ECTRIMS 2021 | Characterizing early versus late PIRA after a first attack of MS

The objective of this study was to characterize PIRA, which is progression independent of relapse activity, in a population of people who had presented with a first attack of MS. So this was the main thing, to understand that, but also we wanted to assess different subtypes of PIRA. So for that we analyzed PIRA occurring very early in the disease course and PIRA occurring late in the disease course. This was the first specification and we also wanted to assess whether PIRA can occur in the absence of any imaging activity, any inflammatory activity in the MRI. So these were the main aims of the study, first to understand what happens in very early disease. Second, what happens when PIRA occurs very early in the disease, very, very early, and third, what happens when PIRA occurs in patients with no prior inflammatory activity.

To carry out the study, we analyzed a cohort of 754 patients with a first attack of MS and we followed them up for many, many years. And then we analyzed the periods free of relapses. And these periods were starting three months after each one of the relapses, except for the first attack, which was the CIS, for which we allowed six months. So those periods where we did not see any relapse were the periods where we analyzed the increased disability. So to say that the patient had had a PIRA event, we analyzed whether the person had shown an increase in the EDSS which was confirmed six months later. When this happened, we said that a person had a PIRA event, and of course, patients could have more than one PIRA event. But for this analysis, for this study, we focused on the first PIRA event.

So the main results of this study were that, in our cohort of patients with CIS, we found that a third had at least one PIRA event, which is a lot of people. And when we analyzed a PIRA that was occurring very early in the disease, within the first five years, we could say that of all patients with PIRA, a third of those will have a PIRA within the five years of disease. And when we analyzed the PIRA that was in the absence of recent MRI activity, we also found that of all patients with PIRA, a third would have a PIRA in the absence of MRI activity. And then when we analyze the characteristics of patients with PIRA early or late, we found that those patients with an early PIRA were older, with more spinal cord lesions, and in general had fewer relapses. And all this suggested that patients with early PIRA had features that were more similar to progressive MS.

So this is why we said that presenting very early PIRA suggests that this early PIRA has occurred as a consequence of a neurodegenerative process. Whereas those patients with late PIRA had a much more inflammatory disease, with more relapses, more brain lesions, and these people probably had their PIRA in the context of an inflammation driven process. This is what we concluded. And then, for those patients who presented PIRA in the absence of recent MRI activity, again, these people were older and they were more likely to have a normal brain MRI. So again, presenting PIRA in the absence of MRI suggested that this PIRA was mainly in the context of neurodegenerative process. These were the main conclusions of the study.

The importance of this study, in the broader context of the disease, is that this study and other studies also tackling PIRA, because PIRA has been assessed by different people in the ECTRIMS Congress, these PIRA studies show that progression probably starts from very early in the disease course, at least in some people, maybe not in everybody, but in a subset of patients, this neurodegenerative process probably is present from the very, very beginning.

So what’s the next step? So knowing that, what can we do? So the next step would be to try and identify those patients who are more likely to present this early predominant neurodegenerative process. Because it is likely, it is possible that these people need different treatment approaches and more linked to the mechanism that is mainly driving disability in those people. So identifying people with an early PIRA, or PIRA in the absence of MRI activity, is very important. And another aspect that can be highlighted from these studies is that maybe the clinical phenotypes in MS need to take into account these differences, when and in what context neurodegeneration or clinical progression appears in the absence of relapses.