EULAR 2025 – RA Panel Discussion Save

You're listening to a RheumNow podcast coming to you from Barcelona, Spain and EULAR 2020 '5. Hope you enjoy it. Hello, everyone. Welcome to RheumNow's day four recap from UR and Barcelona. We've spent the week in Barcelona reviewing the data, going to the sessions, watching the posters, interviewing people, and now we're going to not do a day four recap.

Excuse me. This is our rheumatoid arthritis recap. And I'm joined by our leaders that were covering rheumatoid arthritis. And today, we're going to present what we thought were the highlights from ULAr twenty twenty five. I'm Jack Cush, now back in Dallas, Texas.

I think all of our faculty, except for John, who's still in Barcelona, I want them to all introduce themselves. John, introduce yourself.

Hi, I'm Jonathan Kay. I'm a rheumatologist at UMass Chan Medical School in Worcester, Massachusetts. And even though it looks like I'm still in Barcelona, I'm back in Massachusetts.

Oh, good. Okay. Doctor Day.

Yeah, I'm Rinalini Day. I'm a rheumatology fellow working at King's College Hospital in London.

And Doctor Pope?

Janet Pope, hi everyone. I'm a rheumatologist in London, Canada and I am sitting in a clinic but finished my patients, so all good.

Excellent. All right, so let's begin with Doctor. Day. What was your, one of your highlights in rheumatoid arthritis from this past week of meetings?

Yes. So my highlight was, OP four, which was the ALTO study, which has come out of King College London. So I'm a bit proud of that. So this study was investigating the long term effects of a one year course of abatacept in individuals at high risk of developing RA. And it was actually the follow-up study of Apipra, which we heard about lots last year.

So just in a couple of sentences, Apipra was a double blind placebo controlled trial that enrolled individuals positive RA related autoantibodies, so ACPA or RF. And they had inflammatory joint symptoms, but no clinical synovitis. And participants received weekly injections of either abatacept or placebo for fifty two weeks, followed up for a year. And essentially, results showed that abatacept reduced the risk of developing RA during the treatment and shortly afterwards. So to assess whether these benefits persisted for longer, ALTER was a follow-up study, tracked participants for a median of around six months, so over five years after the initial randomisation period.

And the primary outcome was time to development of clinical rheumatoid arthritis. And essentially, off the two thirteen Apipra participants, around one hundred and forty were in Alto, half and half Abatacept placebo. And during the follow-up period, around one hundred and nineteen participants developed clinical arthritis or required further treatment with DMARDs. And the main difference was between groups occurring within the first year. So twenty nine percent in the placebo group had developed arthritis compared to just six percent in the abatacept group.

And that protective effect diminished over time. So by year four, around two thirds in the placebo arm and sixty percent in the abatacept arm had developed arthritis. Among it should be noted that among those with high risk serological profiles, so high IgG, ACPA levels for example, the benefit of abatacept remained more pronounced persisted longer. So, up to six years in some cases. So essentially, one year course of abatacept, it showed that it can delay the onset of RA for several years in high risk individuals, particularly those with more mature antibody profiles.

And we had a long chat with Professor Cope about this whilst we were in Barcelona. And while the protective effect diminishes over time in the general population, those at the highest immunological risk may benefit most from that early stimulation T cell modulation.

So this group, all of us are very familiar with the clinically suspect arthralgia studies and this study in particular. I wanna ask John and Janet, give me your 30,000 foot view of these data. Let's start with Janet.

Right, so first of all, I think it's kind of neat that giving a year or in the ARIA follow-up, it was six months of abetacept, in this one it was a year, Giving a year of treatment and a high risk population, you will attenuate for a while but eventually the curves are going to almost merge where the rate then becomes pretty similar. So two impressions: number one is you can enrich for a group where seventy percent by five years can get RA. I always wonder if some of them had RA to begin with, that we couldn't detect it clinically, but that's a whole different question. Number two: would it be feasible and or cost efficient to use a drug that's fairly expensive right now, but eventually we'll have a biosimilar and that will lower the cost intermittently? You get your year or even six months worth and you get it again when something's happening again on symptoms.

Wouldn't that be kind of interesting, but we don't know yet.

I'm gonna get to that when we discuss the palindromic rheumatism palabra study. John, what's your overview?

So I think this study is important in that, unlike ARIA or TREAT earlier where patients had MRI evidence of subclinical synovitis, this study required joint pain, but not all of the patients or only a small proportion had evidence of synovitis by ultrasound. So this study is more of a real world pre RA or suspect RA group. The fact that the patients tended to all the two groups tended to cross and both groups had similar findings at four years where the effect of abatacept was not persistent is significant. In these patients, the higher immunologic activity, the greater number of autoantibodies tended to predict a response to abatacept. So the take home from this is that probably abatacept is better in the patients with more autoantibodies at baseline, and it's not as important whether they have subclinical synovitis on MRI, but this might be a treatment for all comers.

Yeah, I think it's a really important point. We do know that ACPA is a risk factor for progression. We do know that double positivity and high titers is a greater risk factor. We've always thought from work of Emory and others that tenosynovitis and subclinical inflammation is another risk factor. And basically with all of these, you're ratcheting up the risk, are you not?

So I wanna ask the panel, first, let me just say that the ARIA study and its long term follow-up, four year follow-up was also presented, showed the same kind of results. ARIA, different. They had to have subclinical synovitis to get in. It was only a 100 patients split between placebo and abatacept. They got six months of abatacept, and they were followed out initially for another twelve months out to month 18.

But now we have out to five point three years as a mean, showed the same thing that the lines stay apart for a while, but and going out to four years, and finally at four years, they come together. The the comments I hear from this, these two studies specifically and others even, is that the separation of the lines that ultimately comes together either means it doesn't prevent RA, and I'm not too impressed with this data, or it means that it delays the onset of RA and it is significant. I wanna know the opinion of you three experts, and maybe I'll chime in with my own. But, doctor Day, what do you think? Is this really important or is this it is what it is and it doesn't prevent RA?

So, yeah, we had a good conversation with Professor Cope about this, I think, at the Congress. It is important for sure. We know that it's not just RA and joint damage. There are comorbidities that come along with this. There are extra articular manifestations that we're probably delaying the onset of by giving people abatacept.

As Janet mentioned earlier as well, did they, or I think it was yourself, perhaps they did have RA, you know, of these patients may well have had RA, we don't know. And so yeah, my take would be that these are important data.

Janet, what do you think?

Well I think it was hydroxychloroquine, so stop RA that wasn't presented here was totally stopping not stopping RA so Plaquenil didn't work. So if it was an inexpensive drug methotrexate or hydroxychloroquine I think we'd be all over it saying if you're high risk just take it, well tolerated, inexpensive etc. However, sorry about that, however I think at this point in time I would say I think it is changing your natural history so you can still get RA if you stop treating. We don't know about treating intermittently, but not these studies, but one of the ones on methotrexate showed that then if you got RA, if we could delay it, if you got RA after you'd stopped treatment and stuff, they often had less pain and suffering, less problems. So I think it is changing the natural history at least for a while, however that's a problem because we're, you know, if we can't get access to it, it's an issue.

John, important or not? I think it's

important. It's interesting that both Araya and Alto are showing convergence of the two groups at four years, which suggests that maybe a retreatment period just before that might extend the duration of delay to seven or eight years. And it may be that intermittent treatment with courses of abatacept in these patients might delay rheumatoid arthritis long enough, with perhaps increasing efficacy over time that we might not see as flora disease or even any disease.

Yeah. So, the ARIA study, previously mispronounced by me as the AURIA study, was o p o is o p o three two five. I'm gonna interject a little off script and talk about the PALABA study because John and Janet brought up the issue of maybe dosing and intermittent dosing. The PALABA study was also presented here, not PALABA, PALABA OP zero one zero five, and it's a study of palindromic rheumatism using the intervention of either hydroxychloroquine or abatacept given standard doses for one year. But at year two, hydroxychloroquine continues on at daily dosing, but abatacept goes to every other week.

And in this study, of twenty four months, it showed hydroxychloroquine developed RA much as you'd expect, almost thirty percent of the patients developed RA. But those on abatacept showed, a greater degree of protection where the lines never did come together. But after, eighteen months, it looked like some people were so maybe being on less Avatacep, was good for a while, but not good enough in the overall scheme of things. But still at the end, it was, five percent versus thirty percent no. I'm sorry.

Eight point eight percent versus twenty eight percent, at twenty four months, showing that, again, like the stop RA trial, hydroxychloroquine doesn't work, but it looks like abatacept does work. And that may be what Janet and John suggested that you you might be able to go with less dosing, but it looks like there may be some less effect like you have when you go with less dosing during DMARD or biologic withdrawal studies. So, again, this adds to the same data in the same way. And I do think that when you can show a delay as opposed to prevention, that that's important because I think you're changing the natural history of disease. You're changing a more robust onset to a more anemic onset.

And I believe that in both these datasets, as well as the treat earlier, maybe in the Palava, Araya and Apipra and Alto that we're gonna have six, seven, ten year outcomes. And we'll see whether this delay had an ultimate effect in how patients needed to be treated because they're gonna need to be treated with other drugs. So, I think it's exciting, this area of research. I think that these are patients, thankfully, we don't see much of, but we still need to know what to do with it. So let's move on to, our next topic.

John, what's your next favorite from the meeting?

Sure. So since we've been talking about possibly spacing abetacept, I'll talk about late breakers six, which was presented by Yuki Amai from Japan, the SORAIRO trial, which is spacing of a TNF blocker and dose reduction of methotrexate in patients with rheumatoid arthritis in remission or low disease activity with oralurizumab and methotrexate. So ozorilizumab is an anti human TNF nanobody, a very small camel type of protein, which is approved in Japan for monthly dosing at thirty milligrams monthly. And SORIRO was a multicenter, open label, randomized, parallel group, non inferiority trial conducted at multiple centers in Japan. And patients with rheumatoid arthritis who were in remission in the long term extension of the Phase IIIII trial of ozorelizumab in methotrexate inadequate responders were randomized to receive either continued treatment with oralolizumab I'll get the pronunciation eventually plus methotrexate, or spacing of ozorolizumab, extending the dosing interval to every six weeks and then every eight weeks, continuing maintenance methotrexate, or continuing ozorilizumab at thirty milligrams monthly with reducing the dose of methotrexate by two milligrams every eight weeks.

And the primary endpoint was the proportion of patients who remained in C. Difficile low disease activity or remission at week forty eight. And what they found was that about seventy to eighty percent of patients with the ozorolizumab spacing or methotrexate dose reduction remain in C. Low disease activity or remission, whereas almost all of those who were continued on full dose ozorolizumab and methotrexate remained in low disease activity or remission. So the study did not meet the pre specified non inferiority margin.

And the ozorolizumab dose reduction, or spacing rather, or methotrexate dose reduction was not non inferior to continued therapy with each at the standard doses. There was no significant radiographic progression in most patients throughout the study period because all of them were receiving the biologic anti TNF as well as methotrexate at some dose. Multivariate logistic regression analysis for C. Difficile low disease activity at week forty eight showed that the predictor was being in C. Difficile remission at baseline or having an albumin greater than 3.8 grams per deciliter.

And rescue treatment with the restoration of full dosing of Azorilizumab I'm getting the pronunciation Azorilizumab and methotrexate was successful in over eighty percent of patients. So the conclusion was that you could attempt medication tapering in patients who were in remission at baseline, but not those who were not in remission. Low disease activity, it was not successful. So this is an interesting study. Even though we don't have a zorolizumab available in this country, one could possibly extend this theoretical basis to other drugs and think about perhaps tapering or spacing in patients who are in remission on standard therapy, but avoiding it in patients who are in disease states beyond remission.

It always seems like whenever you try to space out or reduce, it always comes with a price. And I'm so strongly against doing this or recommending this, but yet we see many, many abstracts at these meetings about tapering or discontinuation. And and I don't know why other than our patients want it, And some of us seem to be going along with it, and it's inevitable in some people. Any others have any strong feelings about this late breaker? Okay.

I think it really drives home the importance of remission for our patients, to be honest. Like low disease activity isn't enough, you need to be at remission essentially. Treat to target.

Yeah, we're going to get to this even further when we discuss coming up the ACR guidelines and the update on the ACR guidelines that was also presented on the last day of the meeting. Janet, what do you want to talk about?

Right. So some of what we just talked about is a segue to one little portion of the RA recommendations that I'm going to talk about that will lead into a study. So it's going to lead into the study OP0327. So Doctor. Smolin et al presented the recommendations, an update in RA, and not much has changed.

I was on those recommendations, as were some of the colleagues from, I guess, all over the place, really beyond Europe. But the recommendations continue to be different from the ACR in that EULAR recommends that pretty much everybody with RA should start on methotrexate. With prednisolone, they don't really talk about the dose or they say glucocorticoids, they don't talk about the route of administration, and then to taper as quickly as possible. We know from lots of systematic reviews that there's still a lot of people end up on chronic glucocorticoids when there's reviews of clinics and within RCTs. There's forty to sixty percent of people with active RA that are up to upscaling their treatment who are on chronic prednisone or prednisolone.

So we know it's not, you know, tapering with an intent isn't always the right intent. So what I liked about OP0327, that's a NORD STARR study. In the NORD STARR study, this is a secondary analysis. But in brief, that was saying we're going to treat people three different ways, three arms, investigator initiated out of Scandinavia, and see who does better or the best. The first group was the oral conventional.

So steroids, glucocorticoids, prednisolone, twenty milligrams a day, tapering by five milligrams every week, and then trying to eventually get them off by thirty six weeks with your usual methotrexate, however you were gonna give your methotrexate. The next conventional was the injection group. So they got so I can't always tell you it's the injections that are are better because they got intra articular injections at every visit that was a mandated visit. They were to inject up to four joints if there were swollen joints. So front end loading, a lot of injections in that group, and they also did triple therapy.

So you're going to have one group that's methotrexate and oral pred, the other group methotrexate intra articular steroids, but also it's total triple. And then the third group was BD mards where they were on methotrexate plus one of randomized certolizumab pegol abatas after tocilizumab. So it's kind of like a way the best study, you're looking at different arms and see who does best over time. So the question here, so the BD MARD group had more people under better control in the long term and some drugs were different than others, But this was to look at, okay, all of them were mandated a steroid taper if they were on oral glucocorticoids and of course the intra articular injection group only got oral steroids if they needed it. They didn't have to mandate taking it at the beginning.

So the bottom line was the group that did most likely to flare when they stopped their glucocorticoids because at thirty six weeks you were to get off. So the standard of care, which is the ULR guidelines group, methotrexate plus oral glucocorticoids, they had the most flares. And the injection group with intra articular steroids or the BDMR group had very little flares when they came off glucocorticoids. So my idea is why are we giving what I guess I could say is perhaps the most, not the most optimal way of getting off glucocorticoids and I think we should jab people more. So in other words, think intra articular in this study didn't look at intramuscular, maybe because you can get off steroids more because we're controlling them, the patient doesn't have access to go refill their prescription in the ER or through their primary care or something.

Anyway, I thought it was a neat idea, neat question, and it does reinforce. I like to use a lot of intra articular glucocorticoids because other studies way back in the day showed that the joints you injected in early RA were less likely to be swollen at a year compared to if they were swollen and weren't injected. So I've always been a believer of IA steroids. If you can get access to them, inexpensive and easy enough to do.

So the problem of course is that RA is a symmetric polyarticular condition. RA patients entering clinical trials often have 12 to 20 swollen joints. That's a whole lot of needling. Doctor Day, in The UK, do you use a lot of intra articular steroids?

I wouldn't say it's a lot. And certainly for the smaller joints, particularly if we've got someone with RA, we'd probably reach more for intramuscular, if we've got that polyarticular picture. I was also wondering about patient acceptance of all of these injections as well. That would be my other thought. But yeah, generally we wouldn't be injecting quite so many The joints as

one thing I can say is, I became a believer not because the trainees can learn because that's a good reason to be a believer, but there's old trials that no one ever talks about and okay they're small but they showed even six to 12 intra articular injections did better than high dose intramuscular. Well, the cumulative dose is probably higher, but ACR 50s were better at three and six months even though we think they're only hanging around about three months. So there are old trials in rheumatology, the Journal of Rheumatology, well British Journal of Rheumatology, now called rheumatology, that show injections are better than I'm and I'm has been shown to be better than oral for the increased effect immediately, but a bit of a good hangover effect.

So is Jen, isn't this a nonissue when you consider that the North Star was a, new onset, treatment naive group with RA who either got this ACT conventional therapy with steroids. Everybody got methotrexate, and then the three other arms were cerdulizumab, apatacep, and an IL-six inhibitor. And the biologic ones, did the best in the long run. At six months, they're all the same as far as efficacy. But at twelve months, twenty four months, thirty six months was clearly that the biologic ones did way better than those that were treated with steroids.

So advocating for either oral or intra articular doesn't seem to hold up when the biologic methotrexate groups did so much better with early onset disease.

You're correct. It is better in the longer term, but other people could step up if they needed to, of course. But the flare rate, the biologics got their oral glucocorticoids as well and the conventional methotrexate plus oral glucocorticoids. So certainly the oral glucocorticoids are difficult to get rid of. You flare more if you're just on methotrexate, you flare less if you're on a BD mart.

But two years down the road if you could front end load on your favorite whatever of your three that they looked at, whichever of those biologics might be your favorite. If you get front end load, that would be most optimal, but that it hasn't changed our standard of care right now because of probably access and also because there's not that much harm in going triple plus intra articular and then escalating up over time. Harm meaning there's not that much worsening before you can get them good again when you step up.

John, what's your take on this steroid analysis from the North Star study?

Well, I think that in my own practice, I typically will give oral steroid when I start methotrexate to control disease activity. I do very little intra articular joint injection in rheumatoid arthritis. With this study, the downside of oral steroids is that there's a risk of increased cardiovascular toxicity, increased risk of serious infections, even with relatively short periods of oral corticosteroids. So, yeah, I'm not sure what else to say. I would favor the biologic arms in terms of the long term efficacy.

So let's go back to, what Janet started with, which was the, UR update to the ACR management guidelines, which came out in 2022 presented by Doctor. Smallen. He made a big point in 2022 about steroids, that all this crazy worry about steroids is was was, not necessary because the data that they showed in their review was that when rheumatologists started steroids at the onset of RA therapy, they were very likely to discontinue the steroids, which I don't say I am a 100% believe believe, but nonetheless, that was a difference between the ACR guidelines, which said, don't use steroids if you can avoid it. Right? Get off them as soon as you can.

Use the lowest dose. But, you know, it was really strongly urging you to not use them. But even now, the 2025 update to the 2022 guidelines still strongly advocate for steroids when you start methotrexate. And I and I think there is this difference of opinion, whether you are kind of becoming the almost like lupus is becoming a a discipline that you need to manage without steroids as pushed by many, that you don't need to make lupus a steroid dependent disease. You know, there are many of us that wanna say the same thing about RA, but then there are many who still wanna believe in steroids.

It is a conundrum. It depends on, you know, whether you are afraid of the side effects or whether you want to extol the benefits. And it's unfortunately, it's usually both that you have to deal with. So I guess let's just talk quickly about steroids and the guidelines, and have they changed your mind, Doctor Day?

I think we're just so used to, well at least in The UK, starting, as John was saying, short course of steroids with the methotrexate just to get people through that bridging period. I can't see that practice changing. Yeah, that would be my take on it.

So Janet, what are you teaching your fellows now with these both guidelines in play?

Right, so because we can be a neutral country in between the European guidelines and the American guidelines. We try to avoid oral because I believe there is a true steroid addiction, but you want to get people better and there has to be a buy in that methotrexate, it can start working in a couple weeks, but you're not going to get optimal response. Maybe six weeks, twelve weeks, even beyond, depending on the doses you use. So we usually give intra articular of the worst joints and then an I'm if they need it as well, or just an I'm as you mentioned earlier, if there's a bunch of little joints. And it's mostly because then we control it and people aren't renewing the prednisone when they run into their family doc or the emergency room or a walk in.

So it's more so that we can control that they're not on loads of oral steroids over time. Because when Doctor. Smolin showed the data, yes, if you are in a trial that is a treat to target of targeting low dose prednisone, you can get more people off. In the real world, there's still forty to sixty percent in all these registries of patients with RA on chronic glucocorticoids. So I think we don't get as many off as we'd like to believe we do.

So the other big thing that I want to ask John about from these guidelines was that previously point of distinction between the ACR and UR guidelines was the use of positive predictive factors, meaning being high titer, rheumatoid factor, having extra articular disease in nodules, you know, having evidence of X-ray erosions, all the things that we know, portend poor outcomes. The ACR dump those as as a key decision point. In 2022, the, EULAR had them in there. Now EULAR gets rid of them, and now they make the even greater jump from it used to be that if you didn't respond to a conventional DMARD, methotrexate, that if you had positive predictive factors that they urge you now to add a biologic. But if you didn't, it was okay to play around with other conventional DMARDs, leflinamide, azathioprine, whatever that you wanna use.

Now they say dump the in decision making, and after you fail your first CS DMARD, you should go to a biologic DMARD or with an asterisk, a JAK inhibitor, assuming that there's no other risk that would prevent you from using a JAK inhibitor. John, do you think this is a good move or not?

I agree. I I think it is a good move. Reluctance to go to a biologic right away in patients who weren't at so called high risk was the cost of the biologic. And especially in Europe, where biosimilars are clearly less costly, it's not a problem to go to a biologic. The long term efficacy of biologic therapy is certainly beneficial in terms of structural progression.

Going back to the ATTRACT trial, even patients in whom disease activity wasn't fully controlled, patients on infliximab had less in the way of structural progression than patients who were not on infliximab who were just in the methotrexate group. So there's not a significant disadvantage to being on a biologic. And I think it's reasonable that all comers, if methotrexate is an adequately controlling disease, that a biologic DMARD or a targeted synthetic DMARD be the next step.

So I think this flies in the face of what commonly happens. I like the recommendation because I'm bothered by the data that says rheumatologists don't change failing therapy fast enough. And they play around with drugs that are cheaper because they think they're supposed to. And they're very slow to start with aggressive therapy. But then again, I live in the capitalist United States Of America, in Canada, and in The UK where they have people breathing down your back about the money you're spending.

What is this gonna do to how you prescribe therapy, Doctor Day?

So we have to have two CSD MARD failure first, and then we can go on to a biologic. And that's that's the rules we have to live by in our prescribing. But it does mean that actually people do progress onto biologics fairly quickly if they're responding, we can escalate them pretty quickly actually. So it's fairly similar. It's not not just one, we have to have two.

So yeah.

Janet, twenty, twenty five years ago, I was told in Canada you had to fail three, before you got on a biologic. So you were starting triple therapy right off the bat so you could do what you needed to do. What are the rules now, and how are you practicing?

Right. So they vary between private and public, and they're not the same province to province. So with that in mind, in general, at least one combination, and some groups would be two combos. But, again, I think as as it's not just as prices go down, as safety, we have, you know, twenty five years of TNF safety. We have fifteen years of a lot of the other safeties, fifteen years now of TOFA.

We had it in 2012. So I think with all that in mind, the safety is quite good on advanced therapies in general, we know the caveats. So what I think would be probably the way we'll adapt this over time is make sure if your patient has active RA that you're treating it effectively and use whatever is in your toolbox. But if it's high scores and it's erosive OA and high pain, please don't start escalating therapies because they're the second opinions I get. And I go, well, sounds like you never had RA to begin with or your RA is great.

I don't say it that way, but you know what I mean. We have to make sure we don't misclassify because these drugs don't treat pain and you're gonna spend lots of buck for no bang if you're treating the wrong thing.

All right, let's go around with one more presentation from each of you. Let's make it as short as possible, Doctor. Day.

Yeah, so this actually follows on really well from that conversation. So it's OP0330. So this was a post hoc analysis of the CARE RA and CARE RA twenty twenty trials. So this basically is addressing that mismatch between the dramatic improvement in inflammation that's seen in RA with treat target strategies, and the persisting patient reported outcomes and high disease burden that can't be seen. So as I said, this was a post hoc analysis, six hundred patients with early RA starting their first DMARDs.

Everyone received methotrexate based therapy and followed up according to treat to target over two years. And then they captured inflammatory and both PROs as well. And essentially, they were looking for disease trajectories based on the DAS28, CRP, swollen and tender joints, HAC, and then the visual analog scales. And they found that there was four disease trajectories. So early persistent improvement, non persistent, partial improvement and persistent impact.

And it's that last group that I wanna focus on, because essentially they were saying that by the end of the study, patients in the persistent impact group were more than twice as likely to be receiving biologic or TSD mods compared to the other groups, despite similar levels of inflammation. So that's kind of what we've just been touching on as well. And so it's just showing us that potential risk of overtreatment. So I really like discussing difficult to treat RA. But this just shows that risk of overtreatment if we simply classify it's difficult to treat because the PROs are not improving, the disease burden appears not to be improving.

So it's really important to distinguish between inflammatory activity and patient reported disease burden, particularly in that early stage. Because some patients may benefit from non pharmacological or other therapies, rather than escalating their immunosuppression.

Janet, you're involved in CARE, aren't you?

No. No. But I know about it. But, yep, it's it's a good project that's going on. I can do two lines if you'd like on we we have to mention the jackpot study because it's there all the time now.

So the jackpot study is a whole bunch of registries combined, so from multiple countries, and they try to adjust for country variation and then within each registry. And there is one from Quebec in there, but mostly from Europe. And this bottom line here was the jackpot study looked at almost 3,000 treatment initiations of an advanced therapy and almost 13,000 were JAKs and split amongst the various JAKs, a little bit of Philgo because it came out later, but almost one third in each of the three other JAKs. TNF 26,000 treatment regimens and then other ones, other MOA. And the bottom line is when they adjust for line of therapy, disease activity, age, smoking, gender, all that, what they found was no cancer ratio that didn't cross the rest.

So no increased cancer of non melanoma skin cancer excluded. So not skin cancers, all the other cancers were looking at non melanoma skin cancer. Only was there, which is very strange, a numerically but not statistically protective effect of non melanoma skin cancer with JAKs compared to TNF or other mechanism of action. But they all crossed the one and the JAK was almost statistically significantly less. But the bottom line is what we're seeing in oral surveillance is really not being reproduced.

On the other hand, level RCT data looking at higher risk population for cardiovascular events and is going to show us more cancer, more cardiovascular. Most regular studies aren't showing that and maybe we already have a bias that we're prescribing and channeling oh a high risk patient of infection or heart disease maybe would go to TNF, infection would maybe go to abatacept. So we don't know who chooses what drug and why in these giant registries.

Jackpot does show up a lot. It's up to 20 registries. It's over 20,000 patients and up to 60,000 treatment courses. The analyses vary tremendously on what gets reported. In this particular report on cancer occurrence where it showed no increase risk for JAKs being used with 3,500 treatment courses versus 27,000 with TNF inhibitors, this study was designed to reproduce the oral surveillance data and and doesn't show oral surveillance like results.

So it's to me, it's an apology trial meant to make us feel good when we have a perfectly good, incredibly well done RCT that is you can't refute. And but now you're trying to refute with made up data and target emulation trials. And we might go so far as to get TriNetX and forty two billion patients, you know, in some database that we can't control for and we really can't do serious propensity matching for. But we see all of these, and I think we have all the data we need on oral surveillance. I use a lot of JAKs in spite of oral surveillance, but I also know who not to use JAKs in.

So I'm not a big fan of jackpot, but if you wanna feel good about what you're doing, think that this data will support that.

I like the Jack Cush version better than the jackpot version. And by the way, it's OP two thirty two for the listeners that wanna look at the study.

Yeah. John, what do you think of Jackpot?

Well, I think it's a large registry, but as you said, the randomized controlled trial oral surveillance is the gold standard. The big problem with oral surveillance is that it's misinterpreted. It's misinterpreted where people say that there's an increased risk of cardiovascular events and an increased occurrence of malignancy with JAK inhibitors. My take is that it just shows that JAK inhibitors don't reduce the risk of cardiovascular events as much as TNF inhibitors, and that malignancies are not lower with JAK inhibitors than with TNF inhibitors.

Yeah, I agree. All right, John, do have another one to discuss?

Yeah, quickie is oral presentation, OP-one 190, which is Dave Chernoff presenting the results of the RESETRA trial, which is the implanted vagus nerve stimulator that's implanted on the left side of the neck just over the vagus nerve, as opposed to the earlobe vagus nerve stimulator, which was a negative trial. So this is a sham controlled double blind study for twelve weeks. Everyone gets the vagus nerve stimulator implanted. And then for twelve weeks, they get one minute a day of stimulation or sham stimulation. And they are followed open label.

Everyone gets stimulation up to week two fifty six. Patients in this trial had high disease activity, a mean -twenty eight CRP of 5.3, mean disease duration about thirteen years. Sixty percent had failed two or more biologic DMARDs. So these are patients with longstanding disease, pretty active disease. The primary endpoint was the proportion of ACR20 responders at week twelve.

And this was statistically significantly greater for the stimulation group, thirty five percent as compared to twenty four percent in the sham group. P equals 0.02. And then when they crossed over and everyone got stimulation, the ACR20 in the open label went up to fifty two percent in both groups by week twenty four. ACR responses were better in individuals who had previously been treated with only one prior biologic DMARD, as opposed to those who had been on two or more. And at week twelve, DAS28 CRP low disease activity or remission was significantly greater in those stimulated, twenty three percent compared to sixteen percent in sham treated, P of 0.015.

And there were significant decreases in the total joint tender joint count and swollen joint count, reduction in new erosions by ramrus. Serious adverse events were very low, two point five percent, mostly hoarseness, pain at the surgical site, or transient vocal cord paralysis. So bottom line is this study with statistical significance shows that this twelve week of vagus nerve stimulation compared to sham stimulation was both safe and effective. Talking about all the problems with cost of drug therapy, potential toxicities of steroids, even of TNF or JAK inhibitors, this non pharmacologic approach is quite interesting and potentially promising, especially for patients who are noncompliant. It's something that's implanted, and it stays there, and stimulation is programmed in.

I think it's an interesting proof of concept, going back to Kevin Tracy's hypothesis that the vagus nerve is able to stimulate an anti inflammatory pathway through the splenic nerve and release of norepinephrine, stimulating acetylcholine release by T cells in the spleen, resulting in a decrease in pro inflammatory cytokines.

Yeah, I mean, but the problem with this has been it's been up and down. Like it was, you know, how long ago? Ten, fifteen years ago that Mark Genovese first presented the data. It was much fanfare. It looked really great.

But then a few trials really showed no effect and and, almost like it was going to die. And now this resurrects it. One of my concerns when I I couldn't I didn't get an answer because I, like, got shut out in questions at the podium, at the microphone was you get an ACR twenty at twelve weeks of 35%. You continue therapy, and it goes up to 52 weeks by week, 24. My question had to do with in when we are doing effective TNF inhibition, you plateau your TNF, ACR 20 responses at week twelve to 14.

And why then, do we see a continued rise? And then interestingly, in the placebo group, they have had the sham thing that wasn't turned on in the first twelve weeks. And then at 12, they turned it on and now they gave once a day, sixty seconds. That sham group on placebo at a 24%, they caught up to the 52% in their next twelve weeks. So I'm really concerned about the dynamics of change and does it indicate a partial degree of TNF inhibition or of cytokine inhibition that it takes more time Or is there and and then I'm I'm really asking that question to wonder, is there potentially another mechanism involved here in in efficacy that we are gonna see?

I'm good with slow responses. Lord knows I use drugs that have slow responses. But, John, what do you think about the slowness of response or is that an artifact of the trial design?

I think it's most likely an artifact of the trial design. The sham response of twenty four percent is somewhat troubling. And the fact that they that both groups achieve the same response after an additional twelve weeks suggests that something is going on that can't be explained physiologically. And I think there's a strong psychological component to this. But psychological is part of the central nervous system and peripheral nervous system.

So much is needed to learn about neuroimmunology.

Janet, what do you think?

Yeah, two quick comments. So the first comment is they stopped the advanced therapy, so they were on CSD Mart. So I would have probably added it to partial responders and maybe you'd get a higher response rate because I don't think it's going anywhere that lower responses added to CSD MARD. The second thing is they had a whole session on difficult to treat RA patients and half the session was on this vagal nerve stimulation and other nerve stimulation. And on one of the early trials that I wonder if it was what Marc Genovich did present as an oral at the ACR many years ago, but I'm not sure whose, but it was one of those trials from a long time ago, They found that it attenuates over time.

So by around year four, most people, even if it was permanently implanted in them, the stimulator, it was basically not doing much of anything anymore. So just like our drugs, it attenuates over time. So number one, I think I would add it to other drugs, not substitute. Number two, I don't think it's going to be a long term solution. However, intriguing.

Very. And coupled with the data that showed last year's ACR, last year's ULAR, Danish population based study showing that if you got vagotomy, you were going to have less RA. Oh, I'm sorry, more RA, if you had a vagotomy, but there are two kinds of vagotomy. The one's truncal and the other one's another one. The truncal ones are the ones that had an increased risk, the other ones didn't.

So there's something about the vagus here that makes it really compelling. But, Minnie, you get last say on this. What do you think?

So I have two I missed this abstract, at the congress. So I had two questions. Firstly, cost. And secondly, PROMs. So not anything other than ACR twenty that might have been measured?

I don't recall patient reported outcomes being measured.

I don't think we've got it.

In terms of cost, it's less expensive. There are two types of vagus nerve stimulators. There's those that involve a stimulator that's implanted in the chest and then wires that go up through the neck to stimulate the vagus nerve. This one, because it's a single, small device that's implanted directly on the vagus nerve, is a less extensive surgical procedure, so it's much less costly. But still, it's a surgical procedure under general anesthesia.

The upfront cost is there, but then the long term cost, it's in there, and it's just a matter of charging it and long term stimulation. But Janet's comment about adding it on to underlying background DMARR therapy is a very good suggestion.

All right. Great discussion. Thanks to John, Minnie, and Janet for bringing their expertise and really going after the great many great abstracts, that were presented at UR on RA. Thank you, the audience. Tune in for more of these, topic reviews that we're gonna have following the meeting.

Take care.