Intrathecal IgM Synthesis Is Associated with Spinal Cord Manifestation and Neuronal Injury in Early MS

Johanna Oechtering; Therese Lincke; Sabine Schaedelin; Bernhard F Décard; Aleksandra Maceski; Annette Orleth; Stephanie Meier; Eline Willemse; Arabella Buchmann; Michael Khalil; Tobias Derfuss; Pascal Benkert; Ingmar Heijnen; Axel Regeniter; Stefanie Müller; Lutz Achtnichts; Patrice Lalive; Anke Salmen; Caroline Pot; Claudio Gobbi; Ludwig Kappos; Cristina Granziera; David Leppert; Regina Schlaeger; Johanna M Lieb; Jens Kuhle; Swiss MS Cohort Study

doi:10.1002/ana.26348

Intrathecal IgM Synthesis Is Associated with Spinal Cord Manifestation and Neuronal Injury in Early MS

Ann Neurol. 2022 Jun;91(6):814-820. doi: 10.1002/ana.26348. Epub 2022 Apr 9.

Authors

Johanna Oechtering^{1

2}, Therese Lincke³, Sabine Schaedelin^{2

4}, Bernhard F Décard¹, Aleksandra Maceski^{1

2}, Annette Orleth^{1

2}, Stephanie Meier^{1

2}, Eline Willemse^{1

2}, Arabella Buchmann^{1

2

5}, Michael Khalil⁵, Tobias Derfuss^{1

2}, Pascal Benkert^{2

4}, Ingmar Heijnen⁶, Axel Regeniter⁷, Stefanie Müller⁸, Lutz Achtnichts⁹, Patrice Lalive^{10

11

12}, Anke Salmen¹³, Caroline Pot¹⁴, Claudio Gobbi¹⁵, Ludwig Kappos^{1

2}, Cristina Granziera^{1

2

16}, David Leppert^{1

2}, Regina Schlaeger^{1

16}, Johanna M Lieb³, Jens Kuhle^{1

2}; Swiss MS Cohort Study

Affiliations

¹ Neurology Clinic and Policlinic, Departments of Head, Spine and Neuromedicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
² Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), University Hospital and University of Basel, Basel, Switzerland.
³ Division of Neuroradiology, Department of Radiology, University Hospital Basel, University of Basel, Basel, Switzerland.
⁴ Clinical Trial Unit, Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.
⁵ Department of Neurology, Medical University of Graz, Graz, Austria.
⁶ Division of Medical Immunology, Laboratory Medicine, University Hospital Basel, Basel, Switzerland.
⁷ Medica Laboratory, Zürich, Switzerland.
⁸ Department of Neurology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
⁹ Department of Neurology, Cantonal Hospital Aarau, Aarau, 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 Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
¹⁴ Division of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.
¹⁵ Neurocentre of Southern Switzerland, Multiple Sclerosis Centre, Ospedale Civico, Lugano, Switzerland.
¹⁶ Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland.

Abstract

Objective: Intrathecal Immunoglobulin M synthesis (IgM_{Intrathecal Fraction (IF)} ⁺ ) and spinal MRI lesions are both strong independent predictors of higher disease activity and severity in multiple sclerosis (MS). We investigated whether IgM_IF ⁺ is associated with spinal cord manifestation and higher neuroaxonal damage in early MS.

Methods: In 122 patients with a first demyelinating event associations between (1) spinal versus (vs) non-spinal clinical syndrome (2) spinal vs cerebral T2-weighted (T2w) and (3) contrast-enhancing (CE) lesion counts with IgG_IF ⁺ (vs IgG_IF ^- ) or IgM_IF ⁺ (vs IgM_IF ^- ) were investigated by logistic regression adjusted for age and sex, respectively. For serum neurofilament light chain (sNfL) analysis patients were categorized for presence or absence of oligoclonal IgG bands (OCGB), IgG_IF and IgM_IF (>0% vs 0%, respectively): (1) OCGB^- /IgG_IF ^- /IgM_IF ^- ; (2) OCGB⁺ /IgG_IF ^- /IgM_IF ^- ; (3) OCGB⁺ /IgG_IF ⁺ /IgM_IF ^- ; and (4) OCGB⁺ /IgG_IF ⁺ /IgM_IF ⁺ . Associations between categories 2 to 4 vs category 1 with sNfL concentrations were analyzed by robust linear regression, adjusted for sex and MRI parameters.

Results: Patients with a spinal syndrome had a 8.36-fold higher odds of IgM_IF ⁺ (95%CI 3.03-23.03; p < 0.01). Each spinal T2w lesion (odds Ratio 1.39; 1.02-1.90; p = 0.037) and CE lesion (OR 2.73; 1.22-6.09; p = 0.014) was associated with an increased risk of IgM_IF ⁺ (but not of IgG_IF ⁺ ); this was not the case for cerebral lesions. OCGB⁺ /IgG_IF ⁺ /IgM_IF ⁺ category patients showed highest sNfL levels (estimate:1.80; 0.55-3.06; p < 0.01).

Interpretation: Intrathecal IgM synthesis is strongly associated with spinal manifestation and independently more pronounced neuroaxonal injury in early MS, suggesting a distinct clinical phenotype and pathophysiology. ANN NEUROL 2022;91:814-820.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Immunoglobulin G
Immunoglobulin M
Multiple Sclerosis* / pathology
Oligoclonal Bands*
Spinal Cord / diagnostic imaging
Spinal Cord / pathology

Substances

Immunoglobulin G
Immunoglobulin M
Oligoclonal Bands