Disease Progression in Multiple Sclerosis (MS): Overview of Relapse-associated Worsening (RAW) and Progression Independent of Relapse Activity (PIRA)


Dr Robert Naismith describes changes in the understanding of acquired disability in Multiple Sclerosis (MS) over the years, with a particular focus on relapse-associated worsening (RAW) and progression independent of relapse activity (PIRRA).

Bruce Hughes, MD: Hello, and thank you for joining this Neurology Live Peers & Perspectives presentation titled, “Disability Progression and Maintenance of Cognitive Function in Multiple Sclerosis.” I’m your host, Dr Bruce Hughes. I am the medical director of the Ruan Multiple Sclerosis and Research Center in Des Moines, Iowa. Joining me today is Dr Robert Naismith, who’s an MS [multiple sclerosis] specialist and researcher at Washington University in St. Louis, [Missouri]. Today, we will be talking about how patients with multiple sclerosis acquire disability and the concept of progression independent of relapse activity or PIRRA. We will discuss current understanding of cognitive decline in multiple sclerosis and share data on how various disease modifying therapies impact PIRRA and cognitive health in multiple sclerosis. Thank you for being here today.

I think we’ll start with how our understanding of acquiring disability has changed over the years and maybe you can make some comments on raw relapse-associated worsening vs PIRRA.

Robert Naismith, MD:Absolutely, as a neurologist and a scientist, you always try to think back to what’s happening in the disease and how to translate that to the patient experience. So whenever I think about multiple sclerosis, you have these different components that are taking place and to some degree alongside each other. So, you have acute inflammation, chronic inflammation and neurodegeneration. So, like with the last iteration of the criteria, what we do in our assessments and practice is we say whether patients have a subtype of MS with or without activity, or with or without progression. And we try to relate that back to the pathogenesis of what’s happening with the disease. And activity is synonymous with new MRI lesions or relapses and those represent blood-brain barrier breakdowns. We have a new lesion that forms over the course of some short period of time. It may have neurologic dysfunction that occurs with it. And then there’s some resolution of that maybe due to reduction of edema, decreased inflammation in that region, and maybe even some remyelination. If you talk about with activity, then that means you have a new lesion. You may or may not have a relapse associated with that. Whereas with progression, that may be due either to chronic inflammation because we know that these acute lesions turn into these chronic lesions and those can cause damage, and then you have neurodegeneration, and that’s what we refer to as progression. And neurodegeneration is the dropout of neurons and axons over time because they’re in this hostile environment that’s proinflammatory, and they’re working very hard to maintain their function. So there are these big metabolic demands that are put on them.

So the patient just knows that they’re doing worse. They come in and say, “I’m not as good as I was last time.” And as a neurologist, we have to figure out what the reason is. The patient only knows that they’re doing worse. And we have to figure out, are they having relapse activity? Are they having a pseudo exacerbation? Are they having paroxysmal symptoms? Or are they having neurodegeneration or progression? Because a lot of patients just say, “I must be progressing.” So we need to sort that all out.

When you think about the ways people worsen, there’s RAW, [which is] relapse-associated worsening. And that refers to worsening due to acute inflammation with a new lesion within the central nervous system with the referable symptom that the patient’s experiencing. Whereas PIRRA is without that acute inflammation. So it could either be from the chronic inflammatory state that these lesions undergo and is actually present throughout the central nervous system or maybe because of the dropout of neurons just over time. These things are interrelated, but they don’t correlate perfectly. So we know that the acute inflammation is early in the disease and this acute inflammation leads to this neurodegeneration, but it’s not a 1:1 correlation. A lot of our treatments are aimed to address that acute inflammation to prevent the chronic inflammation and prevent the neurodegeneration. So RAW is relapse with activity and then PIRRA is worsening of disability without that relapse or that new MRI lesion.

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

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