Multicenter Study

. 2023 Mar 1;80(3):287-297.

doi: 10.1001/jamaneurol.2022.5250.

Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis

Stephanie Meier^{1

2

3}, Eline A J Willemse^{1

2

3

4}, Sabine Schaedelin^{1

2

3

4}, Johanna Oechtering^{1

2

3}, Johannes Lorscheider^{1

2

3}, Lester Melie-Garcia^{1

2

3

5}, Alessandro Cagol^{1

2

3

5}, Muhamed Barakovic^{1

2

3

5}, Riccardo Galbusera^{1

2

3

5}, Suvitha Subramaniam^{1

2

3

4}, Christian Barro⁶, Ahmed Abdelhak⁷, Simon Thebault⁸, Lutz Achtnichts⁹, Patrice Lalive¹⁰, Stefanie Müller¹¹, Caroline Pot¹², Anke Salmen¹³, Giulio Disanto^{14

15}, Chiara Zecca^{14

15}, Marcus D'Souza^{1

2

3}, Annette Orleth^{1

2

3}, Michael Khalil¹⁶, Arabella Buchmann¹⁶, Renaud Du Pasquier¹⁷, Özgür Yaldizli^{1

2

3

5}, Tobias Derfuss^{1

2

3}, Klaus Berger¹⁸, Marco Hermesdorf¹⁸, Heinz Wiendl¹⁹, Fredrik Piehl^{20

21}, Marco Battaglini²², Urs Fischer^{1

2

3}, Ludwig Kappos^{1

2

3}, Claudio Gobbi^{14

15}, Cristina Granziera^{1

2

3

5}, Claire Bridel¹⁰, David Leppert^{1

2

3}, Aleksandra Maleska Maceski^{1

2

3}, Pascal Benkert^{1

2

3

4}, Jens Kuhle^{1

2

3}

Affiliations

¹ Department of Neurology, University Hospital and University of Basel, Basel, Switzerland.
² Multiple Sclerosis Centre, Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
³ Research Center for Clinical Neuroimmunology and Neuroscience Basel, University Hospital and University of Basel, Switzerland.
⁴ Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
⁵ Translational Imaging in Neurology Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland.
⁶ Department of Neurology, Harvard Medical School, Boston, Massachusetts.
⁷ Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco.
⁸ Department of Medicine and the Ottawa Hospital Research Institute, The University of Ottawa, Ottawa, Ontario, Canada.
⁹ Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
¹⁰ Unit of Neuroimmunology, Division of Neurology, Department of Clinical Neurosciences, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland.
¹¹ Department of Neurology, Cantonal Hospital St Gallen, St Gallen, Switzerland.
¹² Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
¹³ Department of Neurology, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁴ Multiple Sclerosis Center, Department of Neurology, Neurocenter of Southern Switzerland, Lugano, Switzerland.
¹⁵ Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
¹⁶ Department of Neurology, Medical University of Graz, Graz, Austria.
¹⁷ Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁸ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹⁹ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
²⁰ Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
²¹ Center for Neurology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
²² Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.

PMID: 36745446
PMCID: PMC10011932
DOI: 10.1001/jamaneurol.2022.5250

Multicenter Study

Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis

Stephanie Meier et al. JAMA Neurol. 2023.

. 2023 Mar 1;80(3):287-297.

doi: 10.1001/jamaneurol.2022.5250.

Authors

Affiliations

¹ Department of Neurology, University Hospital and University of Basel, Basel, Switzerland.
² Multiple Sclerosis Centre, Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
³ Research Center for Clinical Neuroimmunology and Neuroscience Basel, University Hospital and University of Basel, Switzerland.
⁴ Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
⁵ Translational Imaging in Neurology Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland.
⁶ Department of Neurology, Harvard Medical School, Boston, Massachusetts.
⁷ Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, San Francisco.
⁸ Department of Medicine and the Ottawa Hospital Research Institute, The University of Ottawa, Ottawa, Ontario, Canada.
⁹ Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
¹⁰ Unit of Neuroimmunology, Division of Neurology, Department of Clinical Neurosciences, University Hospital of Geneva and Faculty of Medicine, Geneva, Switzerland.
¹¹ Department of Neurology, Cantonal Hospital St Gallen, St Gallen, Switzerland.
¹² Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.
¹³ Department of Neurology, Bern University Hospital, University of Bern, Bern, Switzerland.
¹⁴ Multiple Sclerosis Center, Department of Neurology, Neurocenter of Southern Switzerland, Lugano, Switzerland.
¹⁵ Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.
¹⁶ Department of Neurology, Medical University of Graz, Graz, Austria.
¹⁷ Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁸ Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
¹⁹ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
²⁰ Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
²¹ Center for Neurology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
²² Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy.

PMID: 36745446
PMCID: PMC10011932
DOI: 10.1001/jamaneurol.2022.5250

Abstract

Importance: There is a lack of validated biomarkers for disability progression independent of relapse activity (PIRA) in multiple sclerosis (MS).

Objective: To determine how serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) correlate with features of disease progression vs acute focal inflammation in MS and how they can prognosticate disease progression.

Design, setting, and participants: Data were acquired in the longitudinal Swiss MS cohort (SMSC; a consortium of tertiary referral hospitals) from January 1, 2012, to October 20, 2022. The SMSC is a prospective, multicenter study performed in 8 centers in Switzerland. For this nested study, participants had to meet the following inclusion criteria: cohort 1, patients with MS and either stable or worsening disability and similar baseline Expanded Disability Status Scale scores with no relapses during the entire follow-up; and cohort 2, all SMSC study patients who had initiated and continued B-cell-depleting treatment (ie, ocrelizumab or rituximab).

Exposures: Patients received standard immunotherapies or were untreated.

Main outcomes and measures: In cohort 1, sGFAP and sNfL levels were measured longitudinally using Simoa assays. Healthy control samples served as the reference. In cohort 2, sGFAP and sNfL levels were determined cross-sectionally.

Results: This study included a total of 355 patients (103 [29.0%] in cohort 1: median [IQR] age, 42.1 [33.2-47.6] years; 73 female patients [70.9%]; and 252 [71.0%] in cohort 2: median [IQR] age, 44.3 [33.3-54.7] years; 156 female patients [61.9%]) and 259 healthy controls with a median [IQR] age of 44.3 [36.3-52.3] years and 177 female individuals (68.3%). sGFAP levels in controls increased as a function of age (1.5% per year; P < .001), were inversely correlated with BMI (-1.1% per BMI unit; P = .01), and were 14.9% higher in women than in men (P = .004). In cohort 1, patients with worsening progressive MS showed 50.9% higher sGFAP levels compared with those with stable MS after additional sNfL adjustment, whereas the 25% increase of sNfL disappeared after additional sGFAP adjustment. Higher sGFAP at baseline was associated with accelerated gray matter brain volume loss (per doubling: 0.24% per year; P < .001) but not white matter loss. sGFAP levels remained unchanged during disease exacerbations vs remission phases. In cohort 2, median (IQR) sGFAP z scores were higher in patients developing future confirmed disability worsening compared with those with stable disability (1.94 [0.36-2.23] vs 0.71 [-0.13 to 1.73]; P = .002); this was not significant for sNfL. However, the combined elevation of z scores of both biomarkers resulted in a 4- to 5-fold increased risk of confirmed disability worsening (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) and PIRA (HR, 4.71; 95% CI, 2.05-9.77; P < .001).

Conclusions and relevance: Results of this cohort study suggest that sGFAP is a prognostic biomarker for future PIRA and revealed its complementary potential next to sNfL. sGFAP may serve as a useful biomarker for disease progression in MS in individual patient management and drug development.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Oechtering reported receiving travel grants from Biogen Idec, Novartis, and Bayer; grants from Swiss MS Society; and serving on an advisory board by Roche outside the submitted work. Dr Lorscheider reported receiving grants from Novartis and Biogen; personal fees from Novartis, Roche, and Teva; serving on the advisory boards for Roche and Teva and receiving grants from Innosuisse Innovation Agency outside the submitted work. Dr Cagol reported receiving grant support from the Horizon 2020 Eurostar program. Dr Barro reported receiving travel support from Novartis and Teva. Dr Abdelhak reported receiving research grants from the German Multiple Sclerosis Society, Roche, and Denali Therapeutics outside the submitted work. Dr Achtnichts reported serving on the scientific advisory boards for Celgene, Novartis Pharmaceuticals, Merck, Biogen, Sanofi Genzyme, Roche and Bayer; receiving funding for travel and/or speaker honoraria from Celgene, Biogen, Sanofi Genzyme, Novartis, Merck Serono, Roche, Teva and the Swiss Multiple Sclerosis Society; and research support from Biogen, Sanofi Genzyme, and Novartis. Dr. Lalive reported receiving speaker honoraria 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, Novartis. Dr Müller reported receiving honoraria for travel, honoraria for lectures/consulting, and/or grants for studies from Almirall, Biogen, Celgene, Novartis, Teva, Merck Serono, Genzyme, Roche, and Bayer Schweiz. Dr Pot reported receiving consulting fees and/or travel compensation, used exclusively for research support, for activities with Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. Dr Salmen reported receiving speaker honoraria and/or travel compensation for activities with Almirall Hermal GmbH, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; personal fees from Bristol Myers Squibb, CSL Behring, Novartis, and Roche; and grants from Baasch Medicus Foundation, Medical Faculty of the University of Bern, and the Swiss Multiple Sclerosis Society outside the submitted work. Dr Zecca reported receiving honoraria for speaking/consulting fees or grants from Abbvie, Almirall, Biogen Idec, Celgene, Janssen, Genzyme, Lilly, Merck Serono, Novartis, Roche, Sanofi, and Teva Pharma outside the submitted work. Dr Khalil reported receiving funding for travel and speaker honoraria from Bayer, Novartis, Merck, Biogen Idec, and Teva Pharmaceutical Industries; serving on scientific advisory boards for Biogen Idec, Merck, Roche, Novartis, Bristol Myers Squibb, and Gilead; and receiving grants from Teva Pharmaceutical Industries, Biogen, and Novartis. Dr Yaldizli reported receiving grants from European Committee for Treatment and Research in Multiple Sclerosis/European Magnetic Resonance Imaging in Multiple Sclerosis network, 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, Almirall, Biogen, and Novartis. Dr Derfuss reported receiving speaker fees, research support, travel support, and/or served on advisory boards, data safety monitoring boards, or Steering Committees of Actelion, Alexion, Celgene, Polyneuron, Novartis Pharma, Merck Serono, Sanofi, Biogen, Teva, Bayer-Schering, GeNeuro, Mitsubishi Pharma, MedDay, Roche, and Genzyme. Dr Berger reported receiving a grant from the German Ministry of Education and Research (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 patients with multiple sclerosis. Dr Wiendl reported receiving honoraria for acting as a member of scientific advisory boards from Abbvie, Alexion, Argenx, Bristol Myers Squibb/Celgene, Janssen, Merck, and Novartis; speaker honoraria and travel support from Alexion, Biogen, Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, Genzyme, Merck, Neurodiem, Novartis, Roche Pharma AG, Teva Pharma, and WebMD Global; consultant fees from Abbvie, Actelion, Argenx, Biogen, Bristol Myers Squibb, EMD Serono, Fondazione Cariplo, Gossamer Bio, Idorsia, Immunic, Immunovant, Janssen, Lundbeck, Merck, NexGen, Novartis, PSI CRO, Roche, Sanofi, Swiss Multiple Sclerosis Society, UCB, and Worldwide Clinical Trials; and research funding from the German Ministry for Education and Research, Deutsche Forschungsgesellschaft, Deutsche Myasthenie Gesellschaft e.V., Alexion, Amicus Therapeutics Inc, Argenx, Biogen, CSL Behring, F. Hoffmann - La Roche, Genzyme, Merck KgaA, Novartis Pharma, Roche Pharma, and UCB Biopharma. Dr Piehl reported receiving grants from Merck KGaA and UCB; data safety monitoring board member fees from Chugai, Lundbeck, and Roche; and fees for the preparation of expert witness statement from Novartis outside the submitted work. Dr Fischer reported receiving grants from the Swiss National Science Foundation, Medtronic, Stryker, Penumbra, Phenox, Rapid Medical; consultant fees from Medtronic, CSL Behring, and Stryker; and fees for participation in an advisory board from Alexion/Portola and Boehringer Ingelheim; being a member of a clinical event committee of the COATING study (Phenox) and of the data and safety monitoring committee of the TITAN, LATE MT and IN EXTREMIS trials; and serving as vice presidency of the Swiss Neurological Society. Dr Kappos’ employer (University Hospital Basel) has received and dedicated to research support fees for board membership, consultancy or speaking, or grants in the past 3 years from Abbvie, Actelion, Advancell, Allozyne, Auriga Vision AG, Bayer, Bayhill, Biogen Idec, BioMarin, Celgene, CSL Behring, df-mp Molnia & Pohlman, Eisai, Eli Lilly EU, EMD Serono, Genentech, Genmab, GeNeuro SA, Genzyme, Gianni Rubatto Foundation, Glaxo Smith Kline, Glenmark, Innosuisse, Janssen, Japan Tobacco, Merck Serono, MediciNova, Minoryx Therapeutics, Mitsubishi Pharma, MH Consulting, Neurostatus-UHB AG, Novartis, Novartis Research Foundation, Novo Nordisk, Österreichische Gesellschaft für Neurologie, Peptimmune, Roche, Roche Research Foundation, Santhera, Sanofi-Aventis, Senda Biosciences Inc, Swiss MS Society, Swiss National Research Foundation, Teva Pharmaceutical Industries Ltd, TG Therapeutics, UCB, Wellmera AG, and Wyeth; and Dr Kappos reported having a patent for Neurostatus UHB-AG with royalties paid Payments made to institution (University Hospital Basel); being CEO (employment by University Hospital Basel)MAGNIMS Steering Committee) and a board member of the European Charcot Foundation. Dr Gobbi reported receiving honoraria for speaking/consulting or grants from Abbvie, Almirall, Biogen Idec, Celgene, Genzyme, Merck Serono, Novartis, Roche, Teva Pharma. Dr Granziera reported The University Hospital Basel (USB), as the employer of C.G., has received the following fees which were used exclusively for research support: (1) advisory boards and consultancy fees from Actelion, Novartis, Genzyme-Sanofi, GeNeuro, Hoffmann La Roche and Siemens Healthineers; (2) speaker fees from Biogen, Hoffmann La Roche, Teva, Novartis, Janssen and Genzyme-Sanofi; and (3) research grants from Hoffmann La Roche, GeNeuro, Genzyme, Biogen. Dr Bridel reported serving on scientific advisory boards for Biogen, Novartis, and BMS. Dr Leppert reported receiving grants from Progressive MS Alliance outside the submitted work; and being chief medical officer of GeNeuro. Dr Kuhle reported receiving grants from Swiss National Science Foundation, Swiss MS Society, Biogen, Celgene, Merck, Novartis, Roche, Sanofi, Progressive MS Alliance, University of Basel, Octave Bioscience. No other disclosures were reported.

Figures

**Figure 1.. Serum Glial Fibrillary Acidic Protein (GFAP) and Serum Neurofilament Light Chain (sNfL) in Worsening Progressive Multiple Sclerosis (MS) and Stable MS**
Concentrations of sGFAP (A) and sNfL (B) in worsening progressive MS vs stable MS (stMS) over follow-up time. sGFAP and sNfL concentrations were increased by 64.2% and 42.2%, respectively, in worsening progressive MS vs stMS. Thin lines connect longitudinal data points of individual patients; thick lines show the group regression lines from Table 2, model 1. Only the regression lines are predicted. Estimates including 95% CI and P value of differences between worsening progressive MS vs stMS are added to the plots (B). Marginal effects plots of multivariable mixed models showing the association of worsening progressive MS vs stMS with sGFAP (C) and sNfL levels (D) over follow-up time. After adjustment for potential confounders, sGFAP and sNfL concentrations were increased by 57.5% and 24.8%, respectively, in worsening progressive MS vs stMS (Table 2, model 2). Marginal effects plots for worsening status with additional adjustment for sNfL (E) and sGFAP (F). Additional correction for sNfL levels had a minor association with the difference of sGFAP levels between stMS vs worsening progressive MS status (50.9% increase); however, additional correction for sGFAP eliminated the association of progression status with sNfL levels (Table 2, model 3).

Figure 2.. Serum Glial Fibrillary Acidic Protein (sGFAP) and Serum Neurofilament Light Chain (sNfL) z Scores in Patients With and Without Confirmed Disease Worsening During Follow-up While Receiving B-Cell–Depleting Therapy in Comparison to Healthy Controls
Box plot representation of sGFAP z scores (A) and sNfL z scores (B). Dashed lines indicate mean values in healthy controls (ie, z score = 0) and P values below indicate whether observed values differ from z scores 0 (Wilcoxon signed rank test). In patients with MS (without and with future confirmed disease worsening [CDW] development), sGFAP levels were increased compared with healthy controls (z scores healthy controls = 0; P < .001 for both), whereas the increase of sNfL was less pronounced (P < .001 for both). Development of CDW was associated with higher sGFAP z scores, which was not the case for sNfL.

**Figure 3.. Kaplan-Meier Curves Using Combined Biomarker Data to Predict Time to Confirmed Disease Worsening (CDW)**
Optimized cutoffs of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) z scores from receiver operating characteristic curve analysis, based on the Youden index, were used to dichotomize patient groups. High sGFAP/high sNfL levels were associated with a 4-fold (hazard ratio [HR], 4.09; 95% CI, 2.04-8.18; P < .001) increased risk of CDW compared with low sGFAP/low sNfL levels. The combination of high sGFAP/low sNfL levels showed a slightly reduced risk (HR, 2.32; 95% CI, 0.99-5.42; P = .05). The combination of low sGFAP/high sNfL levels, however, did not show an increased risk on CDW (HR, 1.03; 95% CI, 0.30-3.53; P = .97).

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References

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Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis

Affiliations

Serum Glial Fibrillary Acidic Protein Compared With Neurofilament Light Chain as a Biomarker for Disease Progression in Multiple Sclerosis

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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LinkOut - more resources

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