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Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12 Page 27

but it also was correlated with shorter time to conversion and to disability worsening, for which it was an
independent risk factor [192] . As a consequence, there is strong evidence of its role as a biomarker able to
[3]
predict CIS conversion, and it should be assessed for clinical implementation .
As a treatment response biomarker, serum CHI3L1 levels were measured in 76 RRMS patients under IFN-β
treatment and were found to be increased in the non-responder group compared with the responder one.
As there was such a difference since baseline, it was suggested that non-responders had higher disease
activity and accordingly greater CSF CHI3L1 levels [193] .

Other biomarkers requiring further validation
Several T-cell cytokines have been explored as potential biomarkers for MS, but which are crucial in MS
pathogenesis has not been entirely elucidated yet [194] .

IL-12 and IL-23 respectively induce the differentiation of naive T cells in IFNγ-producing Th1 cells and
IL-17-producing Th17 cells [195] . Both interleukins increase the encephalitogenic potential of T lymphocytes,
but only IL-23 has been found to be a critical molecule in the development of EAE [196] . On the basis of
results coming from EAE models, where animals improved after administration of neutralizing antibodies
against the shared IL-12/IL-23 p40 subunit, a phase II double-blind placebo-controlled trial with the
monoclonal antibody ustekinumab was conducted in 249 RRMS patients, although it did not show
substantial efficacy [197] .

Differently, IL-17 does not seem to be crucial to EAE development, though increasing its severity and
[194]
atypical presentation, maybe through the recruiting of neutrophils and the effect of MMPs . Nevertheless,
increased IL-17 mRNA expression in mononuclear cells was found in MS lesions and in CSF and blood of
MS patients [198,199] , and Th17 cells were found to undergo a more marked increase in CSF during MS relapses
than Th1 cells, which usually prevail in both blood and CSF [200] . A monoclonal antibody against IL-17A
(secukinumab) has proved to reduce MRI activity in MS, but further studies are needed [201] .

Tumor necrosis factor alpha (TNF-α) is a cytokine involved in the pathogenesis of several autoimmune
diseases, including MS, wherein increased CSF and serum levels of this molecule have been detected [202-204] .
Today, it is known that TNF-α may exert different biological effects, depending on the involved receptor,
both stimulating inflammatory processes and apoptosis (via TNF receptor 1) or inducing a pro-survival
pathway and reducing inflammation (via TNF receptor 2). This might explain the failure and the
unexpected results of treatment approaches with unselective anti-TNF-α drugs in MS patients, which lead
to an increase in disease activity in MS [205,206] . The modulation of TNF-α signaling has provided promising
results in EAE, whose remission has been induced by selective inhibition of the soluble form of TNF-α,
[207]
which mainly acts via TNF receptor 1 .

B cell-activating factor (BAFF), belonging to the TNF family, is a maturation and survival factor for B
lymphocytes, whose serum levels have been found to be increased in several autoimmune diseases [208] .
[209]
In MS, increased BAFF concentrations in CSF and in demyelinating lesions have been detected . The
association with disease activity has not been elucidated, since some controversial results have been
reported [1,209] . Moreover, the clinical significance of increased BAFF levels under treatment with some
DMDs is not clear [209] .

PROGNOSTIC BIOMARKERS
Neurofilaments
Neurofilaments (NFs) are components of the neuronal cytoskeleton, responsible for the increase in nerve
conduction velocity in myelinated fibers and for their structural support [210] . Consisting of heavy (NF-H),