EULAR 2025 - Day 6 podcast Save

You're listening to a RheumNow podcast coming to you from Barcelona, Spain and EULAR twenty twenty five. Hope you enjoy it. Hello, everyone. Welcome to our panel review on psoriatic arthritis from EULAR twenty twenty five. Our faculty who covered PSA are here to discuss highlights of this meeting that was held last week in in Barcelona.

We were all there. We were all working from six in the morning till midnight covering this content. We found a lot of content that I think you're going to like. We're going to do sort of, everyone's gonna do two presentations of their favorite things in the meeting, and hopefully, this will be informative for you. Let's begin with introductions.

I'm Jack Cush with RheumNow. I'm joined by Orly.

I am Ohili Naj from Glasgow, Scotland.

Jeeha.

I'm Jeeha Li from Michigan.

Nelly?

I'm Nelly Ziade from Beirut, Lebanon.

Eric. And Eric Ruderman from Northwestern in Chicago.

Excellent. Alright. So let's get into it. Orally, what's your, your lead off the program here?

Yeah. So I wanted to talk to you guys about the oral presentation zero zero eighty nine that was presented by Laura Coates on the first day of the conference and it was about the speed RCT speed stands for, I'm gonna have to read that, severe PSA, early intervention to control disease. So basically, they looked at patients that were naive with PSA, but that had a factor of poor prognosis that was identified as either having polyarthritis, CRP over five milligram per liter, hack over one or erosions at diagnosis and so what they did is they randomized them to 100 people and either a standard kind of conventional synthetic demarred and then step up or a combination of conventional synthetic demar straight away. So either metatrix that ounce or leflunomide. And an arm that had TNF and methotrexate.

So they had a straight away. And the primary the major outcome there was the past as a twenty four weeks. So they were able to show that the people that were treated with either the combination of conventional demars or the TNF. They had a better reduction of the past as and that was significant in both of arms. It was one or point seven.

And the other thing is that the DAPSA was better there was no difference however between the combination straight away and the TNF which I found quite interesting. At week at week forty eight then though what they saw is that the people that had TNF only were still doing better. While they had only six months of treatment. After that, they were going back to original treatment. And in terms of infections, it was it was actually not particularly bad.

I mean, the same things that we see with TNS regardless of infections and more so than in the conventional DMARD arm but I think overall to me what it's telling us is that because we know that in RA if we treat harder earlier the the people that have poor prognosis they still do better after a while. I don't know that that was demonstrated in PSA. It makes sense but I think for me it was quite interesting as a result and I wish we could do more of that in the NHS but we've not we've not been very good at that so far. So, yeah.

So, in a world where money doesn't matter, these are important trials about whether you're treating your mother or your mother-in-law, how aggressive you're going to be. Eric, have there been other best like trials in RA in PSA other than this?

Not really. I mean, the closest we've got is the PSA SEEM trial, which looked at methotrexate versus etanercept versus the combination of methotrexate and etanercept. And, you know, said that etanercept worked better than methotrexate. You know, I talked to Laura about this trial and you know, she was kind of hoping that they could show that the biologic actually worked better, because then they could go to the NHS and make that case when they thought it was appropriate, but it didn't. It was as good as a combination of conventional synthetics, and that left them where they were.

And ultimately they had to come off the biologic because the NHS wouldn't continue to fund it. So that's troublesome because early biologic doesn't leave you set up for the long term. So I don't know. I think if you can't get a biologic, this was promising, but that's been it.

Maybe it changes the way people this kind of data changes the way people practice. Jeehan, Nelly, what do you think?

Well, I think post effectiveness matters a lot. And I'm not sure if measuring the endpoint at twenty four weeks is enough. Maybe we need longer follow-up to see superiority.

But that's why I think that one of the forty eight weeks outcome was really important because then, you know, although they stopped the TNF, they're still doing better at forty eight weeks. So maybe that's the hit that the disease needs at the beginning to kind of like slow down a bit and then you can maybe go back. I mean, we'd have to see longer term, but I think the four to eight weeks outcome was quite interesting in that matter.

Siyah, is there another way to think about this?

Well, don't know if that's what Rimmand said. I think a contract to RA where they're finding this like concept of the window opportunity and more aggressive at the beginning that with PSA maybe depending on the presentation that doesn't hold true is kind of an interesting concept to think about. So I think as Zara said, I'd be more curious in the long term data of this to see where it direct leads us.

Given all the conflict in the world, I'm gonna reduce this to military analogies in that this is like saying your first effort in a war sets the tone for the rest of the war. And we know that's actually not really true. And in this kind of study, and there are many of them, first intervention, does it change trajectory of disease? And is there some long term effect? I think we have to think about these diseases as winning many battles, many short term battles, and primary end points should be six week or four week end points.

And if you don't win those, that that's the study I think where you really now, of course, that can get very, really very, very expensive, and maybe really impractical in a lot of places. But, again, if it's your mother and you're looking to do better, I think you're gonna have to, break out of this kind of mold. This is traditional clinical trial stuff, its design. And then that's not really wrong. It's just that there's a limitation to what you're gonna get out of it.

Let's go on to the next one. Doctor Lee.

Yeah. I think that kind of my the one I'm gonna talk about kinda goes along that, and I think definitely a lot of quotes was the star person when it came to psoriatic arthritis because she just had a plenary where she was bringing up this discussion or concept around domain identification and precision medicine. And in one of our talks, the rising star or potential new treatment was the selective TYK2 inhibitor, ducribacitinib. So the study I'm going present is a late breaking APSIS one by Doctor. Desiree van der Heide from Netherland, and they've done wonderful work in RA.

And this was the largest randomized scale study of this kind in a phase through double blind randomized control of about just over 600 patients. So they were randomized to ducirubicinib to placebo, and they looked at outcomes related to arthritis, skin, and also other domains like pain, functionality, health reported outcomes. And ducruvastatinib all did better, about fifty percent compared to 30% placebo. Now, think that 30% placebo is still a little bit high, and from the abstract, it wasn't entirely clear how much steroids or other treatment they were getting in the background, but all of them were supposedly to be biologic naive. From a skin perspective, again, ducirubicinib did better.

I think one of the benefits and the draw of the TYK2 is that it's more selective. So theoretically, compared to the JAK inhibitors that also hit a lot of the domains of psoriatic arthritis, there should be less side effects. And even though this was just a sixteen week report out of this study, that's what they found. The only negative signal was upper respiratory infection, about five percent in the treatment group and three percent in the placebo group. But there weren't any major serious risk of infections or cardiovascular or cancer risk.

Again, keeping in mind this is a sixteen week. And the other thing they looked at was radiographic changes. Again, I think it's a short amount of time, but the fact that they didn't see any negative signals this early on is promising. So I think if this study does pan out in the long term, it could mean that if we identify the domains of the patients, then instead of having them cycle through anti TNF IL-seventeen twenty three, that potentially TYK2, which is a daily oral medication. And for some, it's very convenient of a factor in terms of adherence that it could be a very plausible and a attractive option.

So, many of you were at this presentation, and one of the biggest parts of the presentation were the X-ray outcomes where in their primary analysis, as they designed it, where they assume that X-ray data would be, normally distributed. You know, doctor Vanderheide said it's not normally distributed, so they had to change their analysis. By the primary analysis, it was not significant. When they changed their analysis to a nonparametric analysis and they looked at different subsets of people to include, complete data, not complete data, that sort of thing, Now the results were significant. My question to you, doctor Lee, is that matter to you that in the primary design, at the endpoint that they set up, they didn't win, but then when they redid the analysis, they did win?

Is that a win for them? Or I wanna hear what people think about that.

I'd be curious if the group, but for me, I think that's definitely more of a secondary measure than a primary outcome measure. Think the primary outcome measure mostly should be based on clinical response. Okay. And that was clearly demonstrated in this study both for the skin and the joint.

X-ray data is going to be a positive or a negative for them, Eric?

I don't know. I mean, if they can get that past the FDA, which I'm not sure they can by using the secondary analysis, even though it was clear their primary analysis, the way they were doing it wasn't appropriate, you know, then they can get in the label and they can talk about it. But overall, I was kind of underwhelmed. I don't think the clinical response to this drug was as good as we would have hoped for. And I don't see it positioning itself as an alternative to a biologic where there's clear cut X-ray benefit and much better clinical benefit.

So that was my, well, me ask others what they thought of the X-ray data. Would they like it or not like it, Nelly, Orly?

Well, is justified to use a nonparametric test when you have non normally distributed data. So, the methodology is justified. The magnitude and the significance in practice, so this is something else. So,

the question really is going to be, do you need the data to be considered a competitor to the biologics? And if you don't have it or don't have it to enough of a degree, are you then going to be positioned differently? Like methotrexate or a primalast or where do you see this fitting in Arley?

Yeah, I mean, I don't know. I kind of like agree with Eric there. I was not massively impressed. I feel as well that you know, the radiographic outcome is in every try right now at 12. I mean is that even relevant sometimes?

I mean I just don't know if how early, how too early, how early is too early when you look at at this type of things and I I I don't know. I I'm not particularly based on this, I would not give that on my first line of treatment, that's for sure.

You know, so their ACR twenty was a 54% and so they had a delta treatment effect of 20%, which is good. I think it's better than what we saw with the Primilast.

Yep.

But maybe not as high as what we saw the other ones but now it's in a different era where trials are harder to do. Placebo responses are higher. So, again, it's it's really hard to know unless you yourself start working with the drug. It'll be interesting to see. It's certainly good enough data to get the drug, on the market, and and and now we'll have another drug to consider for PSA.

Let's move on to our next one. Doctor Zayed.

So, I will talk about sunilokimab. So what is this treatment? This is a nanobody derived from camels that have smaller immunoglobulins that can be used to bind antibodies and produce TNF or interleukin-seventeen inhibitors, lightweight and more specific to what we are trying to target. So it's a novel interleukin-17AF inhibiting nanobody, high affinity and designed to reach really the difficult to reach sites of inflammation. So the first time it was presented, it was at EULA twenty twenty four.

It was an ARGO study, twenty four weeks randomized placebo controlled phase two trial with patients with active PSA. So patients with active PSA were randomized into four groups. Sonelokimab 60mg no induction, 60mg, one hundred twenty mg. And the fourth group was adalimumab and it was not powered for comparison. It was a reference arm.

And the patient receiving placebo switched to the active treatment at week twelve. So the primary endpoint was achieved in previous study, ACR 50 versus placebo. And it was increased further to week 24. So, two zero seven patients. What I'm presenting now is the oral OP0096 presented by Ian MacInnes.

He presented the multi domain and high hurdle outcome of the Argo study. So, the multi domain meaning MDA rates and the concomitant achievement of ACR 70 plus PASI 100. So, at week 24, up to sixty one percent of patients achieve MDA with the treatment and forty five percent to compare with adalimumab. And we know that there was a previous ceiling effect of fifty-sixty percent of MDA in previous studies with different molecules. Now, they pulled the different active arms, more than fifty percent achieved MDA across key subgroups like female patient, obesity, high CRP, high PASI, etc.

And for the composite outcome ACR70 PASI100, it was achieved by up to forty eight percent of patients treated compared to eighteen percent in the adalimumab group. And so the ACR70, which it's hard to achieve, was observed across all active groups with high rates, so more than thirty seven percent. And regarding the skin, sixty three percent of patients achieved complete skin clearance, fifty percent with adalimumab. So it was tolerated, no expected safety findings, so no IBD, no MACE, no depression, and four cases which were two percent mild to moderate oral candidiasis.

So, I wanna ask, Eric who knows a lot of these data really well. These seem inflated numbers to me, but then again, there is no arm here that's placebo controlled. Everybody's going to get drunk. When that happens, the numbers go up.

Yeah.

Five, ten percent minimum. Yeah. You know, the accelerate study, adalimumab versus cerdulizumab. You either got one or the other, no placebo. And they had eighty percent ACR 20s in that study, right?

So, I mean, and that's doesn't, that's not normally not achieved. So, again, how else can we explain? Is this drug really that good? Eric, what do you think?

I suspect it won't be. I mean, I think we'll find out when I do a larger try. You know, this is phase two. You never really know from phase two. I I think it's gonna end up being another IL seventeen inhibitor.

That's not gonna be any different than the other IL seventeen inhibitors we have. I mean, the promise of a nanobody is that it's smaller, and so maybe it's less expensive to manufacture. We know that's not gonna bring the price down. And it's better tissue penetration, which that I think may make a difference in oncology because we're trying to get into tumors. In our diseases where there's incredibly, you know, efficient, blood flow in inflammatory tissue and inflammatory joints, I don't think it's gonna matter.

And so I think this will just be comparable. We'll see when they do the larger trials. I'm not overwhelmed by the, benefit in this trial, and I'm not thinking this is definitely gonna be better than the existing IL-seventeen inhibitors.

You know, when we hear of new drugs, we think new opportunities, we think a chance to be better, more efficacious, safer, maybe even cheaper. In the end, they never are.

They never

And and all the company is left with is something about the entity, right, either in its structure, it's an antibody, it's a dual inhibitor, it's not a JAK, it's a tick. And the question, you know, we're and then we're left holding the bag wondering, is this really unique enough to be an advantage for my patients? And and depends on whether you're an optimist or or or a pessimist. Anybody else have a different view of, because now we're going to have two or three AF inhibitors. There was another AF inhibitor that was presented at the meeting that looked kinda good.

That was a unique construct and whatnot. It's a long ways off from being in the on the marketplace. This drug by Moon Lake is is certainly closer to the marketplace. But does anyone guess go ahead.

Oh yeah Nelly. I've got a question for you because I remember making a video back at ACR about the phase two of and one thing that I had particularly impressed me back then was the high very good response on anti scores which I was quite surprised about and I remember having a chat with some of the authors that were telling me, oh, that's because it's so small, it's going to go into the so much better, right? So, I was just curious to know, what were the, what was the response for anxiety scores? Was that, was that presented?

No, it was not presented at the EULAR.

Okay, so maybe it wasn't that good then. I don't know. We'll have to maybe. Be.

Nelly, they also presented the Tell us about the PROs in the study.

Yes, there was another presentation by Lorgo Szek. It was posted POS0428. So the endpoints were So the same study exactly, but the endpoints were the PROs, PSA, the patient assessment of arthritis pain, PGA, HACGI. And so across all I will not go into, like, the details, but across all these PROs, there was a significant improvement. And but this time, it was in line with what was what was found in the adalimumab arm.

So for the first outcome, it was a little bit superior. However, here, for PROs, it was almost similar. But there were very good improvement at week twelve, which continued until week twenty four.

So Nelly, when you're looking at data like this and you see all the usual primary endpoints, ACR20 or MDA and PASI scores, know, enthesitis, dactylitis, how much value do you as a clinician derive from PROs?

So, PROs are softer outcomes. However, sometimes, especially in PSA, where we have a lot of comorbidities like depression, obesity, which might also affect PROs, I think they have an added value. So first I would look at the harder outcomes. And then if it's similar, then the PROs might make a difference in my choice.

So does everyone believe that, as Nelly does, that it's icing on the cake, that PROs by themselves wouldn't be good enough, but if you add two good, primary outcomes, it's another feather in your cap. Any other considerations or beliefs about PROs?

I don't know that they're gonna drive me to pick a drug on the front end, but they are important because that's what is gonna make the patient stay on the drug. I mean, you know, regardless of all the so called hard outcomes that we focus on, if they have fewer swollen joints, they don't feel well, or they still have pain and fatigue and things that haven't been addressed, they're not going to stay on that drug, especially in a space where there's a lot of options. So, I think they are important.

But don't you think that they are interrelated? So for example, a patient who does have less swollen joints, less pain at night, will have eventually less fatigue and will be more happy with the drug.

Absolutely. But you got to cover all the bases though. The

famous rheumatoid arthritis researcher Ted Pincus spent most of his career teaching us about HAC, clearly a PRO. And that HAC is way more important than any measure we do in a clinical trial. It predicts outcomes better, both in the short run, but more importantly in the long run, especially with regard you know, the big things, death, surgery, hospitalization, money, and cost of care. I mean, so and that's a, you know, that's a PRO. And I I'm a I love HAC.

You can look at an eight question, 10 question hack, and know pretty much everything that's going on with a patient or at least what you're gonna have to talk about in that visit. So I again, I I do like to make minimize PROs, but I'm I when it comes down to it, we're all believers in in them. So let's move on. Eric, what's your big one that you want to present?

Well, I think we talked a little bit of X-ray previously, and I think we can talk about the APeX study, which was a really large study of guselkumab. So, the background on this is that when this drug was approved, the phase three clinical trials, they did not meet their radiographic endpoints at the time, at least with the commercial dose. They met it with the every four week dosing, which we can't get because it's not a labeled dose. But at every eight weeks, when this drug was given one hundred milligrams every eight weeks, it did not meet the radiographic endpoints. So, they set out to show that, in fact, this drug actually prevents structural damage at the approved dose that's used in clinical practice.

To do that, they did a really large study, ten twenty patients with active disease. They really enriched the population. They had to have at least two erosions and a high CRP just to get into the trial. And they were randomized to either one hundred milligrams every eight weeks, which is the approved dose, one hundred milligrams every four weeks, or placebo every four weeks. So that they were all getting injections every four weeks.

And the eight week dose got the usual loading dose that we do in clinical practice. Primary endpoint was ACR response, but the Sharpe score was a major secondary endpoint at twenty four weeks. These were pretty active patients. They had really active disease at baseline with over 20 tender joints on average, 12 swollen joints on average. They had erosions and a high Sharpe score at baseline.

And what the trial showed was, number one, they met their primary endpoint that both doses were better than placebo. Actually, both doses were equivalent, which is interesting because there was no difference. It wasn't powered to detect the difference, but boy, they really sounded the same at every time point through twenty four weeks, the numbers look the same, which suggests that eight week dosing may be adequate for just about everybody. I think people were thinking maybe every four weeks might be appropriate for some, and maybe there's individual patients where they didn't show that. And they didn't meet the radiographic endpoints.

So, at twenty four weeks, both the Q4 week and the Q8 week dosing, were statistically better than placebo, highly statistically better than placebo in terms of radiographic progression. The devil is in the progression that, you know, the two gazelkumab groups had a mean Sharpe score progression over twenty four weeks of just over 0.5 units, and the placebo arm had a progression of 1.35 units. What does that mean? You know, I think you have to be cautious about means. But when you think about it, that it takes somewhere around two or three sharp units for even a good radiologist to see the difference on an x-ray, that ain't much change.

Now, maybe over a lifetime, but nobody's going to leave patients on a drug for a lifetime just for that. And again, all of the change is in, you know, as usual, is in that sort of ten percent of people at the far end of the range. So, they got the structural, progression, and it and it worked. So they'll be able to get this into the label, and it'll be something that they can talk about and we can talk about. Is it gonna change the way we use this drug?

I don't know. I mean, what we're still missing is some sort of data that compares the clinical response with a guselkumab or any IL-twenty three inhibitor with an IL-seventeen inhibitor or a TNF inhibitor. We don't have that. And so until then, don't I know that this changes things, but at least we can feel confident that it does, prevent structural progression at the dose we use.

Eric, was there a difference in skin outcomes between the two doses and placebo?

Not that they spoke about, they didn't give all the details, but, roughly no. The challenge is that you got to be really careful about skin outcomes in a PSA trial because these are not patients with a lot of skin disease, and the ability to improve is a lot less than in a psoriasis trial where they come in with more skin disease. But we know better than placebo for sure. I don't know, but there wasn't a clear difference between the two doses.

But the strength of the twenty three inhibitors is gonna be in the Yeah, no, it worked. And then will the X-ray data now be their strength that they can tout with clinicians as to why you should probably be using a twenty three inhibitor and not a seventeen or a dual seventeen or a tick or a phosphodiesterase inhibitor. You know, the idea is that everyone's looking for an edge. Everyone's looking for something to talk about. And I think Eric's giving us a realistic view of the magnitude of change here is significant, but is it meaningful?

And in twenty four weeks, who knows? Orly, what do you think?

Yeah, I think for me, the question I had about this trial, I mean, I know we need placebo arms and all that, but really, we we we have peoples that already have an erosive disease and we're gonna give this six months of placebo. Are we are we all happy with that? I don't know. I wonder if, I mean, the outcome might have been different but I think that was the exact scenario where you would want an active arm, wouldn't you?

Yeah, and that's one of the problems of clinical trials these days, the ethics of it all. Jeeha, this is a trial not that dissimilar to the dukravacitinib trial. Which one impresses you?

I think I heard both. They're probably similar in terms of it doesn't really sway me one way or another, but I think the amount of effort that went into this study makes me wonder if they were looking really that closely at rostians. They were looking to look at like hand grip strength or functionality to give it more clinical meaningfulness to be able to interpret it. So I don't think I'm Now that I've heard the discussions and a little bit more time to think about it, I don't know, to be honest.

Well, this is just their first analysis, and certainly, they don't have a paper, in play here. I'll be just gonna see if that's what they, what they come up with. Nelly, any comments on the study?

Yes. I think that in these patients who are very heterogeneous, it's not this item only that will make you decide if you want to use interleukin twenty three or duclaventatinib or interleukin seventeen. It's the other phases of the disease, if they have also axial disease, if they have like Crohn's in the family, if they have risk for, I don't know, thrombosis, smokers, etcetera. So all of this will make you decide and not just these two points of progression on radiography. As long as you control the disease and you control it well, I think this is objective.

Yeah. I think those are important points.

I can add, Jack. I mean, I agree with Nelly. I think that radiographic change is kind of stable stakes at this point. It's not going to be a reason you pick a drug, but if you have an instinct to use one particular drug for whatever reason, you know, the particular domains or safety issues or convenience issues, then this at least gives you the comfort that you're preventing progression if you choose to use that drug. But I don't see it as a reason to pick this drug preferentially or any drug largely at this point.

All right, I'm going to challenge our faculty to give me, a two or three sentence synopsis of the next study that impressed them. We need to wrap up pretty quick here. So Orly, go ahead.

Right. So OP0090 combination of biologic and targeted synthetic VMAs in severe PSA patients. Case series. So, you know, no control group, no nothing but we all have a few patients like that in our practice. I certainly do and that makes me feel a bit better to see that the tolerance looked fine in this series.

No severe infections. Obviously it's twenty two patients so but yeah. I think it'd be great to have a kind of global registry of of these patients and up the numbers to feel a bit more comfortable because sometimes that's all we've got.

Yeah, a lot of people want to hear about combination. There are combination trials, well done trials being done that we'll hear about. In the meantime, we're left with anecdotalism. If they had three thousand two hundred patients that were anecdotal stories, maybe I would pay attention to this. 22 or 58, I don't know, means pretty much nothing to me because it's a reporting bias more more than anything else.

Doctor Lee, what what's your short one?

It's to listen to patients as we as clinicians look at efficacy to understand that patients are more concerned about safety issues because there was a poster, POS114, where they surveyed 200 patients to ask about medication non adherence. We know RA, historically, it's high. I would think I was surprised by this because psoriatic arthritis patient had higher non adherence, And one of the main cited reasons was the complexity of regimen, but concern for side effects. So I think we, as clinicians, often focus on efficacy, but we need to be able to better convey risk benefit ratios and trade offs for our patients. So just have them involved in the conversation, in studies and also guideline developments.

Was there any concrete takeaways from this adherence study about how we can be better at adherence in PSA?

It didn't get to the points about how patients want information translated, but I think that's an excellent question and one where there needs to be more explanation about what kind of decision aids or information packets. Is it better coming from a peer or caregiver? I think those are all things that we need to be more cognizant of when we develop these guidelines or how we practice.

Yeah. Eric, why don't you give us your final, short one?

Yeah, so EULAR presented their, assessment and recommendations for difficult to manage and treatment refractory PSA. And this is something we'll be doing in RA and in XBA as well. And GRAPA presented their assessment at the ACR meeting. And basically, somewhere around ten to twenty percent of patients are difficult to manage because they failed at least two targeted therapies and have ongoing disease or problematic managed disease. And within that, about a third of those have truly treatment refractory, where they have inflammatory disease that's not getting better.

The rest of them have central pain or challenges with tolerability or other issues. And I think Graft and Euler ended up at the same place. It gives us a way forward, although their terminology was different, and that's going to take some time to try to get an agreed on terminology for what we call these things.

So the bigger group was complex to manage and

It was complex to manage or, difficult to manage. So ULAR called it difficult to manage, GRABA called it complex to manage. GRABA had patient partners. They didn't like the word difficult in there because it implied that they were difficult patients, that they were difficult to work with. So they took it out.

So, but, you EULAR apparently had patient partners there as well, and they didn't have problems with the word. So that's it. And then the GRAPA group in a subset is difficult to treat. EULAR calls them treatment refractory. I think they're talking about the same people.

It's just they need to probably harmonize the terminology so that we can move forward and try to get recommendations for how to manage that.

What I don't like about this is that the bigger group, complex to manage, difficult to manage, can be up to thirty percent or so are patients. Right. The smaller group, the refractory ones, is a third of that, it's like less 10% or so. Right. And they, But the assumption is that more, excuse me, refractory group are the ones that have inflammation.

I think that that is not true at all. Because they are the more difficult patients and may fail more therapies. If they wanna have it so that one of the criteria is going to be inflammatory markers, right? Evidence of synovitis. I

think it is Jack though. I think that's what they're trying to do. I think that because the issue is those are the people where either changing to a new mechanism or a new drug may actually help. The other ones are people where there may be other issues and maybe adding something to treat central pain, adding cognitive behavioral therapy visit, you know, other things may actually be a better way to go than changing their primary, you know, medical treatment.

See the, but they're trying to do this as a Venn diagram, a big circle and then a circle inside that's smaller and that you can identify those people. And they're the ones get the expensive new drugs, and I don't think that that's true at all. What they did in RA is they just called it difficult to treat RA with a EULAR definition, failed two biologics or more, you know, agreement by the patient and doctor. And then after they made that decision, they came around to the smart decision of saying, you're either a Pira or a Nira. You either have non inflammatory refractory RA or persistent inflammatory RA.

And persistent inflammatories do have inflammatory markers, and you do give them biologics and inflammatory And the nearest are the obesity, fibromyalgia, depressions, and whatever. Again, that doesn't conform to the Venn diagram issue.

Well, it kind of does. I think they're trying to get to the same place. I think they just have to figure out what they're calling them.

I want to hear what Nelly and the rest of the group think of this construct.

So the idea of this is not really meant for us, for clinicians to use, it's more for research. So I think that what they want to say that they want identify people who are homogeneous, a homogeneous group that might benefit from more research in in this area. Because if you put inside the comorbidities, the fibromyalgia, the pain sensitization, and the inflammation, and you use a drug, you will not really have clear outcomes. Whether if you put, like, very similar patients, like those with inflammation, synovitis, high CRP, then you might be able to to reach more meaningful results in a clinical trial. This is how I see it, and this is maybe the rationale of grouping this small group together.

Jia, what do think, Jia?

Where I would like for it to see it go is with all these talk about precision medicine, AI, pharmacogenetics, is right now we're only identifying these patients after they've failed two to five medications, which takes years, and it results in damage accrual. So if there's some way through research or clinical practice we can identify them earlier on, it would be fantastic. I also like that we're now starting to really recognize that there are treatment refractory noninflammatory patients. I think that's really going to shape how we talk about conversations. Also lead to research about does treating multimorbidity related to RA improve response to treatment, improve outcomes?

So we're not practicing within the singularity of rheumatology, but I think one of the notable sessions was rheumatology meets hematology, rheumatology meets cardiovascular. So there's more cross disciplinary pollination and understanding of how to coordinate care. I think that's where the future rheumatology and outcome improvement can be achieved from.

Orly, what's your perspective?

Yeah, actually I've interviewed Stefan Siebert, and we've quite talked about that quite a lot. He was the co convener of the EULA definition. But what we were discussing a lot is stratification and so that goes back to the Pira and the Nira and that's that's how important that is. Because then when we're gonna propose trials we wanna be able to propose adapt trials with intervention that probably won't be not non pharmacological in in the in the in the Nira people, you know, mainly and and how we wanna make sure we make that that happen in a way that targets the right people into that huge big group of difficult to treat.

Eric, make sense of all this for us as we close out.

Yeah, I think, Jack, nobody's saying that the people who don't have inflammatory disease aren't important. I think that's really important, but you've got to know what the issue is. And rheumatologists, even clinical practice, need to address that because those are the people that need duloxetine or some other treatment for their central pain. They need a GLP-one for weight loss. They need things that we don't necessarily always do, but need to start doing, cause we're so focused on the inflammatory piece of disease.

So I think it's both groups that are really important for us to recognize and address in practice.

I wanna thank our faculty for such hard work last week in Barcelona and for a great overview of highlights from the meeting. For those of you out there, there are other topic panels. We have one on RA and also one on SPA. Look for those as either a video or a podcast. Take care, everyone.

Thanks, Jack.

I'm Anthony Chan reporting from EULA twenty twenty five in Barcelona. And here at EULA twenty twenty five, we have seen some interesting posters and abstracts in spondyloarthritis and one that I came across which I was interested is poster two fifty seven and this looking at instruments to assess peripheral arthritis in spondyloarthritis and this was presented by Doctor. Daphne Kapiluznik from Tel Aviv, Israel. I'm very happy that she can actually join us here today to talk about the poster and the abstract. So Daphne, welcome and wonder whether you can tell us a little bit about your poster.

Thank you, thank you very much for the invitation and for your interest in our job. So the idea of this project was to assess different instruments, assess disease activity due to peripheral arthritis. Actually, one of the main objectives of the ASAS PERSPA study, which is a cross sectional linked multinational study, was to assess the comedic properties of disease activity scores, and even though there are a lot of ancillary analysis from this study, we had never assessed this, we had never approached these objectives. So the idea was to look in this case, since it is a cross sectional study, to assess the construct validity of different instruments to assess disease activity due to peripheral arthritis and not focusing only in, for example, azacitidine, are the usual instruments we use in axial spondyloarthritis, but also some other scores from psoriatic arthritis or for rheumatoid arthritis like the DAPSA or DAS28 or 44. So what we did was to assess the construct validity in this case, we did that according to recommendations from OMRAP through the assessment of the hypothesis of correlations of strengths and also to see the ability to discriminate between two different known groups.

And what we found with our results were that even though all the scores had have a good construct validity, apparently, the discrimination between non groups is higher in those composite scores including joint counts. So for example, the DAFSA or the DAS 28 or 44. So of course we need more, some extra analysis and that is, this is the first step for the future projects. For example, now we are, there is an ongoing project from ASAS, the ASAS Paradise Project, where we are aiming to look to assess all the psychometric properties, not only the construct validity, but also discrimination in clinical trials and sensitivity to change or longitudinal construct validity to finally see which is the best instrument and maybe to recommend to start using at least in clinical trials, then we will see in clinical practice, but at least in clinical trials, what should we use to assess correctly the peripheral arthritis as a manifestation of the disease. This will be, it's important to mention also, this will be mainly for axial spondyloarthritis and peripheral spondyloarthritis.

We are not interested in assessing nothing in psoriatic arthritis, which we already have a lot of recommendations. So this will be based in axial spondyloarthritis and peripheral spondyloarthritis.

That is a very impactful and quite important. Certainly in my clinical practice, up to twenty five, thirty percent of our XPAR patients may have some peripheral arthritis and I think the literature also supports that. And with a great drive to do S Test, I wonder how many of these patients that we probably miss some of the assessments because we are not assessing the peripheral arthritis. But yet, as you say, there is no validated instrument if you like to assess these patients. So I think it's a really important study.

You did have some PSA patients I think in your study. And how does that fit with the results and the assessment? Because I noticed there was also dApps being used in the study.

Good that you mentioned the cohort includes the ACES first plaque that includes patient with axial spondyloarthritis, peripheral spondyloarthritis and psoriatic arthritis. So we did the entire analysis in the entire population, so including all diagnosis, and then we repeated separately in each one of the phenotypes and the results were the same. Again, the composite scores, including joint count were the best, they're the one best performing for discriminating between non groups. So even of course in psoriatic arthritis, but the results were the same also in actual spondyloarthritis and in peripheral spondyloarthritis.

It looks like the scores where there were joint counts, DAS28, DAPSA, they perform better in the performance and that's 44 as well. One of the things that I think you were looking at standard mean differences, SMDs of 0.8 as your cutoff. Were you surprised that CRP didn't come out as strongly in that? Yeah.

Only only did it in in the actual spondyloarthritis group, but yeah. And psoriatic arthritis and peripheral spondyloarthritis was it it did it had it it didn't show a good discrimination between non groups. It was also a surprise for us.

Yeah because we always like to think that if you got peripheral arthritis like a swollen knee or ankle, your CRP would be high and if you have it more than the axial up to 50% can be normal. But I think in this study it probably shows that it not as sensitive as we may think. But we of course will have to see future studies. Of course. That's very interesting.

So what would be your sort of next step for this instance? How would you kind of narrow this down to, you know, a more specific assessment tool?

So like I was mentioning, the asset paradigm project, it has already started. So we are what we are doing is we want to look in the literature whether there is data in observational studies or in different cohort studies. Of course, we will have data for ASDAS or VASDAS, we will have less data for DABSa or DAS in patients with spondyloarthritis, so the idea was also to analyze them, so are, one of the plans we have is to ask for the randomized controlled trials data as much as possible randomized controlled trials and to calculate the DAFSA for all the all the scores, but also the DAFSA for the DAFSA and the DAS in some of the versions. Another point, interesting point is that the DAPSA is usually calculated with the swollen joint count 66 and tender joint count 68, and usually trials in next response arthritis only have this the joint count of 44. So I also present in the in this EULAR an abstract of the the development and validity of the DAXA 44.

It was mainly developed to be used in this project, so we will be able also in randomized controlled trials to calculate this DAPSA 44 to see how is the performance. Of course, if there is some trials where the 66 or 68 joint count is available, we will use the original data, but in case we can, we will have that option to do it. And we will calculate, as I said, also the discrimination in clinical trials and also the sensitivity to change, which was not possible in this study.

That will be really useful. Of course, you've got 28, you've got 44 then you've got 68. So, in terms of the assessments, I think the message is for now until we get a validated score is to do one of at least one of them. It's better to assess the peripheral arthritis compared to what we are doing right at the moment. In your study of sixty one percent were males and you had about four thousand more patients.

We always like to think that peripheral arthritis is more female than male in terms of their phenotype. Do we think this is because it's historical and maybe in those times we didn't look as out for them as much?

Yes, it can be that because in this, in the ASSA PERSPAL study, there are also a lot of patients with axial spondyloarthritis with peripheral manifestation, some of them, but if we see the percentage of patients in each one of the phenotype groups, they are mainly axial spondyloarthritis patients.

Yeah, so it's context of axial spondyloarthritis with peripheral symptoms, yeah. That's very interesting and so, you know, that's a very nice presentation and we obviously look forward to your future work and how we can use this in the clinic. I thought this was a very practical presentation. This is why I wanted to discuss this because I think it's useful in clinic for us. So Daphne, thanks very much for your time for presenting We this look forward to for future meetings to see how this develops further.

Thank you.

Yes, thank you. Bye bye. Bye.

Hi everyone, Peter Nash from Griffith University, beautiful downtown Brisbane, reporting for RheumNow at ULA Barcelona twenty twenty five. Let's talk about the novel agents that were presented in the I 17 class at this meeting. There were four of them. Just when you thought the three that you had was all that you needed. The Chinese colleagues presented two of vunekizumab and zaligakimab.

They were IL-seventy nine inhibitors, they were parenteral and guess what, they worked like an IL-17A agent, though had the same safety as an IL-17A agent and they, seem to work both in PSA and AC XBA as you would expect. The two other agents that are interesting, Sonelocumab, if you can say these drug names you're ahead of the pack, is interesting because it's a nanobody 17A and 17F binds to albumin, supposed to have superior soft tissue penetration and the numbers are really quite good for a phase two study as they usually are. They had an active comparator with adalimumab in their trial and they were getting MDAs when they compared their doses sixty milligrams, one hundred and twenty milligrams compared to the active comparator adalimumab. They were getting numbers of the MDA in the fifty to sixty percent range, which is a little higher than the normal thirty five forty percent that we get in the phase three trials. Of course, the ACR seventy and PASI 100 was quite significant in the higher dose in the forty eight percent range driven mainly by the skin responses you'd expect compared to the eighteen to nineteen percent seen with adalimumab and again the ACR seventy was very impressive in the forty percent range and the PASI one hundred you now expect a 100% clearing of skin with these agents was in the 60% range.

So, numbers are impressive safety no new signals. The MOA is supposed to be an advantage. They're going into Phase three and we'll see if the superior numbers as you often see in Phase two holds up in Phase three. The other agent that was very interesting was this agent ORCA-two, doesn't seem to have a difficult to pronounce name at this stage. Now this agent, they fiddled four amino acids in the hinge region, cut off the FC, pegylated it and gave it to, synomologous monkeys and they extended the half life after four to six months and they're aiming to use this IL-17AF monoclonal antibody to be a twice a year injection, if it stacks up, there weren't much in the way of clinical details, but if it stacks up efficacy and safety wise, what an advantage to have a twice a year injection unless of course you get something like IBD or terrible Candida when something that hangs around for six months might not be such a good idea.

So, new agents, two that look like me too's, another nanobody and one long acting agent that might be interesting. Thanks. Hi everyone, Professor Peter, National Griffith University, beautiful downtown Brisbane reporting for RheumNow, EULA Barcelona twenty twenty five. There's a whole series of, the three year long term extension data with bimekizumab. They had, follow ups on their B Mobile one and two, which is non radiographic or radiographic XPA trials.

They had the follow-up on complete and optimal, which is the B DMARD naive and TNFIR trials in PSA. The bottom line is that the stuff continues to work, continue to have the same safety signals, nothing new and exciting, continue to, show efficacy in, males and females at fifty two weeks, although males are a little ahead sixteen weeks, continue to work through all the PROs exactly as you expect and exactly like all the other 17 inhibitors. What was interesting was the incidence of uveitis, which was considered to be lower than expected. All patients, had something like eight forty eight patients in pooled phase 2b and three trials, two thousand five hundred and fourteen patient years of follow-up, then one hundred and thirty patients with a history of uveitis and seven eighteen patients without a history of uveitis. And if you had no uveitis previously, the rate they found was zero point six per one hundred patient years, which is quite low.

Patients with a history, very wide confidence intervals 4.8 per one hundred years, and overall 1.3 per 100 patient years for all patients. So a low rate, and the question they raised was whether blocking F has an important role in uveitis, and it might even be a treatment. They might have to do a formal study to answer that question, as the other seven inhibitors, particularly secukinumab, did a formal study and was unhelpful. That's why I asked McGinnis who presented the CernelIqumab ANF nanobody if they saw any uveitis in the studies published to twenty four weeks with really reasonably small numbers and he was unable to comment as they didn't see any uveitis. But he did make the point that it's too early to make any claims for either of the 17 ANF inhibitors as far as uveitis is concerned.

Thanking you. Hi everyone, Professor Peter Nash from Griffith University, beautiful downtown Brisbane, reporting for RheumNow. Ula Vasalone 2025. I thought I'd just go over a couple of the old presentations, AA92 and AA93. You've heard a lot about treat to target and the STAMP study.

They showed the twelve week data previously, but this is the forty eight week data. And really, they're comparing cicukinumab, three hundred milligrams monthly from day one with methotrexate fifty milligrams a week and one injection eighty milligrams of triamcinolone with conventional agents therapy standard of care like methotrexate twenty five milligram a week and the triamcinolone injection. By the end of, three months, something like four times as many patients had to escalate for the methotrexate at another, drug in this instance, sofosalazine was mandated compared with the patients continuing on the methotrexate seventeen inhibitor. And then after another three months, you had something like four times as many patients escalate from the conventional agents onto a TNF with methotrexate compared to the secukinumab onto a TNF with methotrexate. If you just look at the numbers overall, there was initial benefit of secukinumab speed of onset of ACR twenty, fifty, 70, but by the end of twelve months, those two lines of treatment had come together because a significantly greater number of patients had escalated to a biologic from the conventional agents.

The skin was superior, enthesitis was superior with the biologic from day one. So, it looks like, you can catch up over time. The patients aren't as well as quickly, but, a lot of patients had to escalate onto a biologic something like twenty seven out of sixty from the conventional group and of course the begin the patients agents begin to secukinumab straight away. Something like twenty three out of sixty wound up on a TNF instead of the IL-seventeen inhibitor. The other little presentation, small numbers followed for a reasonably short period of time, but there was lots of guideline type presentations defining difficult to treat PSA.

That is, failed a couple of biologic and advanced therapies but with objective evidence of inflammation either on imaging or, on acute phase reactants compared to those patients who are complex to manage who have no objective evidence of inflammation, either imaging or in bloods, but who have lots of ongoing widespread pain for a number of other reasons such as osteoarthritis damage, fibromyalgia, etc. The implication really is that if you can identify the predictors for difficult to treat, then perhaps combination therapy might be considered early and then you can get control and reduce to a maintenance treatment choice. At the moment, we're doing that with a small number of very difficult patients, but usually get the derms or the gastros to write one drug and we'll write the other. But this small study looked at a number of patients in a case series who had, taken combinations for a variety of reasons, usually flaring skin on someone stable on joints or patients stable on skin but flaring joints. And they looked to see which ones were the safest.

And it looks like there wasn't too much in the way of a safety penalty. There were some mild infections, no one needed hospitalisation and no one needed to stop their drug as a result of infection. They were able to combine TNF with seventeen, TNF with twenty three, TNF with ducravacitinibTIC-two and Primalast. They were able to combine JAK with those agents as well. I wouldn't be combining a TNF and a JAK, I think that's asking for infection, but the seventeen twenty three ducravacitinibs and Apremilast seem to have no safety penalty when used in combination with agents like the TNFs or the JAK inhibitors.

I'm sure we'll increase the use of combinations over time. Formal studies will be very difficult. Registry should be able to help. Case series of bigger numbers in patients with lots of comorbidities that would never make it into a clinical trial followed for long periods of time will be very instructive moving forward. And then strategy studies with combinations inducing remission and reducing therapy to maintenance will also be very helpful.

So thanks again for your attention.

Hello, everyone. This is Bella Mehta reporting for RheumNow from Euler in Barcelona. I'm excited to find this study, which is trying to use PET or CT scans to visualize inflammation in real time in rheumatoid arthritis patients. The poster number or the session number is 0P, oral presentation, 0348. And as many of you know that in rheumatoid arthritis, it's very critical to know how much inflammation does a patient have and to consistently define what area you're looking at or measuring, especially in large or complex joints.

You know, mostly, we do all of this clinically with physical exam, but there's newer techniques with ultrasounds and also PET or CT imaging. Well, I don't know how expensive or if you want all patients to go through this, but this was an interesting study showing what you can do and how to measure or standardize these sort of newer tools as they come across and as their cost decreases or as the exposure decreases for patients. So what the study did was, looked at PET and CT scans for patients and defined and had two approaches to define volume of interest or the area of interest where, you know, multiarticular joints are seen on PET CT, which was one was the fixed sized VOI where, essentially, spherical size adjusted zones are placed consistently across the same joints in the same positions. And then the second thing, is manual delineation, which a lot of people have done in the past, which is much more detailed, customized, but, you know, needed some time and also user expertise to do that. So 20 RA patients with moderate disease activity underwent a whole jaw whole body macrophage targeted PET CT scan before and after TNF treatment.

And then researchers compared the SUV peak or the measure of the tracer up uptake across both VOI methods, which was fixed size or manual deviation. And then they looked at time points and assessed, you know, reproducibility between observers and bit between, like, inter and intra observer reproducibility. And here's what they found, that most most methods produced highly correlated SUV values, especially in the wrists, knees, and ankles, with r square values which which were over point nine. And even more complex joints such as shoulders, hips, the core limitations remained pretty strong. But what they realized is just fixed size VOI, so basically using the same thing in all the patients' fixed volumes of interest, significantly were more reproducible.

So it was 78% versus for manual, it was 63%. That way, what it means is that just standardizing the process in these sort of newer technologies such as fixed fixed size VOI, is robust. It's standardized, and it's an efficient way to quantify this inflammation, when there's a dearth of musculoskeletal radiologists sometimes who are specialized doing this sort of grading for patients with rheumatoid arthritis. And this this is also good for scale too when we wanna use this technology, for example, for many patients, making it usable not only for research but also clinical standardization. Again, the point being that we're using these technologies not every day in clinic because it's a lot of time, cost, and a lot of things involved with this, but this is a technique for using or validating, say, certain therapies.

This would be, like, a definite way to see inflammation, quantify it, and scale it over time if possible. They also suggest that they would be automating this with an AI driven delineation, and that would be interesting because then, you know, these sort of pop up centers can come in, and I have seen these conceptual presentations come up in EULAR and other places where patients can go in, get the CT, and self monitor their disease activity. I am not sure if I'm all in for patients doing that all the time, but it's futuristic. It's important for we as rheumatologists to see and keep an eye on what's happening. And this is definitely something that caught my eye.

Let me know if you would send patients like this for PET CTs, but it's a comprehensive tool. Definitely, we will see some more talk about it in the next few years, at least in research settings, to prove or disprove theories or or medications. And for more of these, do follow me at Bella underscore Mehta on Twitter and RheumNow for more updates.

Thank you.