Exploring biomarkers for diagnosing and monitoring antibody-mediated demyelinating disorders of the central nervous system

Background
The pursuit of target antigens of the central nervous system’s (CNS) immune response has led to the differentiation of multiple sclerosis (MS) from other disease entities, such as aquaporin-4 (AQP4) antibody seropositive neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). This has paved the way for diagnoses based on the pathogenesis of diseases and for personalized clinical management strategies aimed at preventing attacks and disability. Nonetheless, the management of patients with CNS demyelinating disorders remains complex. Specifically, a subgroup of patients with AQP4-/MOG-immunoglobulin G (IgG) seronegative disorders has not yet been fully characterized. Moreover, current diagnostic strategies may be limited in accurately classifying patients with overlapping clinical and serological findings. Similarly, current disease monitoring strategies might be insufficient to distinguish remission from acute disease activity, preventing the timely indication of acute therapies and the escalation of immunosuppression. Therefore, the development of biomarkers is needed to support the clinical management of patients with demyelinating disorders of the CNS.
Aims
This thesis comprises three projects that employed different strategies to assess the necessity for and develop serum biomarkers for the diagnosis and monitoring of patients with demyelinating disorders of the CNS.
Methods
In the first project, we conducted a multicenter, retrospective, longitudinal study including 1339 patients with suspected or confirmed demyelinating disorders of the CNS. We investigated sera, clinical, and paraclinical data for the presence and associated features of MOG-immunoglobulin A (MOG-IgA) seropositivity. In the second project, we expanded on the cohorts from the first study by investigating the performance of the recently proposed MOGAD diagnostic criteria1 in addressing overlapping diagnoses of MOGAD and MS, and variations in MOG-IgG assay results across different centers. Lastly, in the third project, we further expanded on the cohorts from the first project by investigating the dynamics of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) after clinical attacks. Moreover, we assessed the performance of these biomarkers in discriminating the status of disease activity in patients with MOGAD.
Results
In the first project, we identified a subgroup of patients with demyelinating disorders of the CNS who were seropositive for MOG-IgA and seronegative for MOG-IgG and AQP4-IgG (18/1344 [1.3%]). These patients exhibited distinct clinical features compared to those seropositive for MOG-IgG. In the second project, we observed interrater, interassay, and intercenter discrepancies in the diagnosis of MOGAD according to recently proposed criteria1. Lastly, in the third project, we described the dynamics of sNfL and sGFAP Z scores after attacks. Furthermore, we reported an association between increasing sNfL Z scores and attacks (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.8 – 3.7, p < 0.001), as well as a consistently incremental performance for models including sNfL Z scores for discrimination of disease activity status compared to models without (p < 0.001).
Conclusion
This thesis addressed the need for biomarkers to enhance the clinical management of patients with demyelinating disorders of the CNS. Specifically, we described MOG-IgA as a potential novel biomarker for the diagnosis of CNS demyelinating disorders. Furthermore, we provided real-world evidence supporting the refinement of the recently proposed MOGAD diagnostic criteria through various strategies, such as the inclusion of diagnostic biomarkers. Finally, we reported the utility of sNfL as a biomarker of acute disease activity in patients with MOGAD. Moving forward, research should validate these findings and explore the underlying mechanistic aspects associated with the occurrence of biomarkers in CNS demyelinating disorders.