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Page 22 Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12
[73]
distinguish between MS and other diseases, such as neuromyelitis optica (NMO) , anti-MOG associated
[72]
encephalomyelitis , and primary CNS lymphoma .
[73]
In a prospective 2-year study involving 89 patients with CIS, MRZ reaction was associated with a greater
risk to convert to clinically definite MS, showing a greater positive predictive value (70%) than OCB (64%)
[70]
and MRI (64%) . In patients with acute optic neuritis with positive MRZR and MRI, conversion to
clinically definite MS occurred in 86% of them after 4 years, with a prevalence of 73% for MRZR in those
[69]
who converted . Thus, MRZR can further support the diagnosis at onset and assist in discrimination
between MS and other clinically similar inflammatory diseases, representing a complementary diagnostic
biomarker with an intermediate level of evidence [3,74] . Nevertheless, further studies in additional cohorts are
[3]
required .

DISEASE ACTIVITY BIOMARKERS
Nitric oxide metabolites
Due to the role of oxidative stress in MS pathogenesis, nitrate and nitrite have been investigated as disease
[76]
activity biomarkers . Indeed inflammatory processes produce, as a result of the activation of immune cells,
reactive oxygen species, including nitrogen-based oxidants . Moreover, Nitric oxide (NO) seems to have
[76]
much more roles than being a blood flow controller and a synaptic transmitter, regulating the permeability
[77]
of the BBB, exerting immunomodulatory properties and mediating axonal damage and demyelination .
Increased levels of nitrate and nitrite have been identified in body fluids of MS patients in several studies.
Particularly, many studies have reported greater concentrations of these molecules in CSF [78-80] , serum [81,82]
[83]
and urine of MS patients compared with controls. Accordingly, the inducible form of nitric oxide
[84]
synthase has been detected in CSF of MS patients, while not in healthy controls , and its mRNA has
[77]
been found in cerebral tissue of MS patients . Interestingly, interferon-beta (IFN-β) has proved to exert a
[85]
remarkable inhibition of inducible NO synthase expression in astrocytes .
Meanwhile, it is still controversial whether the concentration of NO metabolites is significantly different in
RRMS compared with PMS. Indeed, some studies found higher CSF and serum levels of NO metabolites in
RRMS compared with SPMS [86,87] , while others did not detect any differences [80,88] .

Speculating a role as a disease activity biomarker, the association between NO metabolites and the
occurrence of relapses in RRMS patients has been explored, and several studies have confirmed this
hypothesis [78,89-91] , but longitudinal and multicenter studies are needed.

[78]
In a study by Yamashita et al. , significantly higher nitrite and nitrate levels were detected among patients
in relapse compared with those in remission and patients treated with steroid in the previous 1-2 months.
[90]
Acar et al. found higher nitrate and nitrite concentrations in relapsing patients than in remitting ones,
with the latter ones still showing greater values than controls. Accordingly, NO metabolites predicted
disease activity with 71% specificity and 66% sensitivity. In contrast, few studies reported evidence of
an association between NO metabolites and MRI findings [90,92] , as well as between the development of
[92]
disability and EDSS progression .

Osteopontin
[93]
Osteopontin (OPN) is a sialoprotein, whose role in bone remodeling has long been known . Beyond
this, it is closely linked to the immune system, since it mediates chemotaxis, cell adhesion and signaling,
and it also promotes cytokine and interleukin (IL) function, inducing IL-12 and inhibiting IL-10 among
others. In its soluble form, indeed, it is secreted by and also interacts with macrophages and activated
leukocytes, reduces the inducible form of NO synthase, promoting inflammation. In its intracellular