ACR20 - Day 4.1 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.

Hi. This is Eric Ruderman, coming to you from ACR Convergence twenty twenty for RheumNow. Welcome, and I wanted to talk today about a new therapy that's actually a new approach and a new pathway in psoriatic arthritis. Talk a little bit about the data that's presented at this meeting, and then talk about what this may do and where this may fit in our paradigms for treating arthritis. The new molecule or the new drug is called ducravacitinib.

It is a very specific TYK2 inhibitor. As you'll remember, the JAK family of kinases actually has four different molecules: JAK1, JAK2, and JAK3. And drugs that we've been looking at so far target JAK1, two, or three with varying degrees of specificity, the newer agents a little bit more specific for JAK1. The fourth member of that family, and the reasoning for the nomenclature is lost in history, is TIC2. Not JAK4, but TIC2.

It is a JAK kinase. As you may know, the JAK kinases help with signaling for a variety of different cytokines. They bind to the cell surface receptor, they dimerize and phosphorylate two different JAK molecules at the, intracellular portion of that receptor, often heterodimers of two different JAK molecules. Those JAKs then, phosphorylate and activate STAT molecules, which go down to the nucleus and activate transcription and protein production ultimately. TYK2 is kind of a unique molecule there.

The three agents that we've, or actually four agents almost, that we've seen so far that focus on JAK1, two, and three don't, to a large extent, block TIC2, but to a certain extent they do. With this drug, ducravacitinib, it is a very specific, inhibitor of TIC2. It binds actually not to the ATP binding site on the protein, but to a separate regulatory site on that protein that's distant from the ATP binding site. The benefit of that, theoretically, is that it may have actually more specificity. The problem with specificity with the other JAKs is that that ATP binding site may be similar between different JAK proteins.

TYK2 is theoretically distinct. And the first data that we're seeing at this meeting, in one of the late breaking abstracts, number three in the late breaking abstracts, is the phase two study of ducravacitinib in psoriatic arthritis. The drug has been studied in psoriasis before. The hope for this drug, or at least one of the hopes for this drug, is that interleukin-twenty three signals relatively specifically through TYK2, and so if you can isolate an inhibition of TYK2, you may be able to inhibit IL-twenty three signaling above other cytokine signaling and have a relatively specific target. That's important in psoriasis and psoriatic arthritis because as we know, IL-twenty three, antibodies that inhibit the IL-twenty three molecule, are very effective for treating skin disease.

They're also effective for treating joint disease, as we've seen with gazelkumab and some earlier studies of the other agents, but particularly effective at treating skin disease. The other benefit is that inhibition of IL-twenty three seems at least on the surface to be associated with a somewhat decreased risk of infections and, side effects. So in theory, a JAK inhibitor that's more specific for TYK2, which therefore is more specific for the IL-twenty three pathway, would have benefit in psoriasis and psoriatic arthritis. And that's the idea here. The data says that it works, it doesn't say that it works that much better.

If So you look at the data in the trial that's presented here, it's an effective agent. It's effective at reducing active joint disease as measured by ACR response. It's effective at improving function as measured by the HAC disability index. It improves enthesitis, and MDA responses, minimal disease activity, are higher than with placebo, and the skin response is quite good. Skin response isn't quite in the same ballpark that we've seen with specific IL-twenty three inhibitors.

So one wonders whether this is truly, as you might sort of call it, an oral IL-twenty three inhibitor, or it just sort of inhibits a slightly different pathway. What we don't know is whether IL-twenty three signals through other pathways that may sort of get around this. The safety profile though was quite good. Very few serious adverse events, some minor infections, some rashes. I think it remains to be seen whether the safety profile here is going to be better than the other JAK inhibitors.

So it's a good drug, it seems positive in phase two, the pathway seems to hold promise, and there are other TIC inhibitors in development. Time is going to tell where this fits into our treatment algorithm. We have so many good drugs to treat psoriatic disease these days, from methotrexate, which still works, to a premelast, another small molecule, to TNF inhibitors, IL-seventeen inhibitors, IL-twenty three inhibitors, the IL-twelve twenty three inhibitor, ustakinumab. And what we're struggling with is trying to sort through all those and figure out which is the right drug for the right patient. Having another agent, the TYK2 inhibitor, certainly helps, but what we're going to need as things move forward is data that helps us understand who's the specific population of patients that might benefit more from this than another drug, or perhaps most will.

We'll have to see. Stay tuned. Phase two data is always exciting to see. Later stage data is really going to help us frame the use of the drug and we'll see where that plays out. Thanks for listening and tune into RheumNow for more information on ACR Convergence twenty twenty.

Hi, I'm Doctor. Janet Pope reporting at RheumNow. I hope you're enjoying the ACR twenty twenty, our virtual Congress. I can tell you I'm learning a lot. This is an abstract and the results are kind of solemn to me.

So it's abstract number fourteen sixty two and what this was was a large survey of men who would have exposure as coal miners or other silica exposure. And the question was, do they have inflammatory arthritis and then validating by things like they're on disease modifying drugs, do they have a diagnosis of RA? So the first thing to note is that Kaplan syndrome still exists And for the keeners, you probably already know historically that Kaplan syndrome were people working in the coal mine, obviously men back then, who developed rheumatoid nodules and often had rheumatoid arthritis. And the solemn findings here are that we are still finding rheumatoid arthritis and with a pretty high relative risk in people who are coal miners or other exposure to silica. Number one, why aren't we protecting our workers better?

And number two, this dust exposure can affect the patients and although they didn't look in the abstract, I'm sure it could have secondhand consequences to the family members or people that live in the towns or the cities where coal mining is a big deal. So I think the way that I will change my practice is I'll ask patients about exposures and a work history and obviously to try to advocate for my patients for good safety. I hope you're enjoying ACR and follow us at RheumNow. Thank you.

Hi, welcome to the room now. We have the pleasure of Michelle Petrie with us, and we're gonna talk about some of the things she's presenting at this meeting. Michelle, thanks for joining us.

Thank you, Jack.

Okay. So for the audience, I'm gonna have them get out their pens and paper and write down the abstract numbers of twelve sixty one, twelve sixty two and twelve sixty six. We're gonna talk about the issue of testing for antiphospholipid syndrome and some of its predictive value, in predicting future thromboses. And let's just start with twelve sixty one. You talked about the profile of what you do in your clinic of over 800 patients in the Hopkins Lupus Clinic.

Why don't you tell us about that?

Well, Jack, the problem is lupus is not like primary antiphospholipid syndrome. So for primary antiphospholipid syndrome, people have memorized this thing, triple positivity. If you have lupus anticoagulant and anticardiolipin and anti beta two glycoprotein one, then you're at high risk. But it turns out that doesn't hold true in lupus, where the majority of the thrombotic risk is actually explained by the lupus anticoagulant. And what's really important for everyone to know is that the lupus anticoagulant fluctuates in lupus the same way anti DNA might fluctuate, for example, or low complement.

And so it is necessary to look for the lupus anticoagulant probably multiple times because if a patient has it even twenty five percent of their visits, they have an increased risk of thrombosis.

And you, in your studies looking at how predictive lupus anticoagulant is versus, other testing, you correlate that with not just venous thrombosis, but also arterial thrombosis. And I was surprised that they were almost equal in numbers.

Yes, but remember that everything is multifactorial. So for arterial thrombosis, things like hypertension and other traditional risk factors play a role. So it's not just antiphospholipid antibodies.

Yeah. So the point of the first paper was that liposanic coagulant is by itself is just as good. And the second paper said head to head liposanic coagulant versus double positivity, triple positivity, still lupus anticoagulant still works. What in reality do you do and what do you hinge your decisions or thoughts on? Not necessarily decisions, but you're always doing this as a risk profiling sort of measure.

So my belief backed up by our data is that if someone has lupus anticoagulant, even just twenty five percent of their visits, they deserve prophylactic therapy. And right now, on the evidence, the best prophylactic therapy is a baby aspirin plus hydroxychloroquine.

Did you want to make a case for beta-two glycoprotein?

Well, yes, but you know what's controversial is that we measure IgA. And in Europe where they first, doctor Pango coined the term triple positivity, he was looking at just IgG and IgM. But in our lupus patients, IgA anti beta two might add risk on top of the lupus anticoagulant. So it is worth measuring that isotype and paying attention to it.

So for the audience, I want to give some perspective. Believe that having lupus anticoagulant had a, gave you a twofold or no, sorry, threefold increased risk for arterial thrombosis and almost a fivefold increased risk for venous thrombosis. And then the beta-two was around two or something like that. Am I close on those numbers?

Yes. And so, you know, we're not talking, you know, risk factors of 20 or 30, but we're talking quite a significant increased risk that is clinically meaningful.

Well, and I found these reports of yours very interesting, especially in light of another one that you had that looked at lupus patients and their risk of MI versus CVA, and that the risk factors for them are not the same.

Yes, and I think there are a couple important messages. The first is that strokes really peak in the first couple of years. So I think we used to think that there was this bimodal pattern and all the bad cardiovascular stuff came later. Well, that's not true. Strokes definitely peak early.

And the other important message is that the lupus anticoagulant and low C3, those are really risk factors for stroke, much more so than they are risk factors for myocardial infarction. And that really surprised me because I think of immune activation and other factors being more important in the coronary arteries. But that's the whole reason we do cohort studies. As you're not supposed to guess, we're supposed to base everything evidence. Now we have that evidence.

Yeah, I think it's a really interesting observation. I think many people would probably think about that as maybe what they've seen. I mean, MI has, in my experience, been a later phenomenon, age related, comorbidity related, and obviously lupus activity, I always thought played some role, but I'm not surprised to see that it doesn't play maybe that big a role. Factors that go into MI, in lupus patients later on.

And the other thing that I think is going to surprise people, especially everybody who listened to the plenary session on the Georgia Lupus Registry, is at Hopkins, we do not find African Americans having a higher risk of these events than Caucasians. In our dataset, the two ethnicities are superimposable, but they have different risk factors. So they get to the same frequency of events, but they get there in different ways. So anti phospholipid antibody is much more common in Caucasians than in African Americans. And some things are just such a shock.

If we look at risk factors for myocardial infarction, for example, hypertension is not significant in African Americans. I'm thinking, how is that even possible? But again, I learned a long time ago, let the data speak.

Well, complex, yes, but certainly manageable. We want to thank you for your time, Michelle. As always, you inform us so well.

Thank you, Jack.

Hi there, I'm Jeff Curtis at the University of Alabama at Birmingham. As unfortunately we have become too painfully aware, 2020 has been the year of COVID, and the ACR Virtual Convergence meeting is no exception to cover the topic. As probably all of us who attended the conference know, there were multiple, multiple sessions looking at COVID-nineteen, but I wanted to draw your eye to something that you might have missed. It's late breaker L01. It's the results from the very early experience in about the first four months or so of the pandemic from some of the Boston hospitals, Mass General, Brigham and Women's.

It tried to answer the very important question that frankly is on most of our patients' minds. You know, if they who have a rheumatic disease get COVID, like what happens and how bad is it gonna be? And we've known from other abstracts presented at the meeting, including some patient communities like the Arthritis Power Registry and the Creaky Joints Community that I work with routinely, you know, people are really fearful. There's a huge amount of anxiety. There's multiple abstracts on this topic from a variety of patient registries.

So of course, how afraid patients with rheumatic and musculoskeletal diseases need to be is a source of great concern. From several of the patient surveys that have been reported at this meeting, about at least fifteen percent, and in some surveys higher, of patients are stopping their therapies, mostly without their doctor's recommendation, and in many cases, even without their doctor's knowledge. So is this really warranted? So late breaker one reporting the experience of these Boston hospitals sought to try to inform that question. So it's one hundred and forty three patients.

It's not a huge sample size. And these were all individuals that were confirmed to be COVID positive. They age sex matched them to individuals who did not have a rheumatic disease and then asked the question, you know, what are the downstream outcomes? What's the likelihood that somebody gets hospitalized, ends up in the ICU, needs mechanical ventilation or who dies? You know, how afraid do the rheumatology patients need to be?

So perhaps interestingly enough, the outcomes are far more similar than maybe you and I might have guessed. Roughly forty percent of the people that tested positive that were in this cohort in both the rheumatic disease arm as well as in the comparator non rheumatic disease arm ended up being hospitalized. So mechanical ventilation outcomes were somewhat different. It was almost forty percent of those hospitalized in the rheumatology patient arm, roughly about twenty percent in the comparator arm. So the need for mechanical ventilation was about 1.5 fold higher.

And after controlling for a number of things, that's about where that estimate ended up. A higher risk for mechanical ventilation and ended up not being statistically significant, but it is a fair amount different. I'd point out though that the comorbidity profile of the patients with rheumatic diseases was appreciably higher. You know, about a third of them had RA, roughly twenty percent had lupus, roughly a third were on steroids. So that's a pretty typical rheumatology population.

And then the outcome of course, that is of most concern to everyone is death. And about seven to eight percent of people overall died, but it wasn't different between the two arms of the rheumatology patients compared to alternative comparison arm. And again, it's age sex match, so that's perfectly well controlled by design. So bottom line, what do we learn from this? Well, first, this is still the early experience, and this cohort size of one hundred and forty three people isn't gigantic.

On the other hand, most of those outcomes, hospitalization, death, were pretty similar. You know, ICU admission also not much different. The mechanical ventilation was somewhat different, but in fact they looked at it in terms of calendar trends and, you know, later on in time, perhaps with, you know, some of the existing ICU type protocols that might have got put into place, the need for mechanical ventilation actually looks like it changed and became closer to parity in the rheumatology patient cohort. So unlike perhaps what some patients and clinicians might have feared, the outcomes of actually having confirmed COVID-nineteen infection for rheumatology patients were really not a whole lot different compared to the general population. What's not known and what's left really unanswered is the generalizability.

These are people that are seen and treated and were initially diagnosed at a Boston healthcare system that is clearly not highly generalizeable to non urban settings or rural areas where hospitalized patient care may be quite different than in these Boston hospitals. The other thing, of course, that this abstract doesn't touch at all because it was very much out of scope, are patients with rheumatic diseases on the treatments that we would usually prescribe, are they at higher risk to get COVID infection? And with a study design like this, you can't speak to that. But for the question that it sought to answer, know, are outcomes of people who have confirmed infection worse if you have a rheumatic disease on the usual treatments, it really doesn't seem like it. So I think this is gonna be a helpful practical piece of information.

We need more data, but at least at this moment in time, it really doesn't seem that much different. And I think that provides at a minimum some reassurance and comfort that, you know, people don't have to live with quite as much fear and anxiety as perhaps that they've had up to this point. We still need the usual precautions and common sense and social distancing, but people probably will be somewhat less afraid if we can share some of this data from the L01 late breaker. Thanks for your interest.

Hi, I'm Alexis Simon Mira, assistant professor at Ohio State University reporting now for ACR twenty twenty, and I am here with Doctor. Caitlin Quinn, and I'm going let her introduce her amazing self. And we're going to talk a little bit about large vessel vasculitis and the new imaging techniques that we're going through. So Caitlin, if you'd like to introduce yourself.

Thank you for having me. I'm Caitlin Quinn. I'm a staff clinician at the National Institutes of Health and I mainly work in the vasculitis translational research program there.

So tell me a little bit about the new work that's been in multiple abstracts about imaging for large vessel vasculitis.

So most of the work looking at FDG PET and large vessel vasculitis has been at time of diagnosis. So for the past several years, we've been doing PET scans in a research setting at NIH to monitor disease activity over time and to really try to better understand how PET changes in response to different treatments and can PET predict who may relapse, and can PET predict who may go on to have angiographic progression of the disease over time on MRA or CTA.

So this is really important because it's really hard to one diagnose and there's a huge delay in diagnosis, which has a lot of morbidity for patients. And then two, as rheumatologists, how do you change, you know, DMARDs, steroids for patients in flare? And so this could be a really profound change to the way that rheumatologists practice.

Yeah. So one of the abstracts that we presented at this meeting was specifically looking at change in pet over time in response to tocilizumab treatment, The two recent randomized controlled trials looking at tocilizumab treatment and giant cell arteritis really focused on clinical improvement and laboratory improvement, but imaging was not systematically studied as an outcome measure. So to try to better understand how PET scans change in response to tocilizumab, we had patients who had a PET scan prior to tocilizumab treatment and then at six month intervals while on tocilizumab. And we saw that there was continued improvement over a two year treatment period with a similar amount of improvement in both the first and second years of treatment.

So it's really cool. So do you think the PET seems to have a is it better, like, inter rater variability compared to, like, ultrasound and MRIs and all these different things? Because it's more of a standardized color change kind of view, not that I'm a nuclear medicine doctor by any means and not trying to minimize that.

Yeah. I think it depends on the institution and what imaging modalities people are most familiar with. But the nice thing about PET is you can really, on a scale, detect incremental change over time that sometimes can be harder to do on ultrasound where it's very operator dependent and even on MRA where it's hard to gauge the amount of change and wall thickness or edema over time. So the nice thing about PET is we can really scale and measure improvement over time, which makes it a nice option as an outcome measure, looking at response to treatment.

Well, I think that's super cool. I was like, before we close-up today in those short, quick little interviews, is there anything else, any other shout outs you wanna give or anything else before we close out? Because I think this could really, as you are, as a practicing rheumatologist, I think that this could make a big difference for patients in how we monitor this in disease morbidity and damage if we actually had really accurate ways to follow these patients. So I'm really excited, as a vasculitis doctor to be able to use these things.

Yeah. I think my mentor is Peter Grayson at the NIH and it's been really great to get to work with him and all of our patients that we've learned so much from and then following.

Well, awesome. Well, thank you so much for your time and so amazing work, Caitlin, as you know, you're the fellow for the, right, the VCRC, right? Like in doing all this amazing and the ACR fellow for the vasculitis guidelines. And so I'm really excited for all these things and I'll make you do some more interviews with us.

Thank you so much for having me.

Hello, ACR Converge. I'm Doctor. Rachel Tate reporting to you from West Palm Beach, Florida. Limited data has been published regarding pregnancy in SPA patients. And as a new mom myself and with a strong family history of spondyloarthritis, I really wanted to discuss two abstracts on this important population.

So a study out of Italy and Portugal, this is abstract thirteen twenty four, prospectively reviewed adverse pregnancy outcomes looking for risk factors in this particular patient population. Eighty two patients and ninety four pregnancies observed between two thousand and '9 to twenty nineteen were reviewed. Forty one percent of these particular pregnancies had an adverse pregnancy outcome. These included six preterm births, seven miscarriages amongst other complications. The most frequent APO, as they're calling it, was small for gestational age, and this was in about seventeen percent of these patients.

Most importantly, a history of IBS, more aggressive disease phenotype, and active disease either at conception or during pregnancy increase the risk for an APO in these particular patients. Another study, this is abstract, pardon me, abstract thirteen twenty three looks specifically at pregnancy and axial spondylitis patients. Eight eighty four systemic reviews of case controlled trials, observational studies, cross sectional studies and case series found axSpA in pregnancy in general. Of those, one hundred and thirty were analyzed and a total of 18 trials of 3,100 60 six axSpA patients met criteria for inclusion for this particular trial. This study actually found ultimately that axSpA patients have a higher rate of C section, preeclampsia, intrauterine growth restriction, and a number of fetal complications as compared to a normal population.

Of note, there was a high proportion of these patients with active disease during pregnancy, which the authors felt may be an important key piece to this. And of course, medication use and prescribing habits were very widely varied. So in that particular case, we still need to learn a little bit more about our prescribing habits in order to best treat these particular patients. This is clearly an unmet need area for our patients, and I obviously remain cautiously optimistic that what is best for baby is a healthy mommy with a controlled disease regardless of therapy. Thank you for spending time with me today.

For this and for more updates, check us out at roomnow.com for ACR twenty twenty. And of course, follow me on Twitter uptoTate.