Serum Glial Fibrillary Acidic Protein Dynamics, Disease Progression, and Therapy Response in Multiple Sclerosis

Importance: Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation. Objective: To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA). Design, Setting, and Participants: This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18 629 measurements). Exposures: Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months. Main Outcomes and Measures: Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC). Results: The SMSC and EPIC cohorts consisted of 1709 (13 375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (z score >1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75; P < .001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71; P = .01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP z score unit reduction during the first 2 years receiving fingolimod or B-cell-depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84; P = .01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61; P < .001), respectively. Conclusions and Relevance: In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.

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Journal
JAMA Neurology
Published
2026-08-03
DOI
https://doi.org/10.1001/jamaneurol.2026.2500
Primary Topic
Multiple Sclerosis Research Studies
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article
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article

Serum Glial Fibrillary Acidic Protein Dynamics, Disease Progression, and Therapy Response in Multiple Sclerosis

Rosetta Pedotti, Riccardo Galbusera, Nafiye Genc, Lisa Hofer et al.
JAMA Neurology
Multiple Sclerosis Research Studies
article

Serum Glial Fibrillary Acidic Protein Dynamics, Disease Progression, and Therapy Response in Multiple Sclerosis

Rosetta Pedotti, Riccardo Galbusera, Nafiye Genc, Lisa Hofer, Marjolaine Uginet, Christian Cordano, Björn Tackenberg, Sofia Sandgren, Jannis Müller, Marina Herwerth, Giulio Disanto, Amandine Mathias, Özgür Yaldizli, David Conen, Juan Gómez, Maximilian Einsiedler, Lars G. Hemkens, Marco Hermesdorf, David Leppert, Georgina Arrambide, Sebastian Finkener, Aleksandra Maleska Maceski, Johanna Oechtering, Edoardo Galli, Kiarra Ning, Stefanie Müller, Renaud Pasquier, Amar Zadic, Ahmed Abdelhak, Michelle Hughes, Ari J. Green, Tobias Derfuss, Maria Pia Sormani, Henrik Zetterberg, Chiara Zecca, Catarina Raposo, Bettina Fischer-Barnicol, Patrice H. Lalive, Lester Melie-Garcia, Andrew Chan, Roland G. Henry, Ludwig Kappos, Robert Hoepner, Stephen L. Hauser, Jeffrey M. Gelfand, Fredrik Piehl, Klaus Berger, David Brassat, Cristina Granziera, Pascal Benkert, Jens Kuhle, Claudio Gobbi, Alessandro Cagol, Marcus D’Souza, Michael Khalil, Sabine Schaedelin, Jorge Oksenberg, Caroline Pot, Heinz Wiendl, Veronika Kana, Patrick Roth, Bruce A.C. Cree
article en

Abstract

Importance: Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation. Objective: To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA). Design, Setting, and Participants: This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18 629 measurements). Exposures: Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months. Main Outcomes and Measures: Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC). Results: The SMSC and EPIC cohorts consisted of 1709 (13 375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (z score >1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75; P < .001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71; P = .01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP z score unit reduction during the first 2 years receiving fingolimod or B-cell-depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84; P = .01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61; P < .001), respectively. Conclusions and Relevance: In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.

JAMA Neurology
University of Geneva (CH), Roche (Switzerland) (CH), University of Bern (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 Zurich (CH), University of Münster (DE), Kantonsspital St. Gallen (CH), University Hospital of Bern (CH), Sahlgrenska University Hospital (SE), University Medical Center Freiburg (DE), University Hospital of Basel (CH), Population Health Research Institute (CA), Karolinska Institutet (SE), Sorbonne Université (FR), Laboratory for Biomedical Neurosciences (CH), Assistance Publique – Hôpitaux de Paris (FR), University Hospital of Zurich (CH), University Hospital of Geneva (CH), Pitié-Salpêtrière Hospital (FR), UK Dementia Research Institute (GB), Vall d'Hebron Hospital Universitari (ES), Stockholm Health Care Services (SE), Ospedale Policlinico San Martino (IT), National Hospital for Neurology and Neurosurgery (GB), Kantonsspital Aarau (CH), University College London (GB), Università della Svizzera italiana (CH), University of Genoa (IT), University of Gothenburg (SE), University of Lausanne (CH), McMaster University (CA)
Good health and well-being
Openalex Percentile: Top 10%
Multiple Sclerosis Research Studies
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