番茄社区

番茄社区 brought together three expert leaders for a virtual roundtable discussion on the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS): Moderator , from the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, is joined by , from the University of Colorado Denver School of Medicine, and , from the Université de Montréal in Quebec.

This first of four exclusive episodes examines recent findings on emerging biomarkers for multiple sclerosis in cerebrospinal fluid (CSF) and blood.

Following is a transcript of their remarks:

Ontaneda: Hello, my name is Daniel Ontaneda, I'm a neurologist at the Cleveland Clinic. Welcome to 番茄社区's ECTRIMS 2023 Roundtable. I am super excited to be here, we're all back from MS Milan 2023. And I am accompanied by two of my very dear colleagues and friends, Dr. Gabrielle Macaron, who's an assistant professor of neurology at the University of Montreal, and Dr. Enrique Alvarez, who is an associate professor of neurology at the University of Colorado. So, welcome, Enrique and Gabrielle. It was, one, great to see you guys at the meeting -- I think that's the one thing to highlight, which is great about having in-person meetings again. And the second thing, just to kind of welcome you guys and excited to talk and chat. We decided to make this somewhat informal and reproduce what our typical conversations are when we get together and we talk a little bit about the science that has been presented at a recent meeting.

So we're going to hit a couple of topics. We might veer off the path, we'll talk about data that was presented at ECTRIMS, but also we'll talk about the greater picture of what some of these scientific findings mean. So not staying strictly within the abstracts presented, but perhaps a little bit broader.

And with that, I would like to start off with a first topic, and I think we probably have a resident expert here with Enrique who has done a lot of work here in biomarkers. And certainly biomarkers were super hot at this meeting. I heard a lot of presentations that were super exciting on the imaging side. I say that because I'm an imager. But maybe we should start out with blood and CSF biomarkers. So Enrique, what were the things that caught your eye at the meeting specifically in this topic?

Alvarez: Yeah, for sure. Echo to that it was great to see everybody again. So I think as we look at the story, the evolving story around NfL [neurofilament light chain] and GFAP [glial fibrillary acidic protein] is it's looking at these biomarkers and helping to distinguish that they tell us probably different things. We keep seeing a lot of, kind of at the population-level-type data, really suggesting that NfL matches up great with inflammation and inflammatory markers of disease activity, particularly with contrast enhancing lesions, new T2 lesions maybe a little bit less so. And then GFAP matching up a little bit better with disability.

I think the one thing I would've liked to keep seeing a little bit more is data that comes out at the individual level that helps us see how do we apply this data to individuals and clinical practice. But at the population level, I think it's becoming very clear that these are good markers that we definitely need to -- they're not as straightforward, maybe, as some of our other biomarkers -- and we need to correct for a few things to try and probably make the most sense. We need to adjust for age because the levels go up with age. We need to correct for weight because bigger people like me have a lot more blood and so we dilute out the levels and so we tend to have lower levels and that probably doesn't necessarily mean that I'm healthier, or things like that.

And so I think trying to put those in context, understanding that you can't use it if the creatinine clearance is not within fairly decent normal ranges. And so having at the right context, correcting it out. I think the question around how often do we check them, this is a little bit you have to kind of think about them I think better as contrast-enhancing lesions, that they come and they go and they have a finite half-life. And they're less like T2 lesions in the sense that they don't remember what happened. So you might need to be checking these every couple of months to 3 months.

There was from January, I think, that came out looking at the dynamics from the APLIOS study, which was the autoinjector study for ofatumumab (Kesimpta) really showing that four per lesion, that this has probably about a one-month half-life. Levels kind of go up, and the nice thing is you could see levels actually go up before contrast-enhancing lesions and then they come back down. And that might be a window a little bit as to how smoldering the disease activity is, which I'm sure we'll probably get into a little bit later in the discussion.

Ontaneda: Absolutely, Enrique, definitely we'll get into that. But maybe before we get into the imaging biomarker side, Gabrielle, was there anything that you saw from the biomarker blood perspective, something that maybe might help us better interpret what we make of these biomarkers and how to use them in clinical practice?

Macaron: I think Enrique, you really gave a summary of what the data looks like. And I think there were a couple of studies that caught my eye, but that they are basically saying maybe the same thing. There was from the SPRINT-MS trial that evaluated longitudinally NfL and GFAP in this progressive MS cohort. Those people who were treated with ibudilast versus placebo and were strictly progressive I think didn't have any sign of clinical or radiological activity. And there I think GFAP was more associated with MRI measures and even clinical measures of tissue injury or of progression. I think we can agree that NfL is not a good reflection of this process and maybe we need to look more at GFAP for this population.

Whereas NfL looked more interesting in this other cohort study from this really large scale cohort from MS PATHS. And it was interesting because they looked at different NfL levels at different time points and they divided patients into those who remained stable and then those who increased and stayed up, and then those who normalized or [transiently] increased. And I think the only people who are really associated with worsening long-term were those who were persistently elevated. So it might be a marker of chronic inflammation or ongoing inflammation that makes people get worse. And maybe this reflects relapse-associated worsening or new-lesion-formation-associated worsening, whereas GFAP really gives a different story.

So I'm not sure what you think, but are we maybe, I dunno, heading towards combining the two to better understand our patients from the beginning, or at which point in the disease duration? Not quite sure what to do with that.

Ontaneda: Yeah, yeah. No, I think it's exciting times. I mean, I think the challenge, as Enrique already stated, is taking the markers from the group base down to the individual base. And I think in NfL we're a little bit closer and I think the MS PATHS abstract actually showed that. So just kind of stating, using NfL levels in clinical practice is somewhat hard. I think what we have to try to do is find individual thresholds, that an individual who will be predictive of certain things that will help us make decisions or help us monitor treatment. I think with GFAP, I think we're not exactly there yet. I think there's a little, there's even less that we know about GFAP on the individual level. And I think the reality is that the rate of progression is going to be very different between patients and how you would interpret a change of GFAP that is maybe slowly bleeding out from the central nervous system. I think it's going to be even a greater challenge.

So definitely a lot in store, but the direction of the field is that, like you said, Gabrielle, eventually we have to get to a point where we're going to develop algorithms so that we can actually use these in clinical practice and they can help our patients.

Alvarez: Yeah, I think part of it is the challenge around just understanding the pathophysiology of progressive disease and it's probably going to be several different pathologies and which one of those does it associate with GFAP? And so I think we understand that pathology better. It's going to be harder to understand it, but I think GFAP gives you more of a window into being able to understand that pathology as well.

Ontaneda: Absolutely. Absolutely.

Comment