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Status Update on MS Biomarkers

Biomarkers are needed in multiple sclerosis (MS) to help with early diagnosis, estimate prognosis, and monitor treatment response, and a few candidates look promising, researchers reported.

In a review of the literature, new B-cell-associated blood biomarkers may be useful for predicting conversion to MS, and new markers of axonal damage may help with prognosis, according to Charlotte Teunissen, PhD, of VU University Medical Center in Amsterdam, and colleagues. They reported their findings in Nature Reviews Neurology.

There's still a tremendous need for biomarkers of treatment response and predicting adverse events, especially with the rise of disease-modifying therapies, they added.

Researchers have long been investigating biomarkers for MS in blood and cerebrospinal fluid (CSF). It started with the discovery of CSF-specific IgG oligoclonal bands (OCBs), which turned out to be sensitive diagnostic markers of MS. The search for additional body fluid markers grew from there, the researchers said.

The need for those markers is growing with the increasing recognition of greater heterogeneity of the disease, as well as the rise of pharmaceuticals that would be well served by ways to monitor treatment response and predict adverse effects.

For their paper, Teunissen and colleagues focused on body fluid markers -- they did not review genetic markers -- that have been assessed in recent studies, from 2012 to 2015, and validated in at least two independent cohorts.

For early diagnosis, researchers are trying to predict who will convert from clinically isolated syndrome (CIS) to MS, and several new B-cell-associated candidate blood biomarkers have emerged.

Studies have suggested that B-cell attracting CDC motif chemokine 13 (CXCL13) mRNA has high potential as a prognostic biomarker for CIS conversion to MS -- although its lack of specificity impedes its use as a diagnostic marker for MS. Similarly, Chitinase-3-like protein 1 (CHI3L1) has been shown to be a prognostic marker of conversion, but it needs further replication as a marker for MS, the researchers said.

Since IgG OCBs are a well-established independent prognostic factor for conversion from CIS to MS, IgM OCBs have become a promising prognostic marker for conversion. Other humoral immunity markers being investigated include IgG directed against neurotropic viruses and immunoglobulin free light chains.

Non-coding RNAs are being intensively investigated, but sample sizes are small and need replication in larger cohorts, and neurofilaments as markers of axonal damage are promising for CIS conversion but require more validation, the researchers said.

There's a clear need for biomarkers to subtype MS, but only a few recent studies have addressed this, the researchers found. Some promising candidates include humoral immunity biomarkers such as IgG and IgM OCBs. Early work has also suggested that the non-coding RNA inflammatory markers miR-223 and miR-15b may be able to distinguish primary progressive from relapsing remitting MS.

In terms of biomarkers for MS prognosis, Teunissen and colleagues noted that IgM OCBs have been reported for over a decade to serve as prognostic biomarkers of early relapsing remitting MS, and markers of axonal damage such as neurofilament proteins can be used for prognostic evaluation at a group level, although the value in individuals seems more limited.

Early work suggests CHI3L1 may be a good marker of progression, and the non-coding RNAs miR-92a-1 and miR-454 have been associated with more severe disease.

Still, prediction of prognosis in any given subtype of MS remains difficult and should be assessed in longitudinal biomarker studies, they wrote.

There's a want for biomarkers of treatment response and predicting adverse events in relapsing remitting MS, given the host of new disease-modifying therapies available.

It would be helpful to be able to predict who benefits from a particular type of treatment, such as anti-B-cell therapy like rituximab or ocrelizumab, and who benefits more from S1P receptor subtype modulators such as fingolimod or siponimod.

Anti-interferon antibodies are well established in practice, but no biomarkers predict the development of these antibodies. Several studies have suggested persisting antibodies against natalizumab have clinical relevance for a decreased efficacy of natalizumab.

For adverse reactions, there's a great need to better predict the risk of progressive multifocal leukoencephalopathy (PML) in patients on natalizumab, and to a lesser extent, dimethyl fumarate, they wrote.

PML risk has been associated with presence of anti-JCV antibodies in the blood, which can aid the identification of patients who can continue natalizumab with a minor risk of PML compared with those who need to be switched.

A newer biomarker, C-selectin-expressing CD4+ T cells, has been found to be lower in patients on long-term natalizumab, but further work needs to be done to establish its applicability and additive value.

Finally, IgM-OCBs may also be associated with a decreased risk of PML with natalizumab, although this needs confirmation, the researchers said.

Teunissen and colleagues also looked at biomarkers of neuromyelitis optica (NMO), which was historically considered to be a variant of MS but was defined as a pathophysiologically distinct entity in 2004 with the identification of AQP4-IgG autoantibodies.

The median sensitivity of AQP-IgG, however, is 62.3%, so alternative biomarkers of NMO are needed, they wrote.

Since anti-myelin oligodendrocyte glycoprotein IgG (MOG-IgG) is absent in MS, it's a promising biomarker to discriminate MS from AQP4-IgG-negative NMO, they wrote.

Haptoglobin, an acute-phase protein synthesized by the liver, is elevated in several inflammatory diseases, but its added value over AQP4-IgG for NMO remains to be established, they reported.

Teunissen and colleagues concluded that the field should expect biomarker development for MS to be improved and accelerated with clinical implementation in the near future, adding that the BioMS network has taken several steps to standardize all aspects of biomarker research and validation.

Story Source: The above story is based on materials provided by MEDPAGETODAY
Note: Materials may be edited for content and length

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