ACR 2025 RA Topic Podcasts Compilation 2 Save

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Hey, everyone. This is Jeff Sparks, rheumatologist at Brigham Women's Hospital in Boston. I am reporting from RheumNow for RheumNow at ACR twenty twenty five here in Chicago. Great weather here in October, and I'm gonna give you my perspectives on day one for rheumatoid arthritis. In particular, we're gonna be focusing on novel cellular biomarkers.

So I'm gonna talk about four abstracts, and I think this is an overall a big theme related to the revolution of of cellular therapy and cellular biomarkers within rheumatology. Part of this is just related to it's now feasible to actually collect, extract, and measure things in cells, certainly single cell RNA seq. And this is really being, enabled us to be able to, with huge granularity, actually understand what's going on from a mechanistic standpoint. So the first two abstracts I'll talk about have a similar theme. It's abstract eighty nine and seven seven four.

And these were looking at particular cells called T peripheral helper cells and T follicular helper cells. If you're not familiar with these yet, these would be pathogenic T cells that, seem to be very important in pathogenesis of RA and even other rheumatic diseases, particularly those that are seropositive. And actually, this was enabled by some studies through the Accelerating Medicines Project where looking at synovial tissue, high levels of T peripheral helper cells were actually in the joints of patients with RA disease. Now we're trying to see whether this these bile these cells are actually circulating and whether these blood biomarkers could be novel ways to help diagnose and prevent and look for different treatment pathways. So both of these are characterized by PD one high, also CXCR five either positive or negative, and then ICOS one.

So these are basically cell surface markers that help to distinguish these T cells. The T follicular helper cells and T peripheral helper cells are both basically pathogenic cells. The T peripheral helper cells or TPH cells, again, seem to be very associated with autoimmunity, particularly rheumatoid arthritis. So both of these abstract, number eighty nine and seven seventy four, were looking at this cellular biomarker in people at risk for RA based on seropositivity. The first study, number 89, was looking at clinically suspect arthralgia and looked at people who were, CCP positive and negative, also whether they progressed to RA or not, and then also looking at healthy controls in people with prevalent RA.

And they actually found that both T follicular helper cells and T peripheral helper cells were present in the blood at higher concentrations compared to the non progressors and healthy controls. And that in particular, the T follicular helper cells seem to be most predictive of who would go on to progress to rheumatoid arthritis. So this is data suggesting that these are really important players in the pathogenesis of RA. The second study is seven seven four, and this is a secondary mechanistic biomarker study, using the stop RA clinical trial that I was part of, mostly analyzing the placebo arm. As you probably know, hydroxychloroquine did not affect the future risk of RA, but the hydroxychloroquine could have obscured some of the biologic findings.

So they really looked at placebo arm as sort of a natural history project. And this used multi omics, many different assays to look down to the cellular level to see proteomics, transcriptomics, what is different in the different groups in these patients, all who are seropositive, about who progressed to RA during the trial. And using these non biased approach, they actually found the T peripheral helper cells were, a biomarker that was particularly important. So the T peripheral helper cell, T follicular helper cells, important pathogenesis, perhaps depleting those could be a novel, method to treat RA. The other abstracts I'll highlight are slightly different biomarkers related to cellular mechanisms.

Seven seven five was also a plenary presentation. This was looking at microbial small RNA, within a pre RA cohort, and they found that this, RNA was, present in higher titers in those who progressed to rheumatoid arthritis. They also did some ex vivo studies and said that giving this RNA to, monocytes actually changed the type one interferon pathway. And this is not a pathway we typically think about in RA, and, again, I think it does open up the path to particularly new drug targets. The last I'll talk about is eight thirty two, which is looking at PAD four.

We've talked a lot about PAD. Peptidyl arginine deaminase is the enzyme that catalyzes citrullination and, of course, CCP is citrullinate an antibody to citrulline. There's been prior studies looking at antibodies against the PAD four enzyme. This actually measured PAD four levels themselves, and these were also at higher concentrations in those who were pre RA compared to healthy controls and also was predictive of who might go on to, progress rheumatoid arthritis. So in summary, we have a new some new biomarkers on the horizon, and I think think it's very possible that in the near future, we might even think about using cellular biomarkers to help diagnose and treat rheumatoid arthritis.

Beyond just CAR T, these this cellular era is, opening up new horizons. So, again, this is my impression for RA from day one looking at cellular biomarkers and rheumatoid arthritis. Thanks so much for your attention. Thank you. Hello,

everyone. Welcome to RheumNow's daily recap day two from ACR twenty twenty five. We're all here in Chicago. A great meeting so far. Lots of action.

We've scurried our way back to hotels to get on this Zoom call to do a recap of what we thought was the most notable presentations and abstracts from the second day at ACR. I'm Jack Cush from Dallas, Texas. I'm joined by friends. I'll have them introduce themselves. Let's start with Doctor.

Day.

Yes. Hello. I'm Rinalini Day. I'm a fellow in rheumatology and internal medicine from London in The UK.

Anthony. Hello. I'm Anthony Chan. I'm a consultant rheumatologist from, Reading, United Kingdom.

Excellent. And doctor Lou.

Yep. David Lou from Melbourne, Australia, and I'm still in the conference center having just stepped out of the the Calabrese and Calabrese show the the fake room session. That's a go back and listen to that if you've got the you've got access. It's a great one.

So I really wished I had I could have gotten so you were there. Why don't you give the audience a little preview? This was Lenny Calabrese and Cassie Calabrese had an interesting session on what they called fake room. David, what was it about?

Well, I think they've recorded another video on this, but really it's about trying to work through the heuristics of how we think and about how we keep our minds open. And I think, you know, part of it is about what makes a good rheumatologist? What makes a good rheumatology clinician? And I think one of the bits that really resonated with me is about this comfort, exceptional comfort with uncertainty. I think that's what makes a good rheumatologist, and they were very open to talking about that, I guess, about cases where it looked very much like rheumatology and then turned out to be another mimic.

I don't want to spoil it. You should go and listen to it. It's fantastic.

Excellent. Like the preview. Yeah, I spent a lot of time going over this with the Cat Lavrese family and they were excited about this presentation. So I'm sure it was great. I'm going to listen to it after the meeting as well.

That's what we can do. I mean, partly the audiences listening to this podcast can live vicariously through our experiences, but certainly a lot of this ACR content is out there for consumption after the meeting. And we would certainly encourage you to do that. So we're going to do two rounds of our favorite presentations. Let's begin with Doctor.

Chan.

The first one is ducalvastatin, the TYK2 inhibitor and there was a presentation today August by Lihi Ita. And this was quite interesting because they looked at the proteomic differences between male and female, so sex differences. While they both male and female responded to the treatment, there were differences in how they respond in terms of their proteomics. There were 133 genes that were upregulated in men and 177 in the women. And there were certain genes like the hormone metabolic pathways and the neuro ligand receptor in the women.

Now, was a comment about how this actually plays into it, how what does this actually mean? We don't know. We still need to do research. But what is very clear that there are sex differences in how patients respond to the drug.

Yeah, that's a fascinating subject. Lihi Eater gave a lecture on gender differences in psoriatic arthritis in the spa at RheumNow Live last year. Fabulous lecture. Are women so unresponsive to our best therapies? Why do they seem to have worse courses?

And it's not just that women have different pain perception levels. There's a biologic basis to this. There's a lot, but it's got many different sides to it. The question is, do you see it and how do you deal with it? Minnie, what do you think?

So this is interesting because I was in a session yesterday by Professor Ian MacInnis, where he basically said that we should be thinking of PSA now not just as an inflammatory condition but inflammatory metabolic condition. So that actually then brings in a whole load of different effects which we do know have gender differences, which could partially explain some of the differences in responses that we see some of these drugs.

Yeah. David, do you have a different approach for women with SPA versus and PSA versus men?

Well, and I mean, I don't mean to get on my soapbox about this, but I think it probably speaks to how we've gone about trying to define our disease in the past. I think the data, well, think the ACT SpA story is probably even more damning like that. We've defined the disease really based on kind of norms that we had previously understood about radiographic axSpA, knowing as well that actually we know the burden of non radiographic axSpA comes a lot down. It's more female based, but we see the impacts and the inflammatory burden is is equal between between those two groups. So I think partially just being conscious about that, and I think it's part of the reason why it's important not to devalue non radiographic axSpA.

I don't think it's as simple as we've just got it earlier in the progression. I know that's a topic that's a very controversial topic within axSpA, but it's important for for us at the beginning to start off by not devaluing those type of conditions, because I think that's maybe what we've traditionally done in the past. And that's what the easiest way to start with treating women badly in clinic. I think if we have those preconceived ideas.

Yeah. But I guess what I would end with is that everyone needs to pay attention to this issue. It's an evolving issue. There are things that we can do short of being more aggressive. And what's more, I am already aggressive with everybody.

How can I be more aggressive, you know, based on gender? But I think I still have a lot to learn on this. So, all right, we'll move on to our next one with Doctor. Dett.

Yes, so my abstract was on 1676 from the preventative and novel rheumatoid arthritis therapy session. This was presented by Professor Roy Fleishman, and it's basically the long term safety data from SELECT Compare comparing upadacitinib and adalimumab. I thought this would be a good one to discuss just in the wake of the upad data we saw yesterday from SELECT GCA. It's so essentially the premise of this study was that we have the safety data looking at RA patients on upper fifteen milligrams compared with adalimumab. And essentially, what they've managed to show is that the events that we are most concerned about, so MACE, VTE, malignancies, excluding non melanoma skin cancers, as usual, they occurred at similar rates for both drugs.

And so, like, this is just adding to that growing burden of data that we now have in the wake of oral surveillance, which we were discussing a few years ago at this time, and all of the warnings that came after it. So, it kind of shows that perhaps we're getting a bit more reassuring data now with the long term studies that are coming through.

Yeah, I mean, I'm glad that we see this kind of data. I think we have to, take note of it at the same time. Understand the limitations. Their data was out to how many years? Was it three?

Seven. Seven years. It was long, obviously. But it's also got a selection bias for people that could stay on the drug for a while that they do well. When you do well, you do well and you do well for a long time and that's the club I want to belong to.

And I think there's a value to that for both the prescriber and certainly for the patient. David Lewin, I were involved in a debate, last year at UR on, you know, is the oral surveillance data the only data we should look at? Or should we look at data like the long term extension on select compare or target emulation trials from large data sets modeled after oral surveillance and, but show different results. So David, have you gotten any smarter, wiser, better at a long term perspective on this?

Well, I think we always all are trying to. I think anyone who thinks that they're doing cardiovascular medicine perfectly in rheumatology is probably kidding themselves. At this meeting, I've actually had the chance to talk to a few people I know are, I think, experts in that space. And even they feel like there are things where they know that they would like to work on. One thing I would say that I think has changed a lot of this is it's a lot easier to be able to in that focus on cardiovascular risk when we've got an actionable and maybe GLP-one receptor agonists agonists are going to be the thing that changes that.

We've seen a bit of data on this at this meeting, including in the plenary this morning in PSA, really seeing the reduction in MACE with GLP-one receptor agonists. And I think that is we only having this conversation in five years time for all of the other stuff that I've talked about that we've all talked about. That is going to be the biggest thing to change things.

It's definitely going to be a game changer. Alright. Thank you, Mandy. That was great. David, what do you have that's interesting from today?

I mean, there's so much good stuff today, but I do wanna talk a little bit about GCA, and I want to talk a little bit about the METOGIA study. Not necessarily just because I mean, there are a few interesting things about this study, but it'll bleed into talking about sleep GCA that we talked about with upadacitinib and GCA. But we told you it's a French study, multi center study, comparing methotrexate versus tocilizumab fifty two weeks of therapy for GCA. And then interestingly, they followed for another six months after that fifty two weeks to see what happened. There's a stereotypical with that as well, that's critical.

So we're talking about methotrexate plus prednisone and tocilizumab plus prednisone. We of course know tocilizumab works in GCA, has been registered now for ten years, has approved now for ten years, and we've got good quality data on it. Methotrexate we've had for longer, but we know less about. Methotrexate did underperform compared to tocilizumab in those fifty two weeks. No question about it.

I have to say it did a lot better than I would have thought placebo would have done. And so I think that, you know, I I think as much as the steroids doing the heavy lifting there, you've got to think methotrexate is doing something there. I think one of the really interesting things about this is after those fifty two weeks when the therapy stopped, basically both lines ended up in the same place in terms of relapse free survival. So whether you're on tocilizumab or methotrexate for those fifty two weeks, you ended up in the same place in terms of relapses. And this reflects data that we saw as well with late GCA at this meeting, the two year extension, where if you went from upa to placebo after fifty two weeks, then you dropped down, you had flares straight away, actually after two years everyone came off upa and people were all of a sudden there's a bunch of flares in at one hundred and four weeks.

So unfortunately, I think this means that with GCA, this is going to be as it stands at the moment, none of these are really negating the need for ongoing therapy. And we've got to try and navigate how are we going to go after fifty two weeks, after one hundred and four weeks, and be treating these people forever with upadacitinib or tocilizumab? Are we continuing on with methotrexate after that? We don't have the real answers to that. We need more data.

One other interesting thing about

that as well. Yeah. Oh, the other thing that's a nice side point is there were five cases of PJP in the methotrexate arm, and I have no idea why. We've seen all these other data, data, big insurance data in The US. It's meant to be that with GCA, even with high dose steroid, you're not meant to get PJP.

But there were five cases, and we need to dig into why that's the case because that's really considered all in the methotrexate done.

Interesting. One person died. My review of the PJP literature is methotrexate is always listed as a risk factor, but usually it's only when methotrexate is combined with another immunosuppressant is the risk of PJP become reasonable that you could think about it? I don't know about prophylax against it. Obviously, prophylaxis for, certain, drugs, especially rituximab.

But, that's really interesting. So regarding the methotrexate for tocilizumab, I heard some bellyaching from some folks who are in The UK that they're worried that NICE is going to look at this data and say that patients should start on methotrexate rather than the more expensive tocilizumab. Is that would that be your interpretation?

Well, I think that's what we're doing. Yeah.

Is that what you're doing? Anthony?

That's what already doing in the moment. We have to go through that before we can get to tocilizumab. You have to fail them with methotrexate.

So does the data support that, David?

Oh, no. No. No. Well, no. NICE doesn't always reflect the evidence, unfortunately.

But, you know, I know that, there's a lot of people working on as well what to do after in that relapsing cohort, after the fifty two weeks of tossing, what to do after that, there's studies in The UK, there's studies elsewhere in Europe and The US. So, I think a lot of people working on what to do in that bridging period afterwards where maybe something like methotrexate might be a run on. But yeah, of our UK, all my UK GCA colleagues, very frustrated about what Anthony has just mentioned.

See, I think the data from this study tells us what we know, but may put a number on something that we should know better. And that is when you have GCA, we don't know exactly when the disease goes away and then we don't know when to stop. This study where you have a fourth stop and then you find out what your raised floor is, meaning that there's now there's a relapse rate. It's in a minority, which means the majority don't need to be treated indefinitely. So how do we figure out who those people are that are at high risk for relapse and need ongoing therapy?

The study didn't address it, but someone's going to have to.

Okay.

What do I want to talk about? I think I'm going to talk about STOP RA, which is a study that we already covered. What? But it was presented again here only because it's the final story. Stop RA is an intervention trial trying to prevent the onset of rheumatoid arthritis in at risk individuals who are CCP positive and have arthralgia, but not a lot of other risk factors have no synovitis.

One hundred and forty four patients enrolled, one hundred and forty two I think were the final analysis. Half of them treated with hydroxychloroquine up to six point five milligrams per kilogram and the rest with the others placebo. The study was stopped for futility, meaning it failed in trying to show a benefit to hydroxychloroquine in preventing progression, conversion to RA. And there's really no new signal. You know, they could find no other aspects of this that were insightful as to, is there a subset of hydroxychloroquine that would respond if they were treated differently?

The explanations as to why it failed was one that the hydroxychloroquine group did have higher rheumatoid factor levels and did have more tender joints. Again, nobody's got swollen joints here. And so maybe they did have worse disease and it was too much for hydroxychloroquine to overcome. But I think I brought this report up for a rehash because still I think rheumatologists when faced with someone who's got threatening RA, no swollen joints yet, but tender joints, family history, positive serologies are going to be compelled to want to use hydroxychloroquine. And I would want the audience to remember the words of Kevin Dean, the lead investigator on this, who said, at the end of his talk, the reason this didn't work because it's not the right drug for the right stage of disease.

Hydroxychloroquine is a good drug in RA when it's established. It does a lot of good things. It's adjunctive. But in the early biology, when RA is not RA, but a smoldering and there's a certain set of gears that are put into place. What we learned at this study, as well, I'll probably talk about next, is that there's certain biologic things that are going on, which hydroxychloroquine probably has no effect on.

But some of the other drugs that we presented that seem to be effective like abatacid or rituximab, or maybe methotrexate and seronegatives. Never understood that. But anyway, it's not the right drug and it's not the right time to use it. And I think that you should think twice about using hydroxychloroquine. All right, let's go on to our second one.

This is a fast hit round. Another one from Doctor. Chan.

Yeah, it's the new oral IL-twenty three peptide inhibitor, ICOTROKINRA or ICO. And this was a study where they looked at both adolescent which was interesting today ten percent of that population were between the ages of 15 and eighteen twelve to 18 sorry and they looked at this is in psoriasis, skin psoriasis, good response at sixteen weeks in the placebo and then going up to twenty four, the PASI 90 was seventy one percent and the IGA, the global assessment was zero one score was eighty four percent. Well tolerated, no new safety signals. So again, adding a new a new novel therapy in terms of oral therapy for psoriasis at the moment, obviously we'll have to study a PSA next.

Yeah, it looks interesting. And being oral has got to be great. And I keep waiting for the other shoe to fall, that there might be, you know, some safety, caveat here, but there doesn't seem to be. So, we have to wait and see, how this does when it gets to, you know, there's that horrible thing that none of us can explain. Why does these drugs do so great IL-twenty three, IL-seventeen, dual-seventeen inhibitors do so great in the skin disease, but they all or there seems to be a hierarchy of responses, but they all seem to perform the same in arthritis.

Does that mean the arthritis is just so difficult, or that we just haven't found the right thing? I don't know. And I know Anthony, you follow this literature really well. Do you think this poses an advantage at all for psoriatic arthritis patients?

I think in the early phase of disease, D23 probably has a greater impact, but maybe less so in the latent disease for the arthritis of, you know, in psoriasis.

Good. All right. Minnie, what do have for your next one?

Yeah. So I've got abstract sixteen fifty nine, which is an abstract on RA ILD from Brian England's group, specifically this time looking at the progression of multimorbidity. So as perhaps you might expect, they found that multimorbidity was highly prevalent in this patient group and the more rapidly progressive multimorbidity trajectories predicted higher risk actually of respiratory related hospitalization, which is obviously a big risk already in this group. So it really highlights what I like to talk about a lot of the time to monitor multimorbidity and manage it appropriately within the setting of rheumatology. And that was a study with over 6,000 people.

So quite a large cohort that they followed up there.

So was it as simple as the more multimorbidity you had, the higher the risk of ILD or did I hear you right in saying it was the change in how you develop multimorbidity that put you at risk?

It's the prevalence prevalence of the multimorbidity. So this was over six thousand people already with RAILD. So they were looking at specifically the multimorbidity itself. So for example, cardiometabolic conditions, other musculoskeletal conditions. Yeah.

You know, I don't know. We've published a lot on this issue of multimorbidity on RheumNow. As a reminder, and there is the Charlson Comorbidity Index out there, But honestly, I don't know that any of us really have that in our notes. Like my notes, always the exam and I get the musculoskeletal and it's TJC equals X over 28. SJC equals X over 28.

I do a gas score, which is like the CDI scores, CDI equals. And so those are the parameters. And I put in tender points no matter what. And then I'll write some narrative on stuff. But I don't have a spot per se.

I collect pain. I collect morning stiffness, totally useless morning stiffness, but we love it because we're rheumatologists. But I don't have a spot for what my comorbidity and does anybody have a better way of doing that or a reminder of doing that? David, what do you do?

Well, no. I mean, I think all I know is that we should be doing that better. And I guess it is clearly difficult in everyday practice at the moment to fit it all in. And that's part of the challenge. Because I mean, I guess we're increasingly having to think about cardiovascular risk, you know, the screening for ILD, we're to think about osteoporosis risk, we're trying to think about mental health.

Each of those takes time and it's already pretty crowded. So I think that actually what I feel like I'm moving towards and where we're moving is that a lot of we're gonna have to look for self management tools. And Minnie's the expert here. Don't want to I'm not gonna she she'll have the answers, but I think we need to be looking more at self management tools. And I think we also probably need to be outsourcing a little bit of this in a very structured way as well.

In diabetes, you have full teams to look take care of all the all the comorbidities in a structured way, and to do it consistently. Our rheumatoid arthritis and many of our other diseases have a similar comorbidity burden, yet we don't have that structure. So perhaps what we do need to be doing is actually not trying to do it all ourselves, but making sure that we, in a structured way, bring in the right people into the midst. Let's hope

Yeah. But we're gonna look to you, Manny, to tell us. David, what's your your last one that you're gonna cover today?

Yes. Since we I was gonna tell you about moderate alcohol in the CoreVitas cohort, but we've got a little bit of time. So just want to mention instead what I think I've heard a lot of people talk about today, which is the great AI debate that happened this morning between Doctor. Curtis and Doctor. Yazdani.

So Jeff Curtis and Januz Yazdani went head to head about whether we should be worried about AI in rheumatology. And, you know, I think it's one of those things where clearly this debate does change and evolve quickly over the years. I think one thing that they both clearly agreed on was the need for guardrails. And I'd say, I think as a conclusion out of it, that for us, as an action point, we need to engage with all of this to be able to make sure that we can build those guardrails. If we're bystanders, we're gonna get run over.

So she was worried really about three things. Bias at scale, erosion of skills, and there's really good data about erosion of skills, automation bias, and things like that. And then data regulatory issues, which I think is something which, you know, the the FDA do have some guidance on and do have some guardrails around, but we just need to make sure that we hold people to that and don't let that erode. So, you know, I think that's part of really about AI literacy. We don't all need to be able to sit there and code, but what I think everyone will need some base level of AI literacy then we'll need clinician data scientists who are rheumatologists that can engage at a deeper level just like we have clinician educators or clinician scientists in terms of translational scientists or any of those other things because we need people at that interface as well.

I should put a little plug as well. If you're here in Chicago, come along to 08:30 tomorrow morning because I'm talking about AI in ILD imaging, and I'll hit on some of those in a little bit more depth.

I'm going to be there. And I did an AI session after the great debate. I thought that they did great. At the end, there wasn't there wasn't an audience vote as to who they like better, did they?

Well, they cheered out, and actually, Januz got got the the bigger cheers. But, you know, I I have to admit, I passed Jeff Curtis in the corridor, not my conversation, the the conversation I overheard. And he said, Januz had some pretty good points. So I think, you know, they both I think they both had a strong mutual respect for each other. Let's say that.

And they oh, absolutely. And they both are big believers in AI, but they also have big concerns about AI. And thankfully they're talking about it. What I think is true is that of our audience is listening right now, probably 30% of you are definitely using AI in a strong way. There's a 10%, 20% are dabbling.

There's as much as half of the audience is like, I don't know. This is like so you like the negative story. But I think that at the end of the session I ran today on what was the title? Knowledge is obsolete, you know, using digital, virtual and AI to round things, to fix it is the way to go. I had a question from a young guy who said, I got to go back to my three older mentors and teach them what I learned.

What how do I teach these old Luddites who, you know, really don't want to hear anything about this? And I said, my advice was give them three tools that they can use and tell them how to use it. Tell them about Claude AI, Claude dot AI when they want to write something, you know, letters of recommendation or, you know, dear grandma, whatever. Tell them about perplexity when they want to do research on a topic and then tell them about consensus to do information research curating and background on, you know, ILD with rituximab and what's known about that, you know, and not that there is anything known about that. I just made that one up on the fly, but you can do that with an AI, but you give someone tools that doesn't want to get into it.

And that's how we are going to get better and we are going to get better solely over time. My last piece was still in my brain as a synthesis piece of many different presentations kind of ended and came together today with Mike Brenner doing a wonderful presentation on the biology of RA. It was a Klemperer lecture. What I'm going to say is comes from multiple presentations. So it was a cellular presentation from the Stop RA that talked about the importance of peripheral helper T cells being elevated in people who are going to progress from not having RA to RA.

There's another study that I don't know the authors on that said the same thing and also with follicular helper T cells being elevated in people that are going to progress to RA. And then Mike Brenner, does incredible research, and is a great speaker, talked about the biology of RA, a Th1 driven disease and the evidence for that, and that CD4 cells are important. And it is these CD4 subsets of peripheral helper T cells and the follicular helper T cells that are providing all that B cell help, which is sort of exemplified by the chemokine CXCL13. And then he got into this whole issue of gamma interferon, very involved and that all of that seems to be coming from CD8 positive T cells. And what are they doing?

Well, they're involved in, these Granzyme K, positive cells, GZMK cells, and they're involved in complement D and complement pathway that further amplifies and worsens the disease. I mean, it's a whole different look that's sort of quickly evolving about the role of these T cell subsets in giving, you know, what is obviously an errant adaptive immune response, where lots of cells are involved and you're just trying to figure out who's playing what role. But based on what I just said, I think we're going to be hearing more about targeting of peripheral helper T cells and of Granzyme K positive cells and using CXCL13 as a biomarker that could help us make some decisions. So anyway, I like some of these basic science tie ins with the pathogenesis that I think are going to, you know, there's a lot of this kind of stuff being presented to me. The question is, will it be meaningful five years from now?

But I just in this meeting, I start to connect the dots on these different presentations as all being related as people get getting a better at understanding RA. So a quick little and you know what those diagrams look like when you start trying to map out the pathogenesis of RA. It's like the schematic on a 1950s television. You know, it's too many arrows, too many, you know, things to look at, but they're starting to make it a little bit better. All right, folks, that's the end of today's recap.

For the audience, we'll be doing another recap, day three recap tomorrow, same time, 5PM on October 28. Be there, tell your friends. I want to thank Drs. Chan, Day and Lou for a great discussion. Tune into the room now.

Bye bye.