Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels Reflect Different Mechanisms of Disease Progression under B-Cell Depleting Treatment in Multiple Sclerosis

Pascal Benkert; Aleksandra Maleska Maceski; Sabine Schaedelin; Johanna Oechtering; Amar Zadic; Juan Francisco Vilchez Gomez; Lester Melie-Garcia; Alessandro Cagol; Riccardo Galbusera; Suvitha Subramaniam; Johannes Lorscheider; Edoardo Galli; Jannis Mueller; Bettina Fischer-Barnicol; Lutz Achtnichts; Oliver Findling; Patrice H Lalive; Claire Bridel; Marjolaine Uginet; Stefanie Müller; Caroline Pot; Amandine Mathias; Renaud Du Pasquier; Anke Salmen; Robert Hoepner; Andrew Chan; Giulio Disanto; Chiara Zecca; Marcus D'Souza; Lars G Hemkens; Özgür Yaldizli; Tobias Derfuss; Patrick Roth; Claudio Gobbi; David Brassat; Björn Tackenberg; Rosetta Pedotti; Catarina Raposo; Jorge Oksenberg; Heinz Wiendl; Klaus Berger; Marco Hermesdorf; Fredrik Piehl; David Conen; Andreas Buser; Ludwig Kappos; Michael Khalil; Cristina Granziera; Ahmed Abdelhak; David Leppert; Eline A J Willemse; Jens Kuhle; Swiss MS Cohort study (SMSC)

doi:10.1002/ana.27096

Serum Glial Fibrillary Acidic Protein and Neurofilament Light Chain Levels Reflect Different Mechanisms of Disease Progression under B-Cell Depleting Treatment in Multiple Sclerosis

Ann Neurol. 2024 Oct 16. doi: 10.1002/ana.27096. Online ahead of print.

Authors

Pascal Benkert^#^{1

2

3}, Aleksandra Maleska Maceski^#^{1

3}, Sabine Schaedelin^{1

2

3}, Johanna Oechtering^{1

3}, Amar Zadic^{1

3}, Juan Francisco Vilchez Gomez^{1

3}, Lester Melie-Garcia^{1

3

4}, Alessandro Cagol^{1

3

4}, Riccardo Galbusera^{1

3

4}, Suvitha Subramaniam^{1

2}, Johannes Lorscheider^{1

3}, Edoardo Galli^{1

3}, Jannis Mueller^{1

3

4}, Bettina Fischer-Barnicol^{1

3}, Lutz Achtnichts⁵, Oliver Findling⁵, Patrice H Lalive^{6

7

8}, Claire Bridel⁶, Marjolaine Uginet⁶, Stefanie Müller⁹, Caroline Pot¹⁰, Amandine Mathias¹⁰, Renaud Du Pasquier¹⁰, Anke Salmen¹¹, Robert Hoepner¹², Andrew Chan¹², Giulio Disanto¹³, Chiara Zecca^{13

14}, Marcus D'Souza^{1

3}, Lars G Hemkens^{1

2}, Özgür Yaldizli^{1

3}, Tobias Derfuss^{1

3}, Patrick Roth¹⁵, Claudio Gobbi^{13

14}, David Brassat^{16

17}, Björn Tackenberg^{18

19}, Rosetta Pedotti¹⁹, Catarina Raposo¹⁹, Jorge Oksenberg²⁰, Heinz Wiendl²¹, Klaus Berger²², Marco Hermesdorf²², Fredrik Piehl^{23

24}, David Conen²⁵, Andreas Buser²⁶, Ludwig Kappos^{1

2

3}, Michael Khalil²⁷, Cristina Granziera^{1

2

3

4}, Ahmed Abdelhak²⁰, David Leppert^{1

2

3}, Eline A J Willemse^#^{1

2

3}, Jens Kuhle^{1

2

3}; Swiss MS Cohort study (SMSC)

Affiliations

¹ Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Department of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland.
² Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
³ Department of Neurology, University Hospital and University of Basel, Basel, Switzerland.
⁴ Translational Imaging in Neurology (ThINK) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland.
⁵ Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland.
⁶ Department of Clinical Neurosciences, Division of Neurology, and Department of Medicine, Translational Biomarker Group, Geneva, Switzerland.
⁷ Diagnostic Department, Division of Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland.
⁸ Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
⁹ Department of Neurology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
¹⁰ Service of Neurology and Laboratories of Neuroimmunology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.
¹¹ Department of Neurology, St Josef-Hospital Bochum, Ruhr-University Bochum, Bochum, Germany.
¹² Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
¹³ Multiple Sclerosis Center, Neurocenter of Southern Switzerland, EOC, Lugano, Switzerland.
¹⁴ Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Lugano, Switzerland.
¹⁵ Department of Neurology and Clinical Neuroscience Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
¹⁶ Novartis Pharma AG, Basel, Switzerland.
¹⁷ Department of Neurology, Hôpital de la Pitié-Salpêtrière, AP-HP, Paris, France.
¹⁸ Department of Neurology, Philipps-University, Marburg, Germany.
¹⁹ F. Hoffmann-La Roche, Basel, Switzerland.
²⁰ Department of Neurology and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
²¹ Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.
²² Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.
²³ Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
²⁴ Center for Neurology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden.
²⁵ Population Health Research Institute, McMaster University, Hamilton, Canada.
²⁶ Regional Blood Transfusion Service, Swiss Red Cross, Basel, Switzerland.
²⁷ Department of Neurology, Medical University of Graz, Graz, Austria.

^# Contributed equally.

PMID: 39411917
DOI: 10.1002/ana.27096

Abstract

Objective: To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B-cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events.

Methods: A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores.

Results: Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17-2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95-2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow-up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (-0.92 [-1.23, -0.60], p < 0.0001), whereas levels in patients with PIRA remained high.

Interpretation: Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024.

Abstract

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