2 Biomarkers Seen as Best at Predicting Course of Relapsing MS

The levels of two cerebrospinal fluid (CSF) biomarkers, CHI3L1 and CXCL13, were significantly elevated in people with relapsing and progressive multiple sclerosis (MS) relative to control groups without this disease, and are most likely to predict how relapsing MS will progress, a study reported.

Higher levels of these biomarkers were also associated with a greater risk of conversion to clinically defined MS in patients with a first demyelination event, who are considered as having clinically isolated syndrome (CIS).

The study, “CSF CXCL13 and Chitinase 3-like-1 Levels Predict Disease Course in Relapsing Multiple Sclerosis” was published in the journal Molecular Neurobiology.

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October 5, 2022 News by Lindsey Shapiro, PhD

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MS is defined as a chronic demyelinating — characterized by the loss of the myelin sheath around nerve fibers — inflammatory disease of the central nervous system (CNS; brain and spinal cord). Previous research points to the involvement of B-cells, immune cells that produce antibodies, in the inflammatory process in MS.

This disease’s course is known to vary widely among patients. A rapid and accurate diagnosis, together with the knowledge of risk factors for poorer outcomes (a disease prognosis), “are essential to establish a timely and effective treatment that may substantially modify the disease course,” the researchers wrote.

CSF levels of 8 biomarkers in MS patients assessed

Identifying and validating biomarkers for diagnosing MS and assessing a person’s likely prognosis, for this reason, is crucial.

Researchers in Italy evaluated concentrations in the CSF — the fluid surrounding the brain and spinal cord — of eight biomarkers implicated in MS processes.

Their study included 150 patients: 107 with relapsing MS, 18 with progressive MS, 15 people with other non-inflammatory neurological disorders (ONIND), and 10 with other inflammatory neurological disorders (OIND). People in the OIND and ONIND groups were defined as controls. Among patients in the relapsing MS group were 88 people with CIS and evaluated after a first demyelinating event.

Women predominated in all four groups, but patients’ ages differed among groups — progressive MS patients were significantly older (mean age of 53) than those with relapsing MS (37) and ONIND (41). Progressive MS patients were also older than OIND patients, who had a mean age of almost 48, but the difference was not significant.

None of the patients was receiving disease-modifying therapies (DMTs) before a CSF analysis.

Two analyzed biomarkers were the proliferation-inducing ligand (APRIL), present in MS lesions, and the B-cell activating factor (BAFF), highly expressed in the CNS. Concentrations of both markers in the CSF were significantly lower in relapsing MS compared with progressive MS patients. Specifically, for APRIL, relapsing MS patients had a mean of 60.4 picograms (pg)/mL vs. 95.5 pg/mL for the progressive MS group; for BAFF, the differences were 133.4 pg/mL (relapsing MS) and 175.6 pg/mL (progressive MS).

BAFF levels in relapsing MS patients were lower compared to the control groups, but the statistical difference was only significant against the OIND group (184.1 pg/mL). Among progressive MS patients, APRIL levels were higher than in the two control groups but only statistically significant compared with ONIND patients (69 pg/mL).

Researchers suggested that the “differential [cerebral spinal fluid] BAFF and APRIL levels between [relapsing] MS and [progressive] MS suggest a different modulation of B-cells pathways in the different phases of the disease.”

Another biomarker, the monocyte chemoattractant protein 1 (CCL2), also present in MS lesions, was at lower levels in the CSF of relapsing MS patients (mean of 282 pg/mL) compared with progressive MS (388.5 pg/mL) and ONIND (369.3 pg/mL) group patients. Its levels in progressive MS patients were similar to the two control groups.

Three other biomarkers that are considered key players in inflammation — chemokine ligand 8 (CXCL8), interferon gamma-induced protein 10 (CXCL10), and stromal cell–derived factor 1 (CXCL12) — showed differences in CSF levels when comparing either MS group to control groups. However, most of these differences were not statistically significant.

CHI3L1 and CXCL13 best at predicting progression in relapsing MS

The final two biomarkers analyzed — chitinase 3-like-1 (CHI3L1), linked to inflammation, and B-cell–attracting chemokine 1 (CXCL13), present in high levels in patients with infectious diseases affecting the CNS — were at similar levels for the two MS groups.

CHI3L1 concentrations in the CSF were significantly increased in both relapsing MS (mean of 312.8 nanograms [ng]/mL) and progressive MS (270.6 ng/mL) patients relative to inflammatory (168.8 ng/mL) and non-inflammatory (94.5 ng/mL) controls.

Likewise, CXCL13 levels were significantly higher in the CSF of both MS patient groups — a mean of 19.8 pg/mL for relapsing MS, and 12.7 pg/mL for progressive MS — compared with OIND (mean of 11.1 pg/mL) and ONIND (6.9 pg/mL) patients.

Clinical and radiological data were also assessed in the study. Relapsing MS patients had a median expanded disability status scale (EDSS) score of 1.5, meaning minimal disability, while progressive MS patients had a median EDSS score of 4, meaning significant disability but no walking impairment.

The multiple sclerosis severity score (MSSS; higher scores indicate greater disease progression) was 4.2 among relapsing MS and 7.2 for progressive MS. Both CXCL13 and CHI3L1 levels were found to correlate to some extent with these MS scores.

In turn, no statistically significant association was found between the levels of these two biomarkers and the presence of MS lesions.

Among the initial group of 88 CIS patients, 29 experienced a new clinical relapse during follow-up and converted to clinically defined MS. In these people, higher CSF concentrations were found for CXCL13 and CHIIL13, as well as CXCL10 and CXCL12, compared to those who did not convert.

“Higher CSF concentrations of several neuro-inflammatory biomarkers are associated with a higher risk of conversion to [clinically defined MS] in patients with a first clinical demyelinating event,” the researchers wrote.

The team also assessed if CHI3L1 and CXCL13 CSF levels could predict a future relapse, MRI activity, and disability progression/disease activity in relapsing MS patients. Patients with higher concentrations, they found, were at a significantly higher risk of all three measures.

These two markers were selected because both were at significantly higher levels in MS patients relative to controls, and other analyses showed them to best “distinguish MS patients from controls,” the team wrote.

Overall, “we demonstrated that the CSF CXCL13 and CHI3L1 levels, at the time of diagnostic evaluation, represent very good prognostic biomarkers in [relapsing MS] patients and therefore can assist in the initial treatment choice,” the researchers concluded.

“CHI3L1 and CXCL13 can predict disease activity in [relapsing] MS patients and help to identify patients with more severe disease course independently from other baseline clinical and radiological features,” they added.