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Original Investigation
April 29, 2019

Association of Intrathecal Immunoglobulin G Synthesis With Disability Worsening in Multiple Sclerosis

Author Affiliations
  • 1Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
  • 2Department of Neurology, St, Josef Hospital, Ruhr-University Bochum, Bochum, Germany
  • 3Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland
  • 4Central Information Office German Competence Network of Multiple Sclerosis, Philipps University Marburg, Marburg, Germany
  • 5Department of Neurology, Klinikum Augsburg, Augsburg, Germany
  • 6Institute of Neuroimmunology and Multiple Sclerosis, Department of Neurology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
  • 7Institute of Clinical Neuroimmunology, Ludwig-Maximilians-Universität, Munich, Germany
  • 8Department of Neurology, University Hospital Erlangen, Erlangen, Germany
  • 9NeuroCure Clinical Research Center, Charité–Univeritätsmedizin Berlin, Berlin, Germany
  • 10Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine and Charité–Universitätsmedizin Berlin, Berlin, Germany
  • 11Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Hannover, Germany
  • 12Clinical Neuroimmunology Group, Department of Neurology, Philipps-University of Marburg, Marburg, Germany
  • 13Department of Neurology, University of Leipzig, Leipzig, Germany
  • 14Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
  • 15Department of Neurology, University Hospital Cologne, Cologne, Germany
  • 16Max Planck Institute of Psychiatry, Munich, Germany
  • 17Department of Neurology University of Münster, Münster, Germany
  • 18Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany
  • 19Department of Neurology, University of Rostock, Rostock, Germany
  • 20Department of Neurology & Stroke, Eberhard-Karls-Universität Tübingen, Tübingen, Germany
  • 21Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  • 22Department of Neurology, University of Ulm, Ulm, Germany
  • 23Clinic of Neurology Dietenbronn, Schwendi, Germany
  • 24Munich Cluster for Systems Neurology, Munich, Germany
  • 25Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany
  • 26Neurological Clinic Cham, Cham, Germany
  • 27Hertie-Institute for Clinical Brain Research, Eberhard-Karls-Universität Tübingen, Tübingen, Germany
  • 28Focus Program Translational Neurosciences, Johannes Gutenberg University Mainz, Mainz, Germany
  • 29Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  • 30Rhine-Main Neuroscience Network, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
  • 31NeuroCure Clinical Research Center, Berlin, Germany
  • 32Institute of Health, Berlin, Germany
JAMA Neurol. Published online April 29, 2019. doi:10.1001/jamaneurol.2019.0905
Key Points

Question  Is intrathecal immunoglobulin synthesis associated with disability worsening in patients with multiple sclerosis?

Findings  This cohort study included 673 patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome. Patients with intrathecal IgG synthesis were found to have a higher risk of and shorter time to Expanded Disability Status Scale score worsening in the 4 years after study entry.

Meaning  Intrathecal IgG synthesis is associated with disability worsening in patients with multiple sclerosis; it may be of use for early treatment decisions.

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.

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