Serum Glial Fibrillary Acidic Protein Dynamics, Disease Progression, and Therapy Response in Multiple Sclerosis.
Researchers
Maximilian Einsiedler, Sofia Sandgren, Sabine Schaedelin, Kiarra Ning, Aleksandra Maleska Maceski, Johanna Oechtering, Christian Cordano, Lester Melie-Garcia, Jeffrey M Gelfand, Alessandro Cagol, Roland G Henry, Sebastian Finkener, Patrice H Lalive, Stefanie Müller, Caroline Pot, Amandine Mathias, Renaud Du Pasquier, Robert Hoepner, Andrew Chan, Giulio Disanto, Chiara Zecca, Marcus D'Souza, Lars G Hemkens, Özgür Yaldizli, Bettina Fischer-Barnicol, Tobias Derfuss, Patrick Roth, Marina Herwerth, Claudio Gobbi, David Brassat, Björn Tackenberg, Rosetta Pedotti, Heinz Wiendl, Klaus Berger, Marco Hermesdorf, Georgina Arrambide, Fredrik Piehl, Henrik Zetterberg, Bruce A C Cree, Maria Pia Sormani, Ludwig Kappos, Stephen L Hauser, Michael Khalil, Cristina Granziera, Ari J Green, David Leppert, Pascal Benkert, Ahmed Abdelhak, Jens Kuhle, Lisa Hofer, Michelle Hughes, Nafiye Genc, Amar Zadic, Juan Francisco Vilchez Gomez, Riccardo Galbusera, Edoardo Galli, Jannis Müller, Marjolaine Uginet, Veronika Kana, Catarina Raposo, Jorge Oksenberg, David Conen
Abstract
Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation.
To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA).
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).
Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months.
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).
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.
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.