Tuesday Nite Rheumatology (on 11.11.25) Save

This podcast is a preview of the great lectures and speakers you'll hear at RoomNow live twenty twenty six, February in Dallas, Texas. You can register at roomnow.live. In this podcast, you'll hear some of the speakers and lectures from RoomNow Live 2025, specifically on RA, PSA, SPA, and vasculitis. Hope you enjoy it.

Hello, everyone. Welcome to Tuesday night rheumatology. Tonight on TNR, we're going to do a replay of RoomNow Live 2025. RoomNow Live took place in February 2025 in Dallas, We're going to do it again next February 2026, again at the Westin Hotel in Dallas. You can be there or you can be online.

In tonight's replay, we're going to do the session or pod on psoriatic arthritis. Three great speakers, all devoted to the topic of psoriatic arthritis. This session was sponsored by AbbVie. Many thanks to AbbVie for their support of RheumNow Live. Tonight, we're going to give you three excerpts and a taste of what that session was like.

If you want more and the whole lectures, including the panel discussion at the end, you can go to roomnow.live and purchase that and sign up and get full access to all the lectures or just the PSA lectures. If you do, either sign up for RoomNow Live 2025 or better sign up for RoomNow Live 2026, you're going to get board questions, review questions from 2024, 2025 and 2026. That's my promise to you. Tonight, our program has three speakers, Alexis Ogby, Arty Kavanaugh, and Ken Gordon. Our speakers are going to talk about, can we prevent PSA?

Can we use biologic therapies in PSA? And what do the head to head trials tell us about PSA? Again, I want to remind you to go to roomnow.live to register for our great meeting February. It is Super Bowl weekend. You'll be home in time for the Super Bowl.

Everyone that came was home in time for the Super Bowl. It's a great weekend to travel. The weather is usually good in Dallas. Roomnow.live to register. Our first speaker is going to be Doctor.

Alexis Ogde. Alexis is an Associate Professor of Medicine Epidemiology. She's Director of the SPA and PSA program there. We asked her to address this issue, which is a burning issue in dermatology and rheumatology, and that is if you treat psoriatic arthritis aggressively, can you in fact prevent psoriatic arthritis, no, let's go back. If you treat psoriasis aggressively, can you prevent psoriatic arthritis from happening?

Let's hear what she has to say.

So we know that's the case. And often that needs to be the rheumatologist. So dermatologists don't often put that code in. They'll wait for the rheumatologist to see them and say, yep, this is PSA. But to do that you've got to get into a rheumatologist.

And given that we're all rheumatologists sitting in this room, we know how hard that is. So as we talk through some of the available studies, there's now 10 studies, actually one just published that Jack just sent me the other day. But there's 10 studies examining whether treatment of psoriasis is associated with development of PSA. So this is one list of those. Now as we think about this, these are some tough studies to do.

We really want that randomized control trial and I'm going to end with that. But what we have to date is just observational study. We have millions of patients with psoriasis in The United States, many of them being treated. So can we use observational data to understand this? Well if you think about the risk for PSA, or the incidence of PSA in the patient population that doesn't have PSA, it's actually quite low.

It's only about three point five, or somewhere between one and three percent per year of patients with psoriasis are going to develop a new diagnosis of PSA. So relatively uncommon. That means you need very large populations of patients to study this. So then also if we just look at observational data for face value, what is the risk in these different populations of patients who are not on therapy versus on therapy? So this is in one of our studies from Myr et al.

Published in the Annals of Rheumatic Disease. We found that among patients on no therapy, the one thousand patient years was five. For patients on a biologic therapy, was seventy seven. So it was a big difference because again, those patients who have mild disease aren't really ever going to get the therapy for psoriasis. Also, you're not really observing them as much.

So a lot of these patients come and go, they may be mostly treated by their primary care doctor, not seeing the dermatologist. So we might not be following them as much. Then when you look at the different therapies, there's a different incidence for development of PSA. For a TNF inhibitor, it's about eighty three out of every one thousand patient years. For an IL-seventeen, it's seventy eight.

For a twelve-twenty three it was forty seven. So lower incidence in that group. So why might that be? This is all comers, this is not adjusted, we haven't thought about anything, about any of the other different confounders and how they might play a role. But one thing is that if you have a patient in your dermatology office who has psoriasis and joint symptoms and you think they have PSA, you might say, you know what, we're going to treat your psoriasis, but we're also going to pick a drug that we know is going to be effective for psoriatic arthritis, if in fact that's what you have.

In the meantime, let's get you an appointment for a rheumatologist and you'll see them in the next six to eight months. And then you'll maybe get a diagnosis. But in the meantime, let's get this therapy started. And TNFs and IL-17s are kind of the gold standards, especially when we were doing this analysis about five years ago for development of PSA. So that may be one reason we're seeing a difference.

That's called channeling bias. And in fact when we looked at these different therapy groups, what we found was that if you look at the people who developed PSA, among those who were on a biologic therapy or an oral therapy, they got their diagnosis for PSA within that first year in most cases. So it kind of suggests that that was going on. So they saw the dermatologist, they got their prescription, and then they eventually saw the rheumatologist and got the diagnosis. So we wouldn't say that the biologic therapy in this case caused the diagnosis of psoriatic arthritis, but it was a precursor to.

So I'm showing you all these things to show you how tough it is to do these kinds of studies in existing data. There's a lot of different challenges in using observational data to address these. Joe Marrolin and I wrote a review article on Nature Reviews Rheumatology just to kind of think about all these different biases. And the two key ones are confounding by indication, meaning that we only, you prescribe therapies for a reason. And most of the time we don't document that reason.

If my patient is a smoker and has high cardiovascular risk, I'm probably not going to put that person on a JAK inhibitor. I'm going to put them on a different therapy, for example. And so there's confounding by indication there and it's not going to be obvious from the notes why I did that. And then protopathic bias is, I think the patient has this diagnosis, I'm going to treat them for it. And then we'll follow-up later and see what happens and then the diagnosis follows.

So that's exactly what I just showed you in those previous curves. There's a variety of other things too, like unmeasured confounding. We don't have all of the data. Singla et al, in fact Ken Gordon was one of the authors who's sitting here, so he's going to talk in a little bit and will be on this panel discussion. But they published a paper within TriNetX, which is a large EMR based dataset.

And what they found is that among patients who were on biologic therapy, so they had to be prescribed a biologic therapy, so that narrowed the group of patients. The people who were on an interleukin-twenty three inhibitor had significantly lower likelihood of developing PSA over the next three years. So this caused kind of a lot of discussion in this community about is it appropriate to be treating patients with psoriasis with a particular therapy with the goal of preventing PSA? And even in their paper, just to kind of let you know about the discussion section, says that we don't have enough information for this yet. But it does raise important questions.

So there's still probably channeling bias within these different groups, but it may be that one group would work better than another. Why might that be and why might not that be? So if you look back at some of the pathophysiologic studies of why psoriatic arthritis or spondyloarthritis begins, interleukin-twenty three is implicated in that early pathogenesis. So the biologic plausibility, biologic rationale for this is that if you were to start a patient with psoriasis on interleukin-twenty three, not only is it very effective at clearing their skin or getting down the burden of skin disease, but also maybe it's blocking enough of that interleukin-twenty three that you don't get that signal or that kind of spark to start the disease. That's one theory.

However, it also makes sense that if someone has this preclinical PSA that treating them with one of the other drugs that treats PSA should have a similar effect. Then the other question that comes up is how much is the psoriasis part of this? There's a number of other studies, particularly in animal models, that suggest that activated T cells could, in the skin, could stimulate inflammation in the joint. And it's kind of a long circuitous pathway usually through lymph nodes that you would kind of draw that diagram. And it's not clear by any means yet.

But potentially just getting the skin disease down would help that as well. So lots of biologic rationale. Not sure that I would particularly say that one therapy would be generally better than another here. But we're going to see a lot more of these studies. And part of that is because data is so much more accessible now.

This is another study from TriNetX. This one was just the one that was recently published. I'm showing the ULAR abstract, same first author for the paper. But they did a very similar study to Singlet et al, a few more patients because they used a global version of this dataset and found exactly the same thing. That twelve, twenty three, and 23 were significantly better regardless of line of therapy in terms of preventing PSA.

But again, I would just caution you as you interpret these data in thinking that this means that interleukin-twenty three or twelve twenty three is definitively better. People get these therapies for different reasons. We now know that twenty three inhibitors are the top therapy in the psoriasis world for treatment of psoriasis, for biologic therapy in psoriasis by dermatologists. And we also know that we have a lot of missing data about why people get one of these therapies or another. I've And shown you a variety of other things to think about.

But these populations are different. And when populations are this different, no matter how many types of causal effects models you put together or fancy statistics, you cannot correct for this. So just keep that in mind as you review these papers, you cannot correct fully for confounding by indication unless you have the data to be able to measure it accurately. So lots of different issues with observational study. This means we have to rely on codes.

So someone's got to put in a code for psoriatic arthritis. There's associations not causation, because we're not randomizing or watching forward in time as we kind of give an intervention. We try to do that with fancy statistics and sometimes it works if you're comparing two COVID vaccines, for example, but not so much if you're comparing different therapies that are prescribed for different reasons. Observation bias, patients who are on one set of therapies or followed by one set of doctors can be followed in a different way and different codes will be placed because of that. There's missing diagnoses and missing data as well.

I like to show this study when I'm talking about observational data involving dermatologists, so sorry in advance Ken. But in dermatology, first of all, if you're looking at patients who are diagnosed with psoriatic arthritis, in the six years prior to diagnosis, we looked at all the codes that they were getting. And so if you look above, or any other bar besides this one, you see all kinds of different colors. That's because they're coding joint pain, musculoskeletal disease, enthesitis, depression, reflux. There's all kinds of things being coded.

In dermatology, it is primarily psoriasis and rash. So there's almost nothing about joints here. So should we be relying too much on this data? I like this from COVID, the definition of an epidemiologist. An individual who does precise guesswork based on unreliable data provided by those of questionable knowledge.

And here I just said, they obviously have great knowledge. What they have is questionable data entry skills. So something to consider. And when in clinic, because I know that our dermatologists who do research have excellent data entry skills. So I think of ultimately we need randomized control trials.

We need to be able to select what patients get and then follow them over time. And you can say that's kind of difficult if we're comparing therapy versus a placebo. First of all, it's going to take a really long time for a population to develop PSA because the incidence is low. So we've to follow them for three to four years, maybe five. It's also a huge population of patients that needs to be followed over time because the incidence is so low, one to three percent per year are going to develop it.

And is it ethical to randomize patients to therapy versus no therapy? Well it clearly is for some period of time, and especially in psoriasis where many patients choose to do topical therapies, for example. But maybe not for three to five years. And so that may just not be logical, like patients are going to want to be treated. We also know that psoriasis has many other reasons to be treated, such as reducing systemic inflammation that may have impact an for cardiovascular benefits, may have emotional health benefits.

We certainly can cause, be associated with significant depression. So this is the first trial. It's called the PAMPA trial. There's a publication about the design. This is randomizing patients with moderate to severe psoriasis and at least one risk factor.

So we risk enhance this population. And they're randomized to guselkumab versus placebo. And then I think importantly in this particular study, there's an observational arm. And the reason for the observational arm is many people in the real world don't want to go into a clinical trial. But if we can capture them somehow, then we don't lose them from our population of patients we're seeing.

Otherwise when you look at clinical trials, we're looking at a very narrow spectrum of the patient population. But if we can now compare them to all the potential patients who would be eligible for this and watch those patients over time potentially develop PSA two, we'll have much broader and more relevant information. In this case, they're only getting the drug for six months and then there's a power doppler ultrasound endpoint. So ultrasound is one of the key endpoints here. And then down the road, Caspar is the co primary endpoint.

So lots to learn as we move ahead. So in conclusion, does aggressive therapy for psoriasis prevent psoriatic arthritis? We just don't know yet. So lots to learn here though as we move forward. So and the adventure begins and it has been beginning.

Lots of studies out there, but just beware of the potential pitfalls of these studies.

Great. Our next speaker is going to be Doctor. Arti Kavanaugh, University of California, San Diego. He's run the Innovative Therapies division there for many years. Arti is going to talk about this cool concept of combination biologics.

When biologics came out, it was a no no to combine biologics. It's still in the warning from all the package inserts on biologics, do not mix with other biologics. Yet there's some really interesting data that shows some promise, especially in the area of psoriasis and psoriatic arthritis. Let's listen to Doctor. Cavanaugh.

Potential benefits, you could have additive or synergistic efficacy. Again, can we get one hundred percent of our patients in remission? Maybe we could use lower doses of the treating agents and that may translate into less toxicity and maybe less resistance. If you think about it in an infectious disease sort of way, if you block one pathway and yet the disease comes back, is that being driven by an altered pathway? So maybe you would have less of that.

Caveats, we have no idea what we're doing. You look at the immune system and it's incredibly complex, and not only are there an ever growing number of inflammatory mediators and different cell types, but they interact in these vast networks that are chaotic. It's like throwing a rock into a lake and you see the ripples, and then you throw a rock in a different place, we have very little understanding of what we're actually doing, and therefore we might have unanticipated outcomes. The effects in animals really made us think that we were doing the right thing, but animal models were true about half the time, and the mice never told us which half were true, so we didn't know. And then the diseases are heterogeneous.

So a lot of potential caveats, but we were so taken back by the success in animal studies. There's dozens and dozens of studies that could show you. This shows IL-twelve inhibition, so to block TH1 pathway direction of the immune system, and anti TNF antibodies alone or in combination. You basically, when you look in combination, you pretty much can prevent the disease. So taking different aspects of the immune system, boom, this was absolutely a home run.

TNF and IL-one. We don't talk so much about IL-one. We're talking a little bit more about it now in crystalline diseases, for example. But it was thought to be potentially a really good target. And if you look at a list of immunologic activities for tumor necrosis factor and interleukin-one, they largely overlap.

All the effects on the endothelium, on different sorts of cells, it looks like they do a lot of the same things. So the question is if inhibition of one was not completely erasing the disease, might inhibition of both of them? And that was suggested by, again, animal studies. So if you look at the individual studies, and this looks at a different, this is type two collagen arthritis in rats. If you look at measures of inflammation, the size of the swollen synovium, the pannus, damage to the cartilage, resorption of bone, absolutely miraculous results here.

You have some benefit with either agent, and you see that down at the bottom, there's the control. You do okay with IL-one inhibition, you do better with TNF inhibition, but when you block both of them, boom, you really prevent the disease. So this was the basis for us embarking on trying this in humans. Once we had TNF inhibitors available, absolutely miraculous starting in the late '90s, and then there were inhibitors of IL-one available. So that led to a study which I think surprised lots and lots of people.

And this was published in 2004 but done earlier than that. Mark Genovese published this. So it was exactly that sort of paradigm. You block TNF, in this case with etanercept, either at a regular dose or half a dose, with or without an IL-one inhibitor. And this is anakinra, the natural form, a recombinant form of the natural IL-one receptor antagonist.

You don't see anything. Well you see that the full dose of a TNF inhibitor, tantrasept, is better than the half a dose, but if you look at the efficacy by adding in the IL-one inhibitor, no benefit. But there was definitely a biologic signal that signaled more serious infectious events. So it did something, but it was really bad. There was another study looking at a different approach, TNF inhibition, with or without the T cell co stimulatory inhibitor, abatacept, a drug that we had known about by the time this study was done.

Similar results, you'd be very hard pressed to see if there was any benefit, but there was definitely a signal. There were more serious infectious events with the combination. So these two studies resulted in that black box warning that we developed in rheumatology, we shared with our colleagues who use biologic agents, that you should not use biologic agents in combination. That's still on the packages these days, on the package inserts for the biologic agents. So kind of a dark time and really kind of put the kibosh on doing combination therapy studies, made people very leery of doing them.

There's been other studies since then. Some of them were just negative. In this case, the BTK, the Bruton's tyrosine kinase inhibitor, elsabrutinib, with the jackanibupadacitinib, either alone or in combination. Nice study, very nice study. This is in rheumatoid arthritis, in people who had been on our biologic agent previously.

And basically what you see is that upadacitinib works and it helps to treat the arthritis signs and symptoms. You don't get any benefit, and you don't see much of a signal from the BTK inhibitor. Separate discussion about why does this approach to inhibiting B cells not work, but certainly very negative study in terms of the potential use of combination therapies. Some studies were meh. Maybe there was a little bit of an effect.

This is an interesting study from some years ago with the TNF inhibitor, cerulizumab, and also IL-17A and F inhibitor, vimekizumab. And if you look at the data, you could make a case, just maybe in the upper left panel, as you see here, that compared to the patients who got cerdulizumab alone, maybe things were a little bit better with the combination therapy. In this, it's interesting, there wasn't really much of a negative safety signal. But this is in rheumatoid arthritis. IL-seventeen alone in rheumatoid arthritis doesn't have much of an effect, but this was not felt to be strong enough to pursue in rheumatoid arthritis.

We have looked then at other combinations. Now getting back to psoriatic arthritis, which is a topic of the talk. These are the things we have available to us. So many different agents. We're not going to talk about combinations with the biologics plus the traditional DMARDs, but we have biologic inhibitors, TNF inhibitors, twelve twenty three, twenty three T cell inhibition.

We have a lot of JAK inhibitors now, and there's other things that are coming. So where are we and how might we put together combination therapy in psoriatic arthritis? Well, it's more interesting in psoriatic arthritis, I think, than rheumatoid arthritis. In some ways, arthritis is more simple. You're focusing on the peripheral arthritis.

It's a systemic inflammatory disease. There's certainly evidence that the immune system is active throughout the body, in the extra articular manifestations. But in psoriatic arthritis you really have almost several distinct diseases put together. You have skin psoriasis, you have the peripheral arthritis of psoriatic arthritis, you have the axial arthritis, very much like ankylosing spondylitis. You can have inflammatory bowel disease, which happens much more in your patients with psoriatic arthritis, and it's certainly something that we think about.

You have of course anterior uveitis, or iritis. All of these things in the spectrum of the SPA diseases happen in psoriatic arthritis. And one of the things that we've learned over the years is that while the TNF inhibitors are effective across many, many individual domains for these different diseases, and the same is true in psoriatic arthritis. Many of the other therapies are not. So you have the IL-twenty three inhibitors have not proven effective for axial disease and ankylosing spondylitis.

You have IL-seventeen, which is actually relatively contraindicated in inflammatory bowel disease because the initial studies showed that it was ineffective. So we have kind of a bedside to bench way of approaching these distinct diseases. And psoriatic arthritis, I think, brings the different domains of potential involvement very similar to these other distinct diseases. So what's been done in psoriatic arthritis? Well as I said, part of the reason for talking about combination is that such cool therapeutic approaches these days, it's amazing.

This is one that sort of, I don't know, you could look at these data and draw different conclusions out of it. So this was ABT-one hundred twenty two, which was engineered, as you see on the cartoon, to inhibit both TNF and IL-17A. So the construct will block both. So what happened with the combination? Maybe you can, and it was compared to TNF inhibitor alone, adalimumab, which of course we know and have great data for, to know the extent of the effect size of the benefits.

If you look at the ACR205070, you could make the case that at the higher dose, this dual inhibitor did do better. Maybe the same for the PASI responses. Overall, there was also not much of a signal. So with either agent, with any of the effective agents, maybe a little bit more respiratory infection, but not the signal for serious infection episodes being increased. So this was a potential, but again, the effect size of it wasn't really knock your socks off to say that this was so much better than that, or that this so much better than that, and they kinda got shelved.

There was another approach to inhibiting TNF and IL-seventeen combined, again, with a dual inhibitor. Some issues though potentially with immune complex formation and some side effects related to that, which are more tolerability issues than serious infectious events, but this too did not go forward. So we're kind of dipping our toe in the water over the years with potential combination therapies until this study. So until Vega, and I think everybody has hopefully heard of this study, you see the outline of it at the top. So it's a number of people, two fourteen people with moderately or severely active ulcerative colitis.

And they were randomized to the TNF inhibitor glimumab, the twenty three inhibitor guselkumab, or the combination. And you see the primary outcomes as you see them listed here, all sorts of different responses. What happened? Exactly what we would have hoped for, and that is the combination was much better. So the clinical response with TNF twenty three or both, much higher.

The endoscopic improvement. Histologic remission plus endoscopic improvement, much higher with the combination. And most importantly, there was not an increase in adverse events. So really outstanding data. And if you look on a mechanistic level as well.

So here are the clinical outcomes just shown in a different way graphically. This is, they also did, I mean, it's a lovely study. They did biopsy results of the colon, and what you would see is what you would hope to see with active treatment. So here's very active disease. There are a number of genes that are overexpressed.

The proteins are upregulated in ulcerative colitis. Some are downregulated. When you treat them, you see individually, you do have a benefit, but with combination therapy you see synergy. So you do better than with either therapy alone. So I think this is kind of, we're at the brink now of a new era of combination therapy driven by the outstanding positive data in ulcerative colitis, but now following up in other diseases.

So in psoriatic arthritis, and you see a study here that's ongoing and hopefully will read out this year, The AFFINITY study in psoriatic arthritis. Now it doesn't have all three arms, but it has the gazelkumab plus galimumab, or gazelkumab plus placebo. So 23 plus TNF, or twenty three alone. And then you see from the VEGA study, the twenty three did a little bit better than the TNF inhibitor did. So, and here are all the relevant outcomes that we're very used to seeing in our psoriatic arthritis.

So going to be very interesting. It's really interesting times thinking about combination therapy, especially for people who are around when those negative studies, which are really supposed to work and they didn't. Where are we? Well, we're kind of feeling our way. This is hard to read, but it's just anecdotes.

Yet this is how the VEGAS study came about. There were anecdotes of people using one biologic and the patient didn't have as good a response as they hoped, so they added another. So here you see combinations with different agents, TNF inhibitors, JAK and Ibs combined. Not mentioning, and something that I think we're all doing, is the combination that we do use, and that is a TNF inhibitor plus a PD-four inhibitor, apremolast. The That is the most common.

We're looking at the data from Corvitas lots, and that's by far the most common combination therapy. And I think that's almost a kind of a taken for granted, and we're seeing that, although there hasn't been really a formal study of that as well. There's an interesting presentation at the most recent ACR which looked at this. This is a registry in France where they're putting together this kind of information. And I think this is great.

This is something that I think will be ongoing here as well and that is it takes advantage of the kind of anecdotal things that we're seeing in our clinic. So you send somebody, or the GI people have somebody on a drug and their ulcerative colitis is fine, yet their axial spondyloarthritis is not, or their peripheral arthritis is not. So you add in, they may have them on an anti integrin like vutalizumab, you add in the TNF inhibitor. So we're seeing a lot of anecdotes like this, and we're seeing more diversity of the things in this, like the combat registry, they want to get 1,000 patients in there. And you see the different indications that they have, including even lupus, and you see they have combinations of B cell directed therapies.

But mostly it's refractory patients. And then the question is what do we do with the adverse events? So there are serious adverse events and it really screams out the need for a controlled trial. Because you're going to see these patients are the worst of the worst patients. They have diseases that in the individual treatment by room or by GI or by derm, they're just not doing well.

And of course those are the people who are most likely to have more adverse events. So we really look forward to and really need controlled studies.

So it looks like it's sort of like the PAMPA study and these head to head studies we're going to talk about next and the studies of combination. We got to wait on some of these results before we can put them into practice, right? So I would not recommend using combination biologics. Have I done it? Well, I'm not going to talk about it here where lawyers may be watching.

But again, you would do so at your own risk and with informed consent of the patient. We do need the studies to be done, which is why we look for head to head trials, especially if you're going to do a combination trial, you would do a combination versus a single drug or no drug. But you need an active comparator, a placebo comparator. Anyway, that's what our next speaker is going to talk about. Ken Gordon, a frequent flyer here at RheumNow Live, is a professor of dermatology at the Medical College of Wisconsin.

We've asked Ken to come by and talk about head to head trials in psoriatic disease. Go ahead, Ken.

From a phase two trial, where risankizumab was quite superior to Eustikimab. Now there are other elements about this that are important, including binding of the protein and affinity and avidity for the protein. Yet even with this, the results, even looking at the pharmacokinetics, it isn't quite answer the question, there's more to it than just the pharmacokinetics. And that's why we believe that the blockade of IL-twelve is actually to the detriment in psoriasis therapy. The question that's becoming more prominent right now is, is there a necessity to block interleukin-17F versus just blocking interleukin-17A?

There have been experiments blocking interleukin-17A and F before, the most recent molecules, molecule bimekizumab and then sonolizumab coming in the near future, looking at blocking IL-17A, F, C and F through the receptor with berdalumab. It did in phase two look like it had greater efficacy when compared to zacokinumab and ixekizumab, but when you threw it, when you had some of the events that happened, the medication really never completed its phase, its development. So the question was, do bimekizumab and or zoculokumab, sonelokumab, confer an advantage in efficacy by that binding of IL-17F? The way to do that, is to show randomized clinical trials. So here's the IL-seventeen family, I think you're all probably familiar with it, but you have AA, AF, and FF, which are present in the skin and psoriasis.

They have, A is more immunologically active, F there's a lot more of it, and so what's the role of each of those elements? So here's the B RADIAN study, which was bimekizumab versus secukinumab, and you can clearly see that secukinumab was inferior to bimekizumab in efficacy in the treatment of plaque psoriasis. There's really no difficulty with looking at the data, the data was quite distinct. But the one thing to think about is bimekizumab is a better blocker of IL-17A than secukinumab. Bimekizumab and ixekizumab however have similar blockade of IL-17A, so that's actually the study that should be done, but that hasn't been done to see what the role of blockade of interleukin-17F is in psoriasis.

So you do have a molecule that has outstanding data in bimekizumab, but we would love to have the pathophysiologic answer of, in drugs that have similar affinity and avidity for IL-17A, does the addition of blockade of F make a difference? I would love to see that study, it's not being done as far as I know yet. But the big question that we hear in dermatology all the time, and I have many of my rheumatology colleagues ask me this question, is what works better, an IL-seventeen or an anti IL-twenty three? Many of you, if you've heard me speak before, you'll hear me talk about, you know, what's the disease that's driving the patient to come into the office? Is it psoriatic arthritis, is it the skin?

And so we have lots of patients who might have skin driven therapy, but are in a rheumatology office and they'll want to use an anti IL-seventeen, and they come out to me and say, you know, is the skin difference really there, and so should I try an IL-twenty three first? I think these are all great questions, but I think you have to look at what your goal is before you can say which is superior or not. So the first question is, is long term or short term efficacy more important? And I'll show some data that suggests that they might give you different answers. Does speed matter?

This is one of those questions that if you ask any patient, they'll say, I want to be better yesterday. But we asked a bunch of patients in one of the clinical trials who had very high levels of response. If they got better, we looked at their quality of life information, and we looked at them in the first few weeks when the patients got better faster, and then added a year. And guess what? At about twenty four weeks, the speed doesn't matter to patients anymore.

So unless you have some event that's driving you to get that patient better, and the most common thing I talk about is weddings. Weddings are a big deal in dermatology office. We got to get patients better fast. But Kevin, I'm getting married in two weeks, can you get back to my body of 40% body surface area covered psoriasis better by my photos. Yeah, that's important.

But in Milwaukee, where I don't have a lot of actors or politicians, it's really not that big a deal usually. And then there's the issue of study design. Study design will almost always be driven by a sponsor's goal to show that they are superior to the drug that they're facing. And so a number of these studies have been designed and even published in ways that I think might be considered to be a little misleading. So this is the first study that was the high level head to head, was the ECLIPSE study, was guselkumab versus secukinumab.

And this got a lot, a lot of publicity. The primary endpoint was forty eight weeks of superiority with guselkumab, and non inferiority at week twelve, at week sixteen. Secakinumab is a drug that's known to have loss of response over time. Remember in the psoriasis dosing of secukinumab, you have a huge amount that's given in the first five weeks, and then it falls off after that. We see a lot of patients who respond that five weeks, and you just don't get the blood levels enough to maintain that response over time.

So there is a fall off. And what's other else that's interesting about this trial was that when they were starting to publish, on the statistical hierarchy, it met primary endpoint and the secondary endpoint which was non inferiority, and then lost all the rest of the hierarchy. It didn't meet the endpoints. And so when I got this article to review from the New England Journal of Medicine, I actually said, reject it, they're talking about endpoints that you can't in proper statistics go and even evaluate. The paper was rejected, it got sent to The Lancet, I got it again to review.

And I said the same thing, but The Lancet took it. But for what this says, is for the long and short term, they were about the same in the short term, and the long term geselkumab was a little better. And so, but the differences weren't that massive, that you would necessarily choose, this is better, therefore you would choose one medication versus the other. But this is a known event where secukinumab falls off, which was the reason that the sponsor of the study, who was Janssen, decided to use that versus execizumab as their comparator. But Lilly decided to do a trial looking, the EXORI execizumab versus gasecumab.

And in this case, they looked at twelve and twenty four week data, and you can see at twelve weeks, ixekizumab is superior statistically, and I think that's a clinical difference. But at twenty four weeks, when the anti IL-twenty three has a chance to have its effect and with the longer term dosing has its effect, the data is quite similar. What's really fascinating about this is the twelve weeks were presented and published, even though the twenty four week data was available, so people would look at the ixekizumab being superior. In other words, if you have someone going to that wedding, and you really need to have something predictably to get a high level answer really quickly, that would be a reason to choose ixekizumab. If the patient has really bad psoriatic arthritis, an axial disease for example, that's the reason to choose execizumab.

But if you're looking for the long term, and a patient wants to have fewer shots, using guselkumab is a perfectly reasonable option. So let me talk a little bit about the psoriatic arthritis trials and head to head, because, you know, what I see in the psoriatic arthritis trials is a lot of the comparator as an anchor rather than actual true comparison trial. And I think there are reasons for that, and just want to give you my perspective, a dermatologist's perspective on psoriatic arthritis trials. I can tell you I've worked with a lot of rheumatologists over time, I have a psoriatic arthritis clinic with a rheumatologist, I started one long ago with the guy who was actually my rheumatology fellow when I was a medical resident and doing my rheumatology rotation, who told me definitively don't do rheumatology. That was Eric Ruderman by the way, anyone has any questions.

So, what are my takes? So the available tools for measuring PSA, from a dermatologist viewpoint, do not seem to be sufficient to truly be able to differentiate medications very well. Multiple domains are nice, and I already, I'm going to apologize here. Domains seem to be an effort to do something like, I don't know, documenting every diagnosis from the problem list on that visit. You know, it's something you have when you've forty five minutes or an hour with a patient, not when you got six.

Domains, give me a break. Tell me if the drug works or doesn't, if that patient's better or not, okay? And then I want to say, is the skin better? There's six domains of psoriatic arthritis and skin gets one. Come on, give me a break.

So I want to know, are both the joints and skin getting better? And what does the data mean for patients who have both conditions, and can we choose based on head to head studies? So here's my interpretation. So this is the SPIRIT study, all of you are probably familiar with it, with ixekizumab and adalimumab, and when I start talking to people about psoriatic arthritis, they typically think about using them distinctly. Okay, it worked for psoriasis, and it worked for psoriatic arthritis, And so that's great.

I want to know, and this is the biggest question that it has, that I come up against in the clinic that I work in psoriatic arthritis is, the patient's skin is all cleared, but their joints still hurt. Or less commonly, their joints still hurt, and their skin isn't joints are better, but the skin's still active. How do I go about treating those patients, and what's the drug that's going to do better for each patient within those systems? So I actually think that looking at the, in this case, PASI 100 and ACR 50, which was looked at here, where execizumab was superior to adalimumab, is a perfectly reasonable way of thinking about it. Now, I don't know if the Posi 100 or the Posi 90, or looking to ACR twenty, fifty or 70 is the best way to do it, something we have to figure out.

But, I think it's important to be able to look at both those elements, and think about, is the patient better? And it might be a global assessment, it might be a HAC score in looking at psoriatic arthritis, it might be a DLQI for the skin, but thinking about ways of looking at the two diseases in the same way. I've actually made a suggestion to a number of folks, it hasn't been pulled off, is can we look at data on a sort of a two by two graph, and think about it as Cartesian things, you know, how many people, both psoriatic arthritis and psoriasis are bad, are in the right upper quadrant, how many people do get into the left lower quadrant, is what we want to look for to make these patients better. So the takeaways I have. Head to head studies have played a big role in the development medications for psoriasis.

As you can see, all of our perspectives on what's better for psoriasis, you talking to your dermatology colleagues, you probably have the results of these head to head trials in your mind, whether you know it or not. It's not quite as evident for PSA right now, but when we do do them for PSA, and they will come, I think we have to think about how we go about treating the entirety of psoriatic arthritis, of psoriatic disease, and not just the two little elements together. In general, differences in efficacy, or lack of significant differences, are clear in psoriasis and psoriatic arthritis, it's easier to show distinctions, and I think that might be because our outcome measures are much more distinct than psoriasis. The outcomes of the trials do give important physiological questions, including the role of IL-twelve and IL-17F, but they're not yet definitive, we need some more work, and probably some physiology done on these as well. And there might be distinct differences in outcomes of head to head trials in PSA, if the skin is given equal importance and consideration of joints.

So thank you very much.

So that's it for this edition of Tuesday Night Rheumatology. We want to thank our sponsor AbbVie for supporting this pod on psoriatic arthritis. Again, go to roomnow.live for 2025 content or to register for 2026. We look forward to seeing you in Dallas or to seeing you online. So next week, another Tuesday night rheumatology RNL replay.

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