EULAR 2024 Daily Recap Days 1 & 2 Save

Hello, everyone. Welcome to RheumNow's Daily Recap from UR twenty twenty four. I'm Jack Cush. I'm joined by friends and colleagues. We're here in Vienna.

And let me see. I just want to make sure I got the right view on here. There we go. The gallery view. And we're going to do our daily recap is our effort to make it so that you're at the meeting along with us.

And we've been here in Vienna this week, the meeting started on Wednesday, and it's the end of the day, Thursday here. So we've had two days of going to posters and abstracts. And again, we wanna give you highlights and discussion of what we saw in the first two days. We'll do this every day, Thursday, Friday, and Saturday, and hopefully you'll enjoy these daily recaps. I'll ask my co discussants to introduce themselves.

I'm Jack Cush, normally from Dallas, Texas, but right now in Vienna. Yus.

Hello everyone. My name is Yusuf. I'm a rheumatologist from Leeds, United Kingdom.

Doctor Day.

Hi, I'm Minnie. I'm a rheumatology trainee and clinical fellow from London in The UK.

So we have sort of a UK US sandwich going on here. They're gonna keep me honest and of course I'll protest as best that I can. So our format is we're just gonna go around the horn, each of us presenting some of the things that we thought were particularly interesting from the day before and get feedback from our peers. Minnie, why don't you begin?

Sure, so I was actually in the difficult to treat rheumatoid arthritis abstract session this morning, and my best abstract of the day, I think, was from the Brigham and Women's Hospital. And this was abstract number OP0156. And this was basically validating the EULA definition of difficult to treat arthritis, which we've had now for a few years. But I would not really see many validation studies on this particular set of guidelines and the definition. And while the study was able to successfully identify the subset of rheumatoid arthritis patients who have not achieved low disease activity, it did bring home the fact that we do need more studies like this, so that we're able to more solidly apply the definition to observational studies.

So it brought about quite a lot of interesting discussion.

Thought, Yuz, what do you think? Did you sit in on the D2T session?

Yeah, I didn't get around to be because there's so many parallel sessions.

Sure, sure. I was there too, I made it the focus of my write up for today. And I spent a lot of time on D2T. So all those, we had like five or six abstracts on difficult to treat RA. The Brigham one done by Dan Solomon and colleagues and using the Brass Registry was an aggressive undertaking to understand sort of the validate and whatnot.

They also, they seem to have this idea that we need to agree on what the criteria for D2TRA are. And I don't know that we do. I think they put it out there that you need to be a DMARC failure, that you need to, the patient and the doctor have to be dissatisfied. You know, and I can't remember the third factor in there. And they gave their version of the same thing that was in the original UR definition for D2TRA.

But the interesting thing that they did was they came up with sort of numbers as to how many we can expect. And I think this is a problem, the definition is a problem because if you apply the definition to an established RA cohort, the percentage that I have seen repeatedly using the EULAR definition is 10% plus or minus two, right? But if you use it at an inception cohort earlier, or if you apply it to people who require biologics, the numbers and the percentages of the people with difficult to treat disease changes. In an inception early RA cohort, it goes into single digit numbers. If it's a biologic experienced population, it goes up to twenty percent of people.

And what I found to be challenging and still a big challenge in this area is that everyone's finding the risk factors that look kind of the same. And on one hand, they look very much like RA. So it's female, it's younger, it's swollen joints, tender joints, it's use of prednisone, and erosions are all seeming to be Well, doesn't that sound like RA to begin with? But then the other factors that are also predictive are fatigue and depression, sometimes more tender joints than swollen joints. And isn't that fibromyalgia that makes up a significant number of D2T RA.

So I like this term that's been around in the last year or so about Nira and Pira. And Nira, the non inflammatory refractory RA patients. I mean, those are the RAs that have failed a bunch of biologics and get on, but really have depression and fibromyalgia and damage and other factors. And then the PURA is the persistent inflammatory refractory RA, meaning they have a biologic marker. Are you Minnie, how are you handling this issue of what do you because ultimately you have to identify the population, but then if you identify them, you gotta know what to do with them.

And if they're a Pira or a Nira, they may or may not respond to your next best expensive therapy.

Yeah, so actually, there's a couple of points I wanted to pick up from what you've said. One thing that was repeatedly questioned in the session today was about that tight def It's a double edged sword. It's a very tight definition. There's three things that you have to qualify, well, meet three criteria you have to meet in order to actually qualify for this definition. But another aspect that was brought up was the timing, which I think you've touched on there.

So I think someone in the audience mentioned, you know, there was another abstract, which I can come to later on erosions, but in early RA. But those two things don't necessarily shouldn't fit. And so it's a really while it's really great that this definition has come out, cause it's actually brought difficult to treat RA into the limelight, and we're seeing it more almost as an entity in itself. At the same time, though, can we truly shoebox people with this very tight definition? And I quite like your nearer and purer description actually, for that reason.

Yeah. So this idea of difficult to treat disease has now cropped up in psoriatic arthritis and in SPA, and I've even seen it in lupus. So, Jus, are you getting anything out of these discussions in the world of lupus and how those patients can be better managed?

Yeah, so I think it is coming to lupus as well, slowly. There's one poster that I went earlier. So they even attempt to define what you meant by severe refractory SLE. So there's a group led by Professor Eric Moranz, did a multi center study in Asia Pacific and found that this can be defined as SLE die more than, equals more than 10 and on glucocorticoid and also on conventional immunosuppressants. And what they found in their cohorts, there were actually about fifteen percent people met this severe refractory criteria.

So I think it's quite useful for, you know, if people wants to do some sample size estimation for future study to focus on this group. So certainly there is a move towards defining the severe sort of in the category patient as well. All

right. So Yuz, what did you like as one of your top abstracts in the last two days?

Yeah, so I just want to discuss today abstracts. So the abstract number OP0124. So this is about a treatment target. And as we know, as we now have better therapies for SLE, we can now have a target in the clinical practice as well to achieve. So there's several targets been validated, including the Doris remission and LLDAS.

So basically, this study stems from the recent EULA recommendation last year, which set a target of oral prednisolone less or equal to five milligram per day. If you can stop the steroid, that will be most ideal, but at least less than or equal than five milligram a day. However, the definition of lupus low disease activity, which is the LLDAS consists of oral prednisolone equals to less than seven point five milligram per day. So the question's really whether should the LLDAS-five accommodate to this recent recommendation to Ophiola? And so what they found, they looked at the multicenter cohort in Asia Pacific.

So they then compare between definition using less than seven point five milligram per day versus less than five milligram per day. And what they found, there was no difference in the protective effect in achieving either LL-, well the validated one or LL-five using five milligram steroid in terms of mortality, organ damage and also disease flare. So I think so the conclusion was saying that the LL test currently does not need to change. However, in terms of clinical practice, we know that's probably the minimum target that we can do in the clinic. We should try our best to taper a steroid and to stop as completely as possible.

So there are two things that come out of this that I'm concerned about. One is, you lupus guys and gals like to talk about Doris and LL DAS, and the rest of us who are counting joints and writing prescriptions don't know what the hell you're talking about. So how do you bridge that gap between the practitioner and his or her goals in practice all the knowledge and insights coming from the experts? How do you cross that chasm? Well, how can you simplify that?

Yeah, so I think that's a good question. Even when the in The United Kingdom, when the first SLE guideline was established in twenty seventeen, one of the audits after that guidelines showed poor recording of disease activity measurement using all this validated tool. So I think that's why a lot of move now is trying to improve the education to the physician and also to the fellows to make sure that we use this tool. In terms of the LLDAS definition itself, so I think the assessment is actually it's not that difficult to do because they use SLEDAI 2K score, so it's categorical, so yes or no. And the definition is equals or less than four, and also the steroid requirement, and also the patient has to be on stable immunosuppressant.

So that are the three main criteria for the LLDAS. A

long time ago, the great Ted Pincus said that, we're doing something wrong when the outcome measures in clinical trials don't approximate what's done in practice. So maybe practice needs to step up and do some of these things. For instance, MDA in treating patients with psoriatic arthritis, it's not hard to do, but you need to know what it is that you can actually do it. So there's an educational and sort of an adoption component. Doctor.

Day, have you changed how your endpoints that you go for when managing lupus?

So I'm very much RA, so I don't see too much lupus, but I think increasingly focus on proms as well. And also, there's been quite a lot of work done in that area in The UK and sort of looking more holistically at all of the different extra articular and comorbidity features you can have with lupus rather than focusing purely on the ones which we're measuring when we're doing the larger trials. But yeah, it's definitely not the same disease as RA, as you said.

Yeah, I think change will happen, but it's slowly, and you and your colleagues are going to have to hammer on that to get it. And then, you know, what we're really looking for in lupus is that biomarker that we don't have to achieve in LLDAS or DORIS or a GLASS or whatever the new criteria is going to be next year. But once you, you know, you achieve your urinary IL-sixteen levels that, you know, and maybe we'll get there someday. Jus, do you want to make a quick comment on what seems to be a big theme at this meeting, which is the whole steroid issue? You know, we always talk a lot about steroids, but there's a lot more talk this time about comparing, you know, a sort of a liberal approach to steroids versus a strict approach to steroids.

Do you have some takeaways for the audience about that? What's going on here at UR?

Yeah, yeah, certainly. So in terms of glucocorticoid, there's quite a few aspects of it as well. One in terms of to use less steroid and in severe organ manifestation like lupus nephritis. Certainly, there's one study yesterday in oral presentation, so looking at post hoc analysis of three trials. So AURORA, AURA LV and also AURORA, forth, but closporine versus ARMS, which has a mycophenolate plus high dose steroid.

So what the study found, so they use a propensity match scoring and they found that for remission induction, if you use voclosporin with lower mycophenolate target dose, which is up to two milligram per day plus low dose steroids, followed initially by the three days of intravenous pulses or methylprednisolone. So they showed that you have earlier a reduction in proteinuria and also improved clinical outcome with less toxicity as well. So, so these are all something that we can apply, but also we have to personalise in our patients. So, I mean, who present with really severe drop in EGFR, I think those people that you really need to be even more aggressive potentially using other alternatives like high dose cyclophosphamide and etcetera. So, yeah, so that's one thing in terms of the remission induction for this end organ, but also in terms of the glucocorticoid, there's been a few study as well that talking about stapling steroid.

So for example, like two days or lab track session, they were looking about trying to stop steroid after patient had received a complete response. What they found after nearly about three years of patient achieving renal response, So, about over eighty percent people did manage to taper the immunosuppressant and they saw about ten to fifteen percent rate of flare up. And they also found that some factors that can help us guide tailoring of a tapering of the immunosuppressant and steroid, including if you achieve complete response at the first place and also if you're on hydroxychloroquine and lower C dye at the tapering bits. So, so there's quite a few studies in the glucocorticoid use low dose and also tapering at bisiula.

You know, is quite a buzz and I think it's going to I think it will change the way we manage lupus. Wanted to bring up a session that I looked at yesterday, and it's the answer study, OP0041. And this is a study of non inflammatory pain in rheumatoid arthritis. It's a podium presentation. And this issue of non inflammatory pain comes up over and over.

It speaks to maybe a central pain phenomenon that may not respond to your aggressive anti inflammatory biologic or targeted synthetic therapy. And in the last few years, we've seen these tend to be sub analysis of large studies that basically show that even though drug X, a special biologic or Jack or whatever, showed great improvement, you know, in the ACR 20, fifty, 70, that there still are people with residual pain. They have no swollen joints, but they have residual pain. And what's their deal? You know, we don't like to give narcotics to patients with RA because we feel that if we control the inflammation, we'll manage the pain and narcotics would be unnecessary.

But there may be people, and there are studies about people with non inflammatory pain who are on narcotics and there's a lot not done. Secondly, there seems to be this belief, because a lot of these studies were done by the JAK companies, that maybe the JAK inhibitors have a special edge in doing better at non inflammatory pain than do the traditional biologics led by TNF inhibitors and all the other MOAs. So this particular study looked at a comparison of like over seventeen hundred patients on biologics, and nearly two hundred that were on a JAK inhibitor. And it showed that non inflammatory pain, defined as pain of four or more out of 10 on a visual analog scale, but a normal CRP, right? Versus inflammatory pain, which is pain more than four, but with a higher CRP, right?

That when you looked at people treated with either the biologics or the JAKs, that at the baseline, they all had about a six out of 10 pain, six and a half out of 10 or whatever, and kind of split between inflammatory pain and non inflammatory pain. And then you go ahead and you start either one of the two different classes of therapy, and then you reassess them at three months, six months, and twelve months. And guess what? All the inflammatory pain went away with both drugs, equally so, right? And you know they both are effective at treating inflammation.

But what was left in this cohort of over 2,000 patients was a residual of like, you know, three out of ten, four out of 10 residual pain that wasn't going anywhere, even though they were on effective therapy. So number one, it said that this phenomenon exists. Number two, it said there was no particular superiority of a biologic over a JAK inhibitor with one small exception I'll get to. And three, that, you know, we're probably not addressing this. And again, this ties into Minnie's first report on difficult to treat because that residual pain becomes one of the factors in difficult to treat disease, right?

So, But if it's just pain and it's not pain from inflammation, then what is it? Would giving a biologic makes sense again, there still is a lot unknown. The other factor that they did show in here was that patients treated with abetacet did have more pain, residual pain, non inflammatory pain, than patients who were treated with JAK inhibitors. So that might be like, if was a comparison of just abatacep versus a JAK inhibitor, maybe it might show that the JAK inhibitor was better. Now, biologically, I can't explain that, right?

Know, to Good. Me, it's still

You need a difference in baseline characteristic, for example, because abatacept seems to be using later on in the disease, like when a difference in disease duration or number of previous biologic maybe?

Well, you wonder if it's A, what you suggest that there could be, you know, some channeling bias and entry bias into the cohorts, or secondly, that maybe it's really the biologic difference. Maybe JAK inhibitors are acting centrally in some way that the biologics aren't. And again, this is all up for grabs at this point. But, you know, I personally feel that a lot of it is, you know, either related to damage that's done, and hence these people need analgesics and aggressive analgesics. And if they have damage, they're also now set up for all kinds of central pain problems, including fibromyalgia, complicated by depression, complicated by who knows what else.

But the point is that it is shared decision making and treating the whole patient is what you ultimately need to do. Minnie, what do you think of this kind of data? I think you're familiar with the report.

Yeah, no, it's interesting because as you were speaking, I was also thinking about the limitations of DAS, for example, like, you know, you can have a very high tender joint count, which would signify high levels of pain, but have a completely normal, obviously, CRP, ESR, and no swollen joints. Obviously, this is talking to just the pain vas from what I understand from what you were saying. So yeah, it's fascinating. I do wonder whether there is, as you say, an element of the drug actually doing doing the work, but then, a lot of the people who may be on a Jack or maybe on a Baticept, they are coming back to the difficult to treat definition. They've maybe failed for quite a few different drugs beforehand.

So, yeah, it's it's it's difficult to say. Yeah.

And this exists in lupus as well, Ews, you know what I mean? And then you're gonna deal with this as well. So, and I think that, you know, one of the testimonies to this phenomenon is the differences between SDI and CDI. Those are both measures proposed originally by Doctor. Joseph Smolin, and the SDI and CDI.

The CDI is four parameters, and the SDI is the same four parameters, including TGCSJC other things, pain and global. But the SDI throws into CRP. Turns out in all analyses in RA, the SDI and CDI pretty much are the same with a small edge for the SDI because it's got that CRP. But the amount of a contribution of the CRP in the global measure is like 6% or something like that. So, you know, again, there's still this pain issue that is going to exist even though we're controlling the inflammation.

So Sorry, just a quick one on that one. Did they manage to advocate the use of imaging to help differentiate between inflammatory or non inflammatory in that session? Because certainly in my clinics, I do see a lot of pain, but you don't feel much synovitis because majority of the time synovitis in rheumatoid arthritis patients is much different than what we see in lupus. I tend to order the MSK ultrasound and if there's no inflammation there, subclinical synovitis, I wouldn't really change the biological therapy on that basis.

So I've been covering this data pretty heavily at ACRU LAR for the last five, six years. And I can say that we have not seen. We've seen some studies with sort of CNS imaging, including spec scannings and PET scans to see if there were central mechanisms that could be identified and with some suggestion that there might be some differences here. But I think your approach is maybe more practical and useful. You know, my practical and useful approach to non inflammatory pain is making sure that they sleep well and they don't have depression and that fibromyalgia is managed if it's on the table.

But, you know, getting imaging to one document, you know, residual inflammation or maybe damage, because that could certainly change your therapy. I like that approach. Okay. All right, let's end it with one more from each of us. Doctor.

Day, is there another one you wanna talk about?

Yeah, so actually another really great abstract was not from this particular session, but from the other RA session, talking about RA ILD, it was a global cohort study, really large cohort of patients, basically looking at delineating two clusters of ILD, which we're still trying to do. But this was a really great abstract, which was looking at the phenotypes in the two different clusters.

And how is that going to help the practitioner?

Well, we know that there's different phenotypes from looking at HRCT scanning, but ultimately, you know, these people have different prognoses, will probably require different management. And for example, one of the things that came out from one of the clusters was, you know, certain people who have older age RA and ILD onset or have CCP and RF positivity. They are in one cluster, so perhaps they need treating differently to the people who are in the other cluster, for example.

Yeah, I didn't see this one, but the one that we saw from ACR that looked at the clustering, I think it was a French study showed that one was more traditional as you expect ILD, mostly UIP pattern, a lot of MUC5B promoter abnormalities in that group. Other ones had more NSIP making them a little bit more atypical and their treatment a little less certain. Then yeah, so this is a challenge, as Doctor. Day says, there's a lot at this meeting about ILD. My second report was gonna be on two abstracts, POS 22 about mortality rates with interstitial lung disease, a collaborative study of four countries and nine registries, think.

And a second one, POS 43, about severe and fatal infections. So the mortality rates in the Nordic countries was interesting in that they had RA without ILD on top, and then a non RA, non RA population group, and then RA with ILD, which had a drop off in mortality, but the worst being non RA ILD having even worse mortality over time. So the point is clearly that we know that ILD is deadly and a serious threat to a patient's longevity. What I took out of that study, it's a pretty simple study, but I found it interesting that the RA mortality rate was better than the non RA mortality rate, which made me ask my colleague and friend that I was reviewing this with, Jeff Sparks, Jeff, do you think that's because the RA patients are getting biologic therapy and aggressive therapy? Because we kind of don't really know.

We don't have great data that anything we do really works in RA ILD. And that was a head scratcher for him. And there's another abstract later on in the meeting, it's gonna be presented about RA patients with, there's a Japanese study, RA patients with serial assessment of their ILD with serial FBCs showed that the patients who had LDA had better outcomes. Meaning patients who were better treated with their RA had better overall outcomes. Anyway, my second abstract was about this issue of RAILD having more hospitalizations and more deaths due to infection.

And that story keeps cropping up and it's a single center cohort, but it's really damning evidence and all the deaths were pretty much pulmonary infections. So this is a big problem when your patients are diagnosed with this. I think the point is that if you're this, if you're at ACR, you are, and you're seeing all these ILD abstracts, boy, it's gotta make you worry about, do my RA patients have ILD? And maybe you're gonna have a better threshold for ordering baseline chest x rays, PFTs, and maybe even high res CTs. Jooz, what's your final one?

Yeah, so just a quick round of it. So I've got to, you know, talk about CAR T cells. Of course. Talk about it, you're not at EULA twenty twenty four apparently. As we all know, CAR T cells were in of five successful outcomes of lupus

Wait a second, wait a second. Just go back and deliver that sentence again because your camera hung for a second.

Oh, yeah, apology for that. It's live streaming. So yeah, so I've got to talk about CAR T cells in lupus because if you don't talk about it, you're probably not at EULA twenty twenty four. So CAR T cells have been introduced about two years ago after a series of successful outcomes of five patients by Professor George Shet. So these patients were really refractory, have a high disease activities and had tried multiple potent immunosuppressants including cyclophosphamide and rituximab.

So just to summarise what they did with the CAR T cell was initially did some profound lymphodepletion by giving chemotherapy in fluorozapine and cyclophosphamide. And after that, the blood samples were taken and for apheresis with the T cells, and then they infected with the antigen receptor. So it depends. So usually it's the CD19. And that has been the progression of the CAR T cells.

However, of recently, there's also now not just targeting one like CD19, there's also what they call it C compound, so basically targeting two antigen receptors. So there's a presentation yesterday, OP0017. So this was a phase one open label trial in China. So there were 12 patients presented. So essentially looking at the efficacy and safety of this double pronged approach by targeting BCMA, which is related to the BAF inhibition and also the CD19.

So the hope is that because of BCMA attached to cells, particularly the plasma cells, will also get better removal of autoantibodies. So in these studies, so they had this patient, so 12 of them had severe lupus nephritis, so all of them. And again, they've tried several immunosuppressive therapies And what they found of these seven twelve patients, all of them responded. I think nearly over eighty percent people actually achieved complete renal response indicating proteinuria less than zero point five grams a day and all autoantibodies completely gone. So in terms of safety, because people are concerned, because if you're removing the, you know, the deep inner plasma cells, what they found, they were only two mild infection rates.

So there was one UTI, urinary tract infection and one mild COVID. So what they said before this small number of patients with short term follow-up, it appeared to be safe in these refractory patients. However, as we all know, we all need longer term follow-up data. I mean, even the cohort by Professor George Shed two years ago, the longest that they presented here as well was in, was about eighteen months to two and a half years. So I think we still need longer follow-up to see what happened because the B cells come back and whether they will have a flare up and whether they need more therapy in the future.

Yeah.

So a ton of new CAR T cell abstracts here, different manufacturers, as best I know, there's at least eight or nine companies that are developing CAR T cell therapies for widespread use in autoimmune disease. The question is, do we need it? Will it be safe? Is it something that, you know, Doctor. Dea, do you really think you need CAR T cell therapy to manage all patients with RA, including the difficult to treat ones, where do you think that's going to go?

I think in RA, I mean, we're much luckier and more fortunate than the lupus crowd, because obviously it's been really difficult. We're still trying to make steps towards finding the sort of the main therapy, the killer therapy in lupus. I can see why it's causing a lot of excitement in lupus. I think in RA, I know there's murmurings that, you know, it could be used for all autoimmune diseases, including RA. But I think, yeah, we've got other things which we can maybe try first.

Right. Right. And I think that's going to be the next big step, Muse, in that the company that comes up with the next the the company comes up with a real trial, you know, as tremendous as the work that Doctor. Shed has done, it still is, you know, nine, I'm sorry, 15 patients, open label, uncontrolled, you know, optimal circumstances. You know, show us an early phase two with a control arm or, you know, a rescue arm or some sort of active comparator.

And let's see what happens, and let's see what happens over time. Because we need to know, A, that it really truly is going to work. And then what we need to know is in who is it going to work? Like, what's the selection process for a lupus patient to get these therapies? I wonder, you remember the sequential therapies trials that were done in lupus, where they gave the, what was it?

Balimumab again. Balimumab first, no, I'm sorry. Rituximab first followed by Balimumab, and people were horribly refractory disease, and it showed some, that's a, I wanna say it's a synergized study, and there's two, three of them actually. And those were train wreck patients, really train wreck patients. And it sounded like Doctor.

Schetz were, but I don't feel they were quite as bad. So I still don't know who the right person is for these really aggressive regimens. And that's gotta be defined over time, So

Yeah, just to add to that, probably just quick one. Yeah, you agree. So selection of patient is important, how refractory is refractory, and like you say, there's so many companies now making CAR T cell and also there is a move now toward allogeneic as well. So all these CAR T cells that presented at EULA were all autologous, so from the patient's blood, but it's also now in development for donor in allogeneic as well. And from my personal experience, I would probably see this CAR T cell for the patient who really, really refractory that have not responded to all the biological therapy that we have.

Because the main principle that I can see from the CAR T cell is that profound depletion that you got by doing this. And we know there's other alternative strategies that you can improve depletion. When I measured B cells on patient rituximab, we see about only half of the patient had complete depletion in their blood. So there's other alternative strategies that you can use potentially in the upcoming type two NTCD20 antibodies like obinutuzumab, which has a better depletion property, or maybe like dual blockade therapy. And these treatments are a lot cheaper than what you got and they can have sustained depletion as well.

So, yeah, so I think it's still up in the air and like you say, we we certainly need, like, you know, a better controlled trial with a control arm because I think so far it's all a phase one open label. I think I think we need that. Yeah. Alright.

Lots to learn, and that's why we come to EULAR to find out what's coming up and what we need to pay attention to. I wanna thank doctor Youssef and doctor Day for contributing to this recap. Tune in to more recaps, in the days to come. Take care.