EULAR 2025 Rheumatology RoundUp Hosted by Dr. John J. Cush and Dr. Arthur Kavanaugh Save

You're listening to a RheumNow podcast coming to you from Barcelona, Spain, and you are 2025. Hope you enjoy it.

Hello, everyone. Welcome to you are 2025 Roundup. We do this every year after ACR, after UR. I'm Jack Cush in Dallas, Texas. I'm joined by

Apps Party. Kevin on here in San Diego.

There we go. You know, this is where we get our chance to tell the favorite things of the meeting that just completed in Barcelona. Artie, what what was your opinion of this meeting? Have we returned to normal at big conventions, ACR and EULAR or what do you think?

Yeah. I think EULAR finally learned their lesson and had actual posters, which is definitely the way to go for a meeting. Unfortunately, they turned it into like hot bedding on a nuclear submarine. They had the poster change about every hour. So there were three poster sessions a day, which really made it hard.

You like to like to have the posters up and the presenters there so you can go talk to them. So it was much better to have actual posters, but hopefully next year they don't try to squeeze everything into one small session.

Yeah. I think they were just using limited space and turning over the space like a busy restaurant. And so it was hard. It's hard enough to find the actual authors to speak to them about their papers. I don't know what the deal with EULAR is, why so many people don't stand by their poster, but that is a problem for them.

But there were a lot of good posters and there were a lot of good presentations. So let's get into it. I wanna start off with Alto, A L T O presented by Andy Cope. This is the long term follow-up of the EpiprA study. And you might remember EpiprA from a few years ago.

It got a lot of press. It was a trial and there were a lot of trials and we're gonna discuss, I guess, clinically suspect arthralgia and what to do with those people. This is a trial that looked at abatacep for one year versus placebo for one year. And patients with arthralgia who were ACBA positive, they did not have to have subclinical synovitis to get into the study. And it was one year of therapy and then another year of observation.

And at the end of both the treatment period, there was obviously a significant difference between abatacev treated people versus the placebos. I think like thirty percent of the placebo people developed RA versus six or nine percent, something like that. Clearly significant, clearly a big difference. And then in the one year follow-up where everybody's on nothing, the lines start to come together again. Now in this study, Alto, it's a long term follow-up.

So in the original study, was two thirteen patients in Alto up to six year follow-up where they have good data on about four years, 143 patients. So two thirds of the patients entered into this long term follow-up. And it looked like the claim was that one year of abatacep gave almost an additional three years of benefit. But by the end of that three years or a total of four years, the lines are coming together. And the question is, is that significant?

It clearly isn't prevention, but it's a delay. And then the other big thing from this particular paper was, well, how do you know who's really gonna respond or respond best? They gave the sort of an indication of that in their presentation from 2023, but not in the paper that they published. And that was if you had this extended auto antibody profile, meaning you had five auto antibodies typical of rheumatoid arthritis, two ACPAs, rheumatoid factor, anti carbamylated P antibodies, and another one called ACA, that you've had an even greater effect suggesting, their suggestion was that if you had maybe more disease with more autoantibodies, you're more likely to respond to the aggressive therapy. Arty, how did this sit with you?

Yeah, boy, we've been talking about the whole issue of clinically suspected arthralgia and how best to handle these patients. And this was maybe the most intriguing data that we've seen yet because you have people, you really do see a separation out after one year treatment. You see a separation out going certainly to three years, about to four years, then it falls apart. Then the curves overlap and people who are gonna get RA got RA. But a year of treatment was very promising.

You wonder, and this was in our presentation, we didn't get to ask the authors all the questions that we wanted to, but what if it was the they all had to be active positive? What if you had four of the five? What if you had three of the five? And I'm sure at subsequent meetings they'll dig into the idea of are there other characteristics? And maybe, you know, maybe this isn't one of those areas where you need AI because we like things that make sense, but maybe it doesn't make sense.

Maybe you just look at the data and it's left handed people or people with a tender joint count less than six, something else that would help to separate them. But I think it is getting to be where you may offer patients treatment with informed discussion of the risks and benefits with the hope that you might delay the onset of disease.

Yeah, I like the concept of delaying disease, whether you have the five serotypes or not. Again, did show one figure that if you had the five serotypes, then you got this six year protection. If you didn't, you didn't get the six year protection. You're like everybody else. But why would all of sudden four positive serologies for RA not be as good as five?

That doesn't make a lot of sense to either of us. So I don't know about this. I do like the idea. And the other point I wanna make that I think all these studies are gonna bear, are gonna tell us is that with long term follow-up, we'll know what the impact of a delay is. Does it change the trajectory of disease?

How rapidly one gets disease? Does that change what ultimately happens to these people? And Andy Cope has got a lot of sub studies and long term studies planned for this cohort. So we're gonna see more of it, but this is not the only one. There were other early RA or not early RA, but these clinically suspect arthralgia patients.

RD, I'd be interested in your comments on the PALABA study, not palabra, PALABA. PALABA was a palindromic rheumatism study. And I think that based on these studies, I think palindromic rheumatism is another form of early disease, another form of preclinical disease. What was that? There was abatacin versus hydroxychloroquine in DMARD naive, RF or aqua positive people, a total of seventy patients, not a lot, but clearly a difference of benefit from Abba, no benefit from hydroxychloroquine, which is another version of what we saw in Stop RA last year, but that didn't work.

So, is palindromic groupism another version of RA wannabe preclinical RA and what do I think of this

think it is. And I think we don't use the term anymore. It's kind of like, it sounds old. But I think it absolutely positively exists. Remember, there was a time when there were a lot of early RA studies, and it was less than three years disease, was less than two years.

And we retried to recruit for those studies. And I remember a fair number of patients that you would see, they qualified for the study based on the number of joint counts. Then you see them again for the baseline visit and they didn't have it. And then later on they developed it. So they would fit within the definition of palindromic rheumatism.

And I think it's not necessarily uncommon. I think a lot of people with early disease had that pattern. We always used to say, you know, you get a dose pack of prednisone or methylprednisolone, and then it you're good for a year. Well, you had palindromic rheumatism. It was probably meant to be to go away anyway.

And, yeah, it is interesting, like I said, hydroxychloroquine is almost a negative control here. It showed in stop RA, it did not work at all. And here, the abatacept did, so that if you look out that two years, you had eight point eight percent of the people treated with abetacept developing actual arthritis compared to twenty seven point eight of those treated with hydroxychloroquine and a real clear separation. So it looks like if you're thinking about treatment that abatastin is certainly someplace near the top of the choices that you would make.

No, and that number that achieved with hydroxychloroquine goes to that number we've learned from Kevin Dean and so many others If that you're seropositive with arthralgia, got at least a thirty percent chance of going on to develop RA. It's exactly what happened with hydroxychloroquine, but not the avatacep group. So I thought that was an interesting study. There's a lot of studies. There was a long term follow-up of the Araya study, and that also said of the four years of benefit.

But I think what all these studies are saying to us, and Arty and I've been in the group, and when we were discussing these studies in the past, Araya, Apipra and whatnot, a prairie treat earlier, the argument from half the group was, this stuff doesn't work. Those people really had RA. And well, no, they didn't have RA because they didn't have synovitis and they didn't meet crazy. Wow, they really had RA. I think that the both of us, all the opinions were right in that the closer you get to RA, the more you should be treated.

Meaning with each of these factors, ACBA positive, double positive, first degree relative, acute phase reactant and subclinical. The more you add on, the more you're ratcheting up your way to RA, the more you really do need treatment. And that came out in a recent UR paper or UR risk stratification guideline that said, who's gonna have, who has clinically suspect arthralgia. And when you look at the criteria, as a point driven criteria, but morning stiffness, patient reported swelling, difficulty making a fist, CRP, rheumatoid factor, ACPA, all the criteria for having RA, is it not? And the more that you have, the more you're ratcheting up the risk.

Yeah, showed that years ago with methotrexate in the more recent treat earlier study, found it. But back when in the prompt study, remember they also, found the same thing, namely that if you were really close to having the definition or, satisfying the classification criteria for, RA, then methotrexate really did have an effect. If you were less than that, it it it you got the signal was drowned out by the noise and you didn't. So yeah. And I love those, risk stratification criteria.

It must have been a bunch of old guys sitting around, morning stiffness, difficulty making a fist. That's old school RA treatment right there, isn't it?

Yeah, proves that they wanna talk to patients and examine them. That's the way we should still be going. All right, what do you got, Arti?

Well, the different disease, but kind of seems like a natural follow-up. There was a poster that I liked and you liked and I think a bunch of people liked rheumatoid factor in patients with EGPA. So eosinophilic granulomatosis with polyangiitis. And I think we liked it for a couple of reasons. One, even though the poster presenter was not there, they had their email there and responded really well to questions on the email.

I think they would have been there. The posters, as I said, the sessions were too short. So I like that. I like interacting with the presenter. And also, it was a clinical observation.

So what happened is they made a routine observation in their clinic and, the doctor Luca Iorio said they have about 180 EGPA patients in their clinic at the university where he is and made a clinical observation and then went and looked at it more. Clinical observation was that in your EGPA patients, the patients with rheumatoid factor positivity were a little bit different. They tended to have more severe disease. So then they went and they looked. He did say that it's not everybody, was about eighty three out of the one hundred and eighty EGPA patients had rheumatoid factor testing.

So, they looked at that population who had the testing and the testing was done if they got hospitalized, they had a panel of stuff that they did including rheumatoid factor. And then more recently, they actually started checking it again. But what they found was that the people who are rheumatoid factor positive did a lot worse. They had higher disease activity, much more modernized multiplex, 53 versus thirteen percent. They relapsed much more frequently, forty percent versus two percent.

So it was a pretty good prognostic factor for bad outcome in EGPA. So this was observational. He did say the titer didn't seem to have an impact. They excluded diseases like rheumatoid or Sjogren's that could muddy the waters as far as the diagnosis. So I'm gonna be looking to this.

This is something I think you can look in the clinic and say, why not? You do another tests, they have an EGPA patient, maybe check a rheumatoid factor to see if this washes out because just anecdotally, looked like it was a good strong predictor.

So, well, we don't know mechanistically what this means. We don't, you you have to postulate that, I think it's either one or two things. Somehow there's immune complexes that involve rheumatoid factors being made that contribute to the pathogenesis of what's going on clinically, or that the rheumatoid factor is a biomarker of heightened immunologic activity. We do know from other studies, observational studies mostly, like this study, that for instance, ACPA in ILD is a bad thing, that ACPA in lupus nephritis actually is a marker for patients with more aggressive disease. We know that being double positive, we clinically suspect arthralgia lends to a greater risk, if not more severe disease.

So do you think this means that the markers of heightened immunologic activity, we should be looking for in other diseases as was found here?

Yeah, and potentially, the old association with TNF inhibitors and ANA positivity came only because in the Kennedy Institute where the first studies with infliximab were being done, that was part of their assessment. They did ANAs on everybody, even knowing ahead of time that quite a number, twenty five or so percent of rheumatoid will have an ANA, but they found a lot more. And subsequently, you know that with the TNF inhibitor, you get a lot of people converting from ANA negative to positive. Some of those people actually get clinical manifestations of lupus. It was just an observation they made in the clinic.

And yeah, maybe it's an indicator of something going on with the disruption to the immune system. We just don't know what.

I don't know whether to be excited by this or upset by this. I'm a purist, I don't like ordering a lot of labs. I hate people who do. I don't hate people. Dislike the idea of doing panels and batteries and whatnot, or, and doing them repeatedly, but this also kind of says that I may not know what I don't know here.

And I think this really begs for more, more research, more consideration.

Yep, absolutely.

All right, so I got an interesting one from an early arthritis cohort that looked at patients with RA who are on methotrexate and who were in remission. They've been treated for more than twenty four months, I think they were in remission for greater than six months. And they looked at what happened in those whom that they flared. So again, I'm sort of against the idea that you get a disease under control, you stop the therapy, but in these people, again, it was the numbers who stopped their methotrexate flared and they restarted their methotrexate was sixty three patients. And they looked at what happens to those people?

Can you regain control or not? And the graph that we showed, the graph that we saw is that the vast majority of them regained remission, albeit at a slower rate than they would have probably done, achieved initially. And that is whether you're measuring your success of re control, if you will, by either DAS remission harder to achieve, longer to achieve, or a DAS low disease activity, a little easier to achieve, but about eighty percent at three months regain control. So in one sense, it's kind of good news. The other thing is that if you follow those people out beyond six months, it was well over ninety percent regain control.

So for those of you who want to withdraw therapy and think you're doing a good thing, I would argue against you, but this data says much as has been shown also in, was it RA seam and PSA seam that showed that when you reinstituted therapy, you gained control on majority of individuals. So this is encouraging data.

Yeah. I think this too, this really harkens back to a very old study from The Netherlands. The Tenvolde was the first author, T E N W O L D E, published in The Lancet in the 80s, where they did something very similar. They used some methotrexate, but most of the people were on sulfasalazine or D penicillamine, which the younger people have to Google to figure out what that was, or chloroquine. And they did this same thing where they took people in D permission and stopped treatment.

And the take home point, which I think is a useful take home point for those of you seeing patients, is you can go ahead and you can do it, but you may, you're not gonna get your response back immediately. The chances are you will get your response back, but that could take some months. And I think that's a reason to some people will say, well, maybe don't stop. Maybe you should just cut the dose and interval spread the interval from seven days to ten or something like that. And you know, maybe that's a reasonable compromise.

I think it's important data because I don't recommend it incredibly rarely, but patients do it all the time. They very commonly ask, don't they, if they're doing really well, hey, can I stop? Can I cut back?

Yeah, let me, do a little bit of box score recaps here. I've got to mention the abstract numbers. This one that we just did on methotrexate and regaining was OP-one 107. The first one I did on Alto was OP-three 25. And then the Palava study was OP-one 105.

I think we're caught up. Let's go into the next inning.

Okay. All right. The one I'm gonna pick, let me, it's a good reminder, Jack. This is a late breaker at late breaker 10. And this is the APeX study.

And the APeX study is in psoriatic arthritis. It's a study with the IL-twenty three inhibitor gazelkumab. And the primary endpoint was clinical, the ACR-twenty response at week twenty four. But the major secondary endpoint of interest was the change from baseline in the modified Sharp Vandelheide score at six months. And it was interesting because it follows on from the discover trial and the discover trial, the there was a significant difference in the progression of x rays at the higher dose that was gazelkumab every four weeks, not statistically significant at the, every eight week dose, which is the typical clinically approved dose for psoriatic arthritis.

So this study was done to sort of see if you could prove that there was an actual difference in structural damage. A thousand patients who had actual erosions and a bit of an elevated CRP greater than 0.3 milligrams per deciliter, in addition to having active disease. And they did the axelimab every eight or every four weeks, the clinical responses were almost entirely overlapping and of course the active treatment did better than the placebo. They did demonstrate an effect on x rays. I think it's a super interesting area just to do a little shameless plug or disclosure at our upcoming GRAPA meeting, GRAPA is the group for research and assessment of psoriasis and psoriatic arthritis.

I'm going to debate Will Tillett and I'm going to take the position we don't need to do x rays in psoriatic arthritis anymore. And if you look at this data, you say, yes, it was statistically significant protection from structural damage progression with either dose of gazelkumab. But the amount, the mean change, which of course we shouldn't do, these are very skewed data, so you shouldn't look at averages, but the mean progression was 1.35 with placebo, and with either dose of gazelkumab, it was 0.54. This is in the PSA specific, modified Sharpe and the Heidy score, which goes from zero to five twenty eight. Five twenty eight and we're talking about a difference of one versus 0.5.

So the meaning of that, I don't know that there is meaning to that. I think we're still chasing this from back in the day when we had a lot of X-ray progression in rheumatoid, we had much more X-ray progression in psoriatic arthritis, we just don't see that anymore. So the results are positive, they're consistent, but I don't know. And I think there's so many studies that look in assessments that say, if you don't have joint swelling, you're not gonna get x-ray damage. So you don't need to look at these.

You can just see, look at the patient.

But knowing you well, I also know that if I asked you to argue the other side of that debate, you would do effective job saying this is important. And we do look at x-ray protection as being the marker of a stronger drug. We have a lot of drugs right now in PSA space, and some we're gonna classify as stronger, usually more expensive and newer. And some we might say as being milder. And that includes some of the new drugs that are coming on.

And maybe the differentiator between them going to be, could be the magnitude of their ACR 20 or the delta between their ACR 20 and the placebo rate, but it could be whether or not they have evidence of x-ray protection. In this study, it was at week 24 and the new Crabicitinib presented the same morning by Desiree Vanderheit, it was at week 16. But again, these numbers are incredibly small. They blow up the results. So it looks like they're significant, but they're all less than one.

I struggle with, do we need x-ray results to be a stronger drug right now in the marketplace? And the companies are investing, this is a very large trial, by the is a thousand patient trial that was done. And so this is quite an achievement. And they had to do the right thing. They had to get people who are likely to progress, right?

Meaning that they had erosions, they were had a high CRP, they were more likely to progress and they showed good clinical differences and now they shows X-ray difference. But again, I think if we asked 10 rheumatologists, we might get 13 answers as to whether this is important enough.

Well, I think you can't say you don't care about structural damage because that would mean you're a very bad person. Like I don't care about patients damage. When you look at these, all of the change, even in an enriched population is driven by just a few of the patients. And as you just said, with the other data, you're looking at changes of 0.5 to one. Remember that the smallest detectable change from two very experienced x-ray readers is about two to three.

The smallest difference that has any impact on HAC, a 0.1 change in HAC is about 10. So what are the meanings of these? And I think of course the problem is driven by the ethics of not being able to have placebo controls for a year, which you can't do. We have so many good treatments for PSA. The POETIC studies were done with the Nuclavacitinib at week 16.

Very, very short because you can't have placebo control beyond that, which makes the assessment of a longer term outcome like x rays almost a moot point.

Right, and I'm not sure that using finer, detection methods like high field MRI really makes us smarter, or more certain about these contentious arguments. All right, so my next one is also a poster. Posters are just as good as oral presentations, are they not? Mean, when you go by and I mean, this is one of those posters, I'm just walking by, I'm kind of speed walking by the posters because I don't wanna stop because might never get away. And I saw this one out of the corner of my eye and I actually, I had overshot the runway and had to back up mainly because the lead author, Doctor.

Holzer from Hamburg was there, poster POS ten fifty one, myositis patients in the ICU. That got my attention, right? Because we all take care of myositis. And I got a particular concern that myositis patients have a lot of problems. They got a lot of toxicity because of all the steroids we use.

The outcomes that happen here are dangerous. There are many types of myositis and there's new guidelines that you are put out at this meeting on myositis classification. And I would encourage you to look for those. So this particular poster was a retrospective analysis from a single center of 23 patients with idiopathic inflammatory myositis admitted to the ICU from 2014 to 2022. The main reasons for admission, you ask?

ILD weakness in muscle involvement manifest as either dysphasia or myocarditis or outright weakness. The bad news is that the outcomes were kind of bad. Meaning these patients on average were in the ICU for thirty two days. Two thirds of them required mechanical ventilation. Five out of the twenty three died either from infection or from bleed.

Why they had bleeds, I don't know. Overall, they were hard to manage, they were sick and the outcomes were disappointing. And it's because they were sick going in at admission, eighty seven percent were on immunosuppressants and steroids on admission. And the takeaway message was beware of these people, worry about these people. And the ones who are gonna have the worst outcomes are the ones who present with dysphasia or pulmonary or cardiac involvement right from the outset.

Yeah, we certainly see patients in the hospital with myositis and it's kind of, you know, it breaks your heart that we don't have great therapy as we throw everything at them. They usually got a boatload of steroids before we even get to see him. We go with IVIG. We still use cytotoxin. This is one of those instances where we break out cyclophosphamide, which was always what we gave people who were very ill who had any rheumatic disease in the ICU.

Yeah, we've seen a couple of these this year already and they're tough. There's not a go to therapy that I think is where you say, well, I'm gonna go with this first because there's the best evidence.

Right, I I like this also because it reaffirms what I've been teaching for years that the danger signs of myositis in the hospital is dysphasia, dysphonia, and dyspnea, either because they're gonna get respiratory complications, including pneumonia along on top of their ILD, or because they may have because of the upper pharyngeal involvement, they may have aspiration and go downhill from aspiration pneumonia, etcetera. So yeah, like this poster.

Okay. Well, I get gonna do another poster and I just hesitated, but think we gotta represent what was, you know, showing at the meeting. So CAR T. There's, I think, more CAR T companies and certainly more CAR T studies than there are patients with lupus. And but it's the hottest thing.

Our colleagues in, oncology are using this. It's, of course, chimeric antigen receptor targeted therapies. Many of these are directed against B cell targets like CD19, but also CD20 and other targets like BCMA that are present at different stages of B cell and plasma cell development. Very cool constructs in a way they're like super B cell depleters, and we've had experience with rituximab. Now we have obinutuzumab, which seems to be a much more efficient B cell depleter, but these may be sort of a level beyond that.

There's a lot of issues with it, and I think many people have had experience at their sites with, if there are research sites with trying to get these studies ongoing. You take cells out to put in the chimeric antigen receptor, which requires leukapheresis. Then you have to condition the patients with two CDA and cytotoxin, which of course is very dangerous. Then you give them the CAR, and then, their B cells get depleted, at least in rheumatology, that's where they've been most of them. So, we're seeing more and more of this.

It's interesting. I was reading that the oncologists are up to their fourth generation CAR, and now they have CARs that deliver increased levels. The cell actually produces increased levels of targeted cytokines like IL-eighteen, which can help with the local response to the CAR T. So super cool constructs. I think though, I'm not sure that we'll see them very close to us in the clinic.

There's the cost, the conditioning, which means that you're going to be immunosuppressed to a great extent for a long time. So I think we may see not exactly related, but kind of a similar design and that is with bispecific and trispecific antibodies. So, I picked poster eleven sixty, mozanetuzumab, which is a, obviously from the name humanized, but it's a bispecific antibody that binds CD20 and binds CD3. So it brings the T cells directly in contact with the B cells to eliminate them. And it was a proof of concept study, but what they showed is that a dose escalation, they can get very extensive and pretty prolonged depletion of circulating B cells.

It's easier if you think of it, it's in monoclonal antibody. So it's a very cool, very new, incredibly whiz bang design, but it's a monoclonal antibody. So you think of that, I think, in a much easier way than you think of CAR T with all its, invasive nature of what you have to do to the patients to get that. So I think we're going to see more of, I bet we see more of this. And if you think of other diseases, so right now the CAR Ts have mostly been in lupus, which of course can be severe and life threatening.

Myositis, like you just mentioned, the life threatening. And therefore, if you're doing the risk balance, the riskier the disease, the more risk you're willing to accept with the therapy. So I think that the bispecific and trispecific antibodies will be something we may see more really in the clinic.

So, and I'm going to present a bispecific antibody next, but, regarding CAR T, I think it's great that all this research is being done. I think the excitement of a cure that's long lasting is incredible and sort of mind blowing. But I want to caution the audience on two things. CAR Ts have been successful in management of malignancy, certain malignancy, but not without trouble. There's a lot of trouble.

The FDA, last year had a new box warning on CAR T cells and certain leukemias and whatnot. So these are, and that could be because they're dealing with cancer patients and that's often the case, but CAR T cells don't have a clean slate on safety. And that's gonna be a big concern along with their success. Will the success be as good as Professor Shet has shown us? I mean, I can only pray that that's the case.

I would also secondarily worry about a reporting bias. There's so many studies going on right now with so few patients, and we're gonna see this little drip, drip, drip of information on six patients, four patients, 10 patients, without seeing a really well designed trial. And then you're not gonna see the reports where it failed. And so you need a certain amount of caution, think in interpreting it. I think the excitement is gonna be in 2027, when we start to see some numbers that we can look at and say, oh, now this is the next lesson on CAR T in rheumatic disease.

So I'm gonna wait for that. But I'm excited by this and that's why like the poster from Max Koenig at Hopkins, poster POS 17. He's not quite seven, he's 17. Bispecific T cell engaging antibodies to target TRBV-nine, auto reactive T cells and axial spondyloarthritis. What the hell is Cush talking about?

The label here is TRBV-nine positive T cells. This is T cell beta chain variant that actually is expressed in a high percentage of patients with ankylosing spondylitis. Basically telling you that CD8 positive T cells that bear this are very much involved in sort of class one mediated immunologic activity, if you will. And this is found in a high percentage of patients with spondylitis also in patients with Crohn's disease. And the idea here is maybe if you can deplete the CD8 T cells that are TRBV9 positive, that you'll get control of the disease.

But the question is, as is the case with any depletion technology, B cell depletion. Back in RA, we were doing T cell depletion, anti CD52, anti CD4, and in transplant, anti CD3 T cell depletion, all hampered by infection as their Achilles heel. We worry about that with B cell depletion. We're gonna worry about this with these autoreactive T cell depletions that are TRBV-nine. So he's basically developed using CRISPR technology, a bispecific antibody that will deplete these, he's shown their effects in vitro and in cultures.

And now this is ready, this bite or bispecific targeted therapy is gonna be put into patients with spondylitis. And they've shown that in culture, there's a biologic effect when you use these. So again, I think it's exciting. It might be the next new thing in the management of spondyloarthritis. And it's really early to be talking about this, but I think this has potential to be the next big thing in spondylitis management.

Yeah, I think there's a lot of interest in this. And as you said, scientifically it makes sense and it is increased, the use of that receptor is increased in patients with the SPA spectrum of diseases, including ankylosing spondylitis and inflammatory bowel disease. There's some trepidation about this or weariness of the data, I guess. Almost all of the early data came from Russia. And people hear that and they're like, okay, I don't know.

But data are data. There are studies done all over the world. Traditionally, there have been lots of studies done years back in Eastern Europe in psoriatic arthritis and also ankylosing spondylitis. But, you you wonder, when people reporting side effects, I remember not so many years ago, there was a novel anti IL-seventeen with zero adverse events. And like, that's probably a little bit higher than zero.

So we definitely need replication. Scientifically, it's very interesting, but we really wanna see if it really makes the cut.

So Agreed.

My next one, I I'm I'm seem to be drawn to old old school stuff here. Maybe I'm getting old. This is, poster 173 and it's from AMP. AMP is the accelerating medicines partnership. And they've done a lot of work in rheumatoid arthritis, spatial transcriptomics, super cool, super fancy stuff, looking at the individual cells and the spectrum of inflammatory and other mediators that are differentially regulated in diseases like rheumatoid arthritis, also in lupus, and also now in psoriatic arthritis.

So I'm not sure it will come of this, but it makes great sense that you're looking at a complex area of tissue like the inflamed synovium in inflammatory arthritis or the kidney in lupus with lupus nephritis. And we used to do, we chop up the tissue and just sort of look at it very grossly. Now you can do it much more elegantly, but this is really much more of an old school sort of thing. So they looked at a bunch of their patients that they had had one hundred and seventy two lupus patients followed up to about five years. And they had a indication for a renal biopsy.

And they included of the one hundred and seventy two and grade two all the way through grade five lupus nephritis. So just mesangial change all the way through membranous. A third of the patients had a decrease in their GFR and they lost renal function. They looked at what correlated with that. And very interestingly, the urine protein to creatinine ratio, which was elevated, didn't really change much.

It stayed, at an elevated level, didn't vary a whole lot over time. Some of the things that we love looking at, dsDNA, c3, c4 didn't correlate with the renal outcome. What did correlate with renal outcome is the NIH chronicity index. So the activity index didn't really provide as much information. Now, are people who are treated, so that kind of makes sense, but, it's really the damage.

And I think I like this because I remember years back, studies in lupus nephritis would look and say, what correlates with the renal outcome? And it was hypertension, was above and beyond the most important feature. And I think we've done better in recent years with the care of patients with lupus, especially lupus nephritis. A lot of it is due to ancillary things like being able to control the blood pressure better, like being able to improve the ICU care. So we like the immunology parts of it, but we have to remember, you know, there's other things that are important and that you really if you have damage, that portends a greater risk of renal, function loss.

So the question really is, I like all those teaching points, but it's delivered in a taco shell of spatial transcriptomics as if to make it taste better or sell better. And in the end, it's old school, you know, rheumatology that, you know, tells us the messages. So the question is, I mean, obviously spatial transcriptomics is we're seeing a lot of that now. It's giving us thousands and thousands of data points to look at and consider, but they don't yet pan out. I think it's gonna have to be a merge of technologies.

AI is gonna have to get involved here. We're gonna probably need more sampling. I mean, they had a lot of sampling in this study to get to the next level of understanding and where the understanding results in a better therapy, your next best choice.

Cool. Do got, Jack?

I'm going old school too. There was on the last day, there were three or four guidelines presentations at EULAR. This one was from Professor Patrick Healy talking about classification criteria, EULAR classification criteria for hemochromatosis. You should be seeing hemochromatosis. There's autosomal recessive.

If you're looking at Northern European or Celtic people, they've got a one in three hundred prevalence. That's enough to be a fair amount of people in your clinic. And there surprisingly is very little in the way of research being done in this area about the musculoskeletal manifestation. He went into the history of this, wasn't until Ralph Schumacher sort of made a big issue of the diagnosis and the musculoskeletal manifestations like hemochromatosis that this sort of took off, but not much has happened since. So we do know that again, this is a uncommon thing, although, you know, it's based on HFB gene mutations, most commonly the C282Y mutation.

But they did a three phase process to come up with an expert panel coming up with criteria for the diagnosis that you could classify someone as having musculoskeletal hemochromatosis. And it's a point system and you need to have five or more points out of a total of 11. And if you had the five points or more, 71% sensitive, 93% specific. And what do they hang their hat on? They hang their hat on two points each for joint symptoms before age 50.

That's two points. The absence of DIP involvement, you get two points interestingly for not having something. And then one point each for the rest of them. And I like the iron claw. I had never heard this before and I should have heard it.

And they showed you a fist. And that when the knuckles two and three are much higher than three and four, they call that the iron fish. You can see it with an end on view like this or an up view like that that then these two rise up higher and it's due to the Os involvement of the second and third MCP. So, the iron fist involvement of MCP's two, three or four, hip or ankle surgery, that actually gets you two points, but I don't know why. And then either joint space narrowing or subchondral cyst at MCP's ankles being the main two there.

And the last one hook osteophytes at MCP two or three or the ankle joint. And that's how you got your 11 points and five or more. So it was kind of a really clinically relevant session with some nice teaching pearls, and it really promotes the idea of doing the research in a not so uncommon disorder.

Yeah, it's interesting as you say, definitely see a lot of patients with hemochromatosis just because there's a lot of humans with that. But we have not paid as much attention. I think we sort of said, add pseudogout, you know, let's treat it like that. But it's no, it's more complicated than that. So it's good to see people who are really paying attention to that.

So my next one, maybe I just like the name. This is also a late breaker, late breaker five and it's repurpose. So R E P U R P S S two. And it's a study of leflunomide and hydroxychloroquine in Sjogren's syndrome. Sjogren's syndrome is interesting, isn't it?

There's so little data on things that seem to work. Everybody, all of us use hydroxychloroquine and the best studies of hydroxychloroquine showed it did not work. So and yet we don't have anything else. So we kind of use that. This looked at the combination and this was leflunomide and hydroxychloroquine.

Yeah, with a crossover compared to placebo, twenty milligrams of leflunomide, four hundred of hydroxychloroquine, relatively small numbers of patients. But even with the twenty, twenty five patients per group, they did see a difference in the change in the ESSDAI, the of the ways that we look at disease activity in the Sjogren's syndrome, measures a variety of the important features including glandular, systemic, etcetera. And it was the data were nice in that the SDAI score was really flat in the placebo, relatively small, variance, in the measures. The, active treatment group decreased so that from nine where the placebo group stayed, they were down more around the range of three to four in the SDAI score. They also looked at the CREST, which is a newer one.

This is the composite of relevant endpoints for Sjogren's is similar accounting of the diverse symptoms of Sjogren's, just weighted a little bit differently. And again, it looked like that actually worked. Very practical study, leflunomide, a drug we've had around for a real long time. First in RA, it got a little play in psoriatic arthritis. We know that we can even use it in some cases for vasculitis and here maybe in Sjogren's and I don't know, I might have to try this next time I have a Sjogren's patient.

I hate writing Plaquenil knowing that the data were really negative for the hydroxychloroquine by itself in that large French placebo controlled study a few years back.

Yeah, this is hampered by being A, exploratory and B, low volume and short term outcomes, but it's still a positive report and everything else has failed in Sjogren's despite all our treatments that we use. Defy anyone to show me a good phase two or phase three trial that can back up what you're doing in your Sjogren patients right now. So any kind of positive result, and there are a number of trials that are much larger in phase three that are in progress. So this could soon be a very exciting area in rheumatology. And I'm hoping that that's the case.

Arty, which should I end on? The RA guidelines for RA treatment from Smolin or the interstitial lung disease guidelines also from ULR at this meeting?

Right. Well, the the to me, the RA ones, it's kind of a where's Waldo? Like, where's the difference? They they they they started them by saying how urgent it was to redo them every three years, and you really have to look hard to see what the difference is from the guidelines three years ago. I would vote for ILD.

I agree. ILD was, I think, the more interesting of the two, but still hampered by major advances that we can take to the bank. So you might remember the ACR guidelines, ILD that came out in 2023, where it didn't matter whether the ILD was due to scleroderma myositis, MCTD, Sjogren's or RA, everything was kind of like, our experts say you can use almost anything from mycophenolate to rituximab to cyclophosphamide. And in the case of scleroderma, you could use a tocilizumab and there was no strong recommendations. Now that you are update is pretty much the same except now there's a strong recommendation for if you have systemic sclerosis and ILD that you get tocilizumab and diffuse systemic sclerosis and I'll you get a strong recommendation for to for all the others.

It's kind of it's still conditional recommendations with expert opinion but at least in the case of a they suggest an approach that everyone should go through And that is to worry about it and to certainly evaluate patients who are at higher risk. And the risk factors in RA is age, male, smoking, seropositivity, etcetera, HRP and high disease activity. We said before, the things that we've taught from these meetings that the three S's will put you at high risk, seven fold higher risk for UIP with RA ILD and the sex zero positivity and smoking sex being male. But if you have those, you should be assessed. And if you have ILD, the recommendations that are conditional or immunosuppressive, abatastive, rituximab, JAKs, combinations, and even prophenidate, each having a little caveat to their use.

So maybe we're getting a little closer to clarity, but we still are lacking in the evidence for strong recommendation.

Yeah, I think it is interesting though that they did go out and say that the Nintendon and Perfentadone are things that should be used, kind of implying that that's something the rheumatologist, maybe you shouldn't just punt that off and say, oh, go see the lung doctor. Many of these patients with symptomatic ILD, you do share the care with the pulmonary folks. And certainly they have much greater expertise in looking for pulmonary hypertension, for interpreting really all the different tests, including even just a CAT scan. But this kind of brings that back within the realm of treatments. And as said, it almost kind of says, hey, rheumatologist, you got ILD, this is something to think about in your RA patient.

Agreed. You have another one?

No. Well, oh, I thought that was the end of what you said.

No. Think you're gonna do another one. And I'll make a quick pitch for what I have great hope for that's in an early stage. And these are like early phase twos. There's three drugs in development as gene therapy for OA of the knee.

And these are all delivering IL-one RA intra articularly and it sticks around for a few years and seems to have benefits, at least clinical benefits, there's biologic benefits, and they're gonna go into larger phase two trials. So in a disease that's sorely lacking in any good therapies to have something with promise in avoid the knee, think is a great thing, but that's gonna happen in the future.

If I throw in one more and it'll be quick, so I'll call it the speed. And this is treatment strategy in PSA. It's a kind of a little bit of a wacky design from The UK. And they, basically, they have a large cohort called Monitor, and they're collecting data on it's an inception cohort from The UK, collecting data on combination conventional synthetic, which is methotrexate, leflunomide mostly. They presented SPEED, which was analysis of people in monitor in that cohort who either got standard step up therapy, first methotrexate, second conventional synthetic DMARD.

Eventually they could get biologic therapy, but that's gonna be later. Primary endpoint was twenty four weeks. Bottom line is the people who started out with the early TNF inhibitor did better than those who did either step up or combination conventional synthetic at an earlier time point. So this was something that, you know, we've seen in several trials. I think they need to do these studies in The UK because of access.

And this I think helps make the point that maybe in some people starting with a biologic would be the best way to get them improved.

I mean, these are a rehash of the best trial in RA showing the same point that aggressive early works best. And you could even see the same for PSA seen. Also, that was presented by Philip Meese a few a number of years ago. Again, I think that there's strong data about early aggressive therapy and that if you or your family member, would you not do this preferentially? Would you not fight for more aggressive, more expensive therapy?

And IIII think that's something we need to consider and if you really want to get these people treated aggressively, you actually have to be aggressive in finding them and promoting their referral to your clinics. I just posted a tweet today about cost of therapy analysis and psoriasis, looking at all the biologics and it basically showed that the cost has gone up quite a bit from 2,007 to $20.21, I think it was a '22 where it started out around 10,000 and now it's $47,000 But that if you made a decision to start a biologic in 2021, you could have saved 44% on overall cost by choosing the cheapest drug within the same class. So again, being on the most expensive doesn't mean you have to be on the most expensive. But this is a struggle that Laura and the other people in The UK are gonna have with NICE in getting them to approve such therapy. I agree.

But then they told us, I think that in a year's worth of a TNF inhibitor can be had for less than $1,000 in The UK. So hopefully coming to a pharmacy near you here, that'd be great.

Well, what we're gonna do, Artie, is we're gonna get ourselves a cruise ship, buy our drugs in The UK, and be going up and down the coast of the East Coast and if it works, we'll take it to the West Coast. Sounds like a good business plan. Alright, that's it for you. Our roundup. Be sure to follow the rest of our coverage on RheumNow.

We got a lot of stuff being posted, a lot of good articles, a lot of good videos, and we'll be back at ACR to do ACR Roundup in October of this year. Alright, thanks a lot.

You all in Chicago.