Biomarker could identify patients most likely to benefit from new MS drugs

An MS biomarker linked to disease progression could flag patients most likely to benefit from new drugs, researchers say.

The findings were validated in mice and humans and could shape how clinical trials are run for progressive forms of the disease.

The study examined “compartmentalised inflammation” (immune activity contained within the brain and spinal cord coverings) that is strongly linked to MS progression.

Jen Gommerman, a professor and chair of immunology at the University of Toronto’s Temerty Faculty of Medicine, said: “We think we have uncovered a potential biomarker that signals a patient is experiencing so-called ‘compartmentalised inflammation’ in the central nervous system, a phenomenon which is strongly liked to MS progression.

“It’s been really hard to know who is progressing and who isn’t.”

Canada has one of the highest rates of MS in the world with over 4,300 Canadians diagnosed with the condition each year, according to MS Canada.

Roughly 10 per cent of people with MS are initially diagnosed with progressive MS, which leads to a gradual worsening of symptoms and increasing disability over time.

Patients initially diagnosed with relapsing-remitting MS, the more common form of the condition, can also go on to develop progressive MS.

Valeria Ramaglia, a scientist at the University Health Network’s Krembil Brain Institute and an assistant professor of immunology at Temerty Medicine, said: “We have immunomodulatory drugs that can modulate the relapsing and remitting phase of the disease.”

“But for progressive MS, the landscape is completely different. We have no effective therapies.”

To understand the mechanisms driving progressive MS, the researchers developed a new mouse model that mimics damage in the brain’s grey matter seen in people with progressive MS.

A hallmark of this injury is compartmentalised inflammation in the leptomeninges (the thin membranes that cover the brain and spinal cord).

Using their mouse model, they observed a roughly 800-fold increase in an immune signal called CXCL13 and significantly lower levels of another immune protein called BAFF.

By treating these mice with BTK inhibitor drugs, which are currently being tested in clinical trials to target progressive MS and which target a protein involved in immune cell signalling, the researchers mapped a circuit in the brain that led to grey matter injury and inflammation.

They also found that BTK inhibitors restored CXCL13 and BAFF levels to those seen in healthy mice.

These results led the researchers to propose that the ratio of CXCL13 to BAFF could be a surrogate marker for leptomeningeal inflammation.

To test the findings in humans, the researchers measured the CXCL13-to-BAFF ratio in postmortem brain tissues from people who had MS and in the cerebrospinal fluid (the fluid around the brain and spinal cord) of a living cohort of people with MS. In both cases, a high CXCL13-to-BAFF ratio was associated with greater compartmentalised inflammation in the brain.

Thus far, BTK inhibitors have seen mixed results in clinical trials with people with MS.

Ramaglia says that without an easy way to detect leptomeningeal inflammation, the trials likely enrolled participants who did not have this feature and were unlikely to benefit from the drug. Any positive signals from participants with compartmentalised inflammation would then be diluted.

“If we can use the ratio as a proxy to tell which patients should be treated with a drug that targets leptomeningeal inflammation, that can revolutionise the way we do clinical trials and how we treat patients.”

Ramaglia is continuing to collaborate with Gommerman to explore how the CXCL13-to-BAFF ratio can be used to advance precision medicine for people with MS.

They are working with the pharmaceutical companies behind the BTK inhibitor trials to look at whether the participants who responded the most to the drugs also had high ratios of CXCL13 to BAFF.