Tuesday, 14 October 2025

Monreal E, Fernández JI, Sainz de la Maza S, Espiño M, Villarrubia N, Roldán E, Aladro Y, Cuello JP, Ayuso L, Rodero A, Chico JL, Rodríguez F, Quiroga A, Rodríguez E, Pilo de la Fuente B, Martín G, Martínez ML, García JM, Rubio L, Llufriu S, Comabella M, Montalban X, Álvarez G, Veiga JL, Masjuan J, Costa L, Villar LM. Combining CSF and Serum Biomarkers to Differentiate Mechanisms of Disability Worsening in Multiple Sclerosis

Int J Mol Sci. 2025

"Our study shows that biomarkers can reveal the underlying disease processes in MS and guide early treatment decisions." - Dr. Enric Monreal

Summary:

The combined use of serum and CSF biomarkers for prognostic stratification in multiple sclerosis (MS) remains underexplored. This multicenter observational study investigated associations between serum neurofilament light chain (sNfL), glial fibrillary acidic protein (sGFAP), and CSF lipid-specific IgM oligoclonal bands (LS-OCMB) with different forms of disability worsening, such as relapse-associated worsening (RAW), active progression independent of relapse activity (aPIRA), and non-active PIRA (naPIRA). A total of 535 patients with MS were included, all sampled within one year of disease onset. Biomarkers were quantified using single-molecule array and immunoblotting techniques, and CSF cell subsets were analyzed by flow cytometry. High sNfL z-scores and LS-OCMB positivity were independently associated with increased risk of RAW and aPIRA, collectively termed inflammatory-associated worsening (IAW), while elevated sGFAP levels predicted naPIRA. Patients with both high sNfL and LS-OCMB positivity had the highest risk of IAW. Among LS-OCMB-positive patients, higher regulatory T cell percentages were associated with lower sNfL levels, suggesting a protective role. Conversely, in LS-OCMB-negative patients, sNfL levels correlated with CSF C3 concentrations. These findings support the complementary role of sNfL, sGFAP, and LS-OCMB in identifying distinct mechanisms of disease worsening and may inform early personalized management strategies in MS.

Why do you highlight this publication?

The management of multiple sclerosis (MS) is increasingly shifting toward personalized medicine, with biomarkers playing a central role as they reflect the underlying immunological processes of the disease. Although numerous biomarkers have been described, their combined utility and interplay remain underexplored. In this multicenter study, we evaluated the contribution of the most promising biomarkers and their combinations, highlighting distinct immunological profiles and their potential clinical application. Serum NfL and CSF IgM oligoclonal bands were primarily associated with inflammatory activity, whereas serum GFAP reflected neurodegenerative processes. Their determination at disease onset may help disentangle the pathophysiological mechanisms driving disability worsening-whether inflammation- or neurodegeneration-related. Furthermore, we refined classical clinical outcomes of disability progression and identified the immune cell subsets and soluble factors linked to each biomarker. Altogether, our findings underscore the importance of incorporating CSF and serum biomarkers into early prognostic stratification in MS, thereby facilitating a more tailored selection of disease-modifying therapies.