Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis
Johanna Oechtering, Sabine Schaedelin, Pascal Benkert, Stefanie Müller, Lutz Achtnichts, Jochen Vehoff, Giulio Disanto, Oliver Findling, Bettina Fischer‐Barnicol, Annette Orleth, Andrew Chan, Caroline Pot, Muhamed Baraković, Reza Rahmanzadeh, Riccardo Galbusera, Ingmar Heijnen, Patrice H. Lalive, Jens Wuerfel, Suvitha Subramaniam, Stefanie Aeschbacher, David Conen, Yvonne Naegelin, Aleksandra Maleska Maceski, Stéphanie Meier, Klaus Berger, Heinz Wiendl, Therese Lincke, Johanna Lieb, Özgür Yaldizli, Tim Sinnecker, Tobias Derfuß, Axel Regeniter, Chiara Zecca, Claudio Gobbi, Ludwig Kappos, Cristina Granziera, David Leppert, Jens Kühle, and for the Swiss Multiple Sclerosis Cohort Study
Abstract
Objective We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. Methods We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow‐up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgG IF and IgM IF ). Relationships with the time to first relapse, sNfL concentrations, T2‐weighted (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 IgM IF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgM IF 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 positive for only OCGB or OCGB/IgG IF . Furthermore, quantitative analyses revealed that in patients with IgM IF ≥ median, the time to first relapse and to initiation of high‐efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgM IF < median. Dose‐dependent associations were also found for IgM IF but not for IgG IF with magnetic resonance imaging‐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. ANN NEUROL 2021;90:477–489