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Multiple sclerosis
Original research
Serum biomarker levels predict disability progression in patients with primary progressive multiple sclerosis
  1. Nicolás Fissolo1,
  2. Pascal Benkert2,3,
  3. Jaume Sastre-Garriga1,
  4. Neus Mongay-Ochoa1,
  5. Andreu Vilaseca-Jolonch1,
  6. Sara Llufriu4,
  7. Yolanda Blanco4,
  8. Harald Hegen5,
  9. Klaus Berek5,
  10. Francisco Perez-Miralles6,
  11. Konrad Rejdak7,
  12. Luisa M Villar8,
  13. Enric Monreal9,
  14. Roberto Alvarez-Lafuente10,
  15. Onder K Soylu11,
  16. Ahmed Abdelhak11,12,
  17. Franziska Bachhuber11,
  18. Hayrettin Tumani11,
  19. Sergio Martínez-Yélamos13,
  20. Antonio J Sánchez-López14,15,
  21. Antonio García-Merino14,
  22. Lucía Gutiérrez1,
  23. Tamara Castillo-Trivino16,
  24. Jan Lycke17,
  25. Igal Rosenstein17,
  26. Roberto Furlan18,
  27. Massimo Filippi19,20,21,22,23,
  28. Nieves Téllez24,
  29. Lluís Ramió-Torrentà25,
  30. Jan D Lünemann26,
  31. Heinz Wiendl26,
  32. Sara Eichau27,
  33. Michael Khalil28,
  34. Jens Kuhle2,3,
  35. Xavier Montalban1,
  36. Manuel Comabella1
  1. 1Servei de Neurologia-Neuroimmunologia, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d’Hebron (VHIR), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Vall d'Hebron University Hospital, Barcelona, Spain
  2. 2Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland
  3. 3Department of Neurology, University Hospital and University of Basel, Basel, Switzerland
  4. 4Center of Neuroimmunology, Service of Neurology, Hospital Clinic and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
  5. 5Department of Neurology, Innsbruck Medical University, Innsbruck, Austria
  6. 6Neuroimmunology Unit, València University and Polytechnic Hospital La Fe, Valencia, Spain
  7. 7Department of Neurology, Medical University of Lublin, Lublin, Poland
  8. 8Departments of Neurology and Immunology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal deInvestigacion Sanitaria (IRYCIS), Madrid, Spain
  9. 9Department of Neurology, Hospital Universitario Ramón y Cajal, REEM, IRYCIS, Universidad de Alcalá, Madrid, Spain
  10. 10Environmental Factors in Degenerative Diseases Research Group, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico SanCarlos (IdISSC), Madrid, Spain
  11. 11Department of Neurology, Ulm University, Ulm, Germany
  12. 12Department of Neurology, Division of Neuroinflammation and Glial Biology, University of California San Francisco, San Francisco, California, USA
  13. 13Neurology Department, Multiple Sclerosis Unit, Hospital Universitari deBellvitge-IDIBELL, Universitat de Barcelona, Barcelona, Spain
  14. 14Neuroimmunology Unit, Puerta de Hierro-Segovia de Arana Health Research Institute, Madrid, Spain
  15. 15Biobank, Puerta de Hierro-Segovia de Arana Health Research Institute, Madrid, Spain
  16. 16Neurology Department, Donostia University Hospital, San Sebastian, Spain
  17. 17Department of Clinical Neuroscience, Institute of Neuroscience and Physiology at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  18. 18Clinical Neuroimmunology Unit, Division of Neuroscience, Institute of Experimental Neurology, IRCCS Ospedale San Raffaele, Milan, Italy
  19. 19Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milano, Italy
  20. 20Neurology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
  21. 21Neurophysiology Service, IRCCS San Raffaele Scientific Institute, Milan, Italy
  22. 22Neurorehabilitation Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
  23. 23Università Vita Salute San Raffaele, Milano, Italy
  24. 24Neurology Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain
  25. 25Girona Neuroimmunology and Multiple Sclerosis Unit, Neurology Department,Hospital Universitari Dr. Josep Trueta and Hospital Santa Caterina.Neurodegeneration and Neuroinflammation research group (IDIBGI). Department of Medical Sciences, University of Girona, Girona, Spain
  26. 26Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Munster, Germany
  27. 27Multiple Sclerosis Unit, Neurology Service, Hospital Universitario Virgen Macarena, Sevilla, Spain
  28. 28Department of Neurology, Medical University of Graz, Graz, Austria
  1. Correspondence to Dr Manuel Comabella, Multiple Sclerosis Centre of Catalonia, Neurology-Neuroimmunology Department, Vall d'Hebron University Hospital, Barcelona, 08035, Spain; manuel.comabella{at}vhir.org

Abstract

Background We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS).

Methods A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman’s r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods.

Results Median (IQR) age of patients was 52.9 (46.4–58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0–12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change.

Conclusions Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression.

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Data availability statement

Data are available upon reasonable request.

http://dx.doi.org/10.1136/jnnp-2023-332251

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • NF and PB are joint first authors.

    • Twitter @J_SastreGarriga, @Enric_Monreal

    • XM and MC contributed equally.

    • Contributors NF, XM and MC: Design and conceptualised study; acquisition of the data; drafted the manuscript for intellectual content. PB: Design and conceptualised study; analysed the data; drafted the manuscript for intellectual content. JS-G, NM-O, AV-J, SL, YB, HH, KB, FP-M, KR, LMV, EM, RA-L, OKS, AA, FB, HT, SM-Y, AJS-L, AG-M, LG, TC-T, JL, IR, RF, MF, NT, LR-T, JDL, HW, SE and MK: Acquisition of the data and revised the manuscript for intellectual content. JK: Design and conceptualised study, and revised the manuscript for intellectual content. MC: acts as gurantor and accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.