Johanna Oechtering1, Sabine Schaedelin2, Pascal Benkert2, Stefanie Müller3, Lutz Achtnichts4, Jochen Vehoff3, Giulio Disanto5, Oliver Findling4, Bettina Fischer-Barnicol1, Annette Orleth1, Andrew Chan6, Caroline Pot7, Muhamed Barakovic1,8, Reza Rahmanzadeh1,8, Riccardo Galbusera1,8, Ingmar Heijnen9, Patrice H Lalive10,11,12, Jens Wuerfel13, Suvitha Subramaniam2, Stefanie Aeschbacher14, David Conen15, Yvonne Naegelin1, Aleksandra Maceski1, Stephanie Meier1, Klaus Berger16, Heinz Wiendl17, Therese Lincke18, Johanna Lieb18, Özgür Yaldizli1,8, Tim Sinnecker1,13, Tobias Derfuss1, Axel Regeniter19, Chiara Zecca5,20, Claudio Gobbi1,5,20, Ludwig Kappos1, Cristina Granziera1,8, David Leppert1, Jens Kuhle1. 1. Neurology Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB) University Hospital Basel, University of Basel, Switzerland. 2. Clinical Trial Unit, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland. 3. Department of Neurology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland. 4. Department of Neurology, Cantonal Hospital Aarau, Switzerland. 5. Neurocentre of Southern Switzerland, Multiple sclerosis centre, Ospedale Civico, Lugano, Switzerland. 6. Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. 7. Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland. 8. Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland. 9. Division of Medical Immunology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland. 10. Department of Clinical Neurosciences, Division of Neurology, Geneva University Hospital, Geneva, Switzerland. 11. Diagnostic Department, Division of Laboratory Medicine, Geneva University Hospital, Geneva, Switzerland. 12. Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. 13. Medical Image Analysis Center (MIAC) and Department of Biomedical Engineering, University Basel, Basel, Switzerland. 14. Cardiovascular research institute Basel, University Hospital Basel, Basel, Switzerland. 15. Population Health Research Institute, McMaster University, Canada. 16. Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany. 17. Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany. 18. Division of Neuroradiology, Department of Radiology and Nuclear Medicine, University Hospital Basel, University of Basel, Switzerland. 19. Medica Laboratory, Zürich, Switzerland. 20. Faculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, Switzerland.
Abstract
OBJECTIVE: We aimed to determine whether in relapsing multiple sclerosis intrathecal IgM and IgG synthesis are associated with outcomes reflecting inflammatory activity and chronic worsening. METHODS: We compared CSF analysis, clinical and MRI data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (IgGIntrathecal Fraction (IF) , IgMIF ). Relations to time to first relapse, sNfL concentrations, T2w lesions, MS Severity Score (MSSS), and time to initiation of high efficacy therapy were analyzed in covariate adjusted statistical models. RESULTS: By categorical analysis, in patients with IgMIF median time to first relapse was 28 months shorter and MSSS was on average higher by 1.11 steps compared to those without intrathecal immunoglobulin synthesis. Moreover, patients with IgMIF had higher sNfL concentrations, more new/enlarging T2w lesions and higher total T2w lesion counts (all p</= 0.01). These associations were absent, or equally smaller in patients who were only positive for OCGB or OCGB/IgGIF . Furthermore, quantitative analyses revealed that in patients with IgMIF ≥ median , time to first relapse and to initiation of high efficacy therapy was shorter by 32 and by 203 months (both p < 0.01), as compared to patients with IgMIF < median ; dose-dependent associations were also found for IgMIF but not for IgGIF with MRI defined disease activity and sNfL. INTERPRETATION: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
OBJECTIVE: We aimed to determine whether in relapsing multiple sclerosis intrathecal IgM and IgG synthesis are associated with outcomes reflecting inflammatory activity and chronic worsening. METHODS: We compared CSF analysis, clinical and MRI data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (IgGIntrathecal Fraction (IF) , IgMIF ). Relations to time to first relapse, sNfL concentrations, T2w lesions, MS Severity Score (MSSS), and time to initiation of high efficacy therapy were analyzed in covariate adjusted statistical models. RESULTS: By categorical analysis, in patients with IgMIF median time to first relapse was 28 months shorter and MSSS was on average higher by 1.11 steps compared to those without intrathecal immunoglobulin synthesis. Moreover, patients with IgMIF had higher sNfL concentrations, more new/enlarging T2w lesions and higher total T2w lesion counts (all p</= 0.01). These associations were absent, or equally smaller in patients who were only positive for OCGB or OCGB/IgGIF . Furthermore, quantitative analyses revealed that in patients with IgMIF ≥ median , time to first relapse and to initiation of high efficacy therapy was shorter by 32 and by 203 months (both p < 0.01), as compared to patients with IgMIF < median ; dose-dependent associations were also found for IgMIF but not for IgGIF with MRI defined disease activity and sNfL. INTERPRETATION: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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