Eular 2025 PsA Topic Panel Save
Eular 2025 PsA Topic Panel by Dr. Cush
Transcription
You're listening to a RheumNow podcast coming to you from Barcelona, Spain, and you are 2025. Hope you enjoy it.
This coverage is sponsored by Johnson and Johnson, the organization that believes health is everything.
Hello, everyone. Welcome to our panel review on psoriatic arthritis from ULAR twenty '25. 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 Zadeh from Beirut, Lebanon.
And Eric. I'm Eric Ruderman from Northwestern in Chicago.
Excellent. All right, so let's get into it. Orly, what's your lead off the program here?
Yeah. So I wanted to talk to you guys about the oral presentation 89 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, HAC over one or erosions at diagnosis. And so what they did is they randomized them to 100 people in either a standard kind of conventional synthetic DMARD and then step up or a combination of conventional synthetic demar straight away.
So either metatrix that ounce of facilities in all the flunomides. And an arm that had TNF and methotrexate. So they had aluminum 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 demons or the TNF.
They had a better reduction of the past DAS 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 48 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 actually not particularly bad. I mean, the same things that we see with TNS regardless 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 I, 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. And so that's troublesome because, you know, 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 better.
Yeah, 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, 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 slow down a bit, then you can maybe go back. I mean, we'd have to see longer term, but I think the forty eight weeks outcome was quite interesting in that matter.
Sitha, is there another way to think about this?
Well, don't know if that's what Rimmand said. Think a contract to RA where they're finding this concept of the window opportunity and more aggressive at the beginning, that with TSA maybe, depending on the presentation, that doesn't hold true is kind of 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 going to 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, that that first intervention, you know, 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 that 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'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, in its design. And then that's not really wrong. It's just that there's a limitation to what you're going to get out of it. Let's go on to the next one.
Doctor Lee.
Yeah, think that kind of my one I'm going to talk about kind of goes along that. And I think definitely a lot of quotes that 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 talk, the rising star potential new treatment was the selective TYK2 inhibitor, ducrivastatin. So the study I'm going to present is a late breaking OPSTEA 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 50% 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, ducurbicitinib did better.
I think one of the benefits and the draw of the TYK2 is that it's more selective. Theoretically, compared to the JAK inhibitors that also hit a lot of the domains of psoriatic arthritis, there should be less side effects. Even though this was just a sixteen week report out of the 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 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 that 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. I think the primary outcome measure mostly should be based on clinical response. 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, lets them 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, let me ask others what they thought of the X-ray data. Were they like it or not like it? Nelly, Orly?
It is justified to use a nonparametric tests 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 X-ray 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 aprimolast 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 trial right now at twelve weeks. 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 these 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.
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 a premilast, 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 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 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 sunilokumab. 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 the 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. Soneirochumab sixty milligram, no induction, sixty milligram, one hundred twenty milligram. 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, when they pulled the different active arms, more than fifty percent achieved MDA across key subgroups like female patient, obesity, high CRP, high PASI, etcetera.
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, so it's hard to achieve, was observed across all active group with high rates, so more than thirty seven percent. And regarding the skin, sixty three percent of patients achieved complete skin clearance, fifty percent was 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, five, ten percent minimum. Yeah.
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 not normally not achieved. So again, how else can we explain?
Is this drug really that good? Eric, what do think?
I suspect it won't be. I mean, I think we'll find out when they do a larger trial. You know, this is phase two. You never really know from phase two. I think it's going to end up being another IL-seventeen inhibitor, and it's not going to 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 going to 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, 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 going to 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.
Well, they
never are. 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 Jack, 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
depends on whether you're an optimist 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 kind of good. That was a unique construct and whatnot. It's a long ways off from being on the marketplace.
This drug by Moon Lake is certainly closer to the marketplace. Yes, 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 solokinumab and one thing that I had particularly impressed me back then was the high very good response on anxiety 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 was the response for the anxiety scores? Was that presented?
No, it was not presented at the cellular.
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 Seck. It was posted POS0428. So the endpoints were so the same study exactly, but the endpoints were the p r 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 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 24.
So Nelly, when you're looking at data like this, and you see all the usual primary endpoints, ACR twenty or MDA, and PASI scores, know, antisidus 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. Anyway, 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, regardless of all the so called hard outcomes that we focus on, if they have fewer swollen joints, but 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 the 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 then 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 to 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 hack.
You can look at an eight question, 10 question hack and know pretty much everything that's going on with the 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 APEC 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.
And 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 sharps growth 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 a, 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 works. 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 going to 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, I don't 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. The ability to improve is a lot less than in a psoriasis trial where they come in with more skin disease.
And but we know better
than placebo for sure. Don't know that but there wasn't a clear difference between the two doses.
But the strength of the twenty three inhibitors is going to be in the skin. No, it worked. Then will the X-ray data now be the 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 have people that already have an erosive disease and we're gonna give this six months of placebo. 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 ducravacitinib trial. Which one impresses you?
I think having 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 roceans. They ever think 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 what they they come up with. Nelly, any comments on the study?
Yeah. So 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 the geography. 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, agree with Nelly. I think that radiographic change is kind of table 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, 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 gonna 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 VMADs in severe PSA patients, case series. So 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 than anything else.
Doctor Lee, 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 POS 01/2014 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 a 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're 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 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. So it gives us a way forward, although their terminology was different, and that's gonna 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. Grapa called it complex to manage. Grapa 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. But, you know, EULAR apparently had patient partners there as well, and they didn't have problems with the work. 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 them.
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. The smaller group, the refractory ones is a third of that. It's like less ten percent or so. But the assumption is that more, excuse me, refractory group are the ones that have inflammation. And 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. 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, 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 meds and then and the nearest are the obesity, fibromyalgia, depressions, and whatever.
Again, that doesn't conform to the 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 to 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 very similar patients, like those with inflammation, synovitis, high CRP, then you might be able 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 you think, Jia?
Where I would like for it to see it go is with all these talk about precision medicine, AI, pharmacogenetics, right now we're only identifying these patients after they 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 means 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.
Arly, what's your perspective?
Actually I've interviewed Stefan Siebert and we've talked about that quite a lot. He was the co convener of the EULA definition. But what we were discussing a lot is stratification. 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 adaptive trials with intervention that probably won't be not non pharmacological in the NIRA people mainly. And then how we want to make sure we make 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 because 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 want to 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.
This coverage was brought to you by our EULAR sponsor, Johnson and Johnson. Check out their new data this week on the first and only IL-twenty three inhibitor proven to significantly inhibit progression of joint structural damage in active psoriatic arthritis by visiting RheumNow's virtual poster hall at rheumnow.com.
This coverage is sponsored by Johnson and Johnson, the organization that believes health is everything.
Hello, everyone. Welcome to our panel review on psoriatic arthritis from ULAR twenty '25. 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 Zadeh from Beirut, Lebanon.
And Eric. I'm Eric Ruderman from Northwestern in Chicago.
Excellent. All right, so let's get into it. Orly, what's your lead off the program here?
Yeah. So I wanted to talk to you guys about the oral presentation 89 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, HAC over one or erosions at diagnosis. And so what they did is they randomized them to 100 people in either a standard kind of conventional synthetic DMARD and then step up or a combination of conventional synthetic demar straight away.
So either metatrix that ounce of facilities in all the flunomides. And an arm that had TNF and methotrexate. So they had aluminum 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 demons or the TNF.
They had a better reduction of the past DAS 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 48 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 actually not particularly bad. I mean, the same things that we see with TNS regardless 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 I, 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. And so that's troublesome because, you know, 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 better.
Yeah, 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, 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 slow down a bit, then you can maybe go back. I mean, we'd have to see longer term, but I think the forty eight weeks outcome was quite interesting in that matter.
Sitha, is there another way to think about this?
Well, don't know if that's what Rimmand said. Think a contract to RA where they're finding this concept of the window opportunity and more aggressive at the beginning, that with TSA maybe, depending on the presentation, that doesn't hold true is kind of 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 going to 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, that that first intervention, you know, 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 that 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'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, in its design. And then that's not really wrong. It's just that there's a limitation to what you're going to get out of it. Let's go on to the next one.
Doctor Lee.
Yeah, think that kind of my one I'm going to talk about kind of goes along that. And I think definitely a lot of quotes that 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 talk, the rising star potential new treatment was the selective TYK2 inhibitor, ducrivastatin. So the study I'm going to present is a late breaking OPSTEA 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 50% 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, ducurbicitinib did better.
I think one of the benefits and the draw of the TYK2 is that it's more selective. Theoretically, compared to the JAK inhibitors that also hit a lot of the domains of psoriatic arthritis, there should be less side effects. Even though this was just a sixteen week report out of the 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 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 that 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. I think the primary outcome measure mostly should be based on clinical response. 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, lets them 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, let me ask others what they thought of the X-ray data. Were they like it or not like it? Nelly, Orly?
It is justified to use a nonparametric tests 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 X-ray 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 aprimolast 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 trial right now at twelve weeks. 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 these 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.
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 a premilast, 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 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 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 sunilokumab. 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 the 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. Soneirochumab sixty milligram, no induction, sixty milligram, one hundred twenty milligram. 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, when they pulled the different active arms, more than fifty percent achieved MDA across key subgroups like female patient, obesity, high CRP, high PASI, etcetera.
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, so it's hard to achieve, was observed across all active group with high rates, so more than thirty seven percent. And regarding the skin, sixty three percent of patients achieved complete skin clearance, fifty percent was 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, five, ten percent minimum. Yeah.
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 not normally not achieved. So again, how else can we explain?
Is this drug really that good? Eric, what do think?
I suspect it won't be. I mean, I think we'll find out when they do a larger trial. You know, this is phase two. You never really know from phase two. I think it's going to end up being another IL-seventeen inhibitor, and it's not going to 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 going to 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, 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 going to 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.
Well, they
never are. 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 Jack, 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
depends on whether you're an optimist 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 kind of good. That was a unique construct and whatnot. It's a long ways off from being on the marketplace.
This drug by Moon Lake is certainly closer to the marketplace. Yes, 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 solokinumab and one thing that I had particularly impressed me back then was the high very good response on anxiety 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 was the response for the anxiety scores? Was that presented?
No, it was not presented at the cellular.
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 Seck. It was posted POS0428. So the endpoints were so the same study exactly, but the endpoints were the p r 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 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 24.
So Nelly, when you're looking at data like this, and you see all the usual primary endpoints, ACR twenty or MDA, and PASI scores, know, antisidus 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. Anyway, 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, regardless of all the so called hard outcomes that we focus on, if they have fewer swollen joints, but 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 the 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 then 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 to 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 hack.
You can look at an eight question, 10 question hack and know pretty much everything that's going on with the 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 APEC 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.
And 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 sharps growth 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 a, 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 works. 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 going to 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, I don't 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. The ability to improve is a lot less than in a psoriasis trial where they come in with more skin disease.
And but we know better
than placebo for sure. Don't know that but there wasn't a clear difference between the two doses.
But the strength of the twenty three inhibitors is going to be in the skin. No, it worked. Then will the X-ray data now be the 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 have people that already have an erosive disease and we're gonna give this six months of placebo. 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 ducravacitinib trial. Which one impresses you?
I think having 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 roceans. They ever think 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 what they they come up with. Nelly, any comments on the study?
Yeah. So 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 the geography. 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, agree with Nelly. I think that radiographic change is kind of table 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, 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 gonna 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 VMADs in severe PSA patients, case series. So 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 than anything else.
Doctor Lee, 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 POS 01/2014 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 a 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're 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 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. So it gives us a way forward, although their terminology was different, and that's gonna 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. Grapa called it complex to manage. Grapa 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. But, you know, EULAR apparently had patient partners there as well, and they didn't have problems with the work. 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 them.
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. The smaller group, the refractory ones is a third of that. It's like less ten percent or so. But the assumption is that more, excuse me, refractory group are the ones that have inflammation. And 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. 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, 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 meds and then and the nearest are the obesity, fibromyalgia, depressions, and whatever.
Again, that doesn't conform to the 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 to 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 very similar patients, like those with inflammation, synovitis, high CRP, then you might be able 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 you think, Jia?
Where I would like for it to see it go is with all these talk about precision medicine, AI, pharmacogenetics, right now we're only identifying these patients after they 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 means 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.
Arly, what's your perspective?
Actually I've interviewed Stefan Siebert and we've talked about that quite a lot. He was the co convener of the EULA definition. But what we were discussing a lot is stratification. 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 adaptive trials with intervention that probably won't be not non pharmacological in the NIRA people mainly. And then how we want to make sure we make 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 because 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 want to 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.
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