Investigation of serum ISTHMIN-1 levels in naive MS and RRMS patients

Multiple Sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the central nervous system. T and B lymphocytes, cytokines, chemokines, and disruption of the blood–brain barrier play crucial roles in its pathogenesis. There is still a need for biomarkers that can assist in the early diagnosis and monitoring of disease activity. Isthmin-1 (ISM1), a novel glycoprotein involved in immune modulation, inflammation, and angiogenesis, has been linked to autoimmune disorders, but its role in MS remains unclear. This study aimed to investigate serum ISM1 levels in MS patients, their relationship with disease stage, and their diagnostic performance. A total of 169 participants were included: 56 with relapsing-remitting MS (RRMS), 56 newly diagnosed MS, and 57 healthy controls. Serum ISM1 levels were measured using ELISA. Demographic data, Expanded Disability Status Scale (EDSS), IgG index, cerebrospinal fluid (CSF) oligoclonal band (OCB) positivity, and clinical features (optic neuritis, spinal involvement) were recorded. Group comparisons were performed with the Kruskal–Wallis test, and post-hoc analyses identified the source of differences. Diagnostic performance was evaluated using Receiver Operating Characteristic (ROC) analysis. No significant difference in age and sex was found between the groups. Serum ISM1 levels differed significantly across groups (p<0.001). Post-hoc analysis revealed that this difference was due to higher ISM1 levels in both MS groups compared to controls, while no significant difference was observed between RRMS and newly diagnosed MS (p=0.229). ISM1 levels were highest in RRMS, lower in newly diagnosed MS, and lowest in controls. ROC analysis demonstrated a moderate discriminatory ability for serum ISM1 (AUC=0.698, 95% CI: 0.60–0.79) with a cut-off ≈11.07, yielding 74% sensitivity and 58% specificity. Clinical data showed no significant differences in EDSS or IgG index between RRMS and newly diagnosed MS. However, OCB positivity was significantly higher in the newly diagnosed group (69.6% vs 21.4%, p<0.001). Optic neuritis (64.3% vs 30.4%, p<0.001) and spinal involvement (87.5% vs 71.4%, p=0.03) were more frequent in the RRMS group. Serum ISM1 levels did not correlate with EDSS, IgG index, age, sex, optic neuritis, spinal involvement, brainstem involment or OCB status. Serum ISM1 levels were significantly elevated in MS patients compared to healthy controls. This increase was independent of disease-modifying therapy and appeared to be related to the presence of MS rather than disease stage. ROC analysis indicated that ISM1 is not sufficient as a stand-alone diagnostic biomarker but may serve as a complementary marker alongside clinical and laboratory findings. Compared with studies in rheumatoid arthritis, where ISM1 levels are reduced, our findings highlight disease-specific differences in immunopathogenesis. Larger, multicenter, longitudinal studies are needed to clarify the role of ISM1 in MS and its potential clinical utility.