, MS Centre, University Hospital Basel, Basel, Switzerland.
⁴ Translational Imaging in Neurology Basel, Department of Medicine and Biomedical Engineering, University Hospital Basel, University of Basel, Basel, Switzerland.
⁵ Neurozentrum Oberaargau, Langenthal, Switzerland.
⁶ Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁷ Patient Consultant, Basel, Switzerland.
⁸ Translational Biomarker Research Group, Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁹ Multiple Sclerosis Centre of Catalonia (Cemcat), Vall d'Hebron Barcelona Hospital, Barcelona, Spain.
¹⁰ Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
¹¹ Multiple Sclerosis Center, Neurocenter of Southern Switzerland, Ospedale Regionale di Lugano (EOC), Lugano, Switzerland.
¹² Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
¹³ Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland.
¹⁴ Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
¹⁵ Department of Neurology, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁶ Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University in Prague and General University Hospital, Prague, Czech Republic.
¹⁷ Division of Neurology, Department of Internal Medicine, Bürgerspital Solothurn, Solothurn, Switzerland.
¹⁸ Department of Neurology, Medical University of Graz, Graz, Austria.
¹⁹ Division of Neurology, Department of Clinical Neurosciences, Faculty of Medicine, Geneva University Hospitals, Geneva, Switzerland.
²⁰ Department of Neurology, University of Regensburg, Regensburg, Germany.
²¹ Department of Neurology, University Teaching and Research Hospital St. Gallen, St. Gallen, Switzerland.
²² Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.
²³ Neuroimmunology Unit, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
²⁴ Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), University of Lausanne, Lausanne, Switzerland.
²⁵ Department of Neurology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
²⁶ Department of Neurology, Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
²⁷ Center of Clinical Neuroscience, Neurological Clinic, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany.
²⁸ Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Lugano, Switzerland.
²⁹ Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Bochum, Germany.
³⁰ Departments of Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
³¹ Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.
³² Multiple Sclerosis Centre, University Hospital Basel, Basel, Switzerland.

PMID: 40296363
PMCID: PMC12228887
DOI: 10.1177/13524585251335466

Abstract

Background: Serum neurofilament light (sNfL) chain levels, a sensitive measure of disease activity in multiple sclerosis (MS), are increasingly considered for individual therapy optimization yet without consensus on their use for clinical application.

Objective: We here propose treatment decision algorithms incorporating sNfL levels to adapt disease-modifying therapies (DMTs).

Methods: We conducted a modified Delphi study to reach consensus on algorithms using sNfL within typical clinical scenarios. sNfL levels were defined as "high" (>90th percentile) vs "normal" (<80th percentile), based on normative values of control persons. In three rounds, 10 international and 18 Swiss MS experts, and 3 patient consultants rated their agreement on treatment algorithms. Consensus thresholds were defined as moderate (50%-79%), broad (80%-94%), strong (≥95%), and full (100%).

Results: The Delphi provided 9 escalation algorithms (e.g. initiating treatment based on high sNfL), 11 horizontal switch (e.g. switching natalizumab to another high-efficacy DMT based on high sNfL), and 3 de-escalation (e.g. stopping DMT or extending intervals in B-cell depleting therapies).

Conclusion: The consensus reached on typical clinical scenarios provides the basis for using sNfL to inform treatment decisions in a randomized pragmatic trial, an important step to gather robust evidence for using sNfL to inform personalized treatment decisions in clinical practice.

Keywords: Delphi study; de-escalation; escalation; personalized treatment strategies; serum neurofilament light chain.

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Conflict of interest statement

Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PB, AB-O, VB-H, CB, GD, OF, SF, MH, NK, PK, VP, CP, DU, MU, JV, DL, and PJ have nothing to declare; OY received grants from ECTRIMS/MAGNIMS, University of Basel, Pro Patient Stiftung, University of Basel, Free Academy Basel, Swiss Multiple Sclerosis Society, Swiss National Science Foundation and advisory board/lecture and consultancy fees from Roche, Sanofi-Genzyme, Almirall, Biogen and Novartis; LA served on scientific advisory boards for Celgene, Novartis Pharmaceuticals, Merck, Biogen, Sanofi-Genzyme, Roche, and Bayer; received funding for travel and/or speaker honoraria from Celgene, Biogen, Sanofi-Genzyme, Novartis, Merck Serono, Roche, Teva, and the Swiss MS Society; and research support from Biogen, Sanofi, Genzyme, and Novartis; MC received compensation for consulting services and speaking honoraria from Bayer Schering Pharma, Merk Serono, Biogen-Idec, Teva Pharmaceuticals, Sanofi-Aventis, Genzyme, Bristol-Myers Squibb, and Novartis; Ente Ospedaliero Cantonale (employer) received compensation for C. Go.’s speaking activities, consulting fees, or grants from AbbVie, Alexion, Almirall, Biogen, Bristol Meyer Squibb, Eisai, Lilly, Lundbeck, Merck, Merz, Novartis, Organon, Pfizer, Sandoz, Sanofi, Teva Pharma, Roche; The University Hospital Basel (USB) and the Research Center for Clinical neuroimmunology and Neuroscience (RC2NB), as the employers of CGr, 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; RH received speaker/advisor honorary from Merck, Novartis, Roche, Biogen, Alexion, Sanofi, Janssen, Bristol-Myers Squibb, Teva/Mepha and Almirall. He received research support within the last 5 years from Roche, Merck, Sanofi, Biogen, Chiesi, and Bristol-Myers Squibb. He also received research grants from the Swiss MS Society, the SITEM Insel Support Fund and is a member of the Advisory Board of the Swiss and International MS Society. He also serves as deputy editor in chief for Journal of Central Nervous System disease and is part of the ECTRIMS Young Investigator Committee; DH was supported by the Charles University: Cooperatio Program in Neuroscience, by the project National Institute for Neurological Research (Program EXCELES, ID Project No. 174 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; MK received funding for travel and speaker honoraria from Bayer, Novartis, Merck, Biogen Idec and Teva Pharmaceutical Industries Ltd. and serves on scientific advisory boards for Biogen Idec, Merck Serono, Roche, Novartis and Gilead; PL reports that the Geneva University Hospital received honoraria for speaking from Biogen, Merck, Roche; consulting fees from Biogen, Merck, Novartis, Roche; research grants from Biogen, Merck, Novartis; RL received compensation for activites with Biogen, Celgene/BMS, Janssen Cilag, Pfizer, Merck, Novartis, Sanofi and Roche as well as research support from Biogen and Novartis; JL’s institution has received research grants from Novartis, Biogen, Innosuisse—Swiss Innovation Agency, and the MSBase Foundation, and honoraria for advisory boards and/or speaking fees from Novartis, Roche and Teva. He received conference travel support from Novartis and Bristol-Myers Squibb; SM received honoraria for travel, honoraria for lectures/consulting and/or grants for studies from Almirall, Alexion, Bayer, Biogen, Bristol-Myers Squibb SA/Celgene, Genzyme, Merck-Serono, Teva, Novartis and Roche; JO received research support by the Swiss MS Society and served on advisory boards for Roche and Merck; FP received research grants from Janssen, Merck KGaA and UCB, and fees for serving on DMCs in clinical trials with Chugai, Lundbeck and Roche, and preparation of expert witness statement for Novartis; PR received honoraria for lectures or advisory board participation from Alexion, Bristol-Myers Squibb, Boehringer Ingelheim, Debiopharm, Galapagos, Merck Sharp and Dohme, Laminar, Midatech Pharma, Novocure, QED, Roche, and Sanofi and research support from Merck Sharp and Dohme and Novocure; The CHUV has received for MTh grants for advisory boards, funding for participation in medical meetings from Alexion, Merck, Sanofi, Roche, Biogen, and Novartis; MTi received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma; CT is currently being funded by a Junior Leader La Caixa Fellowship (fellowship code is LCF/BQ/PI20/11760008), awarded by “la Caixa” Foundation (ID 100010434). She has also received the 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain) and a grant awarded by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación de España (PI21/01860) and she has also received honoraria from Roche and Novartis and is a steering committee member of the O’HAND trial and of the Consensus group on Follow-on DMTs; HW declares scientific advisory boards/consultant fee for Biogen, Evgen, Genzyme, MedDay Pharmaceuticals, Merck Serono, AbbVie, Actelion, Johnson & Johnson, Novartis, Roche Pharma AG, Sanofi-Aventis and Swiss Multiple Sclerosis Society, speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Genzyme, Teva, and WebMD Global and his research is funded by the German Ministry for Education and Research, Deutsche Forschungsgemeinschaft, Else Kröner Fresenius Foundation, Fresenius Foundation, the European Union, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies Muenster and RE Children’s Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, and Sanofi-Genzyme; TZ declares advisory boards fees from Biogen, BMS, Merck, Novartis, Roche, Sanofi and Teva; speaker fees from Almirall, Alexion, Biogen, BMS, Hexal, Novartis, Roche, Sanofi, Teva and Viatris; research support from Biogen, BMS, Novartis, Roche, Sanofi and Teva; Ente Ospedaliero Cantonale (employer) received compensation for C.Z.’s speaking activities, consulting fees, or grants from AbbVie, Alexion, Almirall, Biogen, Bristol Meyer Squibb, Eisai, Lilly, Lundbeck, Merck, Merz, Novartis, Organon, Pfizer, Sandoz, Sanofi, Teva Pharma, Roche. CZ is recipient of a grant for senior reseachers provided by AFRI (Area Formazione accademica, Ricerca e Innovazione), EOC; AS received speaker honoraria for activities with Bristol-Myers Squibb, CSL Behring, Merck, Neuraxpharm, Novartis, and research support by the Baasch Medicus Foundation, the Medical Faculty of the University of Bern, the Swiss MS Society and the regional association of North Rhine-Westphalia of the German MS Society (DMSG Landesverband NRW); TD has served on scientific advisory boards, steering committees, and data safety monitoring boards for Alexion, Actelion, Biogen, Celgene, Genzyme, GeNeuro, Merck, Mitsubishi Pharma, Novartis, Roche, Octapharma, and MedDay; has received travel and/or speaker honoraria from Biogen, Genzyme, Merck, Novartis, Roche, and Merck-Serono; has received research support from Alexion, Biogen, Novartis, Roche, the Swiss MS Society, the European Union and the Swiss National Foundation. LK has received no personal compensation. His institutions (University Hospital Basel/Stiftung Neuroimmunology and Neuroscience Basel) have received and used exclusively for research support payments for steering committee and advisory board participation, consultancy services, and participation in educational activities from: Actelion, Bayer, BMS, df-mp Molnia & Pohlmann, Celgene, Eli Lilly, EMD Serono, Genentech, Glaxo Smith Kline, Janssen, Japan Tobacco, Merck, MH Consulting, Minoryx, Novartis, F. Hoffmann-La Roche Ltd, Senda Biosciences Inc., Sanofi, Santhera, Shionogi BV, TG Therapeutics, and Wellmera, and license fees for Neurostatus-UHB products; grants from Novartis, Innosuisse, and Roche. LGH employer RC2NB is supported by Foundation Clinical Neuroimmunology and Neuroscience Basel. RC2NB has a contract with Roche for a steering committee participation of LGH. JK received speaker fees, research support, travel support, and/or served on advisory boards by Swiss MS Society, Swiss National Research Foundation (320030_212534/1), 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.

Figures

**Figure 1.**
Flow chart of the Delphi process.

**Figure 2.**
Escalation algorithms in patients with high sNfL (>90th percentile): (a) From untreated to initiating DMT; (b) From low to medium or high efficacy DMT; and (c) From medium to high efficacy DMT. Example of algorithm: If your patient is currently receiving a low efficacy DMT for at least 9 months and has high sNfL (>90th percentile) jointly consider with your patient to escalate to medium or HET if your patient has NEDA2 plus MRI activity with at least 1 unequivocal new/enlarging T2w lesion or contrast enhancing T1w lesion. DMT: Disease Modifying Therapy; MRI: magnetic resonance imaging; NEDA: No evidence of disease activity was defined as NEDA2 i.e. no relapses and no Expanded Disability Status Scale (EDSS) worsening or as NEDA3 no relapses, no EDSS worsening and no MRI activity.

**Figure 3.**
Horizontal switch algorithms in patients with high sNfL (>90th percentile): (a) From natalizumab; (b) From B-cell depletion therapy; and (c) From cladribine to different mode of action of DMT. Example of algorithm: If your patient is currently receiving B-cell depletion therapy for at least 12 months and has high sNfL (>90th percentile) jointly consider with your patient to switch to a different mode of action HET if your patient has relapses but no MRI activity. EDSS: Expanded Disability Status Scale; DMT: Disease-Modifying Therapy; MRI: magnetic resonance imaging; NEDA: No evidence of disease activity was defined as NEDA2, i.e., no relapses and no EDSS worsening or as NEDA3 no relapses, no EDSS worsening and no MRI activity.

**Figure 4.**
De-escalation algorithms in patients with “normal” sNfL (<80th percentile): (a) From B-cell depletion therapy to extending treatment interval; (b) From fumarates to stopping fumarates; and (c) From low efficacy DMT to stopping DMT treatment. Example of algorithm: If your patient wishes to stop treatment and is >60 years old, currently receiving low efficacy DMT for at least 5 years, has NEDA3 for the past 5 years and has normal sNfL (<80th percentile) jointly consider with your patient to perform 6-monthly cMRI and 6-monthly sNfL measurement and stopping DMT treatment. DMT: disease-modifying therapy; MRI: magnetic resonance imaging; NEDA: no evidence of disease activity was defined as NEDA3 no relapses, no EDSS worsening and no MRI activity.

See this image and copyright information in PMC

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

Affiliations

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

Authors

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Abstract

Conflict of interest statement

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