Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis

Publication

Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis

Journal Paper/Review - Jun 22, 2021

Oechtering Johanna, Naegelin Yvonne, Maceski Aleksandra, Meier Stephanie, Berger Klaus, Wiendl Heinz, Lincke Therese, Lieb Johanna, Yaldizli Ozgür, Sinnecker Tim, Derfuss Tobias, Regeniter Axel, Zecca Chiara, Gobbi Claudio, Kappos Ludwig, Granziera Cristina, Leppert David, Kuhle Jens, Conen David, Aeschbacher Stefanie, Subramaniam Suvitha, Schaedelin Sabine, Benkert Pascal, Müller Stefanie, Achtnichts Lutz, Vehoff Jochen, Giulio Disanto, Findling Oliver, Fischer-Barnicol Bettina, Orleth Annette, Chan Andrew, Pot Caroline, Barakovic Muhamed, Rahmanzadeh Reza, Galbusera Riccardo, Heijnen Ingmar, Lalive Patrice H, Wuerfel Jens, Swiss Multiple Sclerosis Cohort Study

Citation

Oechtering J, Naegelin Y, Maceski A, Meier S, Berger K, Wiendl H, Lincke T, Lieb J, Yaldizli O, Sinnecker T, Derfuss T, Regeniter A, Zecca C, Gobbi C, Kappos L, Granziera C, Leppert D, Kuhle J, Conen D, Aeschbacher S, Subramaniam S, Schaedelin S, Benkert P, Müller S, Achtnichts L, Vehoff J, Giulio D, Findling O, Fischer-Barnicol B, Orleth A, Chan A, Pot C, Barakovic M, Rahmanzadeh R, Galbusera R, Heijnen I, Lalive P, Wuerfel J, Swiss Multiple Sclerosis Cohort Study. Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in Multiple Sclerosis. Ann Neurol 2021; 90:477-489.

Type

Journal Paper/Review (English)

Journal

Ann Neurol 2021; 90

Publication Date

Jun 22, 2021

Issn Electronic

1531-8249

Pages

477-489

Brief description/objective

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 and IgM ). 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 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 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 . Furthermore, quantitative analyses revealed that in patients with IgM ≥ 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 < median. Dose-dependent associations were also found for IgM but not for IgG 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.