RheumNow Rheumatology Round-Up Save

This is an ACR twenty twenty five podcast coming to you from Chicago. Hope you enjoy it. Hello, everyone. Welcome to RheumNow's rheumatology roundup. I'm Jack Cush from Dallas, Texas.

Arti Kavanaugh

from San Diego.

And this is where we get to present our highlights from the twenty twenty five ACR convergence just completed from Chicago, Illinois. We've had but forty eight hours to recover from what was a blazing week in the Windy City. I think we're ready to feed you our knowledge bowl of ACR convergence. In this roundup, as past roundups, we'll be discussing abstracts and presentations of interest from this year's meetings. The abstracts and sessions were chosen by us with selection solely based on innovation, impact, and our interest.

Reproduction is a no no, so don't do it. Arty, it's hard to tell what the attendance is anymore. We don't get those statistics. I do know that there's sort of seems to be a slow return to pre pandemic levels. I did hear that there were over 3,100 abstracts presented at the meeting.

What's your take on the meeting?

Yeah, it's tough to tell. You I look at the crowds and of course that depends on the convention center. This convention center nicely spread out, so you got a lot of steps in going from one session to another, but there wasn't any congested area. The abstracts themselves, the ACR did a great job of having actual posters where you can actually go and look at them and talk to the presenter, which is just the heart of the meeting. And that had good spacing, although they had more abstracts than they've had recently.

A lot of abstracts, as you say, it was never super crowded even with those poster tours around. So it was pleasant. It was nice to go around. Of course, you see old friends, but it was nice to be able to go to the poster, see the abstract and discuss it with the presenter.

Yeah, I really liked the poster hall as well. It was the usual running, how can I get to that building from here in less than three minutes? But that's part of the art and fun of getting to the meeting. Artie, what's your first, favorite abstract?

Well, I'm gonna pick LB21. We try not to do a lot of orals, we try not to do late breakers, but I think it's fair enough to do this one because the the late breaker session was at the very end of the meeting. I think the ACR does that to try to keep people there for the end of the meeting, but a a lot of people are gone. So I think a lot of people may have missed this, And it was hard to get to late breakers this year, meaning they really did break late. They came out really close to the meeting, so I don't know that everybody really got to appreciate how much was in there.

So, LB21, I think, is sort of fascinating. It's the IDH one two somatic hotspot mutations as an independent driver of autoimmune inflammation. So basic idea is you see people and I was intrigued by this because I've seen a couple of people this year that looked like they had Vexis older men with fever, with cytopenias, with rashes, with joint symptoms, with elevated acute phase reactants. I've seen patients who did not have the UBA1 mutation, so they don't have Vexis. They took a group of these and they're looking at several aggregates of data from around the world, from The UK, from the Mayo Clinic, from the All of Us consortium, and they looked for mutations basically just to see if there was anything that in addition to the UVA1.

What they found is isocitrate dehydrogenase, and they found hot spot mutations that were found in over five almost six percent of their group of patients. And these are people with Vexis like symptoms who were not Vexis. Really a very nicely done study and fortunately IDH, the citrate dehydrogenase mutations are seen as importance of cancer. There's a kinase inhibitor of it, a medication that inhibits it specifically that's used in these cancers, including AML and cholangiocarcinoma. They gave that medicine to these patients and they saw some improvement.

The interesting part, I mean, that's fascinating. These are somatic mutations. These are not gene mutations that you see in newborns. These are acquired later in life, often in myeloid cells where they can do a lot of damage and cause a lot of trouble. You don't see them except by whole genome sequencing.

Could be missing a lot of them. And who else has vexus like symptoms? The people with polymyalgia rheumatica, people with seronegative RA. So could it be that we are missing other mutations here? And I think we'll see more and more of these mutations.

And if there's a specific inhibitor that's really precision medicine at its finest. So I thought it was intriguing.

What was the backstory on how these many investigators got together? I know a lot of patients were from Mayo. You know, there were patients with skin and joint and systemic manifestations. That's why the consideration of Vexis, Was it just because they were thought of vexus and not having vexus that they pulled it together and came up with these mutations?

Yeah. I think when you suspect someone of vexus, you like to reach out to a center that has expertise in. And when you do, they will often say, Hey, let's look, send us, get the samples please, and send them to us. So that's, and I would encourage everyone to do that who has these kinds of patients, reach out to some of the centers where they will do this, because that's how they found these.

Yeah, I think it's exciting. I think that other than finding those centers and getting this done specifically, you think these will be picked up by whole exome sequencing?

You have to, it takes a lot of data crunching to find them. That's a difficulty. So yes, best to leave it to those who have the interest and expertise in this.

Yeah, so this is reinforcement of what I've always taught. If you think it's Still's disease, but they don't meet criteria for Still's disease, that's your invitation A, to reach out to someone and B, look into genetic testing. I think that this will help. And yeah, I think it's exciting that a lot of these folks probably are falling into buckets that we're commonly labeling as something else, sweet syndrome, PMR, whatever. Alright.

So my next presentation was the twenty twenty five updated draft guidelines for juvenile idiopathic arthritis with specific therapeutic approaches for systemic disease, polyarthritis, oligoarthritis, dactylitis, enthesitis, uveitis, medication might, they cover a whole textbook in this one session presented by Doctor. Anel and Lavelle and Vihi. They had these individual presentations on subsets. This is an update of the 2022 guideline, I believe. Susan Chenoy presented the systemic JIA, and then others presented polyarthritis, dactylitis, etc.

So what I liked about this was that they focused on Still's disease and they gave you the juvenile perspective, a few things that came down. First, I think the one overall thing that I like to stress from this presentation, which I thought first off, couldn't get into the session, was in the overflow room, the overflow room was busy, was that the guidelines committee took on this new approach of reviewing the guidelines, updating guidelines, but also putting in a new caveat. A new caveat is deprescribing. If you're gonna make rules for how to use the drug and who to use the drug in, maybe you should make rules on when to stop the drug. And this is particularly important in adult STILS.

So they reaffirmed both EULAR and ACR guidelines previously that first line therapy in systemic JIA and STILS is an IL-one and IL-six inhibitor. They also strongly made the recommendation, don't use nonsteroidals. They also made a conditional recommendation that you should probably not be using oral corticosteroids in these patients as your main therapy. It's okay that if they're in the hospital, they get IV and then you start them on an IL-one or IL-six inhibitor, but you should have them on effective anti cytokine therapy where you don't need to use the forty, sixty milligrams of steroids. Now, again, it's gonna be hard to negotiate that with the real world.

And then they also strongly recommend the use of DMARDs as initial therapy for this. Now patients who have MAS with Still's, they strongly recommend corticosteroids systemically in high doses as first and at the same time use an IL-one or IL-six inhibitor. And then when that doesn't work or you can't use that, they recommend the other biologic and then now making the cut is the new FDA approved Emapalumab, the gamma interferon monoclonal antibody. And if that is not available, then traditional therapy, which would include the calcineurin inhibitors and maybe even VP16 etoposide. The other thing that was new about these guidelines is that they said you should be looking for the lung disease that's been frequently rewritten about in systemic JIA, uncommonly seen in adults with Still's disease.

So that's probably a concern, but nonetheless, I think it's a new thing that's out there. For articular stuff, the main recommendation that was kind of new is they recommended DMARDs, biologics, and or conventionals. You can use biologics first line as initial therapy for polyarthritis, enthesitis, dactylitis, and TNJ arthritis. They conditionally recommend against using oral corticosteroids. And the other big thing, if you work very much with pediatric rheumatology, maybe you, like I, have been perplexed as to why they're using SubQ methotrexate.

The new recommendation is oral methotrexate is preferred over SubQ because they have studies that affirm that it's just as good, if not better. So the argument was you guarantee you're getting it, you guarantee the amount of drugs. If you're worried about how much they're getting when you're getting above a certain dose, fifteen in adults, go to split dose oral and you solve your own problem. There are many others that I'll point you to, but I think it was a good session, well attended. And I like the fact that they're staying up on and revising their guidelines.

Yeah, and I think we look to them for the, particularly the systemic because we see fewer of them as adults, but we do see them. I think that, it's nice to have our colleagues in pediatrics who see more of this be able to give us the, what do the data support and where should we go with therapy? Yeah. So So lot of abstracts, on vasculitis, and it's a hot topic, one that we didn't used to do much to, and now we do. There was a study which was, I think, really interesting for discussion, and that was it's called Metogia or Metogia.

This is abstract number eight ninety one, and this was, presented. It's randomized controlled trial, but it's open label of methotrexate versus tocilizumab. Methotrexate was dosed at a reasonable dose, a good dose, that is point three milligrams per kilogram per week and subcutaneous. So Rheumatologic conditions is the dose low is the RA dose, not the the immunomodulatory dose, which this was The tocilizumab sub q one hundred and sixty two milligrams a week. Everyone tapered corticosteroids formulaically, and what they did was sort of was kind of interesting.

They stopped medication at week fifty two and then their primary outcome was at week seventy eight. And I think that's interesting because if you looked at the curves that they showed, you really see a nice separation where atosolizumab is better than methotrexate at week fifty two. But that was not the primary outcome. The primary outcome was at 78 and at week seventy eight, methotrexate was not non inferior, that odd way of looking at things. And if you looked at the curves, they do sort of approach each other.

So when you stop therapy, you get relapses. And these people are off corticosteroids by and large because they had been, you know, many of them had been doing well. And and very notable, though, also was the difference in tolerability. There was one death with tocilizumab and six with methotrexate. Among those six deaths, there were there was one due to Pneumocystis Girovici, PJP, and there were five cases of that.

Only in methotrexate, none in tocilizumab. So how you look at this kind of thing depends on what you bring to the discussion a priori. If you think docilizumab is better, well, you could say this showed it was better, but maybe you shouldn't stop treatment because people relapse. If you thought methotrexate had some usefulness, this might show that. Although there was no control arm with no steroids bearing drug to see how much better methotrexate would have been.

And I think when you use methotrexate in immunomodulatory dose, you will see toxicities with it.

This did get a lot of discussion and a lot of excitement because it was a fairly well done trial. It asked a really important question. I think it's clear that tocilizumab is the go to drug here. The question is methotrexate did well enough that at the fifty two week endpoint that you could say, well, maybe you could use methotrexate. But if you look at the graph and the slope of the graph, methotrexate was going down at that point and it continued to go down after they stopped methotrexate suggesting that you need to continue therapy.

And again, tocilizumab dropped off, the slopes of the graph after they stopped the drug were different. Methotrexate continued in the same slope and tocilizumab dropped off more precipitously approaching methotrexate at week seventy eight. All that to try to describe that there's something different going on between responses to tocilizumab and responses to methotrexate. Anisha Dua and I were talking about this data that says that you can treat tocilizumab patients and they can be in remission, but if you do PET scans on them, they still have vasculitis activity. These people would stop it, or probably it's the large vessel vasculitis that is probably acting up.

What methotrexate is doing is different, and maybe it's not as direct on large vessel vasculitis, it's more about systemic inflammation and other effects that are taking over. But nonetheless, I thought it was a really well done study. If you're forced to use methotrexate, there's some data here to support it, but it's not great. But again, I think it does strongly speak in favor of tocilizumab in these patients.

Yeah, our friend and colleague, Mark Wambakari from The UK had concerns along just what you were saying. That is people whose interest is purely financial might make rules to say, well, you have to use methotrexate first because it was not non inferior. And it was a funny design that doesn't really look like it says that to me, says as you said, Tocilizumab is superior, but you need to keep treating because we will have relapses as we've always known with GCA.

So with the start of biologic therapy in GCA with GACTA, and now with these other studies, rheumatologists are gonna have to make a new decision about how to treat GCA in the future. We've all been locked into high dose steroids, and we all tell ourselves a tale about when we're gonna stop them, but we never do. These drugs are steroid sparing. You're gonna have to keep them going. The question is how long do you keep them going?

So that's my next abstract, abstract number seven seventy six presented by Wolfgang Schmidt, the Select GCA, the two year results. As you know, the Select GCA was previously presented and FDA approved, and is a new option for GCA. In the phase one or period one of the study, over 1,000, four forty patients were enrolled in the first period, which was a one year study of upadacitinib at two different doses versus placebo showing clear superiority for upadacitinib. Then in the second phase of study in year two, patients were re randomized, the ones who were doing well were then rerandomized to either stay on placebo if they were on placebo, and again, they're blinded, or if they were on OPA, they went on placebo or again, two different doses of, OPA fifteen or seven point five. And if you looked at the graphs, it's really quite impressive.

Everybody starts off at one point o, meaning they're all in, having no flare, and then as they fall off in the Kaplan Meier plot, they're getting flares. The people stayed on GCA stayed tight to that no flare line across the board. The ones who were randomized to placebo had this drop off that was pretty steady from week fifty two to week seventy two. And then didn't start to plateau until week seventy six. But even at week seventy six, the people on placebo, about sixty percent flared, forty percent didn't flare, suggesting that there is a subset of people that can do well with short term upadacitinib or steroid sparing, and you don't need to do long term, but that the sixty percent are the ones who are gonna need ongoing therapy.

The lines are really dramatic separation. It is, I think, a really positive study that tells you about what you should do if you use upadacitinib in GCA. The good news is that there were no new unexpected safety signals over the long term. As you might expect, people on the JAK inhibitor had a few more cases of zoster infection, but otherwise nothing to really worry about. Arty, what else did you like about the study?

Well, it's very clear. Usually there's, you say, well, maybe like we talked about in the past study, as you said, this is very, very clear that you do much better if you stay on therapy. Although you could say, forty percent of people, they're doing great. You're over treating forty percent of the people so that the ninety five plus percent of people still do well. They did mention that they didn't show someone asked about the seven point five dose, which was not as good as the fifteen dose and the FDA made them do that for safety considerations.

Turns out the fifteen was safe. The seven point five they said was more like the placebo and now of course retrospectively you could say well gosh maybe they could have gone from fifteen to seven point five and with that if that was exactly the same as fifteen is that any better being on a lower dose but really a very nicely done study and know it's giving us more information about the optimal treatment for GCA and the possibilities. My next is also a session, and this was the FDA session. And the FDA session has been at the ACR meeting for a while. Jack and I were involved in the Biologics Subcommittee years ago, and we pushed for a safety subset of that, an entirely separate safety committee.

And as a result of that, a couple of things happened. One is the reproductive health initiative, which has been super important and valuable. And the other is including the FDA every year at the ACR meeting. So the session this year, I thought was fascinating. They had a couple of very interesting things.

One is new drugs that have been approved and like you said upacitinib I think most people knew about. Inebilizumab is a B cell directed anti CD20 therapy approved for IgG4 related disease. I actually didn't know this. Extended release seventy five milligrams is approved for daily dosing for all the indications of They had some warnings too, which I thought it was good to know about. Nonsteroidals associated with the generalized bolus fixed drug eruption.

You think of that sort of thing being associated with some particularly antibiotics, but it can be associated with nonsteroidals. Sensitivity to mycophenolate, sensitivity to voclosporin, HLH related to Bactrim use. So these were things that the FDA caused notice for. Speaking of the pregnancy, remember they changed and they're moving away from the ABCDX towards the narratives and they had several of those this year based on actual data. Glimab based on data from Scandinavia, the cirilizumab of course there was a study that evaluated that and used the kinumab data from the Otis mother to baby registry and that's now added to the label.

And then interesting, two quick things. One is they give warning about hidden ingredients and here in Southern California we're actually very aware of this. There are a number of people who go to Mexico and come back and they say this pill is great because it's got steroid and muscle relaxant and non steroidal in one single pill and apparently that's common and really around the country. And then they had a little presentation and I just like the term multi specific immune therapies. And this is going to include your bispecific, your tri specific, those kind of medications.

And they talked a little bit about CAR T. The bottom line being that CAR T has to be safe more than it might possibly be in oncology to be in the rheumatologic space. So a things lot happened in the past year from the FDA standpoint.

Yeah, and they didn't make a big thing about, these sessions on safety are always really well attended because people are wondering what's going to happen next or what they might have missed. And I thought it was very well received. I wish they had spent a little more time talking about their FDA updates to box warnings on CAR T that appeared this year, and CAR T therapies being used in oncology, and they really updated the risks regarding secondary malignancies being an issue. Important because there is a tremendous enthusiasm in rheumatology for CAR T and cellular depletion strategies. And while there was a lot at the meeting, I don't know that there was anything that's gonna change where the needle is right now because they're all very early phase one.

We don't have any clinical trial results, we have hints of what may be going on. And I think we should have a tempered, enthusiasm based on what's going on in other fields where CAR T has been shown to be effective, but also carries a significant risk. Unfortunately, we don't have a presentation on CAR T. And I think the question is, when will we see that? How far down the road before we see a phase two trial that is going to be meaningful in CAR T?

Well, that's a big question. What are the regulatory requirements going to be for bringing them to the clinic? Will the agency mandate that you compare the results to a very good B cell depleter like openetuzumab, which was just approved for lupus nephritis. So it's like a supercharged rituximab and the bispecific engagers are a little bit more potent and the CAR T more potent than that. So what do you compare it to?

It's an important question. I think right now it's kind of end of the road salvage therapy for people who have failed almost everything else. And some of the results are super interesting. But I think you said caution is still indicated and certainly you don't take the potential side effects lightly.

Right, omidubicelumab was FDA approved and that's going to be exciting for the field of lupus and more to come on that. The company just announced the positive results on enalumab, which is a dual B cell inhibitor in Sjogren's syndrome. What's important about this is it's a two large phase three trials that pull together have power in showing that we have an effective drug in Sjogren's in phase three. Everything looks good in the phase two and kind of crashes and burns in phase three. They had a positive phase 2b trial and that was the basis upon which they did these studies.

Late breaking abstract LB24 presented by Thomas Graderbeck was, I think, a much talked about study. The question is, is it really positive? Is it positive enough or do you have an if and or but about this? In the two studies, Neptunus one, two seventy five patients, Neptunus two, five zero four patients, roughly the same design, both being placebo controlled, both giving the drug subcutaneously once a month. The Neptunus two had another arm of Q3 months, I think it was, going forward and that turned out not to be important.

They had week forty eight outcomes. To get in, you had to have a certain amount of activity as measured by the ULA Sjogren's Syndrome Disease Activity Index, the SDI, and they use that as their primary endpoint. Again, if you looked at the response rates, placebo and the drug, they came down about the same, but after as you got out to week forty eight, they started to separate. Okay, so there was separation. It took a long while in both Neptunus one and Neptunus two was only significant at the last two endpoints for both trials.

But when you pull the data together, it it did have now enough power to be significant earlier on. So it's not gonna be a drug that works right quick. Right? Unfortunately, in this study, no change in fatigue. No change in salivary flow rates.

But when you do the sub analyses, what they found was patients who had high salivary flow rates as opposed to low, which means that they still had preserved exocrine function did show differences on the outcome. If you had very low salivary flow rates, you were probably close to being a burnt out Sjogren's and this drug is probably not gonna work. Again, the results are positive, great enthusiasm for this because we need a drug for Sjogren's. But there are caveats here that still need to play out. We'd like to see the full report.

We'd like to see more experience. But Arty, what was your take on this?

Think Yanalumab is also a very efficient B cell depleter because there's two different mechanisms by which you can deplete B cells. And we certainly need treatments in Sjogren's. I think you frame the difficulty with Sjogren's and it's really kind of on two different ends. One is people whose Sjogren's has been present for so long that their excrement glands are destroyed and you may not retrieve that. But then at the other end there's the people who have widespread pain and dry eyes.

I call them dry myalgia. And we see those people and that confounds a lot of studies because the outcomes are a bit dodgy in Sjogren's studies. So it's nice to see a study that was done very well. Encouraging also, there was another abstract that was looking at another B cell directed therapy on telotachycept. And it was interesting because as this was discussed, the results were almost too good, meaning particularly there was no safety.

And we've seen teletachycept, atacicept, these are BLIS April directed therapies, Very strong, and they have been shown to be effective in the past, but always at the cost of serious toxicity issues. And in this case, there were none. And it was done in a single country, single population. So certainly this needs to be more broadly examined, but it's super exciting to have agents that can work.

Yeah, and I think that maybe in the sub analyses we'll learn better should get these drugs. They did not exclude fibromyalgia going in. The dry myalgia patients were in there and I think kind of confounded things. The really great placebo responses, which is what you don't want to see when you're developing a drug, are probably due to a lot of factors, including that they were on background, not biologics, DMARDs, up to twenty five percent or so were on steroids. They were allowed to use a little bit of a steroid bump during the study.

So they had some factors in there that kind of boosted that placebo response and negated the Delta, the treatment effect that you were looking for. But nonetheless, it was significant at multiple time points. So we'll see where this goes. All right, what's next?

Next, so I think it was interesting this year looking at the 2,700 or so, more than 2,700 abstracts, a lot of them on lupus. You go back to ACR ten years ago, there wasn't much action in lupus. Now we have lots and lots of studies on lupus. But one that I think is going to have implications for the practitioner was number eight fifty one that urinary tenasin C predicts kidney function loss in lupus nephritis. So this was from the AMP partnership, the accelerating medicines partnership.

One hundred and seventy patients with lupus nephritis. About a third of those developed eGFR loss, forty percent decline from baseline or end stage renal disease. And they looked at the so called what's becoming kind of called the liquid biopsy. And that is looking at urinary proteomics to see can they help predict the actual tissue biopsy. And of course, that's very, very useful.

I think you want the biopsy initially with patients with lupus nephritis. There was another poster from Michelle Petrie suggesting that you know what we really should have biopsies on most patients because you can be surprised by patients having proliferative nephritis three or even four who don't have all the boxes checked. Mean we know that low complement double stranded DNA are positive, but we want a biopsy to start. I think a big clinical challenge is what about the biopsy later on? I think this abstract was super important for that reason.

As patients go along and they may have deterioration in their renal function, for example, a key question is, do you keep treating them? Do you keep hitting them with the immune modulating therapies which can have longer term consequences as well as associated side effects while you're treating them. So they looked at a whole variety of urinary biomarkers and what they found, and I think we've talked about this before because it's super exciting, is that IL-sixteen is a predictor. Urinary IL-sixteen is a potential predictor of active lupus nephritis, there are a couple other biomarkers that go along with that. But tenascin C just jumps out and when you look at their data in volcano plot, it's a huge dot off from all the rest of them suggesting that it's common and that it's important and that correlated with the fibrosis.

So that's something that you would want to know and say if there's excess fibrosis that correlates with the lack of reversibility to further immune suppressive therapy. So not having to expose the patient to a repeat biopsy, that would be an important advance. And I think the liquid biopsy, I think we're going to see that going forward.

Yeah, I really like the renal biomarker story. I think that that's going to be a test I need to see in my profile that I can use. This report from Lee et al was important following Michelle's plenary session, where she talked about biopsying patients with a UPCR of 0.25 to 0.5 numbers that you normally wouldn't do. And seventy one percent had lupus nephritis, including the whole range of things that you don't want to see. I don't want to be doing renal biopsies or repeat renal biopsies.

But again, the experts are telling us we need to do that. I think I should tell the experts, get out the urinary biomarkers. The correlation to activity and chronicity scores with histology, with outcomes is just so tight that to not have them is a real crime. Arty, why don't you just stay on the lupus theme of tacrolimus and mycophenolate? Do you have that one ready?

Tacrolimus and mycophenolate, yep. I think that was interesting for a lot of reasons. We have voclosporin that's approved in The US for the treatment of lupus and lupus nephritis. We tend not to use as much in the way of other calcineurin inhibitors, but they are used in other places around the world, particularly in Asia. So, this was a randomized controlled study of steroids tacrolimus and steroids over mycophenolate and this is in people with proliferative nephritis three or four.

They were also allowed to have membranous involvement of five. Basically, the sustained renal response, which is a good outcome, a pretty high outcome, it looked it was indistinguishable between the two. So about fifty three percent at twenty four weeks up to sixty five percent at forty eight weeks and maintained at that level through ninety six weeks. Adverse events were a little bit different between them but similar. So you saw a little bit more signal of increased creatinine with the calcineurin inhibitor and tremor but leukopenia more with the mycophenolate.

So I think there are people in mycophenolate certainly for many of our Rheum colleagues, lupus nephritis equals mycophenolate. And if you don't respond, more mycophenolate. If you still don't respond, then try the mycophenolate again. So, it's nice to have other options. We know we have B cell directed therapies that are options.

The calcineurin inhibitor, and I think this shows that you can get efficacy with that. I think it's important for us with training programs to really bring it to the young ones that this is a possible class of therapy you should be familiar with and be comfortable using.

To follow-up on the lupus theme, there was a guideline presentation led by Lisa Samaritano and a bunch of great investigators who spent a lot of time on updating the lupus guidelines, specifically organ specific recommendations for non renal lupus. That's the whole thing. They did a big thing last year on renal lupus that created a lot of discussion, a lot of interest. And the difference between renal lupus guidelines and the non renal lupus guidelines is that the renal lupus guidelines, as much as they may have been contentious or difficult, were I think easier because there are a lot of clinical trials in renal lupus that make for strong recommendations upon which you can base your your guidelines. On the other hand, non renal lupus, all the organs, the skin, the joints, blood, the chest, heart, it's all going to be expert opinion.

And that's one of the, both the great things, the art of lupus management is when it's conditional recommendation based on what I think and what my colleagues tell me. But there are some specifics. So the takeaways on non renal lupus guidelines, 65 recommendations, three of which were strong, meaning evidence based. Number one, everybody should be on hydroxychloroquine vitamin H, right? That was in the renal guidelines as well.

Number two, that it's your job to taper steroids by month six to five milligrams or less. A lot of discussion about whether that should be zero or they should stay on a little bit. I'm on the little bit population. Some people say, well, if you have effective therapy, you don't even need a little bit because even four milligrams, three milligrams we've talked about before can still carry some risk. Then the other, strong recommendation is that when your organ system isn't responding, it's kind of a duh recommendation, step up and escalate therapy according to what the conditional recommendations are.

So they had recommendations for mucocutaneous musculoskeletal, serositis, hematologic, neuropsychiatric, cardiac, and vasculitis. They're all green, meaning conditional. Hard to argue really with any of these, they're pretty much things that you would imagine. I'll point out two that make some, I think, worthy of comment. Hematologic leukopenia, there is a conditional recommendation against treating leukopenia if there's no other features of lupus present.

You don't use immunosuppressives in that setting. Now, they didn't say how low it's got to go before you start to really get worried. If you get to an ANC less than 200, I think you're going to be worried about what's going on. But I think the reflex is that because of this, I'm going to use immunosuppressant, they argue against that. Neuropsychiatric mycophenolate anti CD20, IV cyclophosphamide, they're all over the map on this.

I don't think anyone knows a great way of managing psychosis and seizures other than using anti seizures and antipsychotic medicines. There's no strong recommendation about how to treat that as far as steroids which immunosuppressive to use. We still are in need of other studies. I think the only positive, I'll take from this is the good news in lupus drug development is that there are some new drugs being developed with a skin indication, using the classy, criteria set forth by Victoria Worth and colleagues, and using that as an endpoint. Now when we start getting clinical trials mucocutaneous lupus, you'll now see guidelines that'll make some sense about when to use which therapy and which patient.

Are you with

the I bet they get Lisa Semerino Talent to do that, to to give the presentation. She's like she's like the best relief pitcher you have in the bullpen. And the lupus community is like, jeez, we got nothing but conditional. We we better bring out the best. We're gonna bring out Lisa to pitch this last inning and give the presentation at the ACR.

And she does a great job with it. With the steroids, chuckle because did this, you and I did this years ago when we were in Southwestern, in the lupus clinic that we had. You ask us, how do you treat lupus? Oh, you give him steroids at the start and then you taper them off. But when you go and look at the charts, nobody's off steroids.

Everybody's still on. And Anisha did this in giant cell arteritis, abstract seven thirty eight. Everybody's like, Oh yeah, you tapered the steroids off. Two years on, eighty plus percent are on steroids. Now, they're down low and they found that out by asking the patients.

So if you ask the doctors, know, as you say in Texas, I'm fixing to taper the steroids. It doesn't mean I'm gonna, it means I'm fixing to. And we don't do it as much. And I think a lot of that is because the patient's reluctance and as you said, know, is five, should the should they stay on five? You know, is that the worst thing in the world?

So the steroids are always a funny funny question mark. Yeah. So a lot of stuff in spa. One thing I'm gonna mention with is in psoriasis, not in psoriatic arthritis, but I think it's a super interesting topic, that is the icotrokinra. Eicotrokinra, as you can tell from the name, is a receptor antagonist.

The interesting thing is IL-twenty three receptor inhibitor or blocker and it's oral. So I think in psoriatic arthritis and skin psoriasis, very exciting results with the twenty three inhibitors, both in terms of the extent of improvement in skin psoriasis being superior to that achieved with the GNF inhibitors, but really more for their safety. Squeaky clean safety profile is what most people would say. This it's fascinating for those of us old enough to have been around when the biologic agents were new, oh, it was very clear at the start. No, you can't have these as a pill.

Your body will treat them like food, digest the, you know what out of them, and they won't work. But now they have constructs that can work. These are inhibitors that you can take in pill form that do what you think that they would do. So kind of fascinating. This was iconic total.

The abstract number is five fifty five. And they also had a biomarker poster. But in skin psoriasis, very clear difference between the active treatment and the placebo. Ongoing study in psoriatic arthritis, I don't know that I have any reason to anticipate it wouldn't be the same. So we're entering and there are oral versions of TNF inhibitors in development.

There are people looking to develop oral inhibitors of IL-seventeen as well. So are we seeing a paradigm shift away from parenteral therapies towards oral therapies? And does that have any implications in terms of maybe combination therapy? So I think it's exciting just to have those available.

So what is the status of the, you hinted at this last year, about that, combination biologic trials are in process. Where do they stand right now? They're still just recruiting?

Well, the AFFINITY study read out, that was a combination study in PSA. That was gazelkumab monotherapy versus gazelkumab plus galimumab. So a twenty three inhibitor TNF inhibitor. Unfortunately, unlike the VEGA study upon which it was sort of roughly, based, it didn't have all three arms, didn't have the TNF alone. They did not achieve their primary a priori specified outcome, the MDA at week twenty four, but if you looked at people who had just a little bit of elevation in CRP, the combo was superior.

If you looked at more severe or higher levels outcomes even, the combo was superior. The safety was it seemed very, very good, small numbers of patients. So that's been done. There are others that are in the planning stage and ongoing, and I think we're gonna see it. Don't think combination therapy certainly in PSA is not a question of if, it's a question of when and which are the right agents to combine.

Right, so there are a number of presentations this meeting on preclinical RA, clinically suspect arthralgia, and what's going on at the cellular level that leads from a risk to actual inflammatory arthritis. A sub study, there are a few here that I want to group together, abstract seven seventy four, and I think eight eighty three is the next one. Stop RA is a trial that was reported on previously by Kevin Dean that showed in one hundred and forty four at risk individuals who were CCP positive that hydroxychloroquine was no better than the placebo. The study was stopped really for futility for not meeting its primary endpoint. But they have a lot of data that they're going through, and one of the sub studies was about two thirds of the patients underwent a multi omic immunologic profiling that was done in a serial manner.

First in thirty four patients who are on placebo, they looked at single cell sequencing and transcriptomics to come up with some caveats. Then on one hundred patients or so, they looked at cellular populations by flow cytometry or CyTOF. They showed that there were interesting changes in T cells and regulatory T cells in those that went from no synovitis to converting to synovitis. They call those converters. Converters were more likely to have an expanded, albeit a very small population of peripheral helper T cells, both at baseline and that it grew until the time of conversion.

They, also found more of these granzyme CD57 positive CD8 cells, terminally differentiated CD8 cells that were at baseline and also at onset. Cellular inflammatory and cytotoxic pathways are prevalent early on. There was another abstract 89 that Arty and I looked at that was also really exciting for cellular work. They looked at, again, populations that progressed, and they showed that not just peripheral helper T cells, but follicular helper T cells were expanded early on at baseline, and that also would have predicted those that were going forward. From the STOP RA, they came away with some recommendations that would predict who was going to convert.

One was the peripheral helper T cells and two was a higher titer of CCP3. Top twenty percent of peripheral helper T cells and top twenty percent of CD3 titer patients had an earlier progression to disease. Now, all of this is supported by one last abstract about peptidyl arginine deaminase, the PADI, which leads to synchronization that drives CCP. In this study, they looked at three cohorts, a healthy cohort, an at risk cohort at CCP positive and an early RA cohort, and looked at PADI two and PADI four levels. They showed that people who had high PAD four levels were much more likely to progress to inflammatory arthritis and RA, and it was very significant.

What I see evolving here is one, a cellular phenotype, two, other factors that arise in the early biology of disease that are going to push certain people beyond what CCP will do to develop early RA. There was another one about small RNAs that could also predict and highlighted an enhanced role for alpha interferon, maybe he has another early target. I liked that the way this research is going getting towards a better understanding. All these reports, however, don't really help us in the clinic. We still are looking at CCP, the higher the worse, the more multiplicity of autoantibodies, the worse the risk.

But this biology and the understanding of early events can lead to maybe more effective therapies.

Yeah, and it's a super interesting, super important problem. We see these people in the clinic. What do you do, with these patients? And right now, don't, as you said, the understanding of it is really seems like it's evolving and it's making sense and it's giving us, I think, important insights. But for that patient on Monday that you see, are they going to develop rheumatoid arthritis or not?

We want to know with some certainty before we expose them to therapies that can have toxicity. You don't want to over treat people to prevent a disease they were never going to get. That's the problem. That's why I think we're all so sad that hydroxychloroquine was absolutely completely negative because I think we would have used that because the good safety profile. Yeah.

So a couple of quickies. One, gout. We don't talk a lot about gout, but, there's, abstract twenty twelve was a new URAD inhibitor. And I think we really like that because that's really probably the relevant pathology in many, many patients, particularly those with a strong family history of gout. It's allelic polymorphisms in urine that make it more efficient at bringing uric acid back.

So it sort of fits. We've had sulfonpyrazone not well tolerated. We had lisinrad, which had some issues. They have benesperomarone in Europe, which also has some toxicity issues. But I think because it fits so nicely with the pathophysiology, we want to see.

That one was very early study, it did look like in a phase two study that did lower uric acid levels. And then two very quickies, and these are in the, I would put the category as and that is what you could tell your colleagues in different specialties. One is, and I think this happens all the time, this happened to me just before we came to the ACR meeting, You send somebody to pulmonary with rheumatoid and ILD and they say, Oh no, TNF inhibitors make it worse. You can't use TNF inhibitors. And there was a target trial emulation that looked at this, thousand six hundred sixty two.

And as has been shown in other sorts of registry analyses of this sort, people think of rituximab as the best for ILD. This study looked at it piece by piece and you did not find that rituximab was the best. These agents that work in RA work also for ILD. So you can point to that and say, you know, don't say you can't use TNF inhibitor because it's going to make it worse. And then kind of on the same lines, Abstract fourteen thirty four, and that is when you talk to your GI colleagues and say, have a patient with IBD, the GI doctor said, do not use nonsteroidals.

And when you dig into that literature, is absolutely old urban legend. It comes from nothing, from no studies that ever show that they are happy to use a COX-two inhibitor from a really crappy study done years ago as well, which we like because they let us use the COX-two inhibitors. This was a retrospective study using claims data and basically said that you do not have maybe there was an increased risk of hospitalization, which we see with non steroidal users, but that there was not an increase in the worsening of IBD with nonsteroidals.

My last one is going to be a pilot trial about fiber use in RA, specifically in methotrexate treated RA. This was late breaking abstract 15, LB15, a small trial, double blind randomized placebo controlled trial of 49 mild RA patients who were given the intervention of high dietary fiber in the form of inulin, twelve grams per day versus placebo. These RA patients had mild disease, five to seven tender joints, one or two swollen joints. CRP mean was seven milligrams per liter or zero point seven milligrams per deciliter, upper end of normal. And they were on background DMARTs, conventional DMART therapy.

And this was a thirty day, blinded therapy. At the end of thirty days, the patients who were on the fiber had a significant increase in their ULAG good scores. Was like 53 versus twenty four percent, and that was significant. A non significant but obvious change was seen in the methotrexate treated patients especially, where they showed, again, they had a low dash 28 score and it dropped the whole point, one point zero, on fiber, whereas if it was on a placebo, it dropped 0.35. It was clearly a big difference, but the numbers were too low to be significant.

And in data not shown, they had changes in both IL 17 I'm not sorry, Th17 to Treg ratio and Th17 numbers suggesting that maybe there was a microbiome change here. The and there's plenty of research about changing the microbiome to improve drug effectiveness. And this is cheap and easy and until they do the much larger trial, this might be something I play with.

Yeah, of course, diet super hot topic, Patients very, very interested in that. I really like this one. Fiber is actually one of the, more famous names in medicine was Dennis Burkett, who was a missionary and pediatrician from Ireland. And he was a missionary in Central Africa. Everybody remembers him for the lymphoma that he was given his name because he was the first to describe contagious lymphoma ultimately found to be Epstein Barr virus.

But his big thing throughout most of his life was fiber. He was convinced that the absence of certain diseases in Sub Saharan Africa, diabetes, cardiovascular disease, were related to he said the difference was, a tremendous amount of fiber in the typical diet in Africa compared to in the westernized European countries. So fiber, I like the idea of it. It was interesting because we really you and I went to the poster together with some colleagues and really kind of kicked the tires a little bit to see. And it was just well done.

Short, as you said, not the tremendous amount numbers, but no toxicities. And in fact, she said that the patients couldn't even tell. There wasn't a giveaway. It wasn't like their bowel function gave away which group they were in because they did have a control. They had maltose dextrose as a control, so there was no toxicity with it.

I love that abstract.

So I want to close by reminding the audience that RheumNow Live is happening in 2026, February in Dallas. Fly into DFW, it's easy. It's seven minutes from the airport. Arty and I will be co chairing what we think is a fabulous program. You can go to roomnow.live to look at our agenda and to register.

If you look at it, you'll see we got great sessions on spondyloarthritis with Dennis Padubney, Jessica Walsh and Catherine Bakewell. We've got a great session on psoriatic arthritis with Joe Marola, Arty, Andre Ribeiro and Robert Turkle Tau, R. A. With Elena Mayasadova, Kristen Demarell and Jeff Sparks. We got Rohit Agarwal talking about myositis and much, much more.

It's a really great program. I think you'll enjoy it. It's probably the best return on your investment of time and money. Arty, what's happening with RWCS?

Arty, a few weeks later and also should be good. So much going on. But yeah, for the RoomNow live, look at that program, I want to go see it. Course, the sessions are really made to be short and informative and it'll be great. So we hope to see lots of you there in Dallas.

So thanks very much for tuning into Rheumatology Roundup. We'll do it again next year. Enjoy.