Targeting Chronic Inflammation in Progressive MS

MedPage Today 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 American Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS): Moderator Daniel Ontaneda, MD, PhD, from the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, is joined by Enrique Alvarez, MD, PhD, from the University of Colorado Denver School of Medicine, and Gabrielle Macaron, MD, from the Université de Montréal in Quebec.

This third of four exclusive episodes explores the various studies presented on chronic active inflammation in multiple sclerosis (MS).

You can view other videos in this series here.

Following is a transcript of their remarks:

Ontaneda: Maybe we should move on to another topic that I think was also very clearly prominent at the meeting. And I think it’s been the last couple meetings that people have been talking a lot about that, and that’s chronic active inflammation. And it relates to, I think, somewhat to progressive MS and how we can target that. But, Gabrielle, I wanted to know from your perspective: was there anything in the chronic active inflammation space, stuff that you saw at the meeting that caught your eye that you think is worth sharing with the group?

Macaron: Yeah, I mean, I think I agree then that they were all over the place and chronic active lesion, slowly expanding lesion [SEL], paramagnetic rim lesions [PRLs] that were shown in different ways from different perspectives in many, many different abstracts. But I think the starting point is that we do know that these lesions are a reflection of smoldering lesions — let’s not call it smoldering MS — and are a very important culprit in the development of progression and independent of relapse activity.

One study that particularly caught my eye, and I learned something new, was the TSPO [translocator protein]-PET studies showing that some lesions may have a broader rim lesions and those are even more associated with rapid progression or rapid worsening of disability. So yeah, I think in this study, it was a study from Finland, from Dr. Laaksonen, and so what they did is that they actually looked at TSPO uptake in different two millimeter concentric rims around chronic active lesions. And lesions which had broader activity significantly were associated with more rapid worsening on the EDSS [Expanded Disability Status Scale].

And they looked at EDSS cross-sectionally, and they also looked at EDSS change retrospectively to see who were slow progressors and fast progressors. And yes, the presence of even one, I think broad rim lesion, was associated with faster disability progression, but it was also associated with any MRI metrics you can think of that underlies the tissue injury or progression such as gray matter fraction and thalamic volume and normal-appearing white matter, like TSPO uptake in normal-appearing white matter — or not-so-normal appearing white matter we might call it — and overall lesion load and overall chronic active lesions.

So I found that these results were really interesting. And maybe we now have a measurable tool of rapid progression and I think it further confirms the importance of microglial activation in disease progression. And I was wondering when I looked at that, if this should be the primary outcome measure from now on in medication that targets progression.

Ontaneda: Yeah, it’s a fascinating topic, right? The idea that there’s a component of inflammation that is separate to what we have historically considered as a breakdown of the blood-brain barrier. And I think we continue to see accumulating evidence of this.

We had a really interesting North American Imaging in MS education session specifically dedicated to chronic active lesions. And the three modalities were covered in three separate talks. One was PET, that you talked about very eloquently, Gabrielle, about the recent data that was presented from the Finnish group. We had a presentation by Francesca Bagnato also on the paramagnetic rim lesion. And I talked a little bit about slowly expanding lesions. And although many times we kind of think of these interchangeably, I think from a methodology standpoint they’re quite different. And so when you look at specifically at studies that have examined both SELs and paramagnetic rim lesions, there’s a couple of studies that have examined both concomitantly in the same datasets.

And you actually see that the overlap actually is quite small. But it does turn out that those lesions that are both slowly expanding — that you would think that’s your definition of a lesion that’s smoldering, that’s chewing up myelin as its rim is advancing — actually is a large proportion of lesions, only a small proportion of which have paramagnetic rims. But it’s precisely those lesions that are both paramagnetic rim-positive and slowly expanding that are the lesions that show the most tissue destruction and are probably the ones that are most important. And if you asked me to bet, I would probably say those are the lesions that are most likely to lead to be PET-positive for microglial activation.

And I think that what you bring up about PET being an imaging marker, I think is fascinating. For years and years in the imaging community, everybody always says, “Oh, PET’s too hard to do as a multicenter study. It’s too complicated.” But the reality is that although the ligands are a little bit different in the Alzheimer world, they’ve done it. And they’ve done it very successfully to the point that one of the first medications approved that was controversially approved for AD [Alzheimer’s disease] patients was actually based on PET data.

So it kind of gives us an extra bar that maybe we should think a little bit more about how to design these studies, focus on the very specific biological markers, and then move on from there.

I’m not sure, Enrique, if there’s anything that caught your attention on this topic?

Alvarez: Yeah, I mean, I was the outsider looking in for this meeting, and so if you asked me what was the big discussion topic, I would say there were two big ones. One was PIRA [progression independent of relapse activity], which I’m not sure; it was just a discussion topic without really any new data to it, if you ask me. But the other one was this whole discussion around SELs and PRLs and yeah, I mean I’d heard about them, right? But it was always a little bit more of, quote unquote, maybe “fringe.” It was like some piloty-type stuff. And I felt like at this meeting, it really exploded on the scene and really provided a lot of data around the association with higher progression, with more destruction, including some NfL [neurofilament light chain] associations and things like this.

And so I think this is definitely one of these things now that we’re going to have to pay a lot of attention to. That it’s something that as we try to understand this progression process, that this is undoubtedly accounting for some of that, and it might be the more rapid progression early after relapse.

And I think from a big picture perspective, I’m still curious to see how much of the progression in a patient who is more burnt out 20 years after their onset of MS, how much of this pathology is still associated with those patients. I think that’s the part that I’m still kind of struggling with, and that I didn’t really see great data for. But I think it’s one of those areas we just haven’t looked at it that much because we tend to get those patients that are a little bit earlier on to their inflammatory course, and it starting to get harder to study some of those progressive, more advanced patients.

Ontaneda: Yeah, absolutely. That’s definitely the case. And we have a North American Imaging in MS paper, that is a position paper on definitions of paramagnetic rims, slowly expanding lesions, and then PET lesions, chronic active inflammation that’s currently under review. We’re hoping to get it published soon. So for anybody out there, if you want a nice concise update on it, I’m doing my own plug right now, but great.

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