ACR 2024 Rheumatology Roundup Featuring Drs. Artie Kavanaugh and Jack Cush Save

Everyone. Welcome to RoomNow's Rheumatology Roundup from ACR twenty twenty four, where we present highlights of the annual convergence meeting that just ended and was in Washington, D. C. I'm Jack Cush with RheumNow.

I'm Artie Cavanaugh. As you can see, like all of y'all, I'm back at work after a very busy meeting in Washington DC. A lot of material, that's for sure.

Yeah, we're home recovering from what was a really big, great meeting. We'll be discussing abstracts and presentations from the meeting. These were chosen without influence of peers, family members or professional marketers. Our content is solely based on our interest in the research, maybe its impact in innovation and practice. This represents our uncensored views on these topics.

Reproduction of this award winning podcast and broadcast is not advised unless you're looking for a whole lot of trouble. Already, I'm told this that one, that this was one of the most attended meetings since the pandemic, and that this year there were more US attendees than outside The US and that was sort of a new change. What do you think about the crowd?

Yeah, it was good to see. We've been doing this, what Jack, since 2005 and the heart of the meeting is really the posters and every convention center has a different layout, different rooms and lectures and stuff but it's really the posters that's where I gauged the crowd and it was nice it was pretty good crowd there in the going post the poster walking right up getting to meet the people who are trying to defend their their most recent work that they were presenting at ACR. It did look like you came back to maybe the pre pandemic levels and that's a great sign.

Yeah, I think so too. Artie, why don't you start us off with one of your favorites from the meeting?

Okay. I'm picking abstract sixteen seventy nine, and this is the amplified study. The reason I picked this is that one of the topics that we're very interested in is predictors, biomarkers, personalized medicine. What is the right drug for the right specific patient? And largely we don't know.

And Jack and I both went over all the abstracts for the meeting ahead of time, and there must have been 100 on predictors of response in rheumatoid arthritis and other diseases. And we always want these to be something promising. We want a test that will tell us that Mrs. Jones should get drug A and Mr. Smith should get drug B based on either efficacy or safety.

So gosh, we looked at a lot of these. This one looked at this amplified study. Now we've seen the clinical data before, that is that it's a head to head study, abatacev versus adalimumab, ACMA positive patients with early rheumatoid arthritis. Over twenty four weeks, boy, there was not a lick of difference between them. So both did well.

A lot of people responded. ACR 2,050, 70 responses were great. This was a biomarker poster and they looked at changes in circulating peripheral cells and they found some big differences. They found some very distinct differences particularly in B cell population. So the patients treated with abitacept not only did they change their seropositivity, their titers of CCP and rheumatoid factor went down, but they also had an increase in the number of circulating B cells and the number of circulating T cells as well.

The adalimumab group had a greater increase in certain subsets of B cells, and the responders to adalimumab had an increase in Th1 and Th17 cells and also class switch memory B cells and plasmablasts. So on the one hand, you have clinical data, which are not different between the two. The hope had been that you might be able to predict which patient was going to respond to which agent, and you can't. There are these nice changes, but none of them correlated with efficacy. None of them correlated with tolerability.

So in all of the abstracts that we looked at that went for predictors and the methods have gotten just so incredible these days, especially things like spatial transcriptomics, where you can look at a biopsy of an inflamed synovium and look at what cells are present, where they are, and how close they are to each other. It's just fascinating, but we're still missing precision medicine. I think we're just gonna have to keep looking for that at future meetings.

So the great hope of this amplified study was really based on the Apipra and ARIA and other studies in patients with not yet established RA, clinically suspect arthralgia, preclinical RA where you gave abatacep, and they did really well compared to really nothing. There the biology of preclinical disease is certainly different, And maybe going after T cells with Avatacep made a difference before you establish these. These patients were early RA, and they were double positive for RF and ACPA, two thirds of them were shared epitope. The great hope here was that ABBA would distinguish itself compared to ADDA and it did not. The question for me is, maybe it doesn't matter after you already have established disease.

Maybe the only difference here is between what you choose is before they get established disease or maybe these changes that you find biologically, mechanistically, might they mean something two years down the road? We don't know. This trial didn't fulfill any promises for us.

Yeah, we're still lacking. Do you think back many years when you looked at the synovial biopsies and a consistent feature of responders was a decrease in the sub lining CD68 positive macrophage population, very crude back then before we even knew a bunch about macrophage subsets, that just went along with response. It didn't differ by what the treatment agent was. So as much as we have some really cool methods now and some very beautiful illustrations, we're still lacking something of clinical utility.

Yeah, I remember Artie and I were walking from one of these great presentations about biomarkers and proteomics and transcriptomics. He said to me, Isn't this the data we saw twenty years ago about the changes in the synovium? Arti, what you get from your conversations with Hani Gebaloi and others?

Yeah, he said it certainly rings very true. We know a whole lot more, we know a whole lot greater detail, but we're no further down than we were in some ways by looking at those gross gross methods that were used decades ago.

Histochemistry was all we had. Now we got all these sexy things which are really cool, but I don't think it's getting us the answer that we want. My first one is also on RA. I have this preoccupation with seronegative RA. It's a bother for me every time I see one.

This is a follow-up and it's really good data. It comes from Mayo Abstract four fifty eight. And this is a twenty year follow-up study of one hundred and seventy six patients with seronegative disease, and they were double positive, I'm sorry, double negative. They were mostly female, almost twelve years of follow-up. The interesting thing in their data, it's different from other data.

Other data would show that somewhere between forty and up to sixty five percent of patients were seronegative might change their diagnosis if you follow them out ten, fifteen years. In this study with, again, almost twelve years of follow-up, the ten year cumulative rate of change in diagnosis was only fifteen percent. That number, was about, I think, a third or forty percent of them were either spondyloarthropathies or they turned to seropositive RA. Eleven spondees, which is PSA and AS, and then six became seropositive RA, five were OA, three crystal arthritis, three CTDs, I don't know what that is, and one each with infection paraneoplastic RS3PE or sarcoidosis. Those who didn't change diagnosis, twenty seven percent went into remission within ten years.

Then those who stayed with a diagnosis, about twenty percent required future treatment with aggressive therapy, biologics or targeted synthetics. Maybe fewer people changing over time, maybe Mayo they're a little bit better at diagnosing seronegative RAs than other places. But I think it's important to note that this could be the fate of patients who have seronegative RA.

Yeah, one of our colleagues, Mohan Bakari, great doctor from The UK, said, well, maybe we shouldn't put seronegative patients in studies, but that's a very, very different consideration because when you put somebody in a study, you require that they have multiple swollen joints, require that they have erosions, require that they have other factors that make them worth treating. And if you think back way back when we started the first studies in biologics, a very long time ago, If you look in those studies, the seronegative population, had serious RA. So this is very different. This looks at the population level and yeah, it's a mild disease, a lot of drug free remission, a number of people who change diagnosis. So it's quirky subset.

If you look at any clinical trial, you'll see often at the end of a clinical trial, there's one or two people who actually did change their diagnosis and that's not uncommon. And the other thing about the dynamics of change here, these changes were not within the first twelve months. A lot of them were delayed over five years, if not more. So it does take time and it's gonna happen. So you do have to keep an eye on what the fate of a seronegative RA is gonna be.

All right, so my next presentation is Abstract 82, and it's a basic science abstract, but I think we like the basic science abstracts when they have clinical implications. So this is comparative immunology of endothelial anchorage sites between spine, hip, and knee. So if you think of the SPA group of diseases, axial spondyloarthritis, psoriatic arthritis, inflammatory bowel disease, they share many common features, including the punitive role of IL-twenty three. And you see this in the genetic changes. You see this in the tissue expression among these different diseases.

A big puzzle to us then has been the fact that inhibition of IL-twenty three, which is super effective in the skin of patients with psoriasis, is not effective in axial arthritis in ankylosing spondylitis or radiographic axSpA. And that's puzzling. And there's been some conjectures, but this was a nice study. Thought this came from Dennis McGonigle's group in Leeds, and they looked at tissue specimens, and they got these from the spine, from the spinous process, they got them from the hip capsule, and they got them from the knee, And they looked at, perianthesial bone immune cells. This is all during orthopedic surgery.

When they look at these cells, what they found is that, non stimulated, all the tissues made a certain amount of IL-twenty three. They were all capable of producing IL-twenty three. But when you stimulated them, the spine and the hip compared with the knee produced much more IL-twenty three. And there are also some differences. It was more the inflammation of the monocytes and neutrophils are more abundant per gram of tissue in the spine and the hip in the red marrow, but not in the yellow marrow of the knee.

So the clinical implication of this is that maybe IL-twenty three inhibition is, maybe we haven't studied the right dose to see if it's effective in axial spondyloarthritis. And there's some rationale to that. You think of data with the TNF inhibitors where at the PSA doses where all the agents are great, the skin doesn't do as well with the tantorcept. You need more of that. So I thought this is intriguing.

It certainly is a good explanation for maybe why we see that treatment difference when you might have expected IL-twenty three is to work. And there is some preliminary data about psoriatic with spondy where they might respond to IL-twenty three. I think it's exciting, no one's tested the idea of more drug as a potential answer. We need to see maybe by next year whether that'll happen.

There are a couple of studies in psoriasis looking at much higher doses. The idea being that if you treat early psoriasis, maybe you can knock it out. Maybe you can hit it very hard and have a very prolonged clinical response. So maybe we should do those studies in AgSpA.

I reported on this before, I just can't let it go. Emapalumab in Still's disease is a late breaking abstract L19. We've talked about it in one year it was nine patients, another year it was twelve, and then it got up to fifteen. Well, now they've combined a clinical trial with an open label prospective trial, and they've got thirty nine patients, all Still's disease, kids and adults who have serious macrophage activation syndrome not responding to conventional therapies. I think this is critical because I think they have a critical mass on a drug that's already approved.

The drug is emapalumab, it's marketed as GammaFant. It is a neutralizing anti gamma interferon monoclonal antibody. And now with thirty nine patients on an already approved drug, I think they got enough that this could become an FDA approved drug to treat MAS that occurs in Still's disease. Why? Well, it's a twenty to forty percent mortality rate when this does occur in either kids or adults.

So they could pull the data, they got thirty nine patients, they have a scheme which is different as time goes on as to how you dose it. The primary endpoint was a composite of eight clinical measures were designed to basically show the things that you'd expect to see, cytokine storm or macrophage activation syndrome. If you met all eight of those criteria, then you're a complete responder. In the trial, however, only the first time out, I think the number was something like, I wrote it down here, was fifty three or 4% with that definition of primary endpoint. But if they just dropped the LDH, which turned out to be non predictive going with a seven point measure for meeting complete response.

It now responded by seventy six percent with eighty two percent showing MAS remission by the investigator. All the things you'd want to happen happen. Steroid tapering was dramatic. Circulating IL-two receptors dropped, ferritin levels dropped, all the things that you'd want to see, LFTs, etc, all became major, pretty fast responders within the first two weeks of this therapy. I put it out there because I think it's a game changer when it comes to how these patients will be treated in the past.

In the past, was you give them steroids, you put them on an IL-six or an IL-one inhibitor, and then depending on who's involved, they're either getting cyclosporine or etoposide, the responses are never quite. This just seems to be so much better. But I think it's a game changer for the future.

Yeah, and the idea of the cyclosporine and the etoposide, those come from heme people. The cyclosporine, think we know how to manage the toposide with a neuropathy. Boy, that's a tough one. And now when these people come in, they're super sick and they get everything thrown at them, like kitchen sink approach, basically. So something more focused and more mechanistically relevant may be good.

And the tolerability, it seems reasonable. Yeah. And I think back a very long time ago, interferon gamma had been targeted in rheumatoid arthritis studies, and it just didn't work. It wasn't the right mechanism. And I don't believe it was beset by a lot of complications necessarily.

So yeah, this is something that'd be nice to have for a small but important subset of patients for sure. All right, my next one, I got to say, as we went through the abstracts, what were there, 2700, Jack, or '29? If it was a contest among the diseases and of course there's no contest, there's no gambling, but lupus was the winner. Lupus was my gosh, lupus was everywhere. You think back to the ACR years ago, we were begging for things for lupus.

Now you have all sorts of therapeutic interventions. And as always, when you have the therapeutic success that drives further research into diagnoses, into stratification, into looking at other outcomes, creating novel outcomes. And boy, there was a ton of stuff in lupus. I had a medical student here in clinic with me yesterday and he's a third year medical student, has kind of an interest in rheumatology, but he said, hey, there were a lot of CAR T abstracts at the ACR. I was like, well, good on you.

Didn't know that. But yeah, CAR T abstracts are everywhere. I didn't pick one of those to highlight because I think they're all, they're super exciting. Maybe there's something to there, but we have controlled data on there, and we may not have controlled Also, I don't know if the CAR T, I don't know if that's gonna persist, meaning we have better ways to target B cells. We had rituximab, well now we have obinutuzumab, but we also have these bispecific T cell engagers, tri specific T cell engagers.

BiTEs and traits?

Bikes, well, you can't say bikes though, that's a trademark. So now we're gonna have to pay, but bikes, yes, you can say bikes and trikes and cars. I mean, the CAR T thing lends itself to lots of funny names and stuff. I don't know where those going to go, but my abstract was number 1553. This is from Roshiya Tanaka, his group in Japan.

This looks at an oral antagonist of toll receptor seven and eight. Small molecule, very selective in its binding. Of course, toll receptor seven and eight, very reasonable targets in lupus, which we know from genetic studies in looking at the proclivity to develop lupus. And also they're very intimately involved in the immunopathophysiology as we understand it with the changes in nets and self nucleotides activating the plasmacytoid dendritic cell, elaborating a lot of interferon and that activates a lot of downstream effectors which give us many of the manifestations of disease. This was a relatively small study that had basically two studies they combined here.

This looked at placebo versus one hundred milligrams a day versus two hundred milligrams a day, but they had a very clear differentiation from placebo, especially at the higher dose. So they looked at BICLA, the British Islands, CLASI which is a cutaneous and the CLASI activity score, yet mostly focused on a very small number of outcomes, skin arthritis, also looked at double stranded EA and complement levels. Tolerability wise, there's a little bit more, but nothing more than a phase, than a class II AE, a little bit more in the higher dose. So very exciting and it's oral. Among all the therapies that we have for lupus, I like this one because it kind of fits with what we think of as the pathology and it looked kind of cool.

Small numbers need a lot more study.

Yeah, that's what I noticed when it was presented at EULAR as a first run and then also here, the numbers are low, but they're really encouraging. We've been talking about toll like receptors for a while, mechanistically thought to be one of the mechanisms of hydroxychloroquine effects in lupus. But I like the approach in that it's oral, seems to be well tolerated. You're really dying to see what a Phase two is going to look like in this with 200 or more patients in a trial, that would be really exciting. Lupus was the bomb at this meeting and a big event was the rollout of the 2024 ACR updated guidelines on the treatment of lupus nephritis presented by Lisa Samaritano, Maria Delaria, Anka Eskenazi from New York, and Mary Beth Son.

They all did their different parts of this. Large effort, many different committee members. I like that there was a simple version of this. I'll give you the simple version. One, everybody gets a renal biopsy.

Surprising? Hello? I don't think so. But new diagnoses with more than 0.5 grams of protein or flares, get a biopsy is what they say. And then the treatment was based on whether you had class three, four disease or class five disease, or whether you were a kid.

I'm not going to cover the kids. And by the way, all these recommendations are expert opinion. They're conditional. None of these have strong evidence. So you can argue with us all you want.

But nonetheless, the lupus experts in the world are unified in this approach, including the Nephrology Society that was represented on this committee and in this presentation. One, everybody gets prompt glucocorticoids. They get pulse steroids two fifty to one thousand, one to three days in a row, started on forty milligrams, and then weaned down to five within six months. Everybody should be on hydroxychloroquine. You have to put everybody either on an ACE inhibitor or an ARB.

And then they basically say that if you're class III or IV disease, you need three to five years of triple therapy. They consider steroids part of triple therapy, which I find goofy, but nonetheless, triple therapy which would be steroids, and then the other two options are either mycophenolate and belimumab as one option, or mycophenolate and a calcineurin inhibitor, another option, or the urolupus nephritis cyclophosphamide dosing regimen with belimumab. Overall, they tend to really prefer regimens that have mycophenolate rather than belimumab in them. But if you've got a lot of proteinuria, they do recommend the calcium neuroin inhibitors. You were the first back when we were at Southwestern using cyclosporine lupus and then micro then tacrolimus, and now we got voclosporine, a much safer option that's in this mix here.

Say if you have extra renal disease with class three to four, like you to use belumumab. Then they go to class five, and that was presented by Doctor. Askenazi from New York. Again, all conditional. If proteinuria is less than one gram, it's steroids and an immunosuppressant, could be azathioprine, mycophenolate, or calcineurin.

But if it's greater than a gram, they want steroids and triple therapy, mycophenolate and a calcineurin inhibitor. Inhibitor. Then if you've got refractory disease, they say check adherence, double check your doses, escalate your treatment from dual to triple, and if it's triple, then consider using an anti CD20. Oh, by the way, didn't that fail in clinical trials rituximab? I think they're looking ahead to obentuzumab, which is more than a year away being approved in lupus from my assessment, or a combination of drugs that could include steroids with either mycophenololipolumab or calcineurin or investigational agent.

That's it. They do have a section devoted to kids with lupus nephritis because kids are harder to treat. But I thought that they made this very straightforward. I think they did a great job presenting the data.

Yeah, I think there wasn't any surprise really was there. I think it was pretty much what you'd expect. Some of the other, I think the interesting things that know, of course they can't mention CAR T, they can't mention bikes and trikes. They also can't mention the urine biomarkers, which could be super exciting because who wants a biopsy repeatedly in this day and age? So they're out there and the good thing is I think they're going to make everybody feel better because I think this is really what people are doing.

The biomarkers for nephritis are incredibly strong. Andrea Fava presented that again this time. CD168, IL-sixteen and others in the urine and also in the tissues. That's the way to go in the future. But we got to wait for that to come down the line.

All right. My next abstract is number nine ninety five. And I'm just presenting it, Chris, I have a confession. So the title is, what are the carbon footprints of adalimumab originator and biosimilars? And my confession is I just went there to bust their you know whats.

Was like

Wait a second, you're Mr. California, right? Aren't you measuring your own carbon footprint before you go to work every Hey,

I get your carbon footprint right here. So anyway, they looked at the available, it's in Europe, these are French, and they looked at 10 biosimilars of adalimumab, and they looked at the carbon footprint, mostly of the packaging. So the cardboard and the package insert and then the device. So is it a syringe or is it a pen? And then they did a, I guess there's some woke software package that allows you calculate exactly how much that all of these things would represent in terms of CO2 emissions.

And they found that there was a difference maybe as much as a twofold difference among the packaging for the different biosimilars and that this would a year treatment with adalimepen is nine kilograms of CO2 per year. So I gotta say, I, you know, they said the poster hall was full, the poster hall was great. I just went there to break chops, I did.

But was there a winner in carbon footprint?

The lowest carbon footprint was Amjaveta on there, But you should tell you these were all the pens, but you tell your patient to use a syringe. Syringe is lower carbon footprint than a pen. But I this is my confession is I went to the poster, and the poster, there was a fellow standing in front of it. And she was a wee little thing she was and she looked like, you know, the older we get, the younger the fellows get. She looked like she was about 18 and just so earnest and sit and so I was gonna bust in there and say, hey, how did you get to this meeting?

Did you walk here? Did you parasail? Did you fly in a jet and get your own carbon footprint? Like how big is your carbon footprint? But I couldn't.

So I just walked by and said, nice poster.

Marketing for these products has gotten incredibly competitive and difficult. So I firmly expect to be hearing about carbon footprint from my local sales rep. Me, I'm holding out for the prize inside like we did with, what was it? Cracker Jacks. Yeah.

Mean, we've only got the better prize inside, that's what I'm prescribing. All right. If there was another big buzz item at the meeting, it was the GLP-one drugs. There was a lot of presentations in OA beneficial effects, in lupus beneficial effects. We've seen it before in gout.

Abstract 02/1959 was a study of two different GLP-one drugs, semaglutide and terezepatide, which is Mounjaro. 01/1952 patients with RA who went on these drugs, they looked at one year outcomes, and they all showed significant benefits with weight loss of 7%, BMI decreasing almost two to three points, SED rate dropping six millimeters, CRP dropping one milligram per deciliter, lipids, pain, all these things improving on these drugs. Obviously, what goes along with this is better survival statistics, better cardiovascular outcomes. And the question is, what's at what risk and what's it really doing? Only about fifteen percent had GI side effects, about a quarter of the patients had the discontinued drug because of side effects, mostly GI.

Is all this from just losing weight or is there a direct benefit of going after GLP-one and that mechanistically it may make sense? That needs to be worked out in subsequent trials. But I think that if you're a rheumatologist, you're soon to become an expert in weight loss, as you're going to see more and more of these trials in your patients, if not combination trials of these drugs along with your biologics, looking for additive effects?

Yeah, super hot topic, a number of presentations across different diseases. And I think you're right, this is not something that's interesting. I think the only thing holding us back now from prescribing these is the access, is the cost and the denials. Right now they're getting a lot of denials. Had a patient who asked for one and the insurance company told her that if she had a heart attack they would allow her to have it.

But it's like, well, you're supposed to prevent a heart attack. But I, yeah, these these I I learned a bunch and I think you're right. There are there may be differences. Weight loss is great no matter how you lose weight, but it may well be that the GLP-1s have an advantage certainly over the DPP-4s, maybe over the SGL-2s in terms of mechanism. They asked me to participate in one of the workshop seminars and gave me the topic of liver disease.

So I had to do a lot of work on that and it was made much easier because now we know for fatty liver disease, which is the most common form of liver disease worldwide for all patients, but we see it all the time in our clinics, don't we? But now we know that the combo GIP, GLP-one are effective for fatty liver disease. That is just as absolutely fantastic. I did learn, I think one of the things I learned too is in the seminar on these drugs is eat your vegetables first. Was the way they said when everybody loses weight, then when they stop, they gain weight again.

But one of the things you can do is eat your vegetables first. If you do that, it ends up you eat less, eat fewer calories. So that's my take home point from the ACR, eat your vegetables first when you're eating.

I could have gotten that from my mother-in-law, but we went to a big meeting to find that out. Okay, what's next?

All right, the next one I got is, it's one of the cooler ones, I think, and really gets everybody kind of smiling or chuckling. It was a late breaker L20, and it's the automated ultrasound machine from Denmark. Arthur is the name, which I love, of course, but and that's been published on. But what they have now is artificial intelligence. So before they had had Arthur.

Arthur is a robot. So the patient shows up, they put their hand on a tablet, they goop themselves and the ultrasound probe comes over, goes down and does an ultrasound. Now they have Diana, which is the artificial intelligence, which is interpreting. Interpreting, of course, what do we care about? We care about synovial hypertrophy, we care about Doppler activity as a indicator of inflammation.

So this was kind of a further proof of this. They had the robot with the artificial intelligence compared to an on-site rheumatologist who was doing it. And then they had a adjudicator who was the ground truth as they call it in AI studies, who evaluated everyone and saw how well they agreed. The bottom line, the robot did really well. So in terms of agreement on synovial hypertrophy, it was very close to the absolute truth.

The Doppler activity also very interesting, very close to the expert who is looking at this. And I think this has a couple of applications and of course ultrasound is being picked up a lot and the fellows are very much interested in it. One of the things that naysayers have against ultrasound is that it's operator dependent. This takes that away. This is now data.

And I think in rheumatology, our bias probably, well, I don't want a darn machine doing this for me, but is that any different than when echo was new? The cardiologists did the echos themselves. Back in the day when it was relatively new, the obstetricians did the ultrasounds themselves. They don't do that anymore. They're done by technicians.

So this is essentially even one step further because you can do it for the hands. You can't do it for other joints, but I think this may be something that you'd see in the future for those consults that there's none of rheumatologists know it's hard to get in to see us. Well, if you go do an ultrasound and you have synovitis, you get in then right then. If you don't, then you probably don't need to see the rheumatologist that quickly. So not perfect, not for all joints, not for deformed joints, but super interesting.

So this adds to other abstracts we've done in recent time where we talked about finger digital creases disappearing with a swollen joint and doing that in an automated way with a cell phone, finger movement as a range of movement done also with a cell phone. These are tools that can be used for remote patient assessment. They can be done to supplant your detailed physical exam. So that could be even in clinic visit as part of an expedited evaluation. And I like it.

This one, however, is a little bit slow. It's twenty minutes or more for the robot to do that. The good part is the robot talks to the patient. My, you look ugly today. Is that a new hat?

Whatever. For me, it would be bad because the patients might prefer the robot to my personality when it comes to the conversational discourse. But anyway, I think it's an exciting advantage and I'd like to see where this goes. Once you show it works well with a robot a device and whatnot, iterations of that will ultimately get around to using it on a cell phone and seeing how that can be used. I think this is great progress.

My next one is enalumab, another B cell monoclonal antibody abstract 2,580 presented by Meissler and colleagues. Small study, sixty eight patients with lupus who were treated in a double blind twenty eight week placebo controlled trial showing the efficacy of this dual depleter of B cells. It does it by ADCC and also by bath blockade, thinking that's maybe a better depleter of B cells, maybe that's why in this Phase II trial, it looks so positive. They extended those patients another twenty eight weeks, so the placebo patients rolled over to get the real drug and they all caught up in the end, they followed them out to sixty eight weeks. The good news is that I think that this B cell targeted agent had very strongly positive results.

It seemed to go up with time as you went out further and further, looking at all measures, SRI four, SRI six, LL DAS, Doris remission and serologies, looking well. My only worry is it's a Phase II trial. Phase III is where a lot of good lupus drugs go to die. But so far the data looks really encouraging here.

Yeah, I think this might fold into the discussion that we were just having about carts and bikes and trikes. If you have a better B cell depleter, then might that be something that obviates the need for those other therapies, which you know the CAR T very aggressive, at least certainly for those that require the conditioning regimens and hospitalization and you know that that's that's a big very big deal and the intended risks of that. This might be a better option and boy so so so many therapies we have and of course, the B cell therapies are being looked at also in Sjogren's and in scleroderma. So there are a number of abstracts that looked at that as well. I think it's really the resurgence of that mechanism and also the resurgence of those diseases getting much more attention than they ever had.

Yeah. All

right, so my next one, it's, I'm gonna throw in eleven thirty two, which is, think very interesting because it's not even rheumatology. This is the VEGA study, it's a follow-up of that. This is the combination of gazelkumab and galimumab in ulcerative colitis. And here they looked at the biomarkers. Now one of the things advantage that IBD has compared to inflammatory arthritis is that you do colonoscopy and you get biopsies.

So you can look at cell infiltrate, can look at gene expression, so it lends itself to inherent built in biomarkers. So VEGA study is important for several reasons. One that it I think brings back the idea of combination biologic therapy which had been killed by the earlier negative studies in rheumatoid arthritis and there's still black box warnings about that. But we saw it in especially in GI people would sneak in with putting their toe in the water for people with very refractory disease and adding combinations. But this was a proper study which showed that combination therapy, the idea is not dead.

So this is important and it's interesting in ulcerative colitis, but I think we're just a little bit behind it in rheumatology. There's a study called Affinity looking at gazelkumab and glimumab in psoriatic arthritis. And there are a number of, there were two other abstracts, 2640 was January 1460 that looked one was from France, 1460, and the other was from The US claims data, looking at combinations that people are already using. In The US '1, 2640, a lot of people are using biologics and the PD4 inhibitor, but some people are using IL-seventeen and the TNF inhibitor. In the French study, they were combining TNF inhibitors, JAK inhibitors, anecdotally.

And of course, they're in both analyses. They did find maybe a little bit more in the way of infections. But these are really, really refractory patients that they're trying this on. So I think super exciting that combination therapy may be making a little bit of a resurgence.

Yeah, I think it's very exciting because it dispels an old myth that we established back in February about this combination being maybe dangerous with no benefit. But this is what I worry about. The problem is that who are you going to give combination therapy to? You're going to give it to the patients who have the worst disease. We had another abstract at the meeting thirteen ninety three about patients with the worst disease are the ones who have the most amount of side effects.

Which is basically saying that you're set up to lose when you start studying combination therapy or start using aggressive combination therapy in all your failures. Those people are self declaring themselves to be not just recalcitrant, but more likely to have side effects. That becomes a worry in the design of these kinds of trials. When you see a real positive result like that, I think we definitely have to look at this data maybe try to emulate it in some of our diseases, not just in GI. I think if there was another big theme at this meeting was a lot of sessions on steroids, let's minimize steroids, let's withdraw steroids.

I got two that I want to just give you a quick hit on. One was from Diane Lacalle, abstract 2673. Her research using British Columbia claims data, 28,000 steroid users with RA, that's about half their patients with RA, they're on steroids. They basically looked at what happened to the outcomes. They had, as expected, a fair number of cardiovascular and or infectious deaths, almost two thousand five hundred cardiovascular deaths out of twenty eight thousand, and then three eighty seven infectious deaths.

What they found was what we said before in many different ways, that for every year that you were on a steroid, you increase your cardiovascular mortality by seven percent. For every year you're on a steroid, you increase your infectious mortality also by about seven percent. But what happens when you stop the steroid? Do you ever back your baseline risk of cardiovascular or infectious death? It turns out for every one year you stop the steroid, your cardiovascular mortality risk went down one point three percent.

For every one year you stop the steroid, your infectious mortality went down by almost five percent. But the takeaway big ticket item message here was that if you were on steroids a really long time, three or four years or more, you never get back your baseline risk. Meaning what those other people who are just like you who never got steroids got back to their risk of cardiovascular infectious death. So the number was it did not return to normal as it regarding cardiovascular mortality if they were on steroids for two or more years. It was three or more years as far as infectious mortality.

If you were on it for longer than that, you didn't go back to the lowest possible number. That is a carryover effect, and that might be through a number of different factors, but eye opening. Do you think of this data?

Yeah, so it was scary. After you come back to the meeting and go to the clinic, you start looking at all those patients who are on steroids and like, my gosh, know, well, what do we do? Well, you know, the especially for patients for whom the steroids, they know the steroids help and they're a little bit reluctant to taper your PMR patients where you don't have many other options. Your, you know, the rheumatoid patients where they really like that certainly for flares. And I think there's a natural tendency because we're human to kind of kick the can down the road and say, you know, next time we're going to taper, Because you say, let's taper and they give you the colicky baby face and you say, okay, next time we're gonna taper.

But that's how people get on steroids for a long period of time. So these data really kind of scary, honestly. But I think now we have so many therapies, even in conditions like PMR, you do some very exciting data of things other than steroids. So I think we see data like this and it's like, hey, we got to get our act together and get steroids sparing.

I know we got to wrap up, but I want to add on to this discussion. Peter Merkel in plenary session seven seventy four presented data in GPA patients where they were in remission. And on five milligrams of prednisone, they either tapered them or they kept them on. If you kept them on the steroids, you got more flare rates. Not so much if you were on a background of rituximab, it was like nine percent versus six percent more, but not statistically significant.

But if you were not on background rituximab, it was much higher, twenty percent versus two point six percent. And all the flares were minor flares. Point being that it's probably good to stop the steroids and a lot of other sessions devoted to this. Ari, let's do one more each. Okay.

Quick hit, what do you got?

Quick hit, I got $17.45 and this was the oral surveillance and statin use. We're all very familiar with oral surveillance. There have been multiple publications, dozens of abstracts. I think the data is something we know and we understand. I like this one because the point was to look at statin use, which they had done.

But this, I think, has an important message for us, and that is we're kind of under utilizing statins and across all of our diseases. Is an RA, of course, in the oral surveillance, but across all of our diseases, we're under utilizing them, really under utilizing them. But if you add statins, you can decrease the risk. Remember in the study, there was a higher risk of MACE with TOFA compared to TNF inhibitors. But if your patients are on statin, the difference dissipates.

So maybe we need a cocktail for our patients of a GLP-one and a statin and maybe a little Naprosyn thrown in or something. But I think these data are sort of telling us we just can't ignore it and say, go talk to your regular doctor, especially in our younger patients who don't maybe go see their regular doctor.

Again, this does go well with the data shows that we and other doctors are not very good at health maintenance things, and that we really do need to step up and make sure our patients are on these therapies. The important question came up in this session. Those people who you would not use a JAK inhibitor because of their age or because of hyperlipidemia. What if you treated them? Would you now that, does the equation change?

Would you now consider using a JAK inhibitor in those people or continuing it when they previously had success? I think based on this data that Doctor. Giles presented, I would. My quick hit is, it's called the PMR mode study, abstract sixteen ninety seven. It's a one year study of methotrexate or placebo in recently diagnosed PMR patients who had received less than eight weeks of glucocorticoids.

And the endpoint here was glucocorticoid free remission at week fifty two, sixty four patients. But when you looked at their progress over fifty two weeks, the lines are superimposable, meaning placebo did just as well as methotrexate. This has always been the argument in these PMR patients where you're trying to steroid spare. Can you use methotrexate? We often do for lack of having options now that we have sorrelimab and other drugs coming down the line.

I think that it makes sense. By the way, secondary outcomes were no different between methotrexate and again, twenty five milligrams per week is not a dose issue. You could have say, well, maybe the cohort didn't have inflammatory enough disease. You could make that assumption. But there was another abstract at the meeting, abstract 1,700 that did a claims data of people with PMR going on either cerulimab or methotrexate, that they matched up as best they could two ten per group, and ceruleumab outperformed sixty percent versus thirty five percent as far as the endpoint of being off the steroids within six months.

So I think this is changing the conversation on steroids bearing in PMR?

Yeah, I think this is maybe the most important abstract of the meeting, or maybe not most important, but the most impactful because we go back to the clinic, I'm in the clinic right now and your PMR patients. And we always like abstracts that agree with us. I've never been a methotrexate believer, but you look at the data as it is until now, the believers can say, well, there's something. The non believers can say, nah, there's nothing. I think this is super clear.

As you said, you can't say, well, you didn't give a high enough. And you say, it's only sixty two patients, but you could have had six thousand two hundred patients, and there was no way that there was going to be any difference. The lines are exactly the same, saying that I don't think there's a point giving methotrexate to PMR patients. I have fellows here, I'll say, you know, some PMR patients may have peripheral arthritis. You know, they're very RA like.

For them, maybe, but don't treat your PMR. Don't delude yourself that you're going to use methotrexate as a steroid sparing drug. I think, boy, this was super clear data. And this is very impactful, very useful in the clinic like now, today.

So I want to thank the audience for again, hanging with us in Rheumatology Roundup again this year from ACR. ACR next year, Chicago, we're going to be there. We hope that you'll be following us or be there with us for another great meeting. The next two big things that are going to happen in rheumatology are big rheumatology meetings, one in Maui and one in Dallas. Arty, what's going on in Maui in February?

Rheumatology Winter Clinical Symposium. A place to hear about the latest data and chat about it with friends and colleagues in the collegial atmosphere.

Yeah, eleven through fifteen, Arty and I will be there. We'll be doing our wrap up on all abstracts and already we're doing wrap up on SPA and the faculty and program looks really, really good. Rwcs.com, put dashes in there and check out the agenda and faculty, you'll be surprised. Then that's February 11 through the fifteenth, right before that in Dallas, February eighth and ninth, RheumNow Live twenty twenty five. Early bird pricing goes away I think on the thirtieth or December 1.

If you go there and check out the agenda and register and put in the code ACR twenty twenty four, that doesn't make sense, does it? It might be ACR twenty twenty five. Either one to get the early bird discount. But that's RheumNow live. Again, another great meeting, day and a half meeting.

Artie's got a great four day meeting, ours is a Saturday, half day Sunday meeting, whichever fits you. You can, by the way, do this virtually if you like.

Or do both. Great meeting. RoomNowLive would be a great meeting and local for a lot of people. Really easy to get to Dallas.

All right. Thanks for doing this. We'll see everybody next year.

Thank you.

Over now.