Impact of High Efficacy Therapies on Understanding of Disease Progression in MS


Dr Bruce Hughes and Dr Robert Naismith discuss how high-efficacy therapies have impacted the understanding of disease progression and multiple sclerosis care.

Bruce Hughes, MD:The thing that I think is really interesting to me also has been, if you look at our understanding, we used to have this belief that we had RAW [relapse-associated worsening] early in multiple sclerosis, and then PIRA [progression independent of relapse activity] was later in multiple sclerosis. But more compelling information is showing us that PIRA and RAW are occurring concurrently from earlier times in the disease process. And it’s interesting how we try to sort that out, which I think we’ll discuss further with other topics. And kind of what I’d like to move to is brain volume loss. And what do you think about when you think of PIRA and associated brain volume loss? Because we know that MS [multiple sclerosis] brings atrophy at 3 to 5 times the rate of the general population. Can we impact that?

Robert Naismith, MD: I think that the brain volume changes are really critical because it is a new paradigm in the way that we think about MS compared to when both of us just started in this field. When we began, there was that dichotomy that you have this relapsing, remitting phase, and then you have this progressive phase. And that there were 2 things, and there was almost this switch that flipped up. And people looked for signatures and biomarkers of when people became progressive, as if this was just something that happened one day. And I think what we’re learning from the imaging and the immunology and the clinical aspects of it with PIRA and changes in brain volume is that progression occurs in an individual at the very beginning of the disease, and it may even begin before we are aware of the disease. There may be this prodromal period that MS has kind of had the fuse lit, but they haven’t presented yet, but you have this inflammatory state that’s taking place and is causing some of these changes even before they present with their first episode. So the shift in the paradigm is that we don’t have this relapsing remaining stage and the secondary progressive stage, but you have patients that present with relapsing disease. But those elements of progression are present at the very beginning, and it’s a continuum until patients pass their neurologic reserve because this is all hidden because people are able to compensate for the problems that this degeneration is [creating,] up to a point. It might be 10 years, 15 years, 20 years from the disease onset, but there becomes this critical period where they’re no longer able to compensate, and that’s what we call the clinical phenotype of progression because now they’re having the walking issues because of the generation of the corticospinal tracts and the sensory fibers that are the long fibers under the most stress. I think one of the key things that has really revealed this is high-efficacy therapies. When we started our therapies, we’re very good, but people always talked about this treatment gap. We weren’t able to get the relapses down to a very low rate, and now that we have treatments of moderate- to high-efficacy regions, we are seeing that patients [have more] worsening even in the relapsing stage of the disease not due to the relapses themselves. So I think this sort of unmasked that whole phenomenon. What have you seen?

Bruce Hughes, MD: Yeah, I’d say it’s the era of high-efficacy therapies. Using high-efficacy therapies early is starting to pay off. We don’t have great data on impacts of DMTs [disease-modifying therapies] on PIRA, but I think that evidence is building. We have data from a few years ago with ocrelizumab, ofatumumab, and, very recently, ozanimod. Ofatumumab has been shown to have impacts on PIRA, and I think this may tie in somewhat with the concurrent impacts these high-efficacy therapies have on brain volume loss, both total and cortical and deep brain matter structures. We know that can impact on all aspects of how a multiple sclerosis patient is doing. We talk about the patient later when we have dropout, and all of us have seen this, where we say, “You’ve transitioned into a progressive phase of the disease,” because there are more bladder issues and slow, smoldering, spastic gait that just is getting slower and less steady. But I think when we look at the atrophy, what’s only been gaining attention more recently is the impact on what that has on cognitive functioning, and PIRA is maybe a driver early on of cognitive disability, and I’ll even throw in fatigue.

Transcript is AI-generated and edited for clarity and readability.

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