ACR20 - Day 4.7 Save

This is the RheumNow podcast, and you're listening to highlights from the ACR twenty twenty virtual meeting. Our faculty reporters have been doing videos and recordings so that you could stay up to date. Hope you enjoy these and our panel discussions.

Hello, everyone, and thank you for joining us for this RheumNow giant cell arthritis panel from ACR twenty twenty. I'm Richard Conway from Dublin, Ireland. And I'm joined by a truly outstanding global group of giant cell arthritis experts to discuss some abstracts from ACR twenty twenty. We have Sarah Mackie from Leeds in The United Kingdom, Len Calabrese from Cleveland in The United States, and David Liu from Melbourne in Australia. So the first abstract we're going to discuss is the one on maverilumab in giant cell arthritis.

So Sarah, I might ask you to start off on this one.

So this was a report that was presented earlier today by Maria Sidd. So it's a phase two randomised placebo controlled trial of mafamilimab versus placebo in addition to a prednisolone twenty six week taper. So eligible patients had active giants of arteritis and they were either new onset or they were relapsing refractory and seventy patients were recruited. And the primary outcome was time to first flare and the key secondary outcome was sustained remission to twenty six weeks. And the headline results of the study is that it met its primary and its key secondary endpoint with a hazard ratio of 0.38 for time to flare and eighty three percent of the patients in the treatment are interventional and are achieved to stay in remission compared to fifty percent in the placebo arm.

So it looks exciting. It's phase two study. We don't have the full study report, so there's still a lot of things that we'd love to know about the results of the trial, but it's very exciting because it's exciting result on a new biologic, which is not so far licensed for any indication as yet, to my knowledge.

Len, I wonder if you might tell us a little bit about how maverlumab works and why it might be an attractive option in terms of GCA pathogenesis.

Yeah, volunteered to do that and I was thinking here, GM CSF is such an interesting molecule. It's,

know, in

a short generation ago was thought to be a, you know, hemopoietic growth factor and now we recognize it as a central mediator in inflammatory processes, mediation of pain. It's in very advanced trials in a number of diseases, particularly rheumatoid arthritis. And it is not totally clear in terms of a crisp immunologic story which pathways are being involved. It is obviously produced by hemopoietic cells and viscerosomatic cells, can signal hemopoietic cells and viscerosomatic cells. So it's very central kind of like that IL-six, you know, centrality.

Recent studies in the Lancet for another molecule, otilimab, recently in RA, you know, big biomarker study shows that, you know, very little moves outside of acute phase reactants and a lot of things that we're looking for. So preclinical modeling suggests that it is active at the endothelial interface. And you know, these are pretty impressive data and you know, it's all going to be about risks and benefits and the safety signal that was released there was quite favorable at this juncture. There's obviously things that we're concerned about from preclinical modeling based on things like pulmonary alveolar proteinosis and it really has not been seen in any of the global programs thus far. Infections will be on the lookout, leukopenia will be on the lookout obviously.

And then, you know, there's some modeling in bowel and even things like autoimmune thyroid disease that could be looked at. In this little short trial on the basis of the publication, it's looking pretty good so far.

Was maverlumumab before this, it was studied quite a bit in rheumatoid arthritis, wasn't it? Yes,

yes. And I mean, is still advancing in the space and it is effective. The question is, you know, that on a lot of people's minds, is there room for another anti cytokine in this very, very crowded space. But there are advanced clinical trials going on with another molecule, Otilimab, which targets the cytokines that are the receptor and we'll see.

Great. So David, GCA is definitely not a space where there's a lot of cytokine therapies available. Where do you think this might fit into our treatment armamentarium?

Well, I think we're yet to see. Obviously, is phase two data. This is early. We haven't seen this fully reported yet at this meeting. It was late breaking abstract.

So I think there's a lot to play out with this. I mean, the idea is enticing. And from my simple point of view, really, you know, in the Connie Wayne paradigm of t h one and t h 17, that it might be able to affect both pathways plausibly, that that might be impactful. For You you know, know, we've we've seen seen I'm biased because GM CSF, with a lot of the developmental work was done from Melbourne, Australia. So I'm a bit biased on that point of view.

And I think there are some institutions here which will get some royalties if it comes through, so I don't have any stake in them. But, you know, we've seen really nice translational data. So Maria said actually presented some stuff at July 20 '19 showing the genetic signature at the temple artery. So I think it's you know, there's been a nice story to this. But where's it going to sit?

Well, I think, A, we've got to see what happens in the short term, in that early phase for endangered cell arteritis when it comes through. We won't know that now. Obviously, small numbers. We still need to see the full reports on this. But secondly, what I'm really interested in is potentially what it looks like over a longer period longer course of time.

Really, A, of course, what's the steroid sharing potential? But then maybe it has plausibly greater effects on some of the actual intravascular changes that we might see with GCD. And that's highly speculative, and I guess I'm in a position where I can speculate about these things as an initial observer. But yeah, I think we're, I think there's potential that it might have, it might fill a new space, or it may well be in competition with tocilizumab and other IO6 inhibiting monoclonal antibodies.

Certainly, I think that dual targeting of the T helper cell pathways, it is enticing in terms of a longer term treatment, a more complete disease control, and maybe we could completely get GCA into remission, rather than just dampening it down as we fear might be happening with some of our other treatments. So I think we can all agree, it's a really exciting therapy at the moment. It's in very early stages of development, but hopefully, more evidence will be coming out as we go through the next year or so on this agent. The second abstract that we felt was very interesting from this study was from Peter Villager and his group in Berne. And it was the Gusto study, combining an ultra short steroid course with tocilizumab.

And David, I might ask you to tell us a little bit about that study.

Absolutely. Well, I think that overall in GCA, the paradigm has always been about how much steroid can we get rid of. And that we've lived for a long time with giving people a lot of steroids, seeing people gain weight in front of our eyes and get all the complications that we associate with corticosteroid, high dose corticosteroid use. And then tosylism had changed all of that and we've seen the quite marked steroid sparing capacity from that. But the question always is, can we go further?

I guess in a twenty six week wean or fifty two week wean of steroid, there's still quite a lot of steroid going on, more than we'd consider giving to something, to diseases, patients with diseases like rheumatoid arthritis. So, what this is was an investigator initiated, a small study open label clinical trial from Peter Villinger's group, the group which reported the first clinical data in GCA with tocilizumab. And what they did was they had three days of pulse IV methylprednisolone five hundred milligrams, and then no more steroid after that. Tocilizumab after that, and then seeing what happened beyond that. And I remember a few years ago at this meeting, had been some report there had been a report from Japan where they didn't use any steroid and used tocilizumab.

I think there's a lot of faith at that point because we know that tocilizumab doesn't work as quickly as corticosteroids. And that's why has had steroid when built in to the tocilizumab as well. So just to give the high level outcomes. Well, there were eighteen patients who got through to the complete analysis. And of those, fourteen of those achieved remission, but it took them a mean of eleven weeks.

Thirteen of them were relapse free of the twenty four weeks. But then there were three patients who were non responders, one of whom one of who only had PMI symptoms, but two had cranial symptoms, one of whom had a nuance AION and had permanent visual loss. So that seems like a pretty big thing there. Also to note that the inflammatory markers took some time to settle, really. Mean, even with tocilizumab, not entirely sure exactly when, but somewhere between ten days and four weeks in the reporting, we know that infant that took that long for the inflammatory markers to normalize.

Is that kind of time period something that's acceptable or not?

So yeah, and Len, I may ask you, in terms of the immunopathological mechanism or plausibility of a strategy of giving this very short, very high dose steroids in combination with IL-six inhibition. Is that something that makes logical sense to do?

You know, I don't want to be hypercritical. I mean, this is a very important study and these guys are very smart and they, you know, designed it in a very acute way. I would not have designed that study and I don't really think that I would have equipoise to even put a patient in that study to be honest with you. I'll say that for a couple reasons and this is all hand waving and if I had a glass of wine I'd be waving that around too. One, I don't think steroids, pulse steroids have ever cured GCA.

There's this copious literature on pulse steroids for people presenting with acute visual loss where these crazy ophthalmologists give them a gram or two grams a day for three or four or five days, etcetera. And still they have difficulty of getting people off of steroids. I mean, you have that in the background. Secondly, we have known from practice that the greatest risk to permanent visual loss is a history of previous visual loss. Those are our most vulnerable patients and we know that if we can treat them and get them through the first two to three weeks visual loss after that is extraordinarily uncommon.

So I would have opted for giving them steroids for maybe three weeks. You know we went from thinking that you know six months is short steroids. Mean, haven't really been doing that either yet. Three days is, I think it's just a bridge too far right now, but I don't say that in any other way other than Monday morning looking back at this right now, but I wouldn't have done it that way.

So Sarah, do you think about where we're going with steroids and giant cell arthritis and where we might end up?

This makes me wonder about whether maybe we'd always need a little bit of steroid together with biologic therapies. So there was one patient in the treatment time of Gyakta who had acute ischaemic optic neuropathy, who recovered with increase of steroid, but they did have AION and they were on the biologic arm. There was the patient in Seresta, which had a three month taper who had visual loss. And again, was in the treatment arm. And it's just very short steroid tapers.

And you wonder whether the systemic effects of the cytokine inhibition are blunting some of those early warning signals of GCA relapse. So, or maybe the trials have just been unlucky or maybe we always have some visual loss in our cohorts and we just don't, we just choose to ignore it. So I don't know that it's just individual cases and you can't make huge decisions for the world about a guideline decisions based on like n equals one per trial, but it does make me wonder whether a little bit of a tiny dose of steroids maybe might protect some of our patients, maybe our oldest patients, the ones that have got highest risk visual loss. I don't know, there's no one, I don't think we can say from the evidence, but I get a little bit nervous with patients who have those highest risk patients that Len was referring to, oldest ones, the ones who have previously had transient visual loss, worry just a little bit about them taking them completely off steroids if they're also on a cytokine inhibitor as well.

You're not saying we're turning, sorry. Oh, no, you're not saying we're turning a blind eye to our fallibility in this disease, are you?

I think there's a lot of wishful thinking in Giles a lot of writers in there and see what we want to see. So yeah.

I think that is probably a nice note to end this conversation on.

Very nice.

And I would like to thank everyone for watching and remember to go to RheumNow for more updates from ACR twenty twenty. Thanks.

Hello everyone. I'm Jack Cush with RheumNow. Welcome to the Saturday night mid meeting recap already Calvin on I already

doing welcome.

We're going to have the pleasure of a number of our esteemed faculty who've been reporting on the meeting. Join us for short segments. Is like our version of The Tonight Show. We don't have any entry music for Michael and Bella but welcome to our evening recap, Michael and Bella.

Thank you.

Michael and Bella are covering gout they're both from New York City. I'm sure that they've been very busy. Let's just start with a simple question about the meeting. Bella, what's your impression of the meeting so far? What's impressed you the most?

I think, I mean this is my first virtual meeting as it is for a lot of us. And I think the best thing about it is I can go to multiple sessions without running around between like long walks. So I can, I think I am learning much more than usual?

Alright, so I forgot to live stream. And now we're also live streaming to our YouTube channel and to our website. So sorry for that difficulty. Sorry to my friend John Swope, who's managing things. Michael, what's your impression so far?

Well, I'm having a great time. Bell is absolutely right that there are many good things about this. Some not so good things, of course, but honestly, Jack, we've been so isolated for so long, even to be virtually with colleagues is just great. And I was so excited to see some of the awards this week to see, especially to see Jim Odell award. I just think it's the people who got awards.

It's just so well deserved and it's so nice to celebrate with everybody.

Michael, you mentioned some limitations. What is it that you miss about actually being there in person?

Know, Arti, I'm a program director and I've been a program director for a long time. And I'm a little bit like, this is not politics, but I'm a little bit like Joe Biden, a little bit of a huggy guy. And I really miss seeing my fellows who are spread far and wide and giving them a big hug. I'll tell you, there's just nothing like that.

There have been challenges. You know the ACR has done a tremendous job putting all this together but it's been hard watching all those sessions the Fauci sessions that I think blew up the internet. And it was really really difficult to get everybody on but I think people are finding a way around it by clicking on the zoom link and whatnot.

Great community, you know, and, you know, we pulled together. We're very lucky as rheumatologist.

So, Bella, we're about midway through the meeting. One limitation of this virtual platform is that while questions can be asked, there's nothing like standing at someone's poster and you get to reality talk to them. What would you say? Do you say? Gosh, I wish there was a poster because I would have asked this person about this.

I know there's like probably many questions you have about some of the posters presented so far.

True. So you know just walking through the poster room meeting people, also talking about not the one poster that they're talking about but seeing what their vision is, what their future directions is. That's something that you cannot type in a text box. Yes, at least ACR has done it so that we can get each and every questions that we want typed down and people answer back. So it's something but it's not it still doesn't give you the full picture of a lot of abstracts or a lot of thoughts and visions, which are very important, I think, to get future directions in rheumatology.

I know that both of you have been glued to the computer for the last two days, and we wanted you to come on and talk about gout with us. What's, what's, what's taking you so far as far as some of the gout content. Let's start with our faculty lead, Michael pillinger.

Sure. It's actually been quite a good meeting so far. I noted a few themes. One of the themes is that there's definitely been an explosion in studies of genetics and genomics being not a geneticist, find it a little thick to get through, but it's yielding a lot of interesting information. The other thing I noted is maybe some good news about some of our drugs and cardiovascular disease.

I'm hearing a lot of talk about colchicine which is something I've been studying for a long time and coming on the heels of the two big New England Journal studies, people are starting to talk about whether that is going to be something we've got to look at in our patients with disease. And then the last thing I noticed that I think there are a lot of studies about trying to make peg lot of case work better and by approaches with immunomodulation. And I think that's really exciting too, people, nothing works better than peg lot of case for patients who need it when it works and expanding the pool and not having people have immune infusion reactions or have to stop the drug to avoid those. Think it's gonna be very important if they crack this nut.

Before we circle back with that, wanna get Bella's take on what impacted her the most or what stood out for you the most on the abstracts you've seen thus far. Think a lot presented today, right on Saturday?

Yes, there's a lot of abstracts today. The peglorticase ones were definitely something intriguing because before 2018, actually there was a lot of talk about this that before 2018 nobody was using immunomodulation with peglorticase. But after that report and I think November 2018, there's some studies which show spike of using immunomodulation. Now it's up to twenty percent of patients have some kind of immunomodulation with peglorticase. So those were definitely striking.

Also multi morbidity or comorbidity with gout. There's a lot of abstracts. I mean the cardiovascular stuff was known but some of the other stuff like mortality, cost specific like gout specific mortality as well as amputations. A lot of sort of epi sort of studies highlighting multimorbidity, I think those were pretty striking too.

Mike, I know you go through all the abstracts, I think as we all do. As I went through them, I didn't know if I saw much on pseudogout at this meeting. Is there anything?

There is a bit and there are a couple of talks coming up over the next few days. But you're absolutely right that it's been thin and I don't know if that's a selection issue or if the meetings seems to be a little bit abbreviated. We have fewer sessions. There was a nice abstract about bringing gout and pseudo gout together about pyrophosphate in TOFI is something that all knew you take x rays of TOFI and you see calcium, but I don't think it's ever been formally studied before. So, was sort of happy to see that one.

Okay, Bella, know you were midway. I know you looked through the abstracts as well. What do you got coming up? We have still a couple of days. What are you gonna prioritize for things to see for people who say they're not gout mavens but they want to see the important stuff.

What's the key stuff coming up in the next couple of days?

I think a lot of the some of the studies on again immunomodulation with pegloticase. I think there's one or two sessions on Monday that we're looking forward to. And a lot of genetic stuff again for clinicians I don't know how relevant it is because you're not going to be able to send these sort of genetic markers. But definitely interesting for research purposes and maybe going forward to phenotype those patients. So

can we just go back to the immunogenicity issue? It actually started for me with Michael's paper about azathioprine use in pegylota case.

Somebody read that paper.

Yeah, yeah. And I waved it around for a few weeks and people told me stop it. But I did that in my patients as well and it worked very, very well. Michael, how do you see the evolution concept that it's gone from azathioprine then a number of case reports or case series with methotrexate. And now we have a control trial, the recipe trial looking at mycophenolate.

Yeah, well, first of all, a shout out if I might to John Bodson because sort of single handedly pushed methotrexate early. When we started with azathioprine, we were a little nervous about methotrexate and actually Poojikana presented the recipe study today and made the same comment because we figured a lot of our gout patients probably drink alcohol. So we were trying to avoid it. But it's a logical drug. It's a drug we know how to use and ditto CellCept, ditto mycophenolate.

So I think the more the better basically. It looks like there's also an abstract about the MIRROR study, which is the methotrexate study and another abstract actually about azathioprine. So it's kind of a full house and right now I think we're waiting for full information to come in, but it's looking like this is an approach we can use. These are drugs we know and being able to pick and choose among them is probably the way to go because we wanna consider our patients individually. So I think we're getting somewhere.

True. And again, the study that I highlighted twenty percent of us are already doing this. So this is a claims data with peglodocus and twenty percent of patients are on some sort of immunomodulation. People are already doing it. But I don't know, I always worry about azathioprine given in gout patients because while switching or doing something if they start taking the allopurinol or azathioprine together that does get into problems.

So I always worry even though we never started together but for whatever reason, when stepping up or stepping down, that's a potential issue that can happen clinically.

Yeah, I think that's right, Bella. One has to be pretty careful, of course. It's with Crystexxa so you shouldn't be giving allopurinol anyway, but it is a concern. And Jack, when I submitted that paper, one of the reviewers kicked back and told me about a little known paper from the 1970s that allopurinol has actually has urate lowering properties, but not enough to account for benefit. But they said, how do you know the benefit of allopurinol isn't because it lowers your rate?

Probably not.

So let's go to two. We'll get a few minutes that this issue of cardiovascular effects with a book to stat that trial is coming up that's going to be presented I think coming up that's called the was a probe study

fast trial.

Yeah. So, what's seen there and it's going to change our thinking about a book says that which seems to have a pendulum about cardiovascular risks it does it doesn't it does it doesn't and now this study says it doesn't Michael what's your take on this.

I could write a book on this. So, let me start by saying that the FDA did what they had to do. There was a signal in the original phase three studies, it wasn't significant and they asked for a phase four study and that's what the CARE study is. And that had a signal in a secondary outcome that is a serious outcome. And so they had to black box this thing.

But the CARES trial, however well intentioned it was had enormous problems. Bob Turkle Taub was talking about this today. Half the patients didn't finish the trial. Most of the MIs were after people were off the drug and there was no control. So even if it showed what it showed, it didn't show that febuzostat raised risk.

It just showed that it wasn't as low a risk as allopurinol. So we have a few studies that run against it. There's a large study out of choice group that's retrospective with a 100,000 Medicare patients that showed none of this effect. There was a contested study from Europe called the FREED trial that showed none of it. And now this study from Europe called the FAST trial, which looks like it's going to show none of it too.

So how we're going to, how the FDA responds and how we respond is probably different. I think actually the most important thing out of the CARES trial was that patients who didn't take aspirin were the ones who got into trouble if you had cardiac risk and you took aspirin, they you didn't have this problem. You should probably take your aspirin.

Very good. All right, folks wanna thank you for joining us. We're going to ask Bella and Michael to sign off and we're going to bring in our next two guests on The Tonight Show. Welcome, we're going to talk psoriatic arthritis in our mid meeting recap. Joining us is Eric Ritterman from Illinois and Robert Chow from Virginia.

Welcome gentlemen, Robert you're on mute, you want to unmute yourself that's going to be good. All right,

that's a good idea.

It's always the best way to begin. All right. Let's quickly ask you, tell me one thing you like one thing you hate from the meeting so far this virtual meeting, make them quick answers. Robert.

One thing I like is I can neither confirm or deny that I'm wearing my pajamas still. Pajamas pants. The one thing I hate is I don't get to see my colleagues in person.

All right. Eric.

I like the fact that the ACR was nice enough to bring this meeting to my basement for me so I could watch. I actually think that the setup has worked really well. I've been very impressed with the structure of the program and how they put it all together and how you can access everything. That's been pretty easy. I miss seeing people.

That's the hard part. I've missed seeing people for seven months now and that's the hard part.

Get a dog. That's all we can say.

I got to and they bark in the middle of the meeting.

A ton of PSA abstracts, mean, to years past, we're midway through the meeting. Rob, what's a stuff that you've seen so far that you thought was great specific wise?

Right, right. Yeah. So definitely a lot of abstracts on new therapies and continuation extended study, fifty two week extension studies on drugs like secukinumab as far as sustained improvements in psoriatic arthritis with axial manifestations. With selkumab, a fifty two week study, again, sustained response in all major disease domains, improvement in the incitis and dactylitis. You had rifilgotinib, post hoc analysis with improving dactylitis and also the fifty two week extension with improvement on enthesitis.

So definitely a lot of new therapies and probably even more coming up. All

right, Eric was so what what's happened so far two days in what's the top thing that someone who hasn't been paying so close attention to psoriatic arthritis should go back and look at?

Well, think I think the two top things I mean, you know, in contrast to some the other meetings last few years, there hasn't been a ton of ton of sort of new molecules, new stuff. The one exception here are the two, upadacitinib presentations. And those data were presented to you, LARB, is the first time they're showing up at ACR. They're both oral abstract presentations and really good trials on the patacitinib in DMARD failures and then a patacitinib in biologic DMARD failures. And they set the stage for a kind of a shift in our management of psoriatic arthritis, more towards jack inhibitors in the future.

Have either of you seen anything so far that you're going to take home and change your practice over incorporate right away?

Yeah, I mean, I definitely will. I posted a video about this actually about adding more tools to our arsenal. That's what I like to say about especially tailoring treatment to, let's say, an enthesitis predominant patient or dactylitis predominant or skin predominant. But I think, you know, one of the big themes this year is definitely enthesitis. We had a there was a great lecture by Doctor.

McGonigal on enthesitis recently. A lot of studies. We just mentioned a few on enthesitis focusing on enthesitis. There's actually one pretty interesting study that they broke down treatment groups into no treatment slash NSAIDs, conventional DMARDs and biologic DMARDs. And they actually found that I think more than eighty percent of patients had resolution of enthesitis despite the treatment group, which was rather interesting because that sort of throws the question, do you even need to treat enthesitis or tailor treatment for enthesitis?

Eric, what about you?

I haven't seen anything I'm going to take home yet, but what Robert brought up was interesting. One of the new studies here is this Achilles study on on Achilles tendonitis with secukin treatment. So Achilles tendonitis with secukinumab. It's kind of a mix of psoriatic and and ag spa patients who had primarily Achilles tendonitis. And they didn't achieve the kind of resolution that they had hoped for, so they missed their primary endpoint.

A lot of other outcomes were better, and I think that the abstract, you know, Robert alluded to, is sort of interesting because, you know, these people sort of come and go. One of the more challenging pieces of that abstract was that they, you got into the study by having Achilles tendonitis clinically and on MRI and yet when the MRIs were red centrally, a little over half of the patients actually had Achilles tendonitis when read by a radiologist centrally. So, it it brings into the question sort of what is emphyseitis? Is it clinical? Is it imaging?

And how do you sort of sort between that? And how do you, I mean, is a thing we've struggled with for while, it's very arthritis. It's like, much do need to treat in those patients?

So Eric, one of the things, it's not solved at this meeting, but there's a lot of data that addresses that. And just between us and the wall and the one hundred and thirty five people online, axial disease in PSA the same or different than axial SpA?

I don't think we know yet. I mean, I think we keep asking that question. The problem is that there isn't. There's only one study that really looked at it, and that's this maximize trial, which is there's some data here with the MRIs and that that's a study of secukinumab in psoriatic arthritis patients with axial disease. Everything else we've seen is kind of a sub analysis of a PSA trial and and again they they said, well, you have actual disease because the investigator at the site said you had actual disease and and yet when they read those images centrally, a lot of them didn't have the changes they said they had.

So we don't know what it really means. One of the excerpts that I saw that that this week that is kind of interesting, it was an abstract that, came out of, I think it was the psoriatic research consortium where they looked at a group of patients, some with just basic psoriatic arthritis without action involvement, some with action involvement, and they looked at bass die scores and whether it could distinguish between the two because we think of bass die as an axial score. And it was the same in both groups and the response to therapy was the same in both groups, even including question two, which asks you about back pain. So it's it's a challenge to say, you know, I mean one, we don't know who has actual disease, and then how do we decide if the actual part is better or not? It's it's a short and it's going to be and it is a relevant question as we move into the era of IL-twenty three inhibitors, which don't seem to work for the actual disease, at least in axSpA.

Exactly,

exactly, and so they looked at that in the gazelkumab trials and it worked, but it worked by virtue of improvement in composite outcomes that may just reflect general improvement. We just don't know.

And with the ejacunibs coming it raises the stakes also. Exactly, Rob what are you thinking? What are your thoughts on that? Is axial involvement in PSA the same as ankles and spondylitis or axial Spial or is it different?

Yeah, I think it's a hard question to answer as well. Going back to that maximized study though, one interesting they did find was a reduction in MRI lesions, which take it for as you will. I think especially gasecomab coming up. Interesting to see what the JAK and I'm data will show too. But it's a hard answer at this point.

Let me put in my 2¢ on this and that I think it's a good thing it's being addressed. I don't think it's an important question really because I'm just looking for a reason to take over management of a psoriatic patient was for their axial symptoms I'm in. If it's for you know their, their peripheral arthritis whether it's poly or illegal articular. I'm the guy, you know it's like I get bothered when I get sent the skin only people and like why you here when you should be down the road at Alan mentors office the dermatologist so already made an alluded to the jacks are coming on and they're kind of confusing or expanding are pretty expanded market in PSA therapy. It's going to get more crowded when we start using tick inhibition, tick to inhibitors.

Eric, do you think

it may be, maybe. So one of the late breaking abstracts this time is, let me do it, try to see if I can do it right, do cravacitinib.

Marty, how do do it?

Think it's a very clever name, I think it's do you crave acitinib?

Oh, there you go. Do you crave Acitinib? It, you know, and that's the first TYK2 inhibitor we've seen. It's a phase two trial, psoriatic arthritis. It worked, but it didn't look like it was much different than anything else.

And it's sort of billed as, well, IL-twenty three signals through tick molecules, and so that's kind of the pathway. The skin response wasn't that fabulous. It certainly didn't look like the kind of skin response we see with some IL-twenty three inhibitors. The joint response was good, but you know, it wasn't better than what we've had. So I don't know that that's gonna shake things up.

We'll see.

It's coming tomorrow. Rob, we'll go back you go to you and then maybe go to Eric for a quick for the finale. Stuff that's coming up, I know you you you have your your schedule planned, what you're gonna go see tomorrow and and what you're gonna go see the rest of the meeting. Well, us the somebody who said, Hey, I want to see what's best in PSA. What should they see in the next couple of days?

Yeah, got it. I think, an overarching theme for all diseases. So in this meeting, just like the last meeting is machine learning and you have your gut microbiome just like an RA. Same goes with PSA. There's going to be a lot of there's an interesting abstract and gut dysbiosis with radiographic and thesis involvement.

Again, tying in that anthocythis theme, a lot of data, even recent or even on the past few days on machine learning. And there continues to be more machine learning. There is going to be a Phase 2B study in Tildrekizumab IL-twenty three inhibitor. And I believe there's also a late breaking abstract on top of with psoriatic arthritis. And just to tie up with enthesitis again and having a better way of evaluating enthesitis besides just poking at the Achilles and saying, does it hurt?

Yes or no. But I can't poke the other 200 in thesis points though. But you know, there's going to be an ultrasound study in my emphasize coming up in the next few days, which would be interesting. Ultrasound scoring Eric,

what about you? Somebody interested in PSA who hasn't gone through the booklet yet. The booklet? Listen to me, in 1980, who hasn't gone through the program listing online, what should they go see?

I mean, would, to quote you, I do crave a sit there, because I do think that's interesting, because it's a new molecule and it's a new, you know, it is a new pathway and it opens up something new. It's an interesting molecule, because everything we've seen with JAK inhibitors, there's all these sort of heterodimers and they're sort of the inhibition may cross pathways, and this seems to be fairly specific. Whether that results in anything clinical, we'll see, but I think that's going to be an interesting abstract. Besides that, I'm not sure what else is like earth shattering, just a lot of interesting stuff that sort of fills in the holes. It fills in the holes on extension studies with some of the drugs we've had, fills in some long term safety data and some of the drugs we've had, sort of some additional sub analysis of the trials we had to sort of understand in different populations.

You know, as I started with, I don't think there's a lot that's earth shatteringly new in terms of new therapies, but there's just a lot that sort of fills in the blanks with the therapies that we've had so far.

Let me ask both of you or either of you, research at this meeting about a clearing up the issue of what drug is better to use after you failed a TNF inhibitor or more than one TNF number is that an important issue, about your next choice of therapy?

It is I haven't seen much that really helps me there at this meeting, Jack, and maybe you pick something up I missed, but I haven't seen much. Mean, we desperately sort of need head to head studies and we don't have those. We've got two head to head studies that are TNF versus IL-seventeen. As we move into the JAK space, we're going to need to sort of get some direct studies and say, should you use it? Mean, that's the thing in psoriatic arthritis, we've got all these pathways, we can use IL-seventeen inhibitor, we've got IL-twenty three inhibitors, one approved more coming, we've got JAK inhibitors that are coming very, very soon.

But then we don't know which of those to use, and we're going to need some good comparative data. I think just taking two trials and sort of holding them up against each other doesn't give you the answer you need.

You know, in dermatology, they've got a lot of head to head trials, and it seems like it's changed the treatment landscape. Do you think the same will happen in rheumatology.

I hope so, but I don't know. I mean, that's just for some reason they've sort of gone down that path. And that's just been sort of the way they've looked at their drugs. I just haven't seen much of that yet. We've got a couple.

I mean, what we're going to need is truly we're going to need is a head to head that includes a Jack and biologic. That's really the next place we need to go and I don't see anything coming in the near future.

Alright gentlemen, want to say goodbye. Eric and Robert, thanks for joining. On psoriatic arthritis.

Hi, this is Doctor. Eric Dine from Baltimore, Maryland checking in with RheumNow. We just concluded the closing session of the final day of ACR Convergence, and it was a fantastic meeting that was done. Wanted to talk about one of the abstracts from the afternoon session on the final day at ACR convergence. And I'm going to talk about the S4 French cohort, had abstract nineteen ninety eight, which was in regards to patient outcomes on very low dose prednisone.

Why is this important? If you saw the ACR new practice management guidelines that the drafts of which were released earlier today, you saw that there's a big shift away from the use of glucocorticoids even in early RA. And this was a surprise to a lot of people who keep Eva patients on prednisone, but very low doses for long periods of time. So if you take a look at their S4 cohort, find that they looked at three ninety seven patients that were on low dose cohort, low dose prednisone. And so this was sixty five percent of the patients overall in the cohort were on what they classified as a very low dose.

So the mean dose was two point eight milligrams. So again, in that zero to five range. The mean cumulative glucocorticoid dose over time, it does add up. That, know, over eight grams, I'm sorry, eighty grams over time, but, you know, small doses usually zero to one to four milligrams for these patients. And so a lot of physicians would think that these small prednisone prescriptions will not have a significant outcome in the things that we worry about with prednisone when we think about fractures, infections, cardiovascular outcomes.

The duration of treatment though, you know, this was a ten year follow-up study, and the mean duration of treatment on glucocorticoids was forty four point six months. And over time, when they followed the patients, they found that there were a fair number of events for them to analyze. So there are ninety five total events. So they use a cumulative endpoint, looking at deaths, cardiovascular disease, fractures and severe infections. So there were ten deaths in the study, eighteen cardiovascular and thirty two fractures, thirty five severe infections.

When they take a look at the univariate analysis of ten years, you find that the glucocorticoid group was significantly higher of having more events. Seventy one of the total ninety five events were in

that

glucocorticoid group that was strongly statistically significant. We also find that there's a pretty strong dose effect. So the more steroids, the longer you've been on it, the higher the risk. The risk associated with being on steroids, again, we're not talking about five, ten, twenty milligrams, we're talking about one to four milligrams, it increased every year with the time you're on it. So once you pass that six year threshold, you see it as an increased risk factor.

And by ten years, you have a hazard ratio of six point eight being on steroids. So the takeaway from here is that these small prednisone doses, you have trouble weaning off patients below five milligrams. A lot of physicians will think this isn't going to be something that will impact you, they call it the physiological dosing. According to this cohort, find that in all of these patients, the risk of death, cardiovascular fractures and infection and particularly on that dose effect, it was the infections in the cardiovascular that had the biggest impact there. So I think that plays into when I think about the new ACR guidelines, not to put patients on steroids upfront, because we know patients will have difficulty coming off of them.

So trying to start with a steroid sparing agent, certainly if need steroids for acute inflammation, you should treat that, but the goal is not to continue steroid therapy longitudinally. This is Eric Dine with RheumNow. Thank you very much for following RheumNow throughout this conference, and stay tuned to RheumNow for breaking rheumatology information after the conference and our future meetings. Thank you very much.

Hello, I'm Jeff Curtis at the University of Alabama at Birmingham, and I wanted to bring to you a pair of abstracts from the recent ACR Convergence meeting. Although probably the virus that's on most of our minds these days is the SARS CoV-two virus, I don't want us to lose sight of the fact that we've been talking for a long time about a different virus, herpes zoster, and thinking about how we might best mitigate risks for shingles or reactivation of herpes zoster. That for most people, at least in the Western Hemisphere, lies latent in the dorsal root ganglion and is just waiting to reactivate based upon immunosenescence or other factors, including immunosuppressive medications, glucocorticoids, Janus kinase inhibitors, etcetera. So the pair of abstracts that I want to cover addresses the dual questions that are really of most importance. One is does the vaccine work?

And in particular, does the vaccine work in people who are treated with Janus kinase or JAK inhibitors? So a very interesting abstract being presented on Monday at the Convergence meeting, 1997, focuses on individuals who are on JAK inhibitors, the majority of which happen to be on baricitinib, but there's a bit of a mix, who are then getting vaccinated with the adjuvanted subunit virus Shingrix and compares them to healthy controls who don't have autoimmune diseases. Their outcome was immunogenicity. So this is a lab based outcome because you're gonna have a tough time powering for clinical event rate reduction, meaning because the vaccine actually worked to prevent shingles reactivation. Like most vaccine studies, this one, which is coming to us out of Sweden, is focused on a lab based outcome, immunogenicity.

Now do you have an increase in antibody titers or do you have the expected changes in cell mediated immunity? So this abstract compares 40 patients on JAK inhibitors to 20 healthy controls. The outcome was antibody testing by ELISA, so not cell mediated immunity or at least they didn't present those results at this point in time. The cell mediated immunity results are arguably more important, although occasionally more difficult to interpret, but probably have more clinical relevance. That said, and recognizing it is a bit of a limitation, and comparing the two groups, seventy five percent of individuals on a JAK inhibitor had a reasonable response to changes in antibodies.

So their definition of what is a immunogenic response, meaning the vaccine works, was pretty liberal. You didn't have to have antibody titers go up much, only more than 1.2 fold. In the control group of twenty patients, it was a hundred percent that looked like the vaccine worked. But in the RA group on the JAK inhibitors, it was only seventy five percent. Remember that in the ZOE fifty and seventy trials, it was ninety to ninety five percent effective in older individuals that were not on any immunosuppressive drugs or didn't have autoimmune conditions.

So if it was only seventy five percent effective, this clearly is a ways from that. And remember, we haven't even seen the cell mediated immunity results. The other abstract that I wanna speak to is a safety abstract from Cleveland Clinic, where they're asking the second question, the aspects of, you know, is this going to cause our patients to flare? And the issue here that is somewhat sometimes hard to sort out is, is it a disease flare or is it the expected reactogenicity? Reactogenicity just meaning, you know, the vaccine revs your immune system up, you kind of feel bad, you might have a local reaction like a sore arm, but you might have systemic symptoms and that could be pretty severe.

In the healthy older people, it's going up to seventeen percent. So this series of three fifty nine autoimmune patients seen at the Cleveland Clinic were evaluated in a retrospective fashion, looking for a chart review and evidence of treatment changes or disease flare management in the twelve weeks after vaccination with Shingrix. They showed that overall, sixteen percent of people had a flare, and it was higher in some diseases, like twenty four percent. A pretty high proportion had to have something done. They either had to add glucocorticoids almost half, or they need to even change their underlying immunosuppression.

Now, this is retrospective. This is as much as you're gonna glean from chart ascertainment and not what you would get necessarily if you're asking prospectively, where in the first week or so after someone gets the vaccine dose, you're going to have much more reactogenicity based on trial data. So you could argue that this is a reasonable way, certainly a conservative approach, but sixteen percent, maybe as high as twenty four percent in RA, that have disease worsening or FLAIR is probably a high enough proportion that this needs to be on your radar screen so that you don't get calls and people saying, what do I do because you know, they're unhappy, they're doing badly, you've got to clear your schedule. So bottom line, it looks like that the Shingrix vaccine works in RA, but perhaps if you're on a JAK inhibitor especially, it may not work all that well. I think that invites strategies that we might think about.

For example, if you're on a JAK inhibitor, maybe we should be holding the dose for two weeks, for example. That needs to be tested. In terms of safety and reactogenicity, this is not a benign vaccine. We're gonna get calls, there's gonna be flares, there's gonna be disease worsening, and in a substantial proportion of people, it looks like we may need to react to it. That said, the vaccine looks like it is reasonably well tolerated, but definitely needs to be the source of communication in advance for what to do if there's a flare or a potential flare, you know, that might not be the same thing as reactogenicity, which typically lasts a week or less if it's systemic.

So I think that this is helpful accruing evidence that this vaccine is reasonably effective and for the most part well tolerated, but there are some issues. More data to come, obviously.