GFAP and NfL as predictors of disease progression and relapse activity in fingolimod-treated multiple sclerosis

In multiple sclerosis (MS) patients under therapy, the increase of serum glial fibrillary acidic protein (sGFAP) concentrations is associated with the course of 'progression in absence of relapse' (PIRA). While serum neurofilament light chain (sNfL) reflects both response as well as insufficient or lack of efficiency of disease modifying therapies (DMT), the longitudinal course of sGFAP levels as drug response marker for future PIRA in relation to specific types of DMT is less clear. We aimed to compare the predictive capacity of sGFAP and sNfL for PIRA and relapse activity and the longitudinal course in persons with MS (PwMS) treated with fingolimod, based on Z scores derived from normative values. 420 PwMS under fingolimod treatment with follow-up of 9.1 years (IQR: 7.0-11.0) from the Swiss MS Cohort, contributing 2935 longitudinal serum samples, were included. A reference data set for sGFAP established from 4297 healthy controls across three European and North American cohorts was used to calculate Z scores. The longitudinal course and the predictive capacity of biomarkers for time to PIRA and relapse were assessed by Cox proportional hazards and linear mixed-effects models. In controls, sGFAP concentrations were 13.6% higher in females than males and increased exponentially with age. 31.0% of PwMS experienced ≥1 PIRA event. Elevated sGFAP Z scores (>0.75) were associated with increased risk of PIRA (HR: 1.64; 95% CI: [1.16-2.32]; p=0.006), while this was not the case for sNfL. Conversely, elevated sNfL predicted relapses (HR: 1.58 [1.13-2.23]; p=0.008), while sGFAP did not. Both biomarkers decreased under treatment: sGFAP by 0.19 Z score units (ZSU)/10 years (95% CI: -0.27 - -0.11; p<0.001) and sNfL by 0.16 ZSU/10 years (95% CI: -0.27 - -0.06; p=0.002). sGFAP remained elevated in PwMS with future PIRA events (estimate: 0.29; [0.07-0.50]; p=0.009); no such association was found for sNfL. sGFAP and sNfL Z scores provide complementary predictive capacity for PIRA and relapse risk. The decrease of sGFAP under fingolimod is a feature not observed with other types of DMT and may hint to a specific anti-neurodegenerative effect of Sphingosine-1-phosphate-receptor modulators on astrocytes.

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Journal
Brain
Published
2025-11-13
DOI
https://doi.org/10.1093/brain/awaf433
Citations
3
Primary Topic
Multiple Sclerosis Research Studies
Type
article
Field-Weighted Citation Impact
4.41

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article

GFAP and NfL as predictors of disease progression and relapse activity in fingolimod-treated multiple sclerosis

Rosetta Pedotti, Sabine Schädelin, Lilian Demuth, Ari Green et al.
3 citations
Brain
Multiple Sclerosis Research Studies
4.41
article

GFAP and NfL as predictors of disease progression and relapse activity in fingolimod-treated multiple sclerosis

Rosetta Pedotti, Sabine Schädelin, Lilian Demuth, Ari Green, Riccardo Galbusera, Marjolaine Uginet, Marcus D’Souza, Eline A.J. Willemse, Björn Tackenberg, Patrice H. Lalive, Alessandro Cagol, Ahmed Abdelhak, Heinz Wiendl, Claudio Gobbi, Patrick Roth, Jens Kühle, Jannis Müller, Ludwig Kappos, Robert Hoepner, Giulio Disanto, Amandine Mathias, Özgür Yaldizli, Andrew Chan, Catarina Raposo, Michael Khalil, Klaus Berger, David Conen, Juan Gómez, Maximilian Einsiedler, Lars G. Hemkens, Chiara Zecca, Renaud Du Pasquier, Marco Hermesdorf, David Leppert, Pascal Benkert, Caroline Pot, Fredrik Piehl, Sebastian Finkener, Aleksandra Maleska Maceski, Johanna Oechtering, Cristina Granziera, Edoardo Galli, Jorge R. Oksenberg, Lester Melie‐García, Annette Orleth, Suvitha Subramaniam, David Brassat, Mauricio Rodríguez, Amar Zadic
article en
3 citations

Abstract

In multiple sclerosis (MS) patients under therapy, the increase of serum glial fibrillary acidic protein (sGFAP) concentrations is associated with the course of 'progression in absence of relapse' (PIRA). While serum neurofilament light chain (sNfL) reflects both response as well as insufficient or lack of efficiency of disease modifying therapies (DMT), the longitudinal course of sGFAP levels as drug response marker for future PIRA in relation to specific types of DMT is less clear. We aimed to compare the predictive capacity of sGFAP and sNfL for PIRA and relapse activity and the longitudinal course in persons with MS (PwMS) treated with fingolimod, based on Z scores derived from normative values. 420 PwMS under fingolimod treatment with follow-up of 9.1 years (IQR: 7.0-11.0) from the Swiss MS Cohort, contributing 2935 longitudinal serum samples, were included. A reference data set for sGFAP established from 4297 healthy controls across three European and North American cohorts was used to calculate Z scores. The longitudinal course and the predictive capacity of biomarkers for time to PIRA and relapse were assessed by Cox proportional hazards and linear mixed-effects models. In controls, sGFAP concentrations were 13.6% higher in females than males and increased exponentially with age. 31.0% of PwMS experienced ≥1 PIRA event. Elevated sGFAP Z scores (>0.75) were associated with increased risk of PIRA (HR: 1.64; 95% CI: [1.16-2.32]; p=0.006), while this was not the case for sNfL. Conversely, elevated sNfL predicted relapses (HR: 1.58 [1.13-2.23]; p=0.008), while sGFAP did not. Both biomarkers decreased under treatment: sGFAP by 0.19 Z score units (ZSU)/10 years (95% CI: -0.27 - -0.11; p<0.001) and sNfL by 0.16 ZSU/10 years (95% CI: -0.27 - -0.06; p=0.002). sGFAP remained elevated in PwMS with future PIRA events (estimate: 0.29; [0.07-0.50]; p=0.009); no such association was found for sNfL. sGFAP and sNfL Z scores provide complementary predictive capacity for PIRA and relapse risk. The decrease of sGFAP under fingolimod is a feature not observed with other types of DMT and may hint to a specific anti-neurodegenerative effect of Sphingosine-1-phosphate-receptor modulators on astrocytes.

Brain
University of Geneva (CH), Roche (Switzerland) (CH), Novartis (Switzerland) (CH), Karolinska University Hospital (SE), Philipps University of Marburg (DE), University of California, San Francisco (US), Medical University of Graz (AT), University of St.Gallen (CH), University of Münster (DE), University Hospital of Bern (CH), University Medical Center Freiburg (DE), Centre Hospitalier Universitaire Vaudois (CH), University Hospital of Basel (CH), Population Health Research Institute (CA), Sorbonne Université (FR), Laboratory for Biomedical Neurosciences (CH), Hospital Base (CL), Ente Ospedaliero Cantonale (CH), Assistance Publique – Hôpitaux de Paris (FR), University Hospital of Zurich (CH), University Hospital of Geneva (CH), Pitié-Salpêtrière Hospital (FR), Department of Biomedicine Basel (CH), Stockholm Health Care Services (SE), Kantonsspital Aarau (CH), Università della Svizzera italiana (CH), Geneva College (US), University of San Francisco (US), University of Genoa (IT), University of Lausanne (CH)
National Science Foundation, U.S. Department of Defense, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Bayer, GlaxoSmithKline, Sanofi, Gilead Sciences, Biogen, Teva Pharmaceutical Industries, Alexion Pharmaceuticals, Celgene, F. Hoffmann-La Roche, Universität Basel, European Committee for Treatment and Research in Multiple Sclerosis, Merck KGaA, Novocure, TG Therapeutics, GW Pharmaceuticals, Fresenius Medical Care North America, International Progressive MS Alliance, Multiple Sclerosis Society, Bayer HealthCare, National Research Foundation, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Bundesministerium für Bildung und Forschung, Vetenskapsrådet, Westfälische Wilhelms-Universität Münster, Shionogi, Deutschen Multiple Sklerose Gesellschaft, Schweizerische Multiple Sklerose Gesellschaft, Servier, H. Lundbeck A/S, Innosuisse - Schweizerische Agentur für Innovationsförderung, MedDay Pharmaceuticals, Genentech, EMD Serono, Novartis Pharma, Sanofi Genzyme
Openalex Percentile: Top 5%
Multiple Sclerosis Research Studies
4.41
DOIOpen Access PDFOpenAlex
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