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Intrathecal Immunoglobulin M Synthesis is an Independent Biomarker for Higher Disease Activity and Severity in
Johanna Oechtering1, Sabine Schaedelin2, Pascal Benkert2
1Neurology Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel, University of Basel, Basel, Switzerland.
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]: IgGIF and IgMIF ). 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 IgMIF 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 IgMIF 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/IgGIF . Furthermore, quantitative analyses revealed that in patients with IgMIF ≥ 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 IgMIF < median. Dose-dependent associations were also found for IgMIF but not for IgGIF 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.
Insights
Intrathecal IgM synthesis is a key biomarker in relapsing multiple sclerosis (MS), indicating higher disease activity and severity. This finding helps predict relapses and treatment needs in MS patients.
Area of Science:
- Neurology
- Immunology
- Biomarker Discovery
Background:
- Relapsing multiple sclerosis (MS) is characterized by inflammatory activity and chronic worsening.
- Intrathecal synthesis of immunoglobulins (Ig) like IgG and IgM may reflect disease processes in MS.
- Understanding the association between intrathecal Ig synthesis and MS outcomes is crucial for patient management.
Purpose of the Study:
- To investigate whether intrathecal synthesis of IgM and IgG is associated with inflammatory activity and chronic worsening in relapsing MS.
- To evaluate IgM and IgG intrathecal synthesis as potential biomarkers for predicting MS disease course and severity.
Main Methods:
- Compared cerebrospinal fluid analysis, clinical, and MRI data, along with serum neurofilament light chain (sNfL) levels in 530 relapsing MS patients.
- Categorized patients based on oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgGIF and IgMIF).
- Analyzed relationships with time to first relapse, sNfL, T2-weighted lesions, MS Severity Score (MSSS), and time to high-efficacy therapy initiation.
Main Results:
- Patients with intrathecal IgM synthesis (IgMIF) experienced shorter time to first relapse and higher MSSS compared to those without.
- IgMIF was associated with higher sNfL levels, increased new/enlarging T2w lesions, and greater overall lesion burden (p ≤ 0.01).
- Quantitative analysis showed dose-dependent associations between IgMIF and MRI-defined disease activity and sNfL, but not for IgGIF.
Conclusions:
- Intrathecal IgM synthesis serves as an independent biomarker for disease activity and severity in relapsing MS.
- The presence and level of intrathecal IgM synthesis can help predict disease progression and inform treatment strategies.
- This study highlights the clinical utility of assessing intrathecal IgM synthesis in managing relapsing MS.
