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.