Study uncovers a possible biomarker linked to MS disease progression

A new University of Toronto-led study has discovered a possible biomarker linked to multiple sclerosis (MS) disease progression that could help identify patients most likely to benefit from new drugs.

The findings were published today in Nature Immunology and validated in both mouse models and humans. 

We think we have uncovered a potential biomarker that signals a patient is experiencing so-called 'compartmentalized 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."

Jen Gommerman, professor and chair of immunology, U of T's Temerty Faculty of Medicine

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.

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

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

Ramaglia, who co-led the study with Gommerman, notes that until their study, the research field did not have a good model that replicates the pathology of progressive MS.

To understand the mechanisms driving progressive MS, the researchers developed a new mouse model that mimics the damage in the brain's grey matter seen in people with progressive MS. A hallmark of this so-called grey matter injury is compartmentalized inflammation in the leptomeninges, a thin plastic wrap-like membrane that encases the brain and spinal cord. 

Using their mouse model, they also 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 - the researchers mapped out 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 hypothesize that the ratio of CXCL13 to BAFF could be a surrogate marker for leptomeningeal inflammation.

To test the validity of their 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 of a living cohort of people with MS. In both cases, a high CXCL13-to-BAFF ratio was associated with greater compartmentalized 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 results from people with compartmentalized 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 revolutionize the way we do clinical trials and how we treat patients," says Ramaglia.

As she builds her own research program at the Krembil Brain Institute, 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. 

Ramaglia is also planning to look at CXCL13 and BAFF levels in people with early MS to see if it can predict who is likely to develop progressive MS later. 

She credits her time as a research associate in Gommerman's lab as playing a key role in helping her become an independent investigator.

"Jen's lab was a huge stepping stone for me. She gave me the space and independence to build my own research." 

This research was supported by the Canadian Institutes of Health Research, MS Canada, the National Multiple Sclerosis Society and the United States Department of Defense.