AAN 2024 | Differential immune cell modulation with highly vs moderately efficacious DMTs in MS

There was a lot of evidence that’s come out now in the last, say, 10-15 years. Do we start people who are diagnosed with multiple sclerosis (MS) up front on something that’s a little bit more highly efficacious – trying to get that early control of inflammatory activity? Or do we take this treat-to-target sort of approach where you start them on more platform, moderately efficacious medications and sort of escalate if there’s any breakthrough in disease? There’s no definitive answer quite yet, but there is evidence that’s leaning more so towards starting highly efficacious disease modifying therapies (DMTs) early because we get that early control of inflammatory activity. Big prospective clinical trials like TREAT-MS are showing that we have less clinical progression for those people who started early. So, through EDSS, the scores are better for long-term follow-up.

For many years now there’s been interest in cerebrospinal fluid (CSF), but because of the invasive nature of having to do a series of lumbar punctures on patients (which neither the patients nor clinicians are keen to do), the interest in plasma biomarkers has skyrocketed. So, being able to look at those same parameters that we look at in CSF but looking at those in plasma is very, very favorable. Things such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), those are probably two of the most studied and most promising biomarkers. And there are many more, of course, that are coming down the pipeline. NfL, as we know, is more of a measure of relapsing activity. And then GFAP would be more of like disease progression, so those go into the secondary progressive phase or for those who are diagnosed with primary progressive MS. So again, great interest in plasma because it’s a non-invasive test. It’s very easy to obtain, it’s cheap, and we can easily measure it at pretty much any MS center across the country, or across the world.

So, I was lucky enough to be the recipient this year of the S. Weir Mitchell Basic Science Award for neurology residents. I was absolutely astounded and very, very humbled by that. The data that we’re going to present is just going to show the differential effect on immune cell subsets between moderately efficacious and highly efficacious DMTs. We had a great cohort in Newfoundland. It wasn’t possible without the work of Dr Craig Moore and all the people in his lab where we have something called the HITMS database, which is the health research team in multiple sclerosis. We have over 300 plus patients. It’s a biorepository where we have peripheral blood mononuclear cells (PBMCs) cryopreserved on file for many years now. We have patients who we follow for many, many years. So clinical data, and basic science research data, as well as rehab data. What we’re going to show in this specific project is that moderately efficacious DMTs differentially modulate the different immune cell subsets (this includes your CD4 and CD8 T-cells, your B cells, as well as your monocytes), compared to the highly efficacious DMTs. No real surprise probably, that the highly efficacious DMTs like ocrelizumab or ofatumumab (so B-cell depleting medications), deplete B cells more so than the moderately efficacious medications. Also, what was really important, and it ties into the other CSF data, is that those B-cells that are primed to go into the central nervous system (we call those the CD19+CXCR3+ B-cells), are dramatically differentially modulated depending on what DMT you actually use. So, the high efficacious really bring those down, whereas the moderate efficacious ones do not. So, that’s sort of the big takeaway.

Obviously, there’s a lot more work to be done. The plasma cohort was more of an exploratory cohort, so we need to follow these patients and many more patients over a long period of time; correlate it with EDSS, correlate with other clinical parameters that might be a little bit better, and correlate with MRI data as well, because there’s lots of emerging MRI biomarkers that are very, very interesting. But, I see it as part of a one piece of a very big puzzle, but it does have an important part to play. Say, for example, in the data that I’ll show in a couple of days, the differential modulation of T-cells versus B-cells in moderate or high. So if you have someone who’s on moderate efficacious DMT, then you may want to measure NfL, but measure these particular T-cell subsets with it because they correlate so well and allow to show if there’s any disease activity. Then the same thing of course for those who are on highly efficacious. So, one small piece of the puzzle, but important nonetheless.