ACR 2025 RA Topic Panel Save

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Hello, everyone. This is the RA panel from ACR twenty twenty five. This is where we get together after the meeting, those of us that were covering rheumatoid arthritis from Chicago to give you our highlights of what was new, exciting, and certainly much talked about. I'm Jack Cush from Dallas, Texas. I'll ask my colleagues to introduce themselves, Orly.

Hi, this is Orly Najm from Glasgow, Scotland.

Jeff. Hey, everyone. I'm Jeff Sparks from Brigham Women's Hospital in Boston, Massachusetts.

And Jonathan.

Jonathan Kay from UMass Chan Medical School in Worcester, Massachusetts.

Okay, so the ground rules here are we're going to go around with each of us talking about two abstracts that we thought were of high import and certainly things that we were talking about in the hallways. Let's start with Orly. What's your first?

Yeah, so I wanted to talk about 1677. So that was an abstract presented by the LEADS team. And so it was about whether or not first line anti TNF, so no conventional demarc straight onto the anti TNF in early array, would help prevent difficult to treat array five to ten years down the line. And so they used this cohort that used actually early anti TNF and they compared that to some of their historical standard of care cohorts. And so I found the result quite interesting.

So at five years, only one percent of the patient that had received early TNF inhibitors were filling the definition of difficult to treat array compared to seven percent in the standard of care group. So that's quite a bit of a difference. The odd ratio was down to zero point one. And they looked also at drug free remission at five years, and it was thirteen percent versus six. At ten years, patients were also more likely to be in remission.

So that was sixty two versus forty five percent. So I was I found that quite interesting. They also looked at reduction of health costs in terms of early TNF. And so early TNF seemed to reduce 20% annual health costs in particular for those patients that are resistant, they need multiple therapy and have a lot of comorbidities linked to high disease activity and so on. So there was not a cost efficacy study, but that was quite interesting to look into that.

Now, reason why I found this particularly interesting is because if you look at the twenty twenty five EULA updates of the recommendation for rheumatoid arthritis, it's very clearly written there is no benefit to first line TNF or first line biologic. And so it's recommended against and I think that's quite interesting because of course we, in my opinion, we shouldn't give TNF inhibitors to every single early RA patient. But I wonder if in those people that have poor prognosis factors, it should be something we could consider and we need more studies to do that, but I think that'd be quite interesting. That's what I wanted to present.

Orly, do we know when they say it was first line, is it first line biologic or did they get TNF before they got methotrexate?

Induction therapy. Yeah, yeah, yeah. So they get their TNF inhibitor and that's induction. And there is also conventional DMARD, I think. But the one thing I didn't see that was presented at all, so that's not fully answering your question because I didn't see that in the abstract nor in the presentation.

It's also the safety profile that wasn't fully discussed either.

Right. So there's a lot of common sense to this, but it is evidence, of what Fred Wolf told me when I was a fellow long, long ago. Fred Wolf, famous rheumatologist from Wichita, Kansas with bazillion patients and bazillion publications said, Use your best drug first, no matter what the situation is. If we use methotrexate, is it our best drug? We could argue about that.

And this kind of study says, use your best drug first if you think of TNF inhibitors. And the other thing is I think this data strongly supports the idea of a window of opportunity. Jeff or John, you have a comment on this?

Well, I would comment that in The UK, Paul Emery says that a year of biosimilar ailimumab costs less than a year of subcutaneous methotrexate. So in The U. K, it's certainly going to be cost effective or might be cost effective. In The United States, syringe the average sales price of a syringe of Alimumab branded is about $3,750 or $7,500 a month. Biosimilars may be a 15% reduction, some 85% reduction.

But still, that's over $1,000 a month for the TNF inhibitor. So in The United States, it's not necessarily going to be feasible to use a TNF inhibitor first, especially given pharmacy benefit managers limiting our use.

Yeah, but if it's a, you know, if it's your family, you know, certainly you'd like to look at this data and think how am I going to get it? Jeff, what do you think?

Yeah, I think it makes a lot of sense and I'll highlight that they were looking at things like difficult to treat RA, really high bar. This, I think almost no one in the first five years developed difficult to treat RA. And I think that's what you worry about for your patients that, you know, you miss that opportunity, like you said, and they're gonna be recalcitrant and using biologics over and over again. I do agree it's a little bit of a pipe dream at the moment in The US. I I was hopeful that biosimilars might get to that point in The US, but it doesn't seem like anytime soon.

However, I do think there's a the the applicability is, you know,

at what

point how quick do you put someone on TNF? Six weeks after no budging on methotrexate? Two months? I would think about adding pretty early, maybe not first line, but early treatment much earlier than I currently do. So I think it was a very provocative abstract.

Yeah, and I think most of us think of ourselves as being aggressive in managing RA. But then again, you know, I run into John K at the meeting, I find out he's more aggressive than I am. And, you know, I think that we could all be more aggressive and the patient will win because we certainly know how to monitor. But I like this abstract as well. Let's go on to our next with, Doctor.

Sparks.

All right. I'm going to highlight an abstract, late breaker 15. I have to say this is one when I first heard about it. I kinda thought it was a little bit of an afterthought. And every single day, it stuck in my brain, and I liked it more and more and more.

This is about a a pilot, very small trial, randomizing people who are active RA to fiber or placebo for thirty days. The what they use was Inulin. And basically, these people were on background therapy like methotrexate, other CSD marts, and they decided to try fiber. And their hypothesis was all related to microbiome. And interestingly, the fiber actually seemed to have hint that that it it could work.

Very short term results, very small trial, only 26 on fiber, 23 on placebo. But even with those numbers and only after thirty days, those randomized to placebo had a higher EULAR response that was actually statistically significant. And again, I think the more I think about it, the more it makes sense. You know, they were talking about the microbiome, but really a lot of patients have GI side effects. And maybe this is helping tolerability.

Maybe it's helping absorption. And, honestly, this might even be something I do. I mean, I think we need more, but I don't think there's a lot of downside to this and people who are kinda still hanging out with some active disease to help further optimize methotrexate. Guess that I thought this was pretty provocative and I'm really actually looking forward for more fiber trials.

So the thing that was interesting was that all of of them, and most of them were on methotrexate, and there were some on other drugs, mefenomide, sulfasalazine, but we don't know the exact details. They all got better with a UR good response that was significant, but it seemed like the best responses were in those on methotrexate, where you had a bigger drop in dash twenty eight. And that kind of goes along with this idea of changing the microbiome to change the pharmacokinetics, pharmacodynamics of a drug, which is a popular thing in oncology. So I'd like to see more studies on this, a bigger study, three months, six months outcome, but it was provocative. Orly, what do you think?

Yeah, I like this study. It was also picked up by by Laura Coates in the, in the abstract she presented at the end, you know, what abstracts are gonna change my practice? I mean, I think for me, I, I've seen so many studies of dietary interventions, and, and, and very few of them work. And I think a big issue is that is the observance. I think a lot of people just very quickly stop.

But I think maybe one of the reason this works better is because I understand it was administered as tablets. Was it fiber tablets? Yeah. Yeah. So so and I think that might be something that is really helping instead of you know saying people telling people oh it this and that and make sure you add this to your diet.

Because people generally don't do it. So I wonder if that's one of the differences. And yeah, also, I mean, if it works, I'd be super happy to just give fibers to my patients and they do better, that would be an easy one.

Yeah. They used inulin twelve grams per day and a match placebo. It was a double blind randomized controlled trial. The inulin, which we don't know a lot about, is the standard for fiber diets in IBD studies and other fiber diets. So it should be commercially available.

Let's go on to John, what's your big one that you want us to discuss?

So my big one is Abstract seven seventy four, which was presented at the first plenary. This was presented by Jun Enamo from University of Colorado looking at the STOP RA trial. And Jeff and I were participating in the STOP RA trial. That was a trial that looked at individuals who were CCP3 positive, and they were randomized either to receive hydroxychloroquine or placebo for a year and then followed for a total of three years. Bottom line is that there was no difference in progression to rheumatoid arthritis.

About thirty percent of patients progressed to rheumatoid arthritis, whether or not they were treated with hydroxychloroquine. But this study looked at peripheral blood mononuclear cells from the STOP RARA trial from participants and used single cell multiomics, CytSeq, ASAP, Seq, and CyTOF. And they found that at baseline, individuals who progressed to rheumatoid arthritis had elevated T peripheral helper cells in Granzyme K CD8 positive T cells, which indicated activated cytotoxic and inflammatory pathways. There was also upregulation of some genes, granzyme B, CCR4, and TNF genes, and some regulatory loci on the PN22 locus and NK cells was made more accessible. So basically, they found that combining T peripheral cell frequency titer of anti CCP3 and rheumatoid factor, they were able to come up with a predictive model which distinguished patients who progressed from those who didn't.

And they were able to come up with a score for conversion risk. So this is interesting, first of all, in that you can come up with a score that might predict likelihood of progressing to rheumatoid arthritis if you have anti CCP antibodies. But also, it's interesting that T peripheral helper cells were increased at baseline in those who progressed to rheumatoid arthritis. These are the cell type that Deepak Rao identified as being elevated in patients with rheumatoid arthritis. So it suggests that these T peripheral helper cells are present very, very early on.

So there's immune dysregulation early on before the onset of rheumatoid arthritis. And it's somewhat similar to that dysregulation that you see later on in established disease. So I thought this was very interesting, not just in that you can come up with a prediction score, but also that there were some of the hallmarks, some of the cellular hallmarks of rheumatoid arthritis showing up before disease onset.

Yeah. And did you want to throw in the corollary about the, sRNAs also looking?

So there was another paper presented by Michelle Ormsteth from Vanderbilt, abstract seven seventy five. And she found that there were microbial small RNAs, specifically TDR1, which is a transfer RNA derived RNA produced by proteobacteria. So it's made by microbiota. And she looked at samples that were from the SARA cohort, the studies of the etiology of rheumatoid arthritis cohort, first degree relatives of patients with rheumatoid arthritis collected since, I think, 2008 at University of Colorado by Mike Hoelers and Kevin Dean, and found that those who had anti CCP3 positive serology without synovitis, twenty five of them developed rheumatoid arthritis, thirty five didn't. But the baseline plasma TDR1 was nearly eightfold higher in those who remained free of rheumatoid arthritis, and it was independently associated with a lower risk of developing rheumatoid arthritis after adjusting for autoantibodies, the shared epitope, and smoking.

So this is very interesting in that there's a small RNA derived from microbiota, which down regulates the interferon response genes and reduces the likelihood of progressing to rheumatoid arthritis. So these two abstracts together looked at patients before the onset of rheumatoid arthritis and found molecular hallmarks or cellular hallmarks which could predict the onset of rheumatoid arthritis or a lower risk of developing rheumatoid arthritis.

So what I liked about the whole meeting, or a lot of other presentations that are jumped around on this, is that now we're one step beyond CCP. CCP gives you a one third risk, of maybe developing inflammatory arthritis. And then we have these accelerators with these cellular subtypes that might show up earlier. And then PADI-four and PADI-two, mostly PADI-four, driving the risk. And then we have these deterrents like TD1, this SNRP, that is a counter regulatory sort of influence on the process.

And to me, it all came together with Mike Brenner's overview of RA's pathogenesis, which was really brilliant. If you could listen to that recording, he talks about the helper T cells, the peripheral helper T cells and the T follicular cells, along with CXCL13 that are driving B cells to deal with what they do in developing RA and worsening RA. And then on the other hand, you have the CD8 Gramzyme K positives that are driving complement and all that complement will do to amplify the damage and whatnot. Then he got into great research on fibroblasts. So again, these little pieces are coming together and making a nice story.

And I think the better we understand it, we're getting one step closer to maybe really doing interventions that count. You know, SNRNP, she brought up this issue that having high levels of that, were also inhibitory to Alpha interferon, making that another, player in the early development of disease. Jeff, what did you think?

I agree. This is super exciting. Know, so much of rheumatology is talking about cellular therapies, but cellular biomarkers are also, I think, really revolutionizing things. And I'll mention there was even another abstract that also looked at I think it was abstract number 89 that also found helper cells were very important in the risk of future RA in people who are CCP positive. And, you know, we're having we're getting therapies now too.

I thought it was a really interesting late breaker about resnilimab, which is really trying to deplete these pathogenic T cells, both T follicular helper and T peripheral helper. So I think in RA, it makes a lot of sense, and maybe it's gonna be T cell depletion and not B cell depletion that really leads towards this. And I like what you said about an accelerant and a deterrent. Literally, CCP is not everything. You know, at least half of people who are CCP positive, even high positive, don't go on to develop rheumatoid arthritis.

We're really learning a lot from these studies.

Orly, what'd you think?

Yeah. I mean, I think there's different ways to think about this, and there's obviously the super important and interesting pathogenesis part. And so we understand that better and I think it's great. But on the other hand, I'm always a bit wary of seeing all these prediction models that appear and then they either don't perform as well in validation cohorts. And then you never hear about them again.

So if we think about the pathogenesis piece, I'm totally on board. It's really helpful to understand better how things work and how people go on to developing array. Now, we think of the prediction piece, that's where I'm a little bit I think that TDR1 was really impressive in terms of the RA under the curve. It was 0.86 on its own for non progression. And then if you added the clinical data, renal rheumatoid factor and all that, you were 0.9, it very close.

But all the other ones, I'd be always so keen to see how much better they perform than only the clinical data.

So much of what we learned in rheumatology isn't the way we were trained, which is we develop it at the bench and then we take it to the bedside and prove it works. Instead, it's been drugs being made and it's the bedside that teaches us what's important at the bench. But this kind of research could change that back to the traditional model. John, comments on this.

So I agree. I would just comment historically that we've been thinking since the mid 1990s about cytokines, pro inflammatory cytokines, monocyte macrophage derived cytokines as driving rheumatoid arthritis. But in the 1970s, it was thought that rheumatoid arthritis was predominantly a complement driven disease. And then in the 1980s, we were playing around with anti T cell monoclonal antibodies, T cell depleters, and they didn't seem to work. So, you know, these data are showing us that T cells and complement are playing a major role in the pathogenesis of rheumatoid arthritis, bringing us back to where we were fifty years ago.

All right. Yeah. We were smarter than we thought in the end. My one is the RIT study, which you know is about vagal nerve stimulation with an implantable device, a device that received FDA approval. The article is not yet published.

It's finding a home in a journal and I guess will be published in sometime in 'twenty six would be my guess. But RESETRA was presented at the meeting. There were two abstracts, sixteen seventy five and two thousand six hundred and fourteen. Sixteen seventy five were the results of the clinical trial which was presented at EULAR and 2,614 are the imaging results looking at MRI. Again, this is a double blind sham controlled study, two forty two patients with a twelve week primary endpoint, twelve week primary endpoint because it's a device.

And patients stayed on their background therapy and everyone had this capsule size device implanted by a neurosurgeon near their vagus nerve. Some had it turned on, some didn't have it turned on. They're the so called sham group. And what happened was at week twelve, eighteen percent or so those on placebo had an ACR20 response, whereas I think it was like thirty eight to forty two percent had an ACR20 response with the vagal nerve stimulation. How does that work?

Well, there's a feedback loop that basically deep down regulates pro inflammatory cytokines, in my opinion, mainly TNF. So theoretically, these drugs should look like a cytokine inhibitor, if you will. But the dynamics of response are slower than cytokine inhibitors. So while they may have only been forty percent week twelve, when they got out to week twenty four, they were above fifty, sixty, or about 60 or so. But also after week twelve, eleven to thirteen percent of the doctors were allowed to adjust their DMARDs.

So that might have augmented some of those responses. In the end, again, the data, sort of modest, if you will, ACR 20 responses, but then a very low placebo response. And that's why this looks so good. And that's why this got FDA approval. Again, side effects are related to playing around, nothing too serious, but there are a few dysphonia and side effects related to the implant, but they were minor in number.

But how that will be tolerated in the real world remains to be seen. They did show that the people who are on the vagus nerve stimulation, those who are at highest risk for erosive disease had less erosive changes in just twelve weeks. I don't know that I want to see MRI studies at twelve weeks on a brand new drug. I think I want to see x-ray studies for six months and twelve months and two years on a brand new drug. I like the fastenoma that you can identify some changes, as early as twelve weeks, but I don't know, I mean, who amongst you is going be doing MRIs at the beginning and the end of starting a new therapy like this?

So again, this study has had a lot of buzz and there are a lot of people who seem to think this is great and a major addition for those who don't want to have pharmacologic interventions. There are a lot of people who have hesitancies about some of this data. I'd be interested in hearing what my colleagues think. Jeff, you and I discussed this earlier. What was your critique and what do you like about the study?

Well, first, I really like your pun about buzzing because these people got buzzed with the device. The first thing is we definitely need new therapies for our patients and I certainly welcome this. I think it's gonna be pretty hard to understand which patient to choose for this with so many therapies out there. And obviously, it's just a completely different paradigm than we're used to. And the AEs, while in isolation, the numbers were We're talking about vocal cord paralysis and devices becoming inflamed and dysphonia, dysphagia.

To go through all that, do we need you know, really magnified response? And I think that the p value and the delta looks good, but traditionally the ACR 20 is marginal. And I have to say, was a bit surprised that placebo rate was so low. You would think someone who's going through a kind of invasive procedure with a device that they would kind of have high expectations. On the other hand, about half the patients were fairly resistant to therapy and we definitely need options in those patients.

And, yeah, I was a bit intrigued that there's there could they could show some structural change. So I I think overall, it's pretty provocative, and we'll see where what happens. What do you think, John?

I think it's provocative and interesting. The MRI findings were interesting in that there was no effect on hyperemia, but there was a suggestion that bone erosion was slowed. There may be an electrical effect on osteoclasts or osteoblasts, which will be interesting to look at. I think that the main possibility for using this would be as combination therapy because we're hesitant to combine two biologic agents where there might be an increased risk of infection. But adding this to a biologic agent might be a potential way of increasing response to the biologic agent.

Once it's implanted, I would definitely keep using it, right?

Yeah, there was a couple more data that I saw in this presentation that I find quite interested, and one of them was the ninety nine percent of the people that had the device implanted, so basically the whole population kept using it at twelve months. That's quite good for a device kind of study. And also I think it was roughly eighty percent of the TNF inadequate responders that had zero change to their treatment for the whole year following. So, I mean, I personally would enjoy having something to offer to some of the patients for whom, you know, we've been going through three, four lines of therapy and and you know, we're not we're not there yet. So, I welcome this definitely.

There may have been an expectation that it wouldn't work among the patients that were in the study, could explain the low placebo response rate.

Yeah, we certainly would not have known what to expect because this is really new territory.

So Jack.

Jack is back.

Hi, sorry about that.

Alright. We've, we've pontificated on vagal nerve stimulation.

Mhmm.

And we were curious of any other thoughts you might have on that. If you can hear us, Who's the patient you might think about using that for?

Right off the bat, first off, I'm not going to use this until even though it's FDA approved until I can see the raw data in. I saw it presented at ACR and now ULAR, but I want to see the paper, first. I was not part of the study, so I'm not going to be rushing to use it. I would want to see how it performs out there in the real world. Think it's likely to come to a discussion when patients request it.

I think that some of the issues here about giving it because you need to have, it can't be done by any old surgeon. It needs to be done by someone who's trained to do this well. We know when Mark Genovese first started doing these trials, there was a fairly high rate of complications in and around the vagal nerve. And so, but they've gotten smarter about how to implant this and, you know, we're going need to, we didn't know about like, how is it charged? You know, I'm going to have to buy a special pillow to lay on every night to get this thing charged up.

It's actually a neck device, I think that they wear for an hour or so a day when you're watching TV. But there's still too many unknowns to know where it's going to fit in the market. I do know that in the lay public that there's some excitement about this. So, the idea of a buzz here, again, really is appropriate. The question is, where is it?

There's a lot of buzz about CAR T cells, even in disorders where CAR T cells have never been studied or proven to work. So, doesn't mean I'm going to use it. It means I'm still waiting to find really, really good data. Let's move on. Go ahead.

Well, one last point. I wonder, you know, does this help the non invasive external vagal nerve stimulators? The data is not, you know, as consistent as this one, but it certainly would be, a little bit easier to implement.

The auricular ones didn't work very well. No. John, what do you think?

Yeah, no, I was going to say the auricular ones didn't work, but this one isn't directly.

Well, there are some that have had positive data. So it's just an interesting field. Yeah,

It is. It is. And by the way, it's a vagal nerve stimulation has been approved for many, many years from for depression and neurologic Yeah. Epilepsy and obesity now RA. So, this is a curious area and certainly if anything, this approval will spark a lot of discussion and hopefully investigation as well.

Let's do our next round. These being shorter reports beginning with RLE.

Yeah, so I wanted to discuss quickly about methotrexate monitoring. It was a presentation 2571 that looked at a population based cohort. They looked at quite a lot of patients for over twelve years. And the question really was, yes, we monitor our bloods every three months after the initial period. And do we really see abnormalities?

And if so, are they related to organ toxicity? And so they covered really a lot of patient years. It was over 10,000 patient years. And what they showed in the two thousand five hundred patients was that there were about sixty percent of lab abnormalities at least once over time. However, those that were considered to be related attributed to methotrexate to only four percent.

Then when you look at organ toxicity, we go down to five patients out of two thousand five hundred, which was like zero point zero two patient years. And of these fifty percent, actually less than fifty percent had labs abnormalities. So what they were raising really is if we follow-up all these people, it's basically seven thousand hours of medical doctor that you're using for that through the monitoring. And then in the end, you meet fifty percent of the people who actually will have organ toxicity. So the question there really was, is the monitoring we do in its current form working and useful?

Now there's a few caveats obviously, it's a retrospective study, it's looking at electronic medical records that might have missed the methotrexate linked to the organ damage. We must have missed people through this, but I just thought it interesting as conversation starter for whether or not, because these guidelines of monitoring are based on very, very old data. So it'd be interesting to maybe think about that again for our patients.

John, what do you think?

So, bottom line is that we probably are going to get away with not having to monitor as frequently. You know, I typically will not refill methotrexate if the patient hasn't had labs done within three months. But I'm probably okay refilling the methotrexate for a little bit longer without necessarily worrying about getting labs every three months. I'm not saying don't monitor labs, but I think it's a bit reassuring that we can, safely prescribe methotrexate with less frequent monitoring.

You know, what I've seen covering this subject, over the years on RheumNow, there is some data that suggests that, rather than being one trick ponies, that on methotrexate you get Q3 or Q1 month or whatever, that, you know, one rule that fits all is certainly the wrong thing to do. The right thing is maybe, differentiating people who are at risk that need close monitoring, or more careful monitoring and others whom that you can be liberal with. You know, someone who hasn't had, an abnormality with Q3 months times four, you know, is, and you're not changing anything and their comorbidities haven't changed, their renal function hasn't changed, you could probably change that regimen. The whole thing is that you're going out on the limb and this becomes a medical legal decision as opposed to a convenience decision. Jeff, you give us the final smart way to approach this.

Well, I was part of that study, it was really incredible to see it come to fruition. I'll say that the fellows from Mayo Clinic actually reviewed every single lab abnormality and looked to see whether this was clinically significant or not. So I actually honestly have already moved away from this in my practice. I think after the first six months on methotrexate, I'm pretty comfortable toning it down. There's another abstract that actually directly compared three versus six months and there was not really a difference between lab abnormalities.

I think to really convince people you'd have to do some really large pragmatic trial. But I do think we're at that point.

Is this like, I hate to bring this up, but is this where the dreaded TriNetX EHR study was forty million people?

We can do that, Jack. Yeah. We can work on that for you, LAR.

All right. And there's good trinetic studies and then there's questionable. Jeff, your hands, I'm gonna be happy. So I'll look forward to that next year.

All right. I got my marching orders.

Okay. All right. Well, before you do that, just give us your final abstract.

Sure, I'm gonna highlight abstract seventeen fifty one. If you don't forgive me, it's actually from my group, but it's a long time coming. We're really excited about the results. This is from the salary study, which is a multicenter study focused on lung health and new onset rheumatoid arthritis. And we've been this is NIH funded, and this was presented by doctor Gregory McDermott, who's a really talented junior faculty in our group.

And, basically, we got the scans from early RA. This is about four or five months after diagnosis. We did HRCT. And in this study, we use quantitative CT where the computer used a deep learning algorithm to go down to the three d pixel or voxel and make a call about whether it's normal interstitial, emphysema, you know, honeycombing, ground glass, etcetera, etcetera. And so this is and then it sums it up to do a total volume of the lung.

We did this on the early RA patients and healthy controls. And honestly, I didn't really know what to expect. I thought maybe there'd be a bit more abnormalities in RA, but they haven't had it that long. So it was pretty shocking to me. There were actually 9% less normal lung in in the early RA patients.

You know, they've had RA for less than half a year. And, of course, most of it was interstitial, but there was actually more emphysema as well. So I think it was a bit of a proof of concept, and, obviously, it's been a labor of love for for a while. And it also just highlights the potential use of this quantitative CT because it found these subtle abnormalities that I don't think I think if you did gave this to blinded expert radiologists, you would not have seen this difference. So it just tells you the power of computer and AI these days.

So if

I could just

Yeah. Go ahead, John. Do go

for it.

No. I first of all, congratulations on that study. It's very interesting. And it really goes along with what the Colorado group found in the SARA cohort, which is where they looked at patients who were first degree relatives seropositive of individuals with rheumatoid arthritis. And they found that even though they didn't have rheumatoid arthritis, there were some abnormalities in the lung.

There's increased sputum anti CCP production. So in the very early disease, there may be stuff going on in the lung before you start seeing it in the joints. I'm not surprised that that 9% less normal lung in the early rheumatoid arthritis.

That's a lot of lung to have lost. We were really, really surprised it was that much.

So I hear, and maybe I'm wrong in how I'm interpreting this, but I hear parallels between what you're finding with this SAIL study and, SAIL RA and what we talked about earlier in preclinical RA, that if you can find very, very, very early changes that have some predictive value, are you not identifying people who may be at higher risk with greater trajectories or the worst trajectories? Who are the ones who are going to get into the most amount of trouble because, even if things happen nice and normally, you know, they're still in a bad way by the time they're diagnosed in the first five years, but if they're, heaven forbid, if they're delayed, they're going to have worse damage, worse lungs and whatnot. So, we've talked, and you've taught, during that September month of all that ILD stuff we presented about this group of ten percent of people with ILD who are gonna have that ten percent change in FVC, who are a bad trajectory group. I'd like to know if this nine percent, this subset of people with a nine percent loss are gonna be those who are higher risk for that bad trajectory, which translates to higher death rates, higher lung transplantation rates.

How do you start to connect the dots on this?

Well, to really do this, you need longitudinal data. And luckily, we do have two year follow-up and we're working very hard to try to extend it even more. But I think it's got a lot of parallels to treatment of RA. Back in the day, we'd wait till we're really sure it was RA, till we're really sure that things are progressing. And now we're treating people right off the bat.

And we're even thinking about treating even earlier in this window of opportunity, treat aggressive. And lung disease, typically we're waiting until they progress and they've lost a lot of lung by this point. So we're not at that point now in RA ILD, but if we really find people who we know are gonna have these poor outcomes, certainly intervening early makes a lot of sense, but we need trials and we need more data.

You know, in the 80s, we found out if we waited until an RA got erosions, we've already lost the war, right? You can't win any battles. The war has already been lost. All right, let's move on. John, what's your final one for

Final one is abstract thirteen sixty seven from the group at Cypher, where they have a molecular signature response classifier, a transcriptomic assay that combines transcripts with anti CCP antibodies and, I think, rheumatoid factor as well to come up with a score that predicts inadequate response to tumor necrosis factor inhibitors. And a score of greater than or equal to 18.5 is high risk for non response to TNF inhibitors. And they looked at whether GLP-one therapy influences this response. So GLP-one agonists are increasingly used. They are helpful in losing weight, decreasing serum lipids, decreasing cardiovascular risk, improving hypertension, improving sleep apnea, improving everything under the sun.

So they looked at people who were on GLP-one agonists. And they looked at their molecular signature response classifier score. And they looked at two cohorts, Network004, which had two fifty nine samples from 152 rheumatoid arthritis patients. Then there was a data set called a real world evidence data set of nearly thirty five thousand rheumatoid arthritis patients across nearly 1,000 US rheumatology clinics. And what they found was that patients who had a BMI of thirty or greater were nine times more likely to have a score that predicted inadequate response to a TNF inhibitor, forty one percent versus five percent.

And they modeled that a 10% to 20% reduction in BMI could lower the score by 8% to 18%, suggesting that if you lost weight, you might have better TNF responsiveness or at least a score that was less likely to predict TNF inhibitor unresponsiveness. And when they looked at this very large cohort of patients from the real world evidence cohort, they found similar trends. They found that twenty four percent of patients who had a BMI of thirty or greater compared to five percent with a BMI of less than thirty had this high molecular signature response classifier score. And GLP-one agonist users who achieved a BMI of less than thirty had nearly a threefold lower likelihood of an inadequate response to TNF inhibitors. So this suggests that GLP-one agonists may improve responsiveness to TNF inhibitors by achieving weight loss.

And the question is, what does it do to this molecular signature? It will be interesting for them to look prospectively at the molecular signature before and after GLP-one agonist therapy to see what pathways are altered and maybe correlating that with metabolomics to inform us as to what aspect of GLP-one therapy may improve response to TNF inhibitors in individuals who are of less likelihood to respond to this very effective therapy.

Coral, did you have any comment on this?

Yeah, a couple of thoughts about this. One of one of them is the it's it's quite unclear the mechanism. There could be different things, you know? You reduce this activity, you you reduce systemic inflammation, you reduce people weight to increase drugs, biodispensability. And so that's how it works.

Or there is a direct impact of the drug on some adipose tissue that then reduces TNF. We don't have the answer to that. And I think a lot of mechanistic studies are gonna be interesting to know that. The second thing is, how does that compare between RA and PSA? Because we obviously know that PSA is a metabolic disease, has a lot of, and there were posters also presented showing efficacy there.

RA is a different type of disease with a lot of systemic inflammation, higher cardiovascular risk, but not necessarily that much obesity or metabolic disease. So I'd be interested also to have comparison on mechanism and both disease and obviously randomized controlled trials is the next step.

John, do you have any comment?

Me? Yeah.

I called you John.

That's okay. We're blending together, which is a good thing. Massachusetts. Well, about mechanism as a researcher, I think it's obviously super interesting and helpful and helps to lead to new therapies. As a clinician, honestly, don't really care about the mechanism.

We've been using steroids. We don't still quite understand why they work. Hydroxychloric one, methotrexate. If the drug works, it works. That's all I really care about as a clinician.

So and if it's all due to weight loss, so be it. You know? I think there's a great debate about that we have to know every single pathway, but, you know, my my my hunch is GLP-one will mostly work in most diseases due to the weight loss. And if there's some extra benefit to that beyond the weight loss, I'm all for it, but we just need therapies that work. So from a clinical standpoint, let's do some trials, figure out it works and sort out the Becka's and later just get it to our patients that need it.

All right. So let me end with, a rheumatoid in children discussion. On Tuesday at the end of the day or at 01:00, there was an updated guidelines to the JIA, Juvenile Idiopathic Arthritis, guidelines for treatment. Doctor. Zihi and Lavelle chaired the session and new updates were provided for systemic polyarticular, oligoarticular, enthesitis related disease, a new guideline on dactylitis related disease.

They also talked about TMJ and uveitis. I'm going to just quickly review my favorite, which is systemic, which was presented by Susan Shanoi. But I want to start with something I thought was really quite novel in this updated guidelines, approach where, one of the things that was added to the mix was, at the end of their recommendations and reaffirming prior recommendations, adding some new, was they added a category, at the end on deprescribing. The idea is, you know, so much of the recommendations are about when to start a drug and, and how to use it and, and who to use it in. And often there's not a lot about deprescribing and that becomes a very obvious issue in someone who has a inflammatory febrile systemic disease like Still's disease, where you could control the disease with a cytokine inhibitor with or without steroids, but then when do you stop?

How do you know when to stop? They actually built that into their guidelines. Their guidelines came across as either being systemic JIA. Again, the FDA and others have now, and EULAR has said systemic JIA and adult onset Still's are the same disease. It's Still's in the adult or the kid.

Just to be clear about that, systemic JIA without macrophage activation syndrome, they reaffirm earlier guidelines that say that first line therapy should be an IL-one or IL-six inhibitor with no preference for either or. That was a strong recommendation. After that, there's not a lot that's strong. Everything is expert opinion, conditional except, well, there was a strong recommendation about non steroidal shouldn't be used first line. If you look at the literature on stills back to the 70s, non steroidal often use at very high doses.

It's no longer recommended. They also strongly recommend that DMAR therapy like methotrexate azathioprine should not be used. By the way, there's no mention in here TNF, which should not be used as well in Still's disease until you get to the chronic articular phase. A conditional recommendation that was a new thing was that patients should not be given oral corticosteroids as initial monotherapy. They acknowledge that if someone is febrile in the hospital being worked up for sepsis versus inflammatory autoimmune disease, auto inflammatory disease, that they may get parenteral steroids, but that the biologic should be the drug that they go out of the hospital on.

Or if the diagnosis is made on the outside, the point is avoid oral corticosteroids because it's the drug that will get you into trouble and they often stay on it too long. They make the obvious recommendations that if you're not doing good with one biologic, you should switch to another, all right? And that you can use, RA like drugs when they have RA like disease. For MAS, they recommend high dose systemic corticosteroids, and then either an IL-one or IL-six inhibitor. And then if that doesn't work, use either the other IL-one or IL-six inhibitor or Emapalumab, the new gamma interferon inhibitor.

Then lastly, historic drugs like cyclosporine, tacrolimus and whatnot. They made the last recommendation that everyone should be evaluated for the lung disease of systemic JIA, which is a really big issue in pediatrics, not so much in adults. I'm not going to get too preachy about evaluating for lung disease. I've seen tons of Still's patients, hundreds, and it's pretty rare in adults. I've got like three great cases out of over two fifty adults Still's patients I've taken care of.

But it is more prevalent in kids, but they don't understand the biology of it. If it's a drug reaction, if it's constitutive, if it's time based, if it's genetic based, there's a lot of unknowns, but they think it's important to identify early on. So that's it for pediatric rheumatology who came up with a nice addition to their existing guidelines. Any final comments on this?

It's incredible how fast that field has moved and that there's so many options. And obviously that's a patient population. You don't wanna, you know, sit around and wait for them to suffer. So, you know, they are appropriately aggressive and it's great that there are, you know, many drugs that seem to have good efficacy in pediatric population. And Jack, you're the expert for the adult stills whenever I need some help, but I'll take a look at the recommendations too.

It's definitely worth it. And this is a draft guidance. I still think they're gonna make a few tweaks and publish that in 2026 would be the expectation. I think we've had a great session. I want to thank Jonathan and Orly and Jeffrey for their contributions and for their really tremendous hard work.

You should look at the articles that these folks have written and the videos they did at ACR. They're really provocative, really informative. Tell your friends to look at these topic panels. We have one on RAPSA SPA and CAR T that'll be appearing this weekend. Then you should look at the day one, two, three, and four recap panels if you really want to get an overview of what happened while we were in Chicago.

Thanks everyone. Take care.

Bye.