DISCUSSION
The diagnosis of MS requires a comprehensive approach and is based on the evaluation of the patient’s clinical condition and magnetic resonance imaging (MRI) findings. However, MRI is not an infallible diagnostic tool, especially at the CIS stage. CSF examinations plays an irreplaceable role in the diagnosis of MS. Many studies have recently been conducted that focus on the use of new prognostic markers such as neurofilament light chains (NfL) or chitinase-3 like-protein-1 (CHI3L1). They may be beneficial in the diagnosis and prognosis of MS [17]. In our research, we focused on the use of the markers CXCL13 and IL-8 in assessing CIS to MS conversion.
IL-8 is a chemoattractant, a cytokine produced by many tissue cells and leucocytes. It attracts and activates neutrophilic granulocytes and other immune cells in inflammatory areas [13]. In CSF, its levels are elevated during inflammatory processes of the CNS. IL-8 is responsible for opening the blood-brain barrier allowing immune cells to migrate to the CNS [9]. In our study, we identified heightened IL-8 levels in patients diagnosed with clinically isolated syndrome (CIS) and multiple sclerosis (MS), thereby affirming the presence of ongoing inflammatory processes. Previous investigations, including those by Matejčíková et al., have detected increased CSF levels of IL-8 coinciding with the initial clinical manifestations of MS, while concurrently observing decreased IL-8 levels in the serum [10, 20]. Studies by Bartošík-Psujek and Stelmasiak and those by Stelmasiak et al. have further substantiated significant rises in CSF IL-8 levels during relapse episodes [18, 19].
Within our cohort, IL-8 levels consistently displayed elevation across all groups. Specifically, for the CIS-RRMS group, a ROC analysis was conducted, and it revealed that IL-8 in cerebrospinal fluid (CSF) served as a noteworthy predictor for the transition from clinically isolated syndrome (CIS) to relapsing-remitting multiple sclerosis (RRMS), with an AUC of 0.939. The optimal threshold for IL-8 in CSF was identified as 45.6 pg/ml, as determined by Youden’s J statistic, which maximizes the amalgamation of sensitivity (0.9) and specificity (0.836).
These observations imply that IL-8 may prove to be a suitable indicator for forecasting disease prognosis. However, owing to the akin IL-8 concentration levels in CSF also noticed in the other groups (CIS-CIS and RRMS), the practicality of IL-8 in predicting disease progression remains unverified. However in a study conducted by Rossi et al., heightened IL-8 levels were linked to an increased risk of transitioning from CIS to RRMS and a heightened frequency of relapses during the initial two years of the disease [21].
CXCL13 is a chemokine that exerts chemotactic effects on B cells, which play a crucial role in the pathogenesis of multiple sclerosis (MS). This chemokine is produced by macrophages and follicular dendritic cells, and monitoring changes in its concentration can provide insights into the condition of MS patients. CXCL13 interacts with the CXCR5 receptor, acting as a chemoattractant that guides B cells to secondary lymphatic organs. Furthermore, CXCL13 promotes cytokine secretion, facilitating humoral immune responses and the migration of plasma cells and B cells to the cerebrospinal fluid (CSF) [14, 9, 16]. Elevated CXCL13 levels are commonly observed in patients with neuroborreliosis [8]. Numerous studies have investigated the levels and prognostic significance of CXCL13 in patients with clinically isolated syndrome (CIS) and MS. For instance, a study by Khademi et al. in 2011 associated CXCL13 with disease exacerbation and poor prognosis in relapsing-remitting MS (RRMS). High CXCL13 levels were predictive of the conversion from CIS to MS [21]. In a prospective study by Bretschneider et al. in 2010, CXCL13 was found to be relevant in CIS for predicting conversion to MS, underlining its role in the inflammatory cascade linked to the intrathecal B cell response [23]. Lepennetier et al. confirmed CXCL13 as a reliable marker and its utility in predicting disease activity in MS and diagnosing Lyme neuroborreliosis (LNB) and central nervous system (CNS) lymphoma [24]. Additionally, Ferraro et al. in 2015 established a correlation between CSF CXCL13 levels and markers of CNS inflammation, suggesting that CXCL13 levels were associated with earlier conversion to MS and a more aggressive disease course [25]. A study by DiSano et al. in 2020 emphasized the predictive value of the CXCL13 index in comparison to oligoclonal bands (OCBs) and cerebrospinal fluid (CSF) neurofilament light chain in patients with clinically and radiologically isolated syndrome and MS. The CXCL13 index demonstrated significant increases in MS patients with active disease, surpassing both OCB and CSF NfL in terms of sensitivity, specificity, and the identification of future disease activity [26].
Our study findings indicate elevated CXCL13 levels in patients with CIS and MS. Within our cohort, we observed a tendency toward higher CXCL13 levels in patients transitioning from CIS to RRMS. In the CIS-RRMS group, ROC analysis identified CXCL13 in cerebrospinal fluid as a highly significant predictor for the transition from clinically isolated syndrome to relapsing-remitting multiple sclerosis, with an impressive AUC (area under the curve) value of 0.959. The optimal cut-off value for CXCL13 in CSF was determined to be 0.210 pg/ml, based on Youden’s J statistic, providing a sensitivity of 0.95 and specificity of 0.873. Notably, this test demonstrated notably high sensitivity. Alternatively, if a higher cut-off value of 1.795 were chosen, both sensitivity and specificity would be more evenly balanced, each approximately at 0.9, with SE (sensitivity) = 0.900 and SP (specificity) = 0.909.
These findings are in line with previous research underlining the significance of CXCL13 as a biomarker in patients with multiple sclerosis. CXCL13 levels in CSF hold the potential to serve as an additional tool for identifying patients at a heightened risk of transitioning to MS, thereby assisting clinicians in determining the need for early intervention. Nevertheless, further investigation involving a larger patient cohort is imperative to validate these observations.