More Inflammation Biomarkers in Spinal Fluid of PPMS Patients: Study

Biomarkers show weak correlation with PPMS activity and severity

Patricia Valerio, PhD avatar

by Patricia Valerio, PhD |

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Individuals with primary progressive multiple sclerosis (PPMS) have significantly higher concentrations of specific inflammation biomarkers in their spinal fluid than healthy people, an exploratory study shows.

For most biomarkers, levels in PPMS patients were comparable to or lower than those seen in people with relapsing-remitting multiple sclerosis (RRMS). But a weak correlation was found for markers of neuronal damage and myelin loss, known as demyelination, according to researchers.

Inflammation in the spinal canal “may therefore have less relevance in PPMS than in relapsing forms of MS,” the team wrote.

The study, “Relationship between cerebrospinal fluid biomarkers of inflammation and tissue damage in primary progressive multiple sclerosis,” was published in Multiple Sclerosis and Related Disorders. The work was funded by the Danish Multiple Sclerosis Center and Biogen, which markets several MS medications, including Tecfidera.

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Studying inflammation biomarkers in MS

Several disease-modifying therapies (DMTs) prevent relapses and MRI activity and slow disease progression in relapsing forms of multiple sclerosis (MS). However, it is still not understood “why the therapeutic benefits of most DMTs on relapses and MRI activity do not translate into an effect on disease progression in PPMS,” the researchers wrote.

Inflammation in the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord, is believed to be a principal mediator of disease progression in progressive MS. It may partly explain why DMTs are not effective in this patient population.

In people with secondary progressive MS (SPMS), the impact of inflammation seems evident, given that elevated concentrations of pro-inflammatory cytokines — small proteins secreted by cells that promote inflammatory reactions — in the spinal canal were associated with a worse disease course.

Although previous research found comparable CSF concentrations of inflammation biomarkers in PPMS and SPMS patients, it remains unclear to what degree CSF inflammation contributes to the severity and progression of PPMS.

To address that, researchers in Denmark examined CSF samples from PPMS patients who had participated in a randomized Phase 2 trial (NCT02959658) testing Tecfidera (dimethyl fumarate).

Using samples collected at the trial’s start, the team assessed the levels of inflammatory biomarkers in 59 PPMS patients, and compared them with 40 untreated people with early RRMS and 21 healthy individuals, who served as controls.

After adjusting the data according to age and sex, results showed that PPMS patients had increased levels of nine inflammatory biomarkers compared with the healthy controls.

These markers were about 1–2.5 times higher in PPMS patients and included the chemokine ligand-3 (CCL-3), CXC chemokine ligand-8 (CXCL8), CXCL10, interleukin-10 (IL-10), IL-12p40, IL-15, IL-17, lymphotoxin-alpha (LT-alpha), tumor necrosis factor-alpha (TNF-alpha), and vascular endothelial growth factor A (VEGF-A).

The biomarkers also were significantly higher in RRMS patients compared with healthy participants. Most had similar elevations in PPMS and RRMS patients, but IL-12p40, IL-17, TNF-alpha, and LT-alpha were even higher in RRMS than in PPMS.

In addition, RRMS patients had elevations in other inflammatory molecules — CCL-22, interferon-gamma, and IL-27 — and a reduction in IL-7. These molecules were not changed in PPMS compared with healthy participants.

The team then assessed whether the inflammatory biomarkers had any correlation with markers of disease activity and severity in PPMS patients. While most cytokines were closely correlated with each other, only IL-15 was found to be significantly, although weakly, associated with CSF markers of nerve damage and demyelination.

Also, none of the inflammatory molecules correlated with MRI measures of one-year disease activity and severity, including new and enlarging lesions, lesion volume, myelin density in lesions, and brain volume.

In conclusion, the researchers found “clear evidence of ongoing [CSF] inflammation” in people with PPMS patients, but this was “not associated with the extent of neuroaxonal injury, demyelination, and disease severity,” they wrote.

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