EULAR 2024 Rheumatology Roundup Save

Hello, everyone. Welcome to the UR twenty twenty four Rheumatology Roundup, where Arti Cavanagh and I present what we think are the highlights of this meeting that was just completed in Vienna. I'm Jack Cush with RheumNow. I'm joined by

Marty Cavanagh, University of California, San Diego.

All right. So we're now back at home recovering from a long trip and a grueling week of thousands of abstracts and whatnot. In this roundup, we choose for you what we thought were the most important or most relevant. Interestingly, Arty and I chose our abstract separately, and we could have gone with the high science. We could have gone with the new molecules that may or may not ever make it.

What we did really was we chose things that are I think practical and useful. I think that you'll enjoy this. So I want to thank our sponsors for their sponsorship of coverage of UR twenty twenty four. That would be Bristol Myers Squibb and UCB. Thank you for making this a better educational program.

Artie, why don't you start us off?

Okay. Well, Jack said, we just got back from EULAR. EULAR is a really good meeting. I think the pluses, the convention center was very orderly as one of my guests would expect. A, B, C, D.

So you knew where you were. You didn't you didn't spend the first three days trying to figure out what room you were going to. The downside, they didn't have posters. They still had those silly TV screens. And I think the ACR has hopefully learned that people want the posters.

They want to go up there and talk to the fellow presenting their work and standing in front of it. So they don't have them. Hopefully they have them next year. But overall, it's a good meeting. So we tried to pick, there's just so many good things.

An important topic in rheumatoid arthritis, but also now in SPA and PSA, is difficult to treat disease. And difficult to treat rheumatoid arthritis, for example. A big part of that is patients who don't have necessarily inflammation. I thought a poster that spoke to that was by Brigitte Mikkelsen from Kristiansand in Norway, poster 47500475. And the title is ultrasound assessment of impact of anxiety or depression on disease activity in RA.

Very, very simple sort of study, but I think highlights very nicely the challenges that we have with a subgroup of patients who we're trying to treat to target and we have difficulty getting there. So what they did was they took the two hundred or so rheumatoid arthritis patients, starting a biologic DMARR, and they did a screening ultrasound, thirty six joint and four tendon areas. So overall, a score from zero to 120. Asked about anxiety and depression very simply. That is that there's one question on the EuroQOL V, the European Quality of Life questionnaire, that says, I am moderatelyextremely anxious or depressed.

And you score along with that. And then she divided them into patients who had said they were moderately or extremely anxious versus those who were not. And actually fifty four percent of them ticked the box that said they were moderately or extremely anxious. So, and you say, you may say, well, gosh, this is exactly what I would have predicted. Some things are much worse.

So the patient global is worse than those who are anxious and depressed, again, the 109 ninety two. Pain is worse, fatigue is worse, the HAC is worse. Some things are not so different. So the swollen joints, a little bit more in the anxious and depressed people, the SED rate, the CRP, and then most importantly, perhaps the ultrasound. The ultrasound was not different between the two groups.

So I think there are several points from this. One is that this is, first of it's a simple questionnaire. I don't know how many, I think a lot of people use the old Ted Pincus form with the hack and the homunculus. And on there, there's a question about it, the question about anxiety, depression. It turns out it's very simple to inquire about.

And it's important, I think, to address our expectations for treating patients. And that the ultrasound, is a nice way to be the arbitrary, if you will, if there's active disease or not. In the PSA world, they're struggling with difficult to treat versus complex to manage because patients don't like to be called difficult. Who does? And it would be these kind of patients where there's something else going on besides just ultrasound identified inflammation.

So difficult to treat, gosh, Jack, there A dozen, two dozen posters on that, defining it, what to do with it, how do you treat, how do you respond? But I think this is really at the center of this is patients for whom they don't have as much inflammation as we would think traditionally, but still by our composite scores and not doing so well.

I think this is an outgrowth of the UR definition of difficult to treat RA. You define it and then you can study it. And with that definition, I think it was 2021 that came out. We're now seeing this sort of flood of D2T RA studies and now we're seeing difficult to treat SPA, difficult to treat PSA. What I liked about what you said is that in PSA, they're talking about the definitions, but they're also talking about including imaging as part of the definition so that you can get to when they're difficult, whether there's an inflammatory component or there's non inflammatory like anxiety and depression.

In RA, they call this PIRA and NIRA, persistent inflammatory refractory RA versus non inflammatory refractory RA. And I think these are important distinctions and outgrowths of the definition. Again, the numbers of people that we're treating here just in this survey, the numbers of people with anxiety and depressive symptoms is way higher than probably you would have guessed. But that's probably because you're not asking the question.

Or paying attention to it if people say I think we could easily fall into, well, what am I going to do about it? They're anxious because they have a good reason, they lost their job or depressed because they lost their job. But I can't do anything about it. But I think that doesn't get us off the hook because these are the patients who are difficult to treat.

The Dan Bio register last year, they reported that patients with depression, threefold higher risk of mortality. And they're not dying from suicide, they're dying from usual RA causes of death. So this is big. If you're not doing EuroQual5 or the TEDPINKIS form or that RheumNow survey form, which does ask about depression, you should be doing the PHQ-nine, which is a very simple nine question patient self assessment that you can add onto your HACS score. I really can't stress enough that this is something that we need to do going forward.

I think we all see these patients where they see you and they've been on 10 different drugs. How long have they been on each drug? Like one or two months. And you think, oh my gosh, they never got a chance to see if these drugs worked or not. So it's a practical problem.

And also I think a shout out for the, I know a lot of our younger colleagues like the ultrasound. And this I think like so many other bits of data show that it can be very useful to dissect out the inflammatory component versus the non.

Absolutely. My first one is I think a highly relevant question that you deal with every day. The patient is going to go in for an infusion of infliximab or tocilizumab, and the nurse calls and the patient has the sniffles. And do we hold the therapy or do we give the biologic? And I don't know where this has happened as a result of either a misinterpretation of the package insert or taking advice from television ads, but we tend to stop biologic and targeted synthetic therapy very easily.

This abstract, the poster nine eighty one was a Dutch randomized open label trial of eleven forty two patients with either RA, PSA and SPA. The protocol was that when they showed up with a grade two infection, the kind that you would get the call about but not hospitalizable, they were randomized to either continue their biologic or their DMARD or to suspend it. And in this study, were a lot of RAPSA and spas. What drugs are they taking? Well, seventy percent were on conventional DMARDs, forty five percent were on biologic DMARDs, and ten percent were on targeted synthetics.

Targeted synthetics, very short half life. Biologic DMARDs, very long half life. Conventional DMARDs, short methotrexate, long leflinomide. A big mixture in here. And in the end, like five seventy patients in each group, and there was 12 SIEs.

That means hospitalizable IV antibiotics, serious infections, twelve in the interruption group, and only nine in the continuation group, suggesting that they were not significantly different from each other, and if anything, numerically higher in the interruption group. This is randomized evidence that you don't need to stop for any hint of infection in patients taking the drugs that you use. Now, this could have been a pure study by only studying people on long half life drugs or short half life drugs or only with RA or with PSA. But so far this is the best that we have and I think this is valuable.

Yeah. As you said, it's a very important, very practical question. It's very similar in some ways to what do you do perioperatively with the same kind of constraints. Thankfully, there are very few outcomes. So in research, want outcomes to be able to say treatment A versus treatment B and what the differences are.

Here luckily they had a very large number of patients. And if anything, the outcomes favored those who continued on therapy compared to those who discontinued it. It was randomized, which is important. That way there's a great potential for bias where the doctor has a sense about the patient and something that's not entirely evident just by a quick look at the chart, but they got past that because it's a randomized study. So, very strong data, I I I think.

And I think, yeah, most of us, if somebody's hospitalized with a serious infectious event, we'll stop whatever But patient they're as we see in this study, for every, incident like that, we get, a 100 more epic messages that say, do I need to stop this? And especially if so many upper respiratory infections going around seasonally, but certainly a lot that have been around this year. This is very, very practical and very important. I think it may actually have impact for study design as well, where you say, what do you do on research study? And of course, to be conservative, mostly they kick patients out of studies who have signs and symptoms of an infection.

But these are nice data to say that maybe you don't need to.

The best proof of this principle comes from when Ari and I started doing biologic trials in 1995 with infliximab and with etanercept and then with adalimumab. The protocols didn't say that if someone had an infection that you stopped the protocol. No, everybody stayed in the study and you treated the non serious infection, and guess what? Nobody died. But somehow this has morphed into a much more stringent interpretation of some of the rules that are being thrown out there.

Yeah. I think the more the more epic messages you get from a patient, the more likely you are to say stop the treatment. But these are these are as good data as we have that say that maybe you don't need to do that. And of course, the other side, and we've learned this from, the studies on holding methotrexate about the time of vaccination, that if you hold the medicine too long, you run the risk of flaring. And that's not good for anything if you have a flare of the underlying inflammatory arthritis.

So true. All right. What's next?

So my next one is is it's interesting because it was certainly very controversial for a number of people, especially those who consider themselves clinical epidemiologists. And this was an oral presentation. It was OP0010. But there were a couple of related ones that also got people's attention. So we'll talk about the main one first.

This is the title is the title of this abstract is Evaluation of the Risk of Celiac Arthritis in Patients with Psoriasis Undergoing Biological Treatment, Global Population Study, TriNetX. So first is, what is TriNet? That's not the company that made the Terminator and sent them back in time to kill all of humanity. But it's a large database of electronic health records. So a lot of it's in The US and they partner with universities and say, well, give us your data, access to your electronic health record.

And then for that, you can do these searches. So it's kind of incredible. They have a database of two thirteen million people worldwide, but a lot of it is in The US. So like most sort of data such as this, like claims data, what you're looking at is coding. So coding for the diagnosis of psoriatic arthritis, coding for the diagnosis of psoriasis.

The onset date is the first date that there's a code. So a lot of it depends on the code in the medical record. It's a super important question and the idea, which I think makes total sense is if you have skin psoriasis, twenty five percent of those people are gonna go on to develop psoriatic arthritis. We know that from quite a number of studies. We don't know which twenty five percent.

We do know that at least for eighty five percent or so, the skin psoriasis precedes the arthritis. So very naturally, as you talk to your dermatology colleagues and they're so incredibly happy with the results of all of their psoriasis therapies, years ago it was the TF inhibitor, then the twelve-twenty three inhibitors, then the seventeen inhibitors, then the twenty three inhibitors. Now also with the JAK and Ibs and the TYK2 inhibitors, they've done better and they do really, really well. And so the question is, if you control the psoriasis really well with these biologic agents, can you prevent the development of psoriatic arthritis? There's been some studies that have looked at this.

A number of people have gone to their hospital, derm clinic and follow people over time. There are abstracts that say yes, that if you look at patients on a biologic compared to those on just topical therapies, for example, that you're less likely to develop PSA if you treat with biologic. There are, several studies where it's the opposite, where you're more likely to. And as you just overthink about the entire setup, you can clearly say, well, there's a potential for bias. So two psoriasis patients come in, one of them says, yeah, I got really bad skin and I've been aching all over.

The person is more likely to get one therapy compared to another. So there's a potential for bias that you could say works either way. Anyway, this TriNetX gigantic database and the trade off with such data, you got tons of patients. So that always helps with getting to relatively uncommon outcomes, even though this is pretty common. The downside, you're missing really granular data and you're depending a lot on codes.

And the here So, then two thirteen million patients, they ended up having almost a million with psoriasis and just below that with psoriasis who did not have psoriatic arthritis coded. They followed the people over five years. They also did propensity score matching. This really upsets our clinical epidemiology colleagues because you just click a couple of things and you let the computer do it and they say, that's not how you do propensity score matching. There are some tests for the validity that you have to do as you're going along and doing this.

Here it's a black box. You say propensity score, boom, hit the enter key and it spits out the answer. They say they did try to adjust for sex, which is important in terms of outcomes in psoriatic arthritis. The time since psoriasis diagnosis, but remember that's the diagnostic code. Obesity is the chart entered the BMI.

Alcohol and tobacco use also as codes as nail psoriasis and the concomitant use of DMARDs. Interestingly, what they found is that if you compare to the TNF inhibitors as the referent, when you treat with IL-twelve twenty three or IL-twenty three, you decrease the risk of developing psoriatic arthritis compared with the TNF inhibitor. So people like the answer that yes, we can treat the psoriasis so well that maybe people don't develop psoriatic arthritis, but there's just tons of questions with this data. There was a publication on this. This sounds familiar.

There was a publication in Lancet Rheumatology last year in April from Shikha Singla, Mike Putnam, Gene Liu, and also Ken Gordon, a dermatologist. And they used the same database. It had smaller numbers. They did a variety of other sensitivity analyses, but they came to the same conclusion that treatment with the twelve twenty three or the 23, not the 17, is more likely to be able to prevent the development of psoriatic arthritis. There are other abstracts that looked at this, looked at cardiovascular outcomes and came to the conclusion that there was an increased risk of ischemic heart disease and heart failure with TNF compared to IL-seventeen.

Another abstract by a completely different group. Looking at the Jack and Ibs did not find a risk of CBD or VTE or cancers compared to the biologics. Super important questions. But now we have to get into the weeds of the methods and say, are these really accurate and acceptable?

I've been following this question for about three years now of does aggressive treatment of psoriasis avert the development of PSA? I put up a bunch of studies and they're all interesting, all reasonably sized, all methodologically flawed. Yet I do know from our methodologists and epi people that they don't believe the data even though it's published and out there and in reasonable journals. When I saw this report, I thought, 200,000,000 people, we've solved the problem and whatnot. But in the end, it still is an issue of how good is the information going in, or is this a garbage in garbage out situation?

I think this is a little bit like AI, where you ask really complex questions and you press a button and ChatGPT or Gemini or whoever gives you an answer in fifteen seconds that seems pretty straightforward and simple. But what we know from AI, which is generative, is it kind of fills in the blanks in fuzzy ways and often is amenable to mistakes. So I think the answer to the question is still out there and waiting for properly designed cohort analysis with real propensity matching as opposed to black box propensity matching. We were sitting at the gate waiting to take off, Alexis Agde and Jeff Sparks, myself, Roy Fleishman. We were talking about what we'd like to do with this, but what we can't do with this.

The problem was there was more on what we can't do with TriNetX. It still has utility, but you have to have a higher level of access so that you can manipulate the details correctly. But if you just rely on what looks to be a pedestrian AI like program, you're likely to be misled.

Yeah. This is, like you said, super important question. We like the answer and we always like when data agrees with us and supports what we had potentially the biases before that. But this kind of question you would, and the epidemiologist folks like Joel Gelfand have been saying, you really need a double blind study or a randomized controlled study, maybe not double blind, but randomized controlled study to answer this specific question. But you're right, you see 200,000,000 and you think there's to got be something there.

Let me move on to another issue. There was a lot of abstracts at this meeting on clinically suspect arthralgia, progression to inflammatory arthritis. I was really drawn to this one by Choudhury and colleagues from Leeds. It's on how often does palindromic rheumatism evolve into RA or chronic inflammatory arthritis. This is an analysis over about a fifteen year period of one hundred and sixty one palindromic rheumatism patients.

I remember already in our group, were talking about this and we said, who has one hundred and sixty one palindromic rheumatism patients? The answer is Leeds where they have one of the world's most famous early arthritis clinics and they collect tons of these people over time. They can do this analysis. 161 patients, ninety percent DMAR naive followed for over three years. What they're looking to see is the progression to synovitis that is going to be chronic.

In this case, lasting more than three weeks, as opposed to the usual lasting a few days to maybe a week or two and then remitting on its own. What they found was a third of the patients progressed to persistent inflammatory arthritis and ninety one percent of those met criteria for RA. What they've shown, which was seen in a number of other clinically suspect arthralgia abstracts at the meeting, was a scheme whereby you can stratify the risk. And my a priori information or understanding of my five career, six maybe career palindromic groups of patients is that most of them don't progress. The ones that are seropositive do progress to RA.

They developed criteria based on age, smoking, CCP positivity, rheumatoid factor positivity, and you had a score. The more of these factors you had, the more the risk. You could see the people who based on their scores, they either didn't progress at all to inflammatory arthritis where they had a small progression or they had a big time progression. Patients who had many of those features, more than half of them were progressing to a chronic inflammatory arthritis. What I liked about this abstract was that it taught me something I hadn't considered prior to this meeting, which is in the subheading of preclinical RA clinically suspect arthralgia, I'm now going to put palindromic rheumatism in that group because they behave just like all the other undifferentiated and CSA patients that are out there.

Yeah, I think they're probably in the same grouping. I don't know if I've seen some lately. I probably have, but I think we don't see them because get rid for the young ones. The palindrome is the same backwards and forwards. On the plane back, I watched Bonaparte, the movie, and a palindrome was, Abel was I ere I saw Elba.

That's the longest palindrome sentence I know. It's the same backwards and forwards. But we used to see them. Remember back a couple of years, we're doing a lot of early RA studies and people with RA less than two years. And I remember you'd see people and they'd be a good candidate for the study.

And then you'd see them back and get them ready for a study and the arthritis was gone. And was, say, well, is this reactive arthritis? But CCP super high, and then you see them again in a year later and they have rheumatoid arthritis. So I think it does exist, but I think I agree 100% with you. I think it's really in the same ballpark as clinically suspect arthralgia.

And you think of the different definitions as clinically suspect arthralgia, those that require imaging, the argument is, hey, they have rheumatoid arthritis. Don't fool yourself, but not all of them progress. And I think some of them you would then throw into palindromic rheumatism. So it's a term we don't use very much, anymore. And I think the same questions as with clinically suspect arthralgia.

That is, well, what do you treat them with? And we talked to, know, there are a couple other posters, on the treat earlier, the methotrexate study. There was a sub analysis of that was published, it was negative. But there was a sub analysis where if you looked at the ACPA negative patients, closer, the more points they got, meaning points are given for morning stiffness and which joints are involved and elevation in the acute phase reactant. So the more points you got, the better methotrexate looked.

Again, some people say, well, duh, you're just treating rheumatoid arthritis. And we know rheumatoid we know methotrexate works for rheumatoid arthritis. So what's the big deal? But it's certainly a hot topic. And I think you're seeing interest from companies in trying to treat this.

Although, and Jack had a nice review in RheumNow, I think you may be able to still get all the slides from all the failed studies. And really the studies are pretty much failed. What do we we have the Prairie study of rituximab. We have prompt and treat earlier with methotrexate. We have, Arera and Aripra with, the CTAHR And then the the the Stop R8, which was my favorite.

Was really hoping that would work, the hydroxychloroquine, and then failed. We have all failed studies in the clinically suspect arthralgia. We're still not there.

And I think it is because there are so many that are going to one remit and not actually go into, will not develop inflammatory arthritis like the palindromics that don't progress. And then we have this subgroup that thirty percent just by being ACPA positive will progress to RA, but seventy percent won't. Hany Gabaloway at RheumNow Live gave a great lecture on this. And he said that even if you are strongly ACPA positive, doesn't mean that you're going to progress at some point. It means that you have a seventy percent plus chance of actually regressing and never progressing, even though you've got the risk factors.

It still is a big clinical challenge and unfortunately we're left with not a lot of choices. If

there was a buzz, if something was making the cover of a magazine, certainly in lupus, but I think in other diseases in rheumatology, it'd be CAR T therapy. Boy, is hot. I think there are more studies than there are patients going on. Lots of different people looking at this. And of course, CAR T is the chimeric antigen receptor T cell, which you can really very effectively target a cell type.

Been used a lot, of course, in oncology, as one would expect, where if you have a B cell lymphoma, you can have a CAR T targeted at an antigen expressed on the lymphoma cell and really very completely eliminate them. The same with myeloma, which you pick antigen expressed on plasma cells. And it's been looked at in lupus, which makes sense. We know that B cell therapies work in lupus. Rituximab, there are some negative studies, but I think all of us believe that it works.

Obinatuzumab, lots of things that, belimumab, you know, therapies that we have. So this would be kind of a super, B cell eliminator. The data so far are really anecdotal. The anecdotes look great. They're talking about cure and not having to treat people again.

And of course, this is a discussion that we had some years ago with stem cell transplant. Your immune system's bad. Let's whack your, you know, get basically take out your stem cells, purify them, ablate your immune system, give you back your immune cells, let you start over. And it has some semblance to that because they have an induction regimen that they do along with the CAR T. Anyway, number of CAR T abstracts.

One that I just want to highlight a little bit and that was poster three forty. This is effects of CAR T cell treatment on B cell immunity in systemic autoimmune diseases. So this is from the group in Erlangen and Garik Shet and his group have been out in front of doing this and have, I think, maybe more anecdotes than anywhere else in the world. It was, I think, an interesting proposal to look at not just the clinical aspect, not just how well they did, but the reconstitution. So with rituximab, we don't really know a lot from watching the, B cells come back.

Some people like Thomas Doner have looked at this and to say, well, can we predict anything based on what type of cells and what subsets of B cells particularly come back and when to make any clinical predictions. So with some therapy like CAR T where it's somewhat risky, it's incredibly expensive, but you talk about remission or a cure, it's very important to know what's going to happen after therapy in terms of what cells are coming back. So they looked at a number of patients that they had. They had 12 patients, eight with lupus, two with myositis, and two with scleroderma. Gave him the CAR T, and this is with a CD19 CAR T, and then looked at what came back early, meaning about four months after the treatment compared to a year after the treatment.

And as you would expect, and maybe as you would hope, they were more naive cells in the early reconstitution and that persisted to the late. You did see some memory cells come back and also some, plasmablasts were seen. And yet the overall, reconstitution did look like maybe you could make the case that they were getting, another shot, getting a more, a new immune system and more, naive, immune system that hopefully may not make the same mistakes listening or leading to the ultimate expression of lupus in those patients. So it's interesting and with such an intense and expensive therapy, you really want to know as much about it as you can. But there were a dozen CAR T abstracts there.

Jack, what do you think CAR T?

I I'll give all the accolades I could possibly give to Doctor. Shet and his colleagues and now many other groups that are going to follow in their footsteps, likewise with small cohort anecdotal studies. Again, the great news is it's incredibly effective and incredibly safe. But I don't know of anyone that's in this clinical trial business or in the immunologic world who believes that this therapy is going to be incredibly effective and incredibly safe in everyone. So that's why we need development and why we need properly done trials.

So We have to choose our cohorts carefully as to who we're going to study. We have to choose our targets. I think one of the big areas of development is whether we're going to use the model that Shet use, which is autologous cells that are manufactured or whether we're to be using off the shelf allogeneic or other forms of B cell depleters that will do the same thing, maybe easier and less expensive to make. So a lot of decisions have to be made going forward. I thought it was 40 companies, I think it's over 100 companies that are actually playing around in this.

I fear Arty and I are ones that go to the meetings and try to look at all the content, I fear this is going to be like the early days of biosimilars, tons of research, none of it worth reporting because it's not yet ready for prime time. But at some point it's going to be worth reporting. I'll remain optimistic, but I am still worried about the safety because the FDA has come out this year with a number of significant safety warnings about CAR T cell, whether it's CD19 or BCMA CAR Ts that are being used in cancer, and there are significant safety concerns, box warning safety concerns. You could attribute that all to the host and they're all being treated for cancer, But it is still the same construct and agent that we would be looking to use. With a great deal of interest, going to hold our breath and watch.

Yeah. As with the stem cells, as with other things like also targeting plasma cells, lenalidomide, the thalidomide derivative. The adverse events and the acceptability and the risk benefit are very different in oncology than they are in lupus. And especially now that we do have lots of lupus therapies, I think it's almost more a question of appropriately using the therapies that we have in our patients. And I hate to create the term, but difficult to treat SLE is where you would see these.

And Georg's initial eight patients with lupus, they pretty much had failed everything anybody could spell and got all the immune modulating therapies that we could possibly use. So they were the difficult to treat, but that's really the, that's going to be the subset, I think that you would find would be most appropriate for this kind of an intensive therapy.

Yeah. All right. So my next one is a poster. I got two posters on the same topic, poster four, eight and poster two twenty two. And they both speak to the principle of maybe there's hope for ILD and RA.

As one who's followed this literature, I've been quite disappointed that as despite all the many patients who developed this complication, which could be ten percent to twenty percent of patients, that we still don't have an effective therapy for these folks. Nantatinib gets approved based on its ability to not improve the disease, but to leave it flat on a trajectory curve, meaning it doesn't get any worse. That's good because these are devastating outcomes. But anyway, there were two abstracts. One was from Japan, one hundred and eighty patients who had Q6 month high res chest CTs and an RA population.

The interesting thing about this particular study is that they scored the chest CTs in a manner which is not necessarily standard, but they did have a scoring method and they could define patients who progressed and who got worse and who had severe disease, etc. Then of course, they matched that against the activity of the rheumatoid arthritis. They showed that people that were in low disease activity had less than half the amount of new ILD development compared to those who were not in low disease activity. It was twelve percent versus twenty seven percent. There were many other ways that they looked at this and I found this encouraging, suggesting that there might not be one drug like, for instance, everyone wants to go to rituximab or maybe even a newer drug like a JAK inhibitor.

There probably isn't one drug. Maybe the drug that works in controlling their RA might be the best drug that they have. The second abstract that we looked at was an analysis of five year mortality in patients with RA ILD and ILD in general in the population. It draws on data from Denmark, Finland, Iceland, Norway, or Sweden. They showed that you had two groups.

Had nobody in the population who had no ILD and their mortality numbers were flat and really didn't change. If the population had ILD, they had a depression and an increased rate of mortality. The the I'm sorry, the worst was the controls with ILD. The second to worst was the RAs with ILD, which I found surprising. I would have thought RA plus ILD is going to be worse than ILD alone.

And it turns out it wasn't. And the question is, why wasn't it as bad as population ILD alone? There isn't a good answer because the design of this was just pretty much observational based on ICD-ten codes from hospital records. But I would postulate that it's because RA patients are on immunosuppressives and maybe on biologics, and maybe that is what's changing the slope of their outcome. It could be that the population ILDs would include other diseases that might actually be worse and include maybe even IPF patients and whatnot.

I found these abstracts to be interesting because they hint at the idea that the best we can do in managing RA ILD is manage RA to the utmost and hope that the ILD follows suit until we have a better therapy, or if you feel maybe they're a candidate to receive the one that's approved, which is an entendum.

Yeah, certainly an important issue. Possible explanation for what you're saying is why the RA people did better is acquisition bias or lead time bias. People with RA go to the doctor. And if you go into the doctor and you may say, Oh yeah, hey, by the way, I'm short of breath. And I think all rheumatologists now are aware that ILD is a thing and they know to look for it and you're going be getting an x-ray before you start any therapy.

So I think that may have contributed to it. But yeah, I think, and the other, I mean, with ILD, I think that may be where we see the artificial intelligence in terms of the interpretation of the radiographs of the CAT scans. Always befuddles me. Those reports are a mile long and I never know if one radiologist is going to give me a different answer than another radiologist, and they do on the CAT scan. I think having a formulaic way to assess those is going to be important, especially to look at things like progression.

And we have therapies now. So we have the, as you said, we have the Nintendonib and Perfentadone and Rociguat, and then we have all our immune therapies. So we have treatments and I think, now the availability of treatments everywhere in medicine and certainly in rheumatology drives the interest in assessing the disease and doing better with the disease.

Yeah, think that you're right, that RA patients are followed more and have more medical attention maybe then other groups, that's probably a strong factor in there as well. Okay.

So my next one, anybody who's watched Jack and I over the years in the Rheumatology Roundup after ACR and now in RheumNow doing the Europe, EULAR Roundup, We try to go to the posters and stay away from the super highlighted sessions like the late breakers. But this one, I think we just couldn't ignore it. It's an abstract that Jack has actually featured a lot on RheumNow and has a lot of people discussing it, which I think is good because it's something that needs to discuss. That's the giant cell arteritis, the randomized controlled study of upadacitinib called SELECT GCA. So just amazing how far the treatment of giant cell arthritis has come in a very short time from steroids.

Steroids were the answer, steroids were it. Only thing that we had then the IL-six inhibitors came. Now we have some positive data with IL-seventeen and now with ejacunib. Very, very exciting. I just saw a patient this afternoon and, she was on tocilizumab, actually did well in two years.

She seems to be relatively inactive. And she thinks the tocilizumab caused her diarrhea and other GI side effects. And she doesn't want to take it again. And I said, I'm not sure that's it. But she she said, what else is there?

And I said, well, maybe there is other stuff out there. So this study, upadacitinib at a low dose, seven point five milligrams or at a standard RA dose, fifteen milligrams a day, plus twenty six week steroid taper compared to placebo with a year taper. That's one of the things about GCA steroids are the standard. So the studies are tricky because you are comparing everybody has to get steroids and then you see how well you can taper them. In this case, they could have been a new onset GCA or relapsing and it was seventy percent new onset, thirty percent relapsing.

They couldn't have been on more than twenty milligrams of prednisone when they entered the study nor prior more than forty milligrams a day and naive to not exposed to JAKs or IL-six inhibitors within a month. Treatment outcome was remission at week fifty two and they did a number of other analyses, including, remission plus acute phase or actin norm normality, time to flare, use of steroids. The bottom line is that, it worked Very exciting. The high dose seemed to work better. So the primary outcome was forty six percent for the fifteen, forty one percent for the seven point five, twenty nine percent for the placebo.

Remember, the placebos are on a long steroid taper. So the lower dose didn't reach statistical significance in that outcome, but it did in some of the others and they ordered them and some of them were significant for the lower dose as well. As you do hope for and as you'd expect, the steroid exposure was less. So total sixteen hundred milligrams for the upa group versus two thousand three hundred about for the placebo. So a lot less prednisone.

And the lower dose was used in part, remember the oral surveillance found that age was a very big risk factor for the ultimate outcomes that they saw in that study. So they used a lower dose because almost by definition, people with giant cell MRIs are going to be older, which kind of gets them behind the eight ball in terms of having risk for MACE. But they didn't see it. They didn't see much of a signal in this. Now it was only the number of patients in this study, it was four thirty patients in the study.

It was encouraging. So very exciting data in that, Jakinibs may be up there now as a treatment for giant cell arteritis, which is just super interesting how far we've come in this.

I have a lot of questions about this study. It has gotten a lot of buzz. Are There a lot of people who are excited at the session and we're talking about after session. My first questions have to do with, I'd love to see these GCA trials where the primary or secondary endpoint is steroid use overall. If it's really successful, you'll get off the steroids quicker and more completely.

But that's going to be hard to do. Everyone worries about abandoning the steroids in these folks, especially in the first twelve weeks. Everyone wants to go for six months and that's a bit of a problem. I wonder if the buzz on this study had something to do with the fact that this is an oral prep. The other ones that are out there, tocilizumab, the IL-seventeen drugs, those are going to be IV infusions.

My impression is that the uptake of tocilizumab and GCA has been really slow despite John Stone's great study and sub analyses of GIACTA and whatnot. The number of us that are jumping into using tocilizumab are very few. Yet I think there are more patients that would benefit from it as opposed to staying on steroids forever. That's a gigantic problem in this subset. And then the last point that you mentioned is, are you really going to give a JAK inhibitor to a 68 year old white person with GCA and the potential for extracranial vascular involvement and God knows what else.

I think that there are some rheumatologists I've heard that say, Boy, that makes them nervous. I don't know that it should, but I think that future trials will have to define if the safety here is a major concern in this population or whether it's going to be like what we're using, but maybe more effective or easier to use. There are still a number of questions going forward. I think we're going have to see another big trial. There are some other trials of JAK inhibitors in PMR and also in GCA, but not as well done as this select GCA study.

Do we need to define difficult to treat GCA?

Well, there you go. We're going to be the difficult to treat practitioners basically. You'll subset your clinic by RA on Tuesday and GCA on Thursday, that sort of thing. We'll see. All right.

My last one is on a study that we've talked about before, and that's the Paisley study, the ducravacitinib study. As you know, ducravacitinib was approved for use in psoriasis and it's enjoyed some success. In 2022, we saw the results of the SLE trial with ducravacitinib, the TYK2 inhibitor, showing in a cohort of three sixty plus patients using a number of different doses and a primary endpoint of an SRI for week thirty two that fifty eight percent on ducravacitinib three milligrams BID responded with an SRI for compared to thirty four percent of placebo saying, We're off to the races using a TYK2 inhibitor in lupus. In this study, OP0048, it's a sub analysis of the PAISLEY and not a three sixty three, but of one hundred and one patients who had chronic skin disease, looking specifically at skin responses. So maybe some of the critique of the TYK2 inhibitor is it's good, it looks like it works, it's just not overwhelming in psoriasis and psoriatic arthritis.

The question is, what's its role going to be in lupus and where are you going to use it? In this study, assess skin responses by what I think is a standard validated tool of the Class C50 and the Class C70, a high level response and a much higher level response. Then looking at forty eight weeks, what happened to those who received either placebo or what were the doses? The three milligrams BID, six BID, twelve once a day. In the end, the Class C fifty at forty eight weeks was fifty six to seventy percent.

And that's impressive. What kind of skin disease are we talking here? This CLE group, chronic lupus skin disease included acute LD, malar rash, etc. Discoid LE, subacute LE, and another group called chronic cutaneous lupus. Those are the ones that we struggle with.

What I like about this is it's trying to go for a lupus indication using an organ specific endpoint as opposed to the SRI-four and these global lupus response definitions, which I think are fraught with pitfalls and high placebo response rates and pitfalls in trying to prove that it works in lupus. Why not prove that it works in lupus nephritis or in lupus lung disease or hematologic disease? I like the skin disease, but I'm hearing from the clinical trialists in dermatology is that the FDA is having a hard time accepting the class C50, class C70 as a primary endpoint upon which you can power and design trials. That may be a holdback on this indication for what looks to be an effective drug in lupus.

Yeah. There's great experience with the JAKs in a variety of autoimmune skin diseases. You look at the topical, the ruxolitinib. They have other topicals in development. Look at atopic dermatitis.

Look at alopecia areata. Our dermatology colleagues are kind of blowing past us with the use of the JAK inhibitors. I think the TYK2 makes great sense in it. I agree with you. I think it's a problem to use those composite indices because there's so much noise that you can lose the signal.

I think focusing on one aspect and the studies focusing on lupus nephritis has been much cleaner than the studies looking overall at bylag and SLIC and the SRA4 and whatever, those things, they're inherently more, confusing with different domains that could be going in different directions. So I see nothing wrong with the skin domain as an outcome. Think hopefully the agency does accept that. I think, it'd certainly be nice to have. We don't a ton of great options for, lupus skin disease.

We try mycophenolate. I don't think that works very well. There are hydroxychloroquine and vitamin H, everybody has already gotten that. And if they're coming to your office and still complaining about skin, the black quinol wasn't enough, so they're difficult to treat cutaneous lupus. I think we do need the options.

And I think hopefully the experience from our derm colleagues is going to be something that will help us get access to this.

So I think there's, two Phase three trials in progress in lupus and to grab a second and they're probably going to go after an SRI for or Biclo or something like that. But hopefully they'll do more sub analyses that might force this issue about skin responses. Anyway, that's it for ULAr twenty twenty four in Rheumatology Roundup. Make sure you look for our Rheumatology Roundup at ACR twenty four this year going to be in Washington DC. We're looking forward to that.

We also want to remind you that RheumNow Live is on for next year, February 2025 in Dallas, Texas, or virtually in your living room. Either way, we'd love to have you and look forward to that registration begins next month in July. So Artie, thanks for your input. This was great.

Thanks for tuning in and best wishes to everybody a great summer and we'll see you in the fall.