Christiane Gasperi1, Anke Salmen2,3, Gisela Antony4, Antonios Bayas5, Christoph Heesen6, Tania Kümpfel7, Ralf A Linker8, Friedemann Paul9,10,11,12, Martin Stangel13, Björn Tackenberg14, Florian Then Bergh15,16, Clemens Warnke17,18, Frank Weber19,20, Heinz Wiendl21,22, Brigitte Wildemann23, Uwe K Zettl24, Ulf Ziemann25, Frauke Zipp26,27,28,29, Hayrettin Tumani30,31, Ralf Gold2, Bernhard Hemmer1,32. 1. Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. 2. Department of Neurology, St, Josef Hospital, Ruhr-University Bochum, Bochum, Germany. 3. Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland. 4. Central Information Office German Competence Network of Multiple Sclerosis, Philipps University Marburg, Marburg, Germany. 5. Department of Neurology, Klinikum Augsburg, Augsburg, Germany. 6. Institute of Neuroimmunology and Multiple Sclerosis, Department of Neurology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany. 7. Institute of Clinical Neuroimmunology, Ludwig-Maximilians-Universität, Munich, Germany. 8. Department of Neurology, University Hospital Erlangen, Erlangen, Germany. 9. NeuroCure Clinical Research Center, Charité-Univeritätsmedizin Berlin, Berlin, Germany. 10. Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité-Universitätsmedizin Berlin, Berlin, Germany. 11. NeuroCure Clinical Research Center, Berlin, Germany. 12. Institute of Health, Berlin, Germany. 13. Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany. 14. Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, Marburg, Germany. 15. Department of Neurology, University of Leipzig, Leipzig, Germany. 16. Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany. 17. Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. 18. Department of Neurology, University Hospital Cologne, Cologne, Germany. 19. Max Planck Institute of Psychiatry, Munich, Germany. 20. Neurological Clinic Cham, Cham, Germany. 21. Department of Neurology University of Münster, Münster, Germany. 22. Hertie-Institute for Clinical Brain Research, Eberhard-Karls-Universität Tübingen, Tübingen, Germany. 23. Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany. 24. Department of Neurology, University of Rostock, Rostock, Germany. 25. Department of Neurology & Stroke, Eberhard-Karls-Universität Tübingen, Tübingen, Germany. 26. Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 27. Focus Program Translational Neurosciences, Johannes Gutenberg University Mainz, Mainz, Germany. 28. Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 29. Rhine-Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany. 30. Department of Neurology, University of Ulm, Ulm, Germany. 31. Clinic of Neurology Dietenbronn, Schwendi, Germany. 32. Munich Cluster for Systems Neurology, Munich, Germany.
Abstract
Importance: Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed. Objective: To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome. Design, Setting, and Participants: Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018. Exposure: Patients were offered standard immunotherapies per national treatment guidelines. Main Outcomes and Measures: A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated. Results: Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found. Conclusions and Relevance: Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.
Importance: Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed. Objective: To determine a possible association of intrathecal IgG synthesis and early disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome. Design, Setting, and Participants: Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018. Exposure: Patients were offered standard immunotherapies per national treatment guidelines. Main Outcomes and Measures: A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated. Results: Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 [95% CI, 1.15-3.58]; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found. Conclusions and Relevance: Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.
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Authors: Enric Monreal; Susana Sainz de la Maza; Lucienne Costa-Frossard; Paulette Walo-Delgado; Javier Zamora; José Ignacio Fernández-Velasco; Noelia Villarrubia; Mercedes Espiño; Daniel Lourido; Paloma Lapuente; Inmaculada Toboso; José Carlos Álvarez-Cermeño; Jaime Masjuan; Luisa María Villar Journal: Neurol Neuroimmunol Neuroinflamm Date: 2021-07-22
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Authors: Miriam Schlüter; Eva Oswald; Stephan Winklmeier; Ingrid Meinl; Joachim Havla; Peter Eichhorn; Edgar Meinl; Tania Kümpfel Journal: Neurol Neuroimmunol Neuroinflamm Date: 2021-07-01