. 2022 Mar;21(3):246-257.

doi: 10.1016/S1474-4422(22)00009-6.

Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study

Pascal Benkert¹, Stephanie Meier², Sabine Schaedelin¹, Ali Manouchehrinia³, Özgür Yaldizli², Aleksandra Maceski², Johanna Oechtering², Lutz Achtnichts⁴, David Conen⁵, Tobias Derfuss², Patrice H Lalive⁶, Christian Mueller⁷, Stefanie Müller⁸, Yvonne Naegelin², Jorge R Oksenberg⁹, Caroline Pot¹⁰, Anke Salmen¹¹, Eline Willemse², Ingrid Kockum³, Kaj Blennow¹², Henrik Zetterberg¹³, Claudio Gobbi¹⁴, Ludwig Kappos², Heinz Wiendl¹⁵, Klaus Berger¹⁶, Maria Pia Sormani¹⁷, Cristina Granziera¹⁸, Fredrik Piehl¹⁹, David Leppert², Jens Kuhle²⁰; NfL Reference Database in the Swiss Multiple Sclerosis Cohort Study Group

Collaborators, Affiliations

Collaborators

NfL Reference Database in the Swiss Multiple Sclerosis Cohort Study Group:
Stefanie Aeschbacher, Muhamed Barakovic, Andreas Buser, Andrew Chan, Giulio Disanto, Marcus D'Souza, Renaud Du Pasquier, Oliver Findling, Riccardo Galbusera, Kevin Hrusovsky, Michael Khalil, Johannes Lorscheider, Amandine Mathias, Annette Orleth, Ernst-Wilhelm Radue, Reza Rahmanzadeh, Tim Sinnecker, Suvitha Subramaniam, Jochen Vehoff, Sven Wellmann, Jens Wuerfel, Chiara Zecca

Affiliations

¹ Department of Clinical Research, Clinical Trial Unit, University Hospital Basel, University of Basel, Basel, Switzerland.
² Neurologic Clinic and Policlinic, MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland.
³ Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁴ Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
⁵ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.
⁶ Department of Neurosciences, Division of Neurology, Unit of Neuroimmunology and Neuromuscular Diseases, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland.
⁷ Department of Medicine, Cardiology Division, Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland.
⁸ Department of Neurology, Cantonal Hospital St Gallen, St Gallen, Switzerland.
⁹ Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
¹⁰ Department of Clinical Neurosciences, Service of Neurology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
¹¹ Department of Neurology, Bern University Hospital, University of Bern, Bern, Switzerland.
¹² Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden.
¹³ Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK.
¹⁴ Department of Neurology, Multiple Sclerosis Center, Neurocenter of Southern Switzerland, Lugano, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
¹⁵ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
¹⁶ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹⁷ Department of Health Sciences, University of Genoa, Genoa, Italy.
¹⁸ Neurologic Clinic and Policlinic, MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland; Department of Medicine and Biomedical Engineering, Translational Imaging in Neurology Basel, University Hospital Basel, University of Basel, Basel, Switzerland.
¹⁹ Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; Center for Neurology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
²⁰ Neurologic Clinic and Policlinic, MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland. Electronic address: jens.kuhle@usb.ch.

PMID: 35182510
DOI: 10.1016/S1474-4422(22)00009-6

Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study

Pascal Benkert et al. Lancet Neurol. 2022 Mar.

. 2022 Mar;21(3):246-257.

doi: 10.1016/S1474-4422(22)00009-6.

Authors

Collaborators

NfL Reference Database in the Swiss Multiple Sclerosis Cohort Study Group:
Stefanie Aeschbacher, Muhamed Barakovic, Andreas Buser, Andrew Chan, Giulio Disanto, Marcus D'Souza, Renaud Du Pasquier, Oliver Findling, Riccardo Galbusera, Kevin Hrusovsky, Michael Khalil, Johannes Lorscheider, Amandine Mathias, Annette Orleth, Ernst-Wilhelm Radue, Reza Rahmanzadeh, Tim Sinnecker, Suvitha Subramaniam, Jochen Vehoff, Sven Wellmann, Jens Wuerfel, Chiara Zecca

Affiliations

¹ Department of Clinical Research, Clinical Trial Unit, University Hospital Basel, University of Basel, Basel, Switzerland.
² Neurologic Clinic and Policlinic, MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland.
³ Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
⁴ Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
⁵ Population Health Research Institute, McMaster University, Hamilton, ON, Canada.
⁶ Department of Neurosciences, Division of Neurology, Unit of Neuroimmunology and Neuromuscular Diseases, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland.
⁷ Department of Medicine, Cardiology Division, Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland.
⁸ Department of Neurology, Cantonal Hospital St Gallen, St Gallen, Switzerland.
⁹ Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
¹⁰ Department of Clinical Neurosciences, Service of Neurology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
¹¹ Department of Neurology, Bern University Hospital, University of Bern, Bern, Switzerland.
¹² Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden.
¹³ Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden; Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK.
¹⁴ Department of Neurology, Multiple Sclerosis Center, Neurocenter of Southern Switzerland, Lugano, Switzerland; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
¹⁵ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
¹⁶ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹⁷ Department of Health Sciences, University of Genoa, Genoa, Italy.
¹⁸ Neurologic Clinic and Policlinic, MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland; Department of Medicine and Biomedical Engineering, Translational Imaging in Neurology Basel, University Hospital Basel, University of Basel, Basel, Switzerland.
¹⁹ Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden; Center for Neurology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
²⁰ Neurologic Clinic and Policlinic, MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland. Electronic address: jens.kuhle@usb.ch.

PMID: 35182510
DOI: 10.1016/S1474-4422(22)00009-6

Abstract

Background: Serum neurofilament light chain (sNfL) is a biomarker of neuronal damage that is used not only to monitor disease activity and response to drugs and to prognosticate disease course in people with multiple sclerosis on the group level. The absence of representative reference values to correct for physiological age-dependent increases in sNfL has limited the diagnostic use of this biomarker at an individual level. We aimed to assess the applicability of sNfL for identification of people at risk for future disease activity by establishing a reference database to derive reference values corrected for age and body-mass index (BMI). Furthermore, we used the reference database to test the suitability of sNfL as an endpoint for group-level comparison of effectiveness across disease-modifying therapies.

Methods: For derivation of a reference database of sNfL values, a control group was created, comprising participants with no evidence of CNS disease taking part in four cohort studies in Europe and North America. We modelled the distribution of sNfL concentrations in function of physiological age-related increase and BMI-dependent modulation, to derive percentile and Z score values from this reference database, via a generalised additive model for location, scale, and shape. We tested the reference database in participants with multiple sclerosis in the Swiss Multiple Sclerosis Cohort (SMSC). We compared the association of sNfL Z scores with clinical and MRI characteristics recorded longitudinally to ascertain their respective disease prognostic capacity. We validated these findings in an independent sample of individuals with multiple sclerosis who were followed up in the Swedish Multiple Sclerosis registry.

Findings: We obtained 10 133 blood samples from 5390 people (median samples per patient 1 [IQR 1-2] in the control group). In the control group, sNfL concentrations rose exponentially with age and at a steeper increased rate after approximately 50 years of age. We obtained 7769 samples from 1313 people (median samples per person 6·0 [IQR 3·0-8·0]). In people with multiple sclerosis from the SMSC, sNfL percentiles and Z scores indicated a gradually increased risk for future acute (eg, relapse and lesion formation) and chronic (disability worsening) disease activity. A sNfL Z score above 1·5 was associated with an increased risk of future clinical or MRI disease activity in all people with multiple sclerosis (odds ratio 3·15, 95% CI 2·35-4·23; p<0·0001) and in people considered stable with no evidence of disease activity (2·66, 1·08-6·55; p=0·034). Increased Z scores outperformed absolute raw sNfL cutoff values for diagnostic accuracy. At the group level, the longitudinal course of sNfL Z score values in people with multiple sclerosis from the SMSC decreased to those seen in the control group with use of monoclonal antibodies (ie, alemtuzumab, natalizumab, ocrelizumab, and rituximab) and, to a lesser extent, oral therapies (ie, dimethyl fumarate, fingolimod, siponimod, and teriflunomide). However, longitudinal sNfL Z scores remained elevated with platform compounds (interferons and glatiramer acetate; p<0·0001 for the interaction term between treatment category and treatment duration). Results were fully supported in the validation cohort (n=4341) from the Swedish Multiple Sclerosis registry.

Interpretation: The use of sNfL percentiles and Z scores allows for identification of individual people with multiple sclerosis at risk for a detrimental disease course and suboptimal therapy response beyond clinical and MRI measures, specifically in people with disease activity-free status. Additionally, sNfL might be used as an endpoint for comparing effectiveness across drug classes in pragmatic trials.

Funding: Swiss National Science Foundation, Progressive Multiple Sclerosis Alliance, Biogen, Celgene, Novartis, Roche.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests ÖY received grants from ECTRIMS/MAGNIMS, University of Basel, Pro Patient Stiftung, University Hospital Basel, Free Academy Basel, Swiss Multiple Sclerosis Society and advisory board/lecture and consultancy fees from Roche, Sanofi Genzyme, Allmirall, Biogen, and Novartis. JO served on advisory boards for Roche and Merck. LA served on scientific advisory boards for Celgene, Novartis Pharmaceuticals, Merck, Biogen, Sanofi Genzyme, Roche, and Bayer; received funding for travel or speaker honoraria, or both, from Celgene, Biogen, Sanofi Genzyme, Novartis, Merck Serono, Roche, Teva, and the Swiss MS Society; and research support from Biogen, Sanofi Genzyme, and Novartis. AC received compensation for activities with Actelion, Almirall, Bayer, Biogen, Celgene, Sanofi-Genzyme, Merck, Novartis, Roche, Teva, all for hospital research funds. He receives research support from Biogen, Sanofi-Genzyme, and UCB. He serves as associate editor for the European Journal of Neurology. DC received speaker fees from BMS and Pfizer and consultation fees from Roche Diagnostics. TD received speaker fees, research support, or served on advisory boards, data safety monitoring boards, or steering committees of Actelion, Alexion, Celgene, Polyneuron, Novartis, Merck, Biogen, GeNeuro, MedDay, Roche, and Genzyme. TD received research support from the Swiss National Science Foundation and the Swiss MS Society. TD is secretary and member of the executive board of ECTRIMS. RDP has received honoraria for advisory boards from Biogen, Celgene, Merck, Novartis, Roche, and Sanofi-Genzyme. KH is an employee and stockholder at Quanterix Corp. MK has received funding for attending meetings or travel from Merck and Biogen, honoraria for lectures or presentations from Novartis and Biogen and speaker serves on scientific advisory boards for Biogen, Merck, Roche, Novartis, Bristol-Myers Squibb, and Gilead. He received research grants from Biogen and Novartis. PHL received honoraria for speaking from Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi Aventis, and Teva; consulting fees from Biogen Idec, GeNeuro, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, and Teva; and research grants from Biogen Idec, Merck Serono, and Novartis. JL has received research support from Innosuisse Innovation Agency, Biogen, and Novartis and served on advisory boards for Roche and Teva. CM has received research support from the Swiss National Science Foundation, the Swiss Heart Foundation, the KTI, and University of Basel; Abbott, Astra Zeneca, Beckman Coulter, Brahms, Idorsia, Novartis, Quidel, ortho clinical Diagnostics, Roche, Siemens, Singulex, Sphingotec, and University Hospital Basel, as well as speaker honoraria/consulting honoraria from Amgen, Astra Zeneca, BMS, Bayer, Daiichi Sankyo, Osler, Novartis, Roche, Sanofi, and Singulex, all outside the submitted work. YN's institution (University Hospital Basel/Research Center for Clinical Neuroimmunology and Neuroscience Basel, Switzerland) has received financial support for lectures from Teva and Celgene, grant support from Innosuisse (Swiss Innovation Agency) and grant support from Novartis and Roche. CP received consulting fees or travel compensation, used exclusively for research support, for activities with Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. AS received speaker honoraria or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme, and research support by the Swiss MS Society. TS has received travel support from Actelion, Alkermes, and Roche. He is a part-time employee of the MIAC AG in Basel. JV has received speaker honoraria from Allmiral Hermal GmbH and Roche. SW is Chief Medical Officer and cofounder of Neopredix. JW is an employee of MIAC AG, Basel, Switzerland; he received speaker or consulting honoraria or research grants from Actelion, Alexion, Biogen, Idorsia, ImmuneBio, Novartis, Roche, Sanofi, and is or was supported by the Eu (Horizon 2020), the SNCF, German Ministry of Science, and the German Ministry of Economy. CZ received honoraria for speaking/consulting fees or grants from Abbvie, Almirall, Biogen Idec, Celgene, Genzyme, Lilly, Merck Serono, Novartis, Roche, and Teva Pharma. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, and JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a cofounder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. HZ has served at scientific advisory boards for Alector, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen, and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program, outside of the submitted work. CG received honoraria for speaking/consulting fees or grants from Abbvie, Almirall, Biogen Idec, Celgene, Genzyme, Merck Serono, Novartis, Roche, Teva Pharma. LK's employer (University Hospital Basel) has received and dedicated to research support steering committee, advisory board, and consultancy fees (Abbvie, Actelion, Almirall, Auriga Vison AG, Bayer HealthCare, Biogen, Eisai, EMD Derono, Genzyme, Genentech, F Hoffmann-La Roche, Japan Tobacco, Janssen Pharmaceuticals, Merck, Minoryx Therapeutics SL, Novartis, Sanofi, Santhera, Senda Biosciences, Shionogi BV, TG Therapeutics); speaker fees (Bayer HealthCare, Biogen, Celgene, Genzyme, Janssen Pharmaceuticals Inc, Merck, Novartis, Roche, and Sanofi); support of educational activities (Allergan, Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Roche, Pfizer, Sanofi, Shire, and Teva); license fees for Neurostatus products; and grants (Bayer HealthCare, Biogen, European Union, Innosuisse, Merck, Novartis, Roche Research Foundation, Swiss MS Society, and Swiss National Research Foundation). HW received honoraria and consultation fees from Bayer Healthcare, Biogen, Fresenius Medical Care, GlaxoSmithKline, GW Pharmaceuticals, Merck Serono, Novartis, Sanofi Genzyme, and Teva Pharma. KBe received a grant from the BMBF (within the German Competence Net Multiple Sclerosis) plus additional funds from Biogen, all to the University of Münster, for an investigator-initiated adverse event registry for people with multiple sclerosis. MP has received consulting fees from Biogen, Merck, Teva, Genzyme, Roche, Novartis, GeNeuro, and MedDay. CGr's employer, The University Hospital Basel, received the following fees: advisory board and consultancy fees from Actelion, Novartis, Genzyme and F Hoffmann-La Roche; speaker fees from Biogen and Genzyme-Sanofi; research support by F Hoffmann-La Roche Ltd. She has also received speaker honoraria and travel funding by Novartis. FP has received research grants from Merck KGaA and UCB, and fees for serving on DMC in clinical trials with Chugai, Lundbeck, and Roche. DL is Chief Medical Officer of GeNeuro. JK received speaker fees, research support, travel support, and served on advisory boards by the Progressive MS Alliance, Swiss MS Society, Swiss National Research Foundation (320030_189140/1), University of Basel, Biogen, Celgene, Merck, Novartis, Octave Bioscience, Roche, Sanofi. All other authors declare no competing interests.

Comment in

The prognostic value of neurofilament light chain in serum.
Sellebjerg F, Magyari M. Sellebjerg F, et al. Lancet Neurol. 2022 Mar;21(3):207-208. doi: 10.1016/S1474-4422(22)00034-5. Lancet Neurol. 2022. PMID: 35182499 No abstract available.

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Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study

Collaborators

Affiliations

Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

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