Multiple Sclerosis progression and the impact of Progression Independent of Relapses

MS Plus acknowledges the traditional custodians of the land this podcast is recorded on, the Wurundjeri people of the Kulin Nation. We pay our respects to their Elders past and present.

Jodi: Good afternoon, everybody and thank you for joining us today to talk about a really important topic. One thing that we observed was that there was a couple of new terms that have come into the MS language of late and left some people feeling quite confused and not quite sure about what they mean, and one of those was progression independent of relapses. And so that sort of went, well, what does this really mean in terms of disease progression? And should I be worried? And should I be confused? So, what we decided to do was to get together some of the best brains in in MS, which is Professor Helmut Butzkueven and Associate Professor Anneke van der Walt and ask them the question of what this really means and what the impact of this is like, of what, what PIRA really means. And does it change what people need to do? And does it change the way that we see and understand MS? So, to try and get the two of the best brains together was pretty challenging. So, what we decided to do was to video them. We went to their office and videoed them to ask the questions that you have about this.

So just to reassure you that this presentation serves as a general guide and it's essential to consider your own individual circumstances because everybody's different and you need to talk to your appropriate health care professional for specific advice about you.

So many of you might have heard of Professor Helmut Butzkueven and Associate Professor Anneke van der Walt. Helmut has been over 20 years. I think he tells us that, but he's been 30 and I know that he's been over 30 years of experience as a clinical neurologist. He's the head of the MS team and Neuroimmunology clinic at the Alfred Hospital. He's also the director of the entire neurology clinic at the, at Alfred Health. He's the managing director of MS based foundation that is a global organization that is tracking data of over 70,000 people enrolled in 130 centers globally, of people living with MS to help get a better understanding of MS.

Anneke van der Walt is an academic neurologist with a subspecialty training in MS and neuroimmunology and she's the head lead of MS and neuro ophthalmology research group at the Central Clinical School at Monash Uni. Cutting off to me and putting on the video. for joining me, I'm Anneke van der Walt.

Thank you for joining me Helemt and Anneke. I've heard about this new term that describes MS. I don't know if it's new, but to a lot of people with MS, they're wondering what this means and what this means for them, and it's called PIRA. So, Helmut, can you tell me, what is PIRA? What are we talking about when we hear the term PIRA?

Helmut: It's a difficult question, Jodi. It's not exactly new. Some people with multiple sclerosis get worse. And you can get worse as a direct result of a relapse on the tech. Say you have optic neuritis, you lose vision in one eye, that partially restores, but not completely, so your vision is worse now. And that concept is called relapse associated worsening RAW. If you get worse, and that that worsening is sustained. So, you don't just get worse for a moment, but for 6 months or 12 months. But there's no relapse that anybody has noticed or recorded. And it's usually more of a slower worsening rather than a rapid worsening of a relapse. Then that's now been termed progression independent of relapse activity. Which is a mouthful and that progression independent of relapse activities is PIRA. I think it's become much more of an important concept because of the treatments that we have available for relapsing MS in Australia are fantastic and a lot of people are on those treatments and they're not actually having either none or very few relapses and none or very few new lesions. But some people, not many, but some people find themselves still getting worse and because the relapse associated worsening is so rare now, I guess we're paying more attention to this PIRA. Does that Makes sense makes sense.

Jodi: Yeah.

Helmut: And then in terms of clinical trial studies this is now becoming a target, like, are people on a particular drug less likely to have a PIRA event compared to another drug or placebo or whatever, compared to, so the pharmaceutical companies are interested in developing new drugs to try and stop or reduce this type of progression as well.

Jodi: Anneke is it matched to any type of MS? Like does it mean progressive MS or is it when you second degree progressive MS?

Anneke: I think that's the interesting part about this particular definition, Jodi, is that it can be, you can have this from early on in MS with any type of MS. So, whereas, you know, we often you know, we think about progressive MS as people who have accumulated a certain degree of neurological impairment. So say people who are already you know at the stage where they're struggling to walk 500 meters and things like that, you sort of would say, well that is a hard sign that you might be at risk of becoming secondary progressive for instance, but with PIRA you can develop this change and a slight change in your neurological function from the very beginning of MS. So that is where these definitions matter because that's often where treatments are being targeted at this group of people with early relapsing remitting type of MS. So, understanding that you can see this type of change in function early on and that that could perhaps be, you know, we could change the way that progresses with a treatment is becoming a very, you know, important concept for us to have.

Jodi: And how would someone know that they had, could you tell? Can you ask your neurologist and say, Dr. van der Walt do have I got PIRA?

Anneke: Well, I think that is also a very, that is very challenging, to be honest, because when we look at the studies that's been done on this, I think the first thing to say is that these events are actually really rare. So, especially in highly treated people. But if they do occur, they do explain a lot of neurological disability and progression. So, but how do we know if that's happened? So, it's comes back to the, you know, the age all problem that we've had have in MS and that it's very difficult to examine someone. When they come for a clinic visit and say, okay, you are now X percent worse compared to previously. Because those sorts of things, you know, you have to actually change a lot before we can pick it up in a neurological examination and that would change your EDSS score, which is sort of the standard measure that we use. So, what a lot of the studies that's looked at PIRA have assessed is multi domain function. So, these are things like particularly cognition bowel and bladder function we'd be talking about upper limb dexterity, so sort of subparts of how your neurological system comes together to give you an overall ability to function.

And we're not very good at measuring those things. You know, so we do measure them as part of our neurological examination, but it's difficult to show that it's changing if you're not doing a specific assessment. And then the other thing that's challenging is that it could be difficult for some person living with MS to notice that because we're often talking about a 10 or 20 percent change which could be very subtle. So, it's not something that, you know, someone might notice, because to them that's just their normal. You know people adjust to that level of function, they don't remember that maybe two years ago they were 10 percent faster at doing this mental calculation. So, how do we actually define that and we need better tests that we do in real time really to try and understand this.

Jodi: Helmut, what sort of tests are they looking at to help understand that better?

Helmut: Well, good question. So, in clinical trials and in some clinics, we do EDSS scores, which are based on a, which is a neurological disability Scales and it's really a composite of the neurological examination that you do, your vision, eye movement, strength, feeling, and reported function on bowel and bladder. And we do that, we try and do that systematically and it gives us a score. And if you change in that score and that change is sustained, that's the definition of PIRA. But it's really something that's only done in some clinics and in most people's clinical care, that's not part of their clinical care.

And how else could you tell, and Anneke mention it we are working very actively on patient self monitoring type tools or devices, either things that people do like measure their reaction time or how fast they walk. More things that the phone usually, the phone does for you without you even noticing. You know, if you have an iPhone and if you carry it on you, it'll more or less record your steps and you can look in my health and I'm sure the Google phones have the same thing and you can see how many steps you've taken and what velocity. So, I think it's going to end up being down to those sort of measures to help us identify this for most people.

I wanted to go back a little bit to this relationship between progressive MS and PIRA if that's okay.

Jodi: Yep. And can you throw in the explanation of, is it different to smouldering MS? Lots of people ask us that question, so well in that brief.

Helmut: So, in a way you could think about primary and secondary progressive MS as a whole lot of PIRA’s. You know, if you had a worsening and another worsening and another worsening and another worsening and you didn't have any relapses. That's probably our understanding of progressive MS, the gradual, slow, but somehow relentless worsening. But PIRA events can actually just occur by themselves, and so it doesn't mean that you have secondary progressive MS.

There was a very large study that we've spent a lot of hours contributing to Jodi in a previous life, the Tysabri observational programme, or the TOP study. This really looked at people for more than 10 years, 14 years some of them, on Tysabri, Natalizumab. And it identified PIRA events in about 1 in 8, over time. But very rarely do people have a second one. Like even after years of observation, so as Anneke said, these are actually quite rare. And it doesn't necessarily mean the same thing as Secondary Progressive MS. Now smouldering MS. Also, somewhat a reinvention of an old concept, the old concept was based on pathology, so examining somebody's brain after death, essentially, where you can look at lesions, not just on MRI scan, but actually under the microscope, and what people noticed was that some lesions seem to be burned out, like in the center, some old lesion. But on the edge of it was ongoing immune activity, ongoing inflammatory activity often actually associated with ongoing neurological damage. So, nerves continue to be damaged, even though the lesion appears to be old. So that used to be called chronic active lesion. The smouldering MS is more of an MRI concept, looking and finding these things, which are probably exactly the same thing on MRI scans. Now we can't quite get that currently out of standard reports from routine MRI scans that you have for 20, 25 minutes but they're working on it. They're working on trying to, to measure or show these minuscule changes in the rim. And also, because the inflammation around the outside contains quite a lot of iron, there's sort of a related concept of measuring whether lesions have an iron, like a ring of iron around them, essentially. Probably also, again, the same idea of the same thing.

Now that phenomenon seems to be quite closely related to a risk of Progressive MS, Secondary Progressive MS. So that, if you don't have these types of lesions, you're very unlikely to get Progressive MS. So, we are thinking backwards, that maybe that's an explanation for this other huge question that I often get in clinical care, which is, Doctor, why am I getting worse, but my MRI, but you're telling me my MRI scan hasn't changed? And, and it may well be all because of this. So, this may be a way that we can measure Secondary Progressive MS risk or Secondary Progressive MS worsening in the future. It probably has less to do with PIRA.

Jodi: I was just about to ask if you have a PIRA event is that indicative how you're going to go in the long term when they did those long term studies when they found those people who had fewer events?

Anneke: No, I think it's what similar to what Helmut said before, it's sort of if you have one event and this also depends on how it's defined, you know, because I think we also see that the way that this has been defined in studies are very, very different. So, we often do see people. Get worse for a while. So, they say their bladder function gets worse, but then six months later It gets a bit better again So it's really important to understand if you look at a study on PIRA that how have they defined this? Is this getting worse over three months or six months? Does it mean that you could never get better, you never had to get better again before it's called PIRA. Does it mean that if you had a new MRI lesion in between, even if you had no relapses, you know, can you really say that PIRA is related to inflammation? So, so I think, you know, the definitions in this case, it does actually matter. But I think what we see in clinic is that we often do see people who look like they're getting worse and then they'll get a bit better again. So, I think, you know, having those sort of true PIRA events that we would consider worsening without any improvements, they take a while to confirm really and they're pretty rare.

Jodi: Right so how would you, what advice would you give to someone who thought that that's what was happening? Who thought that they were getting worse, and it could be smouldering MS or it could be age, or it could be PIRA. How do you or what advice would you give someone, and what would you do in clinic if you were seeing someone who said that they were getting worse? Because now there seems a lot of reason to, a lot of, it is quite confusing in that sort of, and it is the answer, it is the question a lot of people have.

Anneke: Well, I think I have to say when I have been faced with these questions it often is really, you know, I'm often in a position that I could actually give to the person telling me there's a lot of reassurance that it's not that. And that is because we do collect in our clinic a lot of additional information on say memory function and all of these extra things that I can sort of say, look, I know you feel that it's worse, but when I look at these very sensitive tests that it's not getting worse. But, you know, let's have a look and make sure there's no other explanation because we also have to remember that if someone does feel worse from MS, there could be something else going on. So it could be that someone, you know, has another medical problem, or is overwhelmed by other things in their life and it's good for us to take a very holistic perspective to someone reporting these types of worsening.

And that we sort of take it as a red flag to say let's have a really good look here before we just say, before we say this is MS. Because there's often other reasons and it's often not changing. But what, if there's any uncertainty and you just cannot work it out, you know, it often is a, you know, what I think we would do in our practice is have another look again. So, you know, sort of saying, okay, well you think it's worse now, let's assess it, let's see you again in three months or six months, let's have another look at your MRI scans, let's see if we can find anything here that is truly indicative of a progression event. And you know, if there is any role then for, for changing treatment, you know, and I think that's a difficult question because we, again, don't know how these drugs will perform if we look at this specific outcome measure. But there's certainly more protection to be gained from higher efficacy drugs, and I think, you know, I don't think anyone would argue that.

Helmut: I think it's difficult to, okay, this might have some patronizing, but I can back it up with data. How people feel about themselves. Do they feel worse? Do they feel better? Do they feel the same as last time? Can be related to something like PIRA but it's actually usually not. Because PIRA is a very, very slow thing and there are lots of other things that intervene in people's lives. People may feel much better because they've just got some great physiotherapy. Or they feel much worse because there's a major family crisis or they have some other disease and PIRA itself and also secondary progression, they are very slow things that we actually tend to adjust over time.

So, Anneke and I, together with other people, have spent a lot of time looking at reaction time as a sensitive sort of measure of worsening that is usually sub clinical by which we mean people can't really can't really tell they're getting worse. And if you look at people who are definitely getting worse on this, which is not many, but there are people who are definitely getting worse, so they're reacting slow and slow and slow and you ask them, do you think you're doing worse or better or the same? They can't tell. So, it's definitely worth, if somebody's feeling worse, it's definitely worth having a good look at everything.

Jodi: And all the other things that might be contributing to that.

Helmut: Physical health, emotional health, exercise. Even though the evaluation of you know of lesions and is there in fact disease activity that we can see? Is there symptomatic or in fact disease treatments that we can optimize? Because oftentimes, people can feel better again.

Jodi: I guess that sort of comes to light, which is a part of the answer to my next question, which everyone would ask, I'm sure, is, can I prevent it? Can I prevent that? What can I, what can I do to prevent these things going on? Is there anything, you know, those sorts of things make sense, but any other, what advice would you give to someone to say how can I prevent these things?

Anneke: I think, you know, the truth of the matter is the same as it is for preventing Progressive MS, and we firmly know from studies and from our own experience that the sooner we treat people with MS, with the most effective drug, the more likely we are to protect their brain and prevent progression down the track. And that's actually also been shown with PIRA events that people who have been exposed to high efficacy disease modifying treatments definitely have a much longer period before they'll have an event like that. So, it was a delay with quite a few years actually. So, I think that is still one of the biggest tools in our, you know, that we have is to sort of, to use very, very good treatments early, as early as possible. And for us to monitor that and make sure that we adjust it if it's not working. But there is no doubt that you know exercise general health, lifestyle, healthy diet, engagement with other people with MS, all of these things play an incredible role in keeping a person with MS healthy.

So, all of those pillars really have to be addressed and its hard work, you know, it's a lot of work to think about all these aspects of your health all the time and spend the time on it. And that often small investments, especially with lifestyle can have huge long term benefits and I think it's important that you know, we never forget that and that we keep that as part of our management strategy.

Jodi: Very important. Brain health. Keep the brain healthy. Helmut do you think, understanding a bit more about these PIRA events will change treatment for MS 10 years down the track? It's a big question.

Helmut: I think it is one way, together with these slowly enlarging regions, that people who are conducting trials, mainly the pharmaceutical company, are looking at these as outcomes to see if they can modify them or change them. If there's still some chronic inflammation going on, are there some drugs that we're not currently using that might stop that from happening? So, I think in that sense it might change the landscape because there may be trials in the future conducted looking at that. If you've got a slowly expanding lesion or an active lesion, you might go in this trial and then the trial outcome might be to see if it can stop that. Or if you have a PIRA, you might go in a trial to see if or the trial might simply be focused on stopping PIRA events. We're all looking for the magic recipe of how to really measure MS. MS, this is kind of, in a way, what this conversation is also about because we think that that's going to unlock a whole big, massive potential of future trials for better treatments for any form of progression.

Jodi: Which is exciting to think about, you know, the more you understand, the more able to put these pieces together. And it seems very complicated from what you said to, you don't really wake up one day and know you're having a PIRA event. It seems far more complex than that. And I think that's really important for people to understand when something goes wrong. That it is like pulling apart different pieces of the puzzle and understanding all the different, all the different things can impact MS getting worse. And paying attention to lots of different aspects of it from what you're telling me, there's no single test that can say, today is a PIRA day.

Helmut: I think also if you're feeling, because it's an imperceptibly slow thing, if you're feeling much worse today than yesterday, or you're feeling much worse this month than last month, there's something else going on. It's not that incremental change that we might see with PIRA. If you notice a big difference in your function, something else has happened. In fact, it's not PIRA.

Anneke: It's just so insidious that people probably won't notice it.

Jodi: Okay. Yeah.

Anneke: Which is hard.

Jodi: It is, it is. But whilst the more we learn the more we're able to unpack and find answers to those questions as well too.

Well, it's good to end on the more we learn the more we answer the questions. Lots of people have asked a similar question, which I think Helmut and Anneke answered to a degree, is neurologically stable but symptoms are I'm not stable. And I think if I could coin in my 25 years of nursing, MS nursing practice one question that I was asked the most frequently, it was probably that. And we do know that chronological age is the biggest driver of change in MS. So, as you age it is likely as well, too that has an impact on your MS symptoms. And so that's one of the big reasons why people change. That's the biggest driver of change is that. MS symptoms are notoriously fluctuating just by nature anyway. Lots of people told me that they had symptoms that would have good days and bad days and sometimes periods of when they were doing well. But I think as Helmut and Anneke highlighted there, like, there's many, many reasons why symptoms could be getting worse. And it's really important to check in with that and think it from, think about it from a holistic perspective to say, why are my symptoms getting worse? What other things could be going on here if I don't have any other changes in that sense of neurologically stable. I think that there's also we don't completely understand disease progression in MS as well too, so that sort of adds a further element of challenge to answering that question.

One person asked about what is the difference between PIRA and SPMS? I think we've asked, I think Helen and Anneke answered that really well that it's not that PIRA is an event and not that happens and occurs and then sort of, that there is a resolution. So that's the difference when secondary progressive MS is something that is just, that is an ongoing progression by nature. There still seems to be lots of variances in the definition of PIRA. When I've done my research about what is PIRA, I've found that some people did describe disease progression that would be related to secondary progressive MS in the same way that they described PIRA. So, I still think there's a little bit of a debate about what exactly PIRA means.

Are MRIs the true and singular measure of progression? No, by no means of by no stretch of the imagination is MRI the single, singular measure of progression. I recall when I started nursing that MRI was used a certain machine called a Tesla. Like that's the sort of, that's the level of MRI. I'm not technically, technical enough to completely understand that. But the machine was rated 1. 5. Most of you probably have heard of that what, what an MRI machine is rated as and this was one, the one that we started with was 1. 5 Tesla. And then as things changed in MS, then it got to a 2 and then a 3and then I went to America and they were doing, you know, 7 and 8 and 9 tesla MRIs. And that meant that each time they got better the MRI got better. And so, what was really interesting about that was that every time the MRI got upgraded, you could see more lesions, which in a way just testifies to the fact that the MRI is not, is not completely the tunnel of truth. It helps in many, many ways, but it's certainly not the measure of progression. And I think it's a combination, like many things, it's a combination of clinical picture, MRI and other factors as well too. And neurological assessment is a really important one too. You can often tell people's strength from time to time, from examination to examination. And some neurologists, that's all, were amazing at how they could do a neurological examination and know that people have got worse and say, I think your strength is a little bit worse. Have you noticed that? Or that your reflexes are a little bit worse, mostly with strength, the strength is a little bit worse. Have you noticed that? Or you know, bladder, bladder function is a little bit worse. Have you noticed that? So, there's lots of measures of progression.

Someone said they haven't had new symptoms in MS for years and 2023, they developed MS related clinical anxiety and might their MS be active again? So, I hadn't heard the term MS related clinical anxiety, so I did have a little bit of a google did a little bit of research on that one, so I was glad I got that question in early. So that, so I think there's still debate about whether, what are all the elements of why there is an increased incidence of anxiety in people with MS, and there does seem to be an increased incidence of anxiety, and will often divide anxiety, into state anxiety and trait anxiety. And state anxiety is related to systems processes and what's going on around you. Trait anxiety is much more pathophysiological or there's a cause for it and there seems to be potentially some interrelationship between the cytokines and pro inflammatory cytokines and increasing rates of anxiety. Very hard to pull that apart because of the difficulties in. measuring exactly the physiology of anxiety. So, I certainly, you know, I didn't see, I didn't come up with any particular answers for that about whether that was, whether that is. But again, I guess it's that holistic picture to say the question was, is MS active again? I guess it's that question of that holistic picture of investigating all the other potential reasons why that anxiety might be in place or what, what's going on in that. So that was a very complicated question and unfortunately, I don't really have the answer for that one, but it might be good to talk to your the person who diagnosed that MS related clinical anxiety to get a better understanding of that of how that diagnosis came to be and whether they had any concerns that in that diagnosis that there was more, for instance more inflammatory processes going on and also has it been sure that you've investigated any other possibilities for what that is, for what that could cause. And it also depends a little bit on what treatment you're on and other factors like that.

So, some other questions that we have. I'm very interested in joining the platypus trial, but my neuro is not with MS space. How do I enter the trial? So, the platypus trial is a trial that they'll be doing probably in about six months. So, they get all the centers organized. Unfortunately, not all MS centers are in MS space. So, if your center is not, I think you can give us a call and we can help you identify which centers are and aren't part of MS space. MS space does have a website. I'm not quite sure whether they include every centre there, but they certainly can help you if you want to engage with the MS space directly. The team at MS space can help direct you into a different centre depending on what state you're in and where it is. Unfortunately, there's no trick around that one. I think you really need to be going to a centre. Now that doesn't necessarily also mean that you can't have, if you've got a really great relationship with your existing team, that doesn't necessarily mean that you can't be part of two different clinics. Just a little bit more effort involved in that one. So, there's just, give us a call and we're happy to talk you through what that might involve in.

Another question, I was diagnosed with PPMS gradually, gradual worsening every year. Reliant exercises to keep well. Anneke Helmet mentioned drug therapy, I understood drug therapy is not available for PPMS. Technically, yes, in Australia there is no current drug therapy available for on PBS for PPMS. There are some clinical trials going on in different clinical, I know some of them in Melbourne. Again, probably MS Research Australia would be the ones to contact to say where are the trials going on for trials of treatment in people with MS. And at the moment it is just Ocrevus that I'm aware of. But there may be other ones. The best way to access therapy when it's not available on PBS is through clinical trials. So, it might be worth getting in touch with MS Research Australia and they have a database of all the clinical trials that are going on at the moment and who is and isn't eligible. They are also part of the Progressive MS Alliance and so they do MS Australia and MS Research Australia, and they do a lot of work in that space. So, they will certainly be the ones to help you navigate, where there might be any drug treatment available.

Is there a diagnostic measure of PIRA? And Helmut and Anneke talked about that. That there isn't any diagnostic measure, which does make it very tricky. I think I remember coming out of that interview thinking, I still am not quite 100 percent sure. But I think that's probably just a testament to the fact that we do have new, new knowledge and new changes all the time.

And is PIRA more common in progressive MS? That was also answered as well too. So yeah, there's lots of questions that they already answered in the webinar about what is PIRA and how it relates to others. And importantly, what is also smouldering MS was another really good thing that I think Helmut described really well as a difference and a strong potential measure down the track for ongoing inflammation that people weren't aware of. And there's lots of different terms for smouldering MS. And so, they can be called dark rings or iron deposit rings on the type of MRI scan called a T1.

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