Rechercher
image du produit
Lancet Neurology, The

S'abonner

Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study - 17/02/22

Doi : 10.1016/S1474-4422(22)00009-6 
Pascal Benkert, PhD a, †, Stephanie Meier, MSc b, †, Sabine Schaedelin, MSc a, Ali Manouchehrinia, PhD e, Özgür Yaldizli, MD b, Aleksandra Maceski, MSc b, Johanna Oechtering, MD b, Lutz Achtnichts, MD g, David Conen, MD i, Tobias Derfuss, MD b, Patrice H Lalive, MD l, Christian Mueller, MD d, Stefanie Müller, MD m, Yvonne Naegelin, MD b, Jorge R Oksenberg, PhD n, Caroline Pot, MD k, Anke Salmen, MD h, Eline Willemse, PhD b, Ingrid Kockum, PhD e, Kaj Blennow, PhD p, Henrik Zetterberg, PhD p, q, r, Claudio Gobbi, MD j, o, Ludwig Kappos, MD b, Heinz Wiendl, MD s, Klaus Berger, MD t, Maria Pia Sormani, PhD u, Cristina Granziera, MD b, c, Fredrik Piehl, MD e, f, David Leppert, MD b, Jens Kuhle, MD b, ⁎
for the

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

a Department of Clinical Research, Clinical Trial Unit, University Hospital Basel, University of Basel, Basel, Switzerland 
b Neurologic Clinic and Policlinic, MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel, University Hospital Basel, University of Basel, Basel, Switzerland 
c Department of Medicine and Biomedical Engineering, Translational Imaging in Neurology Basel, University Hospital Basel, University of Basel, Basel, Switzerland 
d Department of Medicine, Cardiology Division, Cardiovascular Research Institute Basel, University Hospital Basel, University of Basel, Basel, Switzerland 
e Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden 
f Center for Neurology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden 
g Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland 
h Department of Neurology, Bern University Hospital, University of Bern, Bern, Switzerland 
i Population Health Research Institute, McMaster University, Hamilton, ON, Canada 
j Department of Neurology, Multiple Sclerosis Center, Neurocenter of Southern Switzerland, Lugano, Switzerland 
k Department of Clinical Neurosciences, Service of Neurology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland 
l Department of Neurosciences, Division of Neurology, Unit of Neuroimmunology and Neuromuscular Diseases, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland 
m Department of Neurology, Cantonal Hospital St Gallen, St Gallen, Switzerland 
n Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA 
o Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland 
p Clinical Neurochemistry Laboratory, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska University Hospital, University of Gothenburg, Mölndal, Sweden 
q Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK 
r UK Dementia Research Institute at UCL, London, UK 
s Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany 
t Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany 
u Department of Health Sciences, University of Genoa, Genoa, Italy 

* Correspondence to: Prof Jens Kuhle, Multiple Sclerosis Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel, Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel 4031, Switzerland Multiple Sclerosis Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel Neurology, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research University Hospital Basel University of Basel Basel 4031 Switzerland

Summary

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.

Le texte complet de cet article est disponible en PDF.

Plan


© 2022  Elsevier Ltd. Tous droits réservés.
Ajouter à ma bibliothèque Retirer de ma bibliothèque Imprimer
Export

    Export citations

  • Fichier

    •

  • Contenu

    •

Vol 21 - N° 3

P. 246-257 - mars 2022 Retour au numéro
Article précédent Article précédent
  • Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study
  • Kristina Ibañez, James Polke, R Tanner Hagelstrom, Egor Dolzhenko, Dorota Pasko, Ellen Rachel Amy Thomas, Louise C Daugherty, Dalia Kasperaviciute, Katherine R Smith, WGS for Neurological Diseases Group, Zandra C Deans, Sue Hill, Tom Fowler, Richard H Scott, John Hardy, Patrick F Chinnery, Henry Houlden, Augusto Rendon, Mark J Caulfield, Michael A Eberle, Ryan J Taft, Arianna Tucci, Genomics England Research Consortium, Ellen M McDonagh, Antonio Rueda, Dimitris Polychronopoulos, Georgia Chan, Heather Angus-Leppan, Kailash P Bhatia, James E Davison, Richard Festenstein, Pietro Fratta, Paola Giunti, Robin Howard, Laxmi Venkata, Matilde Laurá, Meriel McEntagart, Lara Menzies, Huw Morris, Mary M Reilly, Robert Robinson, Elisabeth Rosser, Francesca Faravelli, Anette Schrag, Jonathan M Schott, Thomas T Warner, Nicholas W Wood, David Bourn, Kelly Eggleton, Robyn Labrum, Philip Twiss, Stephen Abbs, Liana Santos, Ghareesa Almheiri, Isabella Sheikh, Jana Vandrovcova, Christine Patch, Ana Lisa Taylor Tavares, Zerin Hyder, Anna Need, Helen Brittain, Emma Baple, Loukas Moutsianas, Viraj Deshpande, Denise L Perry, Subramanian S. Ajay, Aditi Chawla, Vani Rajan, Kathryn Oprych, Patrick F Chinnery, Angela Douglas, Gill Wilson, Sian Ellard, I Karen Temple, Andrew Mumford, Dom McMullan, Kikkeri Naresh, Frances A Flinter, Jenny C Taylor, Lynn Greenhalgh, William Newman, Paul Brennan, John A Sayer, F Lucy Raymond, Lyn S Chitty, John C. Ambrose, Prabhu Arumugam, Marta Bleda, Freya Boardman-Pretty, Jeanne M. Boissiere, Christopher R. Boustred, Clare E.H. Craig, Anna de Burca, Andrew Devereau, Greg Elgar, Rebecca E. Foulger, Pedro Furió-Tarí, Joanne Hackett, Dina Halai, Angela Hamblin, Shirley Henderson, James Holman, Tim J.P. Hubbard, Rob Jackson, Louise J. Jones, Melis Kayikci, Lea Lahnstein, Kay Lawson, Sarah E.A. Leigh, Ivonne U.S. Leong, Javier F. Lopez, Fiona Maleady-Crowe, Joanne Mason, Michael Mueller, Nirupa Murugaesu, Chris A. Odhams, Daniel Perez-Gil, Dimitris Polychronopoulos, John Pullinger, Tahrima Rahim, Pablo Riesgo-Ferreiro, Tim Rogers, Mina Ryten, Kevin Savage, Kushmita Sawant, Afshan Siddiq, Alexander Sieghart, Damian Smedley, Alona Sosinsky, William Spooner, Helen E. Stevens, Alexander Stuckey, Razvan Sultana, Simon R. Thompson, Carolyn Tregidgo, Emma Walsh, Sarah A. Watters, Matthew J. Welland, Eleanor Williams, Katarzyna Witkowska, Suzanne M. Wood, Magdalena Zarowiecki
| Article suivant Article suivant
  • Advances and controversies in frontotemporal dementia: diagnosis, biomarkers, and therapeutic considerations
  • Bradley F Boeve, Adam L Boxer, Fiona Kumfor, Yolande Pijnenburg, Jonathan D Rohrer

Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.

Déjà abonné à cette revue ?

Elsevier s'engage à rendre ses eBooks accessibles et à se conformer aux lois applicables. Compte tenu de notre vaste bibliothèque de titres, il existe des cas où rendre un livre électronique entièrement accessible présente des défis uniques et l'inclusion de fonctionnalités complètes pourrait transformer sa nature au point de ne plus servir son objectif principal ou d'entraîner un fardeau disproportionné pour l'éditeur. Par conséquent, l'accessibilité de cet eBook peut être limitée. Voir plus

Accès rapides

Mon compte

Aide & support

Plateformes Elsevier Masson

Déclaration CNIL

EM-CONSULTE.COM est déclaré à la CNIL, déclaration n° 1286925.

En application de la loi nº78-17 du 6 janvier 1978 relative à l'informatique, aux fichiers et aux libertés, vous disposez des droits d'opposition (art.26 de la loi), d'accès (art.34 à 38 de la loi), et de rectification (art.36 de la loi) des données vous concernant. Ainsi, vous pouvez exiger que soient rectifiées, complétées, clarifiées, mises à jour ou effacées les informations vous concernant qui sont inexactes, incomplètes, équivoques, périmées ou dont la collecte ou l'utilisation ou la conservation est interdite.
Les informations personnelles concernant les visiteurs de notre site, y compris leur identité, sont confidentielles.
Le responsable du site s'engage sur l'honneur à respecter les conditions légales de confidentialité applicables en France et à ne pas divulguer ces informations à des tiers.

Tout le contenu de ce site: Copyright © 2026 Elsevier, ses concédants de licence et ses contributeurs. Tout les droits sont réservés, y compris ceux relatifs à l'exploration de textes et de données, a la formation en IA et aux technologies similaires. Pour tout contenu en libre accès, les conditions de licence Creative Commons s'appliquent.