Melanie Cole (Host): Welcome to Better Edge, a Northwestern Medicine Podcast for physicians. I'm Melanie Cole, and we have four Northwestern Medicine physicians for you today in a thought leader panel highlighting clinical trials in Rheumatology, Clinical Perspectives: A Discussion on scleroderma, vasculitis, and lupus trials.

In this panel are Dr. Eric Ruderman, who will be moderating, he's the Associate Chief of Clinical Affairs and a Professor of Medicine in the Division of Rheumatology at Northwestern Medicine; Dr. Irene Blanco, she's a Professor of Medicine in the Division of Rheumatology, the Director of Lupus Clinical Services, and the Co-Director of the Clinical Research Ethics Consultative Service; Dr. Anisha Dua, she's a Professor of Medicine in the Division of Rheumatology Fellowship Program Director and the Director of the Vasculitis Center at Northwestern Medicine. And Dr. Carrie Richardson, she's an Associate Professor of Medicine in the Division of Rheumatology and the Co-Director of the Scleroderma Center at Northwestern Medicine.

Dr. Ruderman, I turn it over to you.

Eric Ruderman, MD (Moderator): Well, thank you Melanie. As a general rheumatologist, I have to say it's really exciting to be here with three subject matter experts who deal with some of our more unique diseases. Dr. Richardson, who takes care of scleroderma, Dr. Blanco here, who takes care of lupus; and Dr. Dua, who is our expert in vasculitis of all forms. To start things off, we're going to talk about clinical trials today. And I wonder if we could just start more generally and tell me, what are the sort of main goals of clinical trials in Rheumatology these days? Not so much disease specific, but generally across our specialty.

Carrie Richardson, MD: I think it's been really exciting because, you know, for a long time our focus has been specific drug pathways and there's definitely been much more of a trend towards trying to alter the immune system or reset the immune system. And I know we'll talk a little bit about this, but I think we're talking about, you know, potentially instead of making incremental gains, there's the possibility of potentially restarting the whole process that caused the autoimmunity in the first place. And that's been really exciting.

It's still very early phase and we have to see how things are going to play out, but I think there's at least the promise that we're going to be doing something different with the more recent clinical trials with bispecific engagers potentially coming on the scene with CAR T-cell therapy, different ways of creating CAR T-cells, and that's very exciting.

Irene Blanco, MD: To piggyback off of that, you know, the diseases that we all focus on, and particularly myself and Dr. Richardson, have been sometimes frustrating to honestly take care of just because we haven't had many of a really good armamentarium in terms of medications, right? So, really being able to pioneer new therapies for really some of our sickest patients is so exciting.

I mean, lupus itself, you know, every time you would open up a journal, it's like, "Well, this medication didn't meet primary endpoints, and this medication didn't mean primary endpoints. And you just go through the cycle of hope over and over and over again. And patients get so excited and they're so interested to participate and they're so willing and engaged, and yet, you know, we finally feel like we have something potentially that's going to move forward to really be a game-changer for these patients.

Anisha Dua, MD: Yeah. I think more broadly, I think in Rheumatology, we all use so much steroids. And so, there has been a lot of interesting research, I think personally in the vasculitis space, but also across Rheumatology on the impact of low-dose long-term steroids, which our patients are stuck on and high dose steroids. And so, we have a lot more research, I think, going into steroids strategies. And then, also, interesting research looking at sort of prevention of rheumatic diseases. And so, I think those are two areas that are also super interesting right now.

Eric Ruderman, MD (Moderator): Great. Well, thanks. Maybe we'll start drilling down a little bit. And I'm going to start with you Dr. Richardson. In the scleroderma world, are there either recent clinical trials or trials that are going on right now that you think are particularly promising, and may have an impact on clinical practice?

Carrie Richardson, MD: Yeah, it's a great question. So, I think what's happening in scleroderma now is very exciting. You know, when I started fellowship, we had zero FDA-approved medications. And now, we have two, which is not a lot, but it's a whole lot more than we had before. And there's been this flood of interest, you know, from foundations and philanthropists and from industry to try to develop better therapies for scleroderma.

So, that's really exciting in general that there's been so much interest in developing better treatments for our patients who really need more options than just two FDA-approved therapies. But I think there's a couple innovations I think that have been really helpful. So one, you know, we have a platform clinical trial design, which I think is really exciting because it potentially saves the time and money and startup effort of getting a trial going. And you can add multiple therapies so it can potentially accelerate drug development. That's our Conquest Clinical Trial Platform, and it potentially reduces the chance that somebody would get a placebo. So, the patient would be more likely to get an active drug if there's two or three therapies in there.

So, I think that potentially has the ability to advance scleroderma treatment. And I think repurposing medications, like some of the medications that are used for lupus and idiopathic pulmonary fibrosis that are already shown to be safe and FDA approved for other conditions and using those to treat aspects of scleroderma. I think that's potentially a way to accelerate new therapeutics. And so, that's been really exciting that, that has been moving forward in that direction.

Obviously, I think CAR T-cell therapy in different modalities of, you know, creating CAR T-cells, I think that is very exciting. It's a whole different way of approaching the condition than what we've traditionally done with a lot of our clinical trials. So, that's exciting. So, that's, you know, from the therapeutic aspect.

And then, I think a lot of what we have happening on the clinical and translational side, which is really the behind-the-scenes work, you know, these initial steps that you would go through to eventually get a drug to market.

I think some of the research that we have happening in the lab and in the bench is very exciting. So, I think some of Dr. Perlman's work on potentially looking at the immune system and how that interplays with gastrointestinal symptoms and scleroderma, I think that's very interesting because GI symptoms have traditionally been overlooked for a lot of our patients in clinical trials. And that's something that has a huge impact on quality of life. David Cella of our Clinical and Translational Science Institute, he's been working on actually looking at more patient-focused outcomes. And so, that when we develop a new drug, it's actually targeting the symptoms that patients experience. You know, for example, a lot of our patients experience fatigue, and that's something that we have traditionally not really centered on. But I think looking at what matters to patients may make the potential new drugs more impactful.

And then, I think some of our research focuses on the fundamental causes of autoimmune diseases like scleroderma. So, that's some of the work being done by Dr. Debbie Winter, Dr. Matt Dapas, Dr. Natanya Field, where they're actually looking at what starts this process of autoimmunity. And I think ultimately these types of research may help us get to better, more targeted treatments. And I think we're moving towards precision medicine where we're looking at hopefully being able to look at an individual patient and What their specific risk factors are, or their specific origin of scleroderma, and potentially targeting therapies better to match an individual patient.

Eric Ruderman, MD (Moderator): Can I ask you to expand on something? You mentioned the platform trials. For people who aren't really familiar with that, maybe just sort of briefly-- I don't want to get into the weeds-- but sort of briefly, like what is the concept behind those? How does that really sort of advance sort of the clinical trial approach?

Carrie Richardson, MD: Yeah. So in practical terms, I think, you know, if you're just looking at a clinical trial, it seems so simple, right? You know, often there are about a year long and it seems, okay, you get a medication or placebo and that seems so straightforward. But the actual process involved to get a clinical trial up and running is hugely time-consuming and incredibly expensive and it's a barrier to drug development. And so, the platform clinical trial basically takes that startup and you still have that initial investment of time and energy where you have to get the regulatory approvals and make sure everything is set up for the clinical trial, that safety protocols are in place. But basically, once you have the platform up and running, it can potentially run in perpetuity. And so, the platform doesn't end when the trial ends after one year. It is as you have promising drugs-- so for example, we have our platform clinical trial, and there's a drug that's been very promising in idiopathic pulmonary fibrosis on that platform, and we're repurposing that for scleroderma, as you get new promising drugs, you can add them to the platform.

And so, again, you know, if there's traditional clinical trials, it's been one-to-one randomization. That's pretty typical. But a lot of patients will want a chance, a better chance of getting that active therapy. And so, if we have three promising drugs, you could have a 3:1 chance of getting randomized to the active therapy, which, you know, hopefully it should make that more-- you know, something that's more exciting to patients, that there's a higher chance of getting that active therapy.

And there's a potential too, that on this platform, if you know, drug A doesn't work quite as well as we would expect, you could potentially go into drug B. So, it's a potential way to accelerate the medications that we can investigate whether they work in scleroderma, it's potentially a way to minimize that chance of getting the placebo. So, I think it's a very exciting possibility for being able to be more patient-focused, being able to listen to what patients want, which is, you know, having a chance at having something better and having a chance at having that active therapy. And I think hopefully speeding up some of those regulatory issues that can slow down drug development.

Eric Ruderman, MD (Moderator): Yeah. If I remember correctly, that was the sort of process that led to a lot of the early treatments in the COVID pandemic. It was a platform trial that got some of those early treatments because we didn't know, and there was a time pressure and was able to look at a lot of different drugs at the same time, and then follow up on the stuff that seemed to be effective and drop the stuff that wasn't. So, that's really interesting.

One more question on scleroderma idea is that there's a lot of comorbidities and a lot of other diseases that go with the sclero or other organ systems involved beyond just the things we think about. Are the trials sort of are getting us closer to handling some of that? You mentioned the GI tract. Are there other areas where you see change coming?

Carrie Richardson, MD: So, I do think you know there have been changes in the way that we measure clinical trial outcomes. So instead of traditionally looking at something called the modified Rodnan skin score, which is still a primary outcome in some of the clinical trials. There's a push to look more at multiple outcomes. And so, the CRIS, which is a combined outcome of scleroderma, different domains in scleroderma, I do think, you know, our industry partners are listening when we're talking about, we need to look at what happens with the GI tract. And that is something that the industry partners are interested in looking, because typically none of our drugs have really moved the needle on GI outcomes. And it's something that definitely warrants more investigation. And there is an interest in looking to see in some, especially in some of these novel therapies, do we see any outcomes in terms of the GI tract? And so, it'd be very exciting to see if there is a signal there. And I think, you know, when it comes to GI tract and certain outcomes, we don't have as refined of outcome measures to measure the difference, um, before and after treatment.

And I think that's a challenge in studying scleroderma GI disease. Our gI doctors here are really world class and do some really innovative things with looking at different ways of doing endoscopy and FLIP and manometry and have really pioneered some of these techniques. So, I'm really excited that we're going to be driving that process forward here at Northwestern because we have some unique tools to be able to measure GI disease. But I think that is still something where there needs to be more investment in terms of looking how to measure some of these, you know, non-lung, non-skin outcomes in scleroderma

Eric Ruderman, MD (Moderator): Fair enough. All right. Let's shift gears and turn maybe to vasculitis a little bit. And Dr. Dua, you are certainly our expert there, and it seems like every time we turn around in the last two or three years, there's a new clinical trial data set coming out in vasculitis. Tell us a little bit about the things you think have been most exciting and, you know, where is this taking us in terms of management across the spectrum of the vasculitis-related diseases that we're seeing.

Anisha Dua, MD: It's awesome. There's been so much going on. And honestly, yeah, you're right. Every time you look, there's kind of a new big trailer, new big development, and I'm so happy to be in vasculitis at this time because of just how much we've learned in terms of targeting different types of patient outcomes, a lot of different types of vasculitis, that there are more head-to-head clinical trials, which I love to see, looking at two different active comparators which was done with like any GPA with benralizumab versus mepolizumab. So, that was recently approved. There have been a lot of recent FDA approvals and a lot in the pipeline actually that are hopefully coming out that we can use to treat our patients.

And I'm happy to get into some of the specifics. But I think as we get more and more options, before, it was really cyclophosphamide and steroids. And so now, there are just so many more options and as we understand the different targets and then, like Carrie's mentioning, the different sort of areas that are really being most effectively managed or treated by those different types of mechanisms. We can really take that patient that comes in and think about what their phenotype is because each person is different, and try to use that to help guide us in selecting therapies. Because in vasculitis now, there are actually more than one option, and that's just never been the case. So, again, I'm having to talk about specifics, but that's kind of where--

Eric Ruderman, MD (Moderator): Well, actually to follow on that, so, in GPA, the recognition that of how well rituximab worked really changed the game, because that has become standard of care and it's a manageable disease for most people now in a way that it never was before.

I guess in other areas like giant cell arteritis, for example, is there a single therapy that you think is going to make that difference? Or, you know, there's a lot coming out, is there one thing that's going to really--

Anisha Dua, MD: Well, yeah, I think first of all in GPA, just to back up for a second, yes, rituximab is effective, and it's amazing and it's changed sort of the playing field. But there even with rituximab, there are people that are refractory that relapse, and we're still using a lot of steroids upfront. So with complement inhibitors, we now are able to get them off of steroids, which I mentioned before a lot quicker, which is fantastic.

But yeah, shifting over in to GCA, you know, that again, the treatment for a long time, up until just a few years ago was steroids and steroids and steroids in these elderly patients who have a lot of comorbidities and suffer a lot of side effects. And so, tocilizumab came around and that really shifted things and was incorporated into our guidelines. And now, I think very soon there will be-- oh, actually in Europe, I think it happened-- approval for upadacitinib. So, looking at JAK inhibitors, there's some good phase II data on IL-17 inhibitors. And again, with these patients who are coming in with all different sorts of baseline either comorbidities or intolerances, it's really important for us to be able to see how these different mechanisms can help different patient populations with the same disease, but really different responses to these different targets.

Eric Ruderman, MD (Moderator): And you mentioned guidelines. I mean, the new treatments coming out, are they beginning to enter guidelines and are we going to have to update the guidelines twice a year going forward? I mean, how are we going to handle all that?

Anisha Dua, MD: It's actually incredible how fast stuff-- because, you know, I helped with developing them and it was something that, even the stuff we published very few years ago, and it was such a long process, is a little bit outdated. And so, we are definitely getting new therapies that will have to be sort of introduced into these guidelines. And already, I can say there are multiple on the table that probably need to be incorporated. They're originally designed as living documents, but I don't know how living they are. I mean, it's a lot to go through to try to develop these. But I think education is a huge part. And so, even if they're not in the guidelines, making sure we're going out and talking about sort of these different opportunities and options will be super important in making sure that patients get access to the different treatments.

Eric Ruderman, MD (Moderator): Yeah. I know there was an effort a few years back in the ACR to sort of retool the way guidelines are done so that you don't have to redo them each time and this whole living idea. So, thankfully, that's there to a certain extent now. And it allows us to be a little bit more nimble and add more things.

Anisha Dua, MD: Yeah. Hopefully. Yeah, I hope so.

Eric Ruderman, MD (Moderator): Lupus. Lupus has been a challenge for a very, very long time. And I think you touched on this, Dr. Blanco, is that, you know, so many different things have been tried and they don't hit their endpoints. And there's been this ongoing question of, is it the way the trial was designed? Is it the drug? Is it the target?

Anisha Dua, MD: All of the above.

Eric Ruderman, MD (Moderator): Start there. And how has that helped us sort of figure out where do we go now?

Irene Blanco, MD: Definitely. I mean, Carrie and Anisha both touched on this, lupus is a very heterogeneous disease. It literally affects every single organ system. And so, how do you make a clinical trial that looks at endpoints, right? When one patient enrolled in the trial may be predominantly skin and joints, another patient may be more serositis and autoimmune hemolytic anemia, like are those two different diseases? Are those two different conditions? How do you then have a disease activity measure that actually really accurately conveys changes in disease and then subsequent outcomes.

So, it's been so hard to think about how you enroll these patients, how you then determine whether or not you actually see an improvement. And so, you know, we've moved from the SLEDAI to the SELENA-SLEDAI to the BILAG, to then an adjusted BILAG, which is the BICLA to the SRI4, really getting towards trying to really assess those outcomes.

And to your point, really starting to think about those patient-reported outcomes, fatigue, enormous for all of our diseases, right? And patients also want to really think about being a part of the medications that are really going to target what most impact them, right? And having those industry partners and those philanthropy partners, starting to really listen to the patient voice is so, so, so critical. And the fact that we have such a strong patient community that is so active in the designing of clinical trials. So like through the Lupus Research Alliance, industry partners can actually empanel a patient panel in essence to sort of like get feedback on their protocols, which is absolutely incredible.

I think little by little we're starting to really adequately nail down the targets. And we now have remission criteria, which for the longest time we didn't have before. So, you know, the DORIS Remission criteria can now actually create a situation where we have a treat-to-target approach for lupus, which we never had in the past.

And in terms of all of the treatments that are coming out and coming down the pipeline, you know, to Anisha's point, like because it's such a heterogeneous disease, we can now look in terms of the different medications that are in the pipeline and the ones that have been published, and to really think, well, if the patient's presenting with X, Y, Z, I may just choose, you know, medicine A. And if they're presenting with 1, 2, 3, I may choose medicine B. And it's that precision medicine that's really tailoring a treatment regimen to what the patient has that we just really weren't able to do before. And the fact that we have so many options now is so exciting. So, upadacitinib, right, is potentially going to be a fantastic option for our lupus patients. You know, phase II data looks fantastic. Preliminary phase III data is slowly coming out hopefully. We'll be part of the phase III data for using upadacitinib in lupus. You know, CD40 ligand originally was potentially a powerhouse medicine, but there was a horrible safety signal in these patients. However, there's a new version of CD40 ligand, which is showing tremendous promise without that safety signal. So potentially, we will have a safe CD40 ligand inhibitor for these lupus patients. And again, if it's just as promising as it was way back when. It could be a tremendous option.

And really, the latest clinical trial, which was the frankly bombshell that was published in the New England of obinutuzumab for lupus nephritis, which we just came out with our guidelines, right? So, you know, the nephrologists came out with their guidelines in 2024. The ACR literally just published their lupus nephritis guidelines.

Eric Ruderman, MD (Moderator): And they're out of date.

Irene Blanco, MD: And potentially, they're out of date because obinutuzumab has just shown such tremendous efficacy to really reach a complete renal response in patients with lupus nephritis so that it begs to question, you know, then how does that fit into the algorithm? And I think that's where we actually have options now to really think about the algorithm and to say, you know, maybe for that very, very severe patient where they're coming in in multi-organ failure where they're having many disease manifestations, do we go to CAR T early, right? Do we hit a hard reset on the immune system early, sort of like an induction, and then potentially move into a maintenance with other medicines? We're not there yet. But it's very interesting to think about like, are these potential options for patients? And the fact that we just have all of this at our disposal and all of this here at Northwestern. It's really exciting to be a part of all of these trials right now.

Eric Ruderman, MD (Moderator): Let me follow up on something you mentioned earlier on. And as a clinician who's not a lupus, I mean, that's not my area of expertise, the various outcome measures seem somewhat daunting. This lead either. And you know, you laugh because there's a lot in those. So as these drugs come to market and as these become available for clinical practice, how do clinicians who aren't familiar with that whole process decide if they're working or not working. I mean, do we have to go to learning, all learning how to do a SELENA and a BILAG on a regular basis or are there other ways we're going to be able to really sort of judge success or non-success and whether we need to move on?

Irene Blanco, MD: Yeah, I mean, I think potentially biomarkers and my original area of focus when I was first in training and then as first early faculty member, was urinary biomarkers for lupus nephritis. And that is still a constant goal, right? Because a kidney biopsy when done in, you know, really great hands is a very potential safe procedure, however, can have risks and can actually lead to some pretty significant morbidity. So if we can avoid the procedure, avoid the cost, avoid the time, avoid the potential risk, getting a quick urine sample to understand where the inflammation is and what's happening actually in the kidney. And our hope would be to even be able to determine pathology, right? Think biomarkers, but also really educating the clinician about that treat-to-target approach is going to be critical.

You know, to everyone's point, I think too many lupus patients have hung out for way too long on unacceptable levels of steroids. And it's because for so many years we've had absolutely no treatments or very poor treatments and inadequate treatments. And so, you know, we'd say, "Well, prednisone is pregnancy-safe. So, just leave them on the 10 of prednisone, leave them on the 15 of prednisone," or you know, "Oh, well, they failed X, they failed Y, they failed Z. I have no other treatment options. You know, they're actually responding to the steroids, just leave them on it." And then, we see the long-term sequelae, right? Where you know, the earliest patient, the youngest patient I had to have a major heart attack was 38 years old, right? Because of her chronic steroid use. A lot of our patients develop very early-onset osteoporosis, avascular necrosis, I mean, diabetes, you name it, right? So, how do we really educate our general rheumatologist, especially outside of academic settings? I think you sell yourself short. I think you could treat some very sick lupus patients, but really educating our colleagues in the community that may not see as sick patients as often. So, they may not necessarily feel as comfortable in taking that treat-to-target approach, right? And saying, I want to get them down to less than five milligrams a day of prednisone. I want to ideally get them to zero. You know, I want to get them on a very quick physician global assessment, get them down to less than, you know, 0.5 or actually down to zero. And to frankly keep pushing, you know? We shouldn't have a defeatist approach to our patients, especially when so many of them impacts, you know, decades of quality of life.

Eric Ruderman, MD (Moderator): And newer safer drugs may get us there too.

Irene Blanco, MD: Definitely.

Eric Ruderman, MD (Moderator): Being very aggressive with cyclophosphamide is a very exactly different story than being aggressive with some of these newer agents.

Irene Blanco, MD: And being aggressive with meds that they feel very comfortable with, right? So if, you know, the general rheumatologist in the community's very, very comfortable with upadacitinib, right? So if that's an option for your patients and my patients, it's fantastic.

Eric Ruderman, MD (Moderator): All right. Let's turn, in the last part here to the area that I think we're all tremendously excited about, and that's, and that's car T therapy. And you, you touched on this earlier, and Dr. Richardson, the idea of suddenly changing the course of disease in ways we've never done before.

Dr. Monka, you, you know, lupus is the first place we've started to see this. Mm-hmm. Why don't you sort of tee us off and, and, and. What are we doing with CAR T therapy to start with? Just briefly, and then what, where do you see that going?

So, um, briefly. Um, so in essence, T-cells, um, exist right within our body in order to attack the multiple infectious sources that are attacking us every day.

But also to clear out, um, you know, cells that need to be clear out for various reasons. So potentially, you know, just naturally killing cancer cells, et cetera. Um, in the oncology space, these T-cells, um, particularly from patient's own T-cells, have been genetically modified in order to target, um, lymph lymphomas and myelomas, um, to.

Really, you know, clear out these cells, especially for patients that have been refractory to other treatment regimens. Um, the typical target and the one that we're looking at in, um, predominantly the, our autoimmune diseases. But you can make it to different targets. So this is where, you know, the, the magic of either putting.

In a, um, targeted approach, either through the chimeric antigen. Um, it's either through like CRISPR technology or you can use a viral vector in order to infect these cells so that on the cell surface there is a car inserted, um, which then. Programs the T-cell to look for a certain antigen on these B cells.

And for many of the CAR Ts in our space, it's either, um, BCMA or um, CD 19. And we're doing a lot of the CD 19 trials here. And so that is a target that will really be able to go these T-cells, because of their privileged access within the immune system, can really penetrate down deep into the tissues and really attack those resident B cells within the tissues.

Um. In lupus, we use a medicine that was alluded to for vasculitis, rituximab, and we had two major clinical trials, both the explorer and the lunar trial, which actually did not meet primary endpoints. Um, and for those of us that do a lot of lupus, we know that rituximab works great in some patients and really doesn't do much in others, right?

But in CAR T so far. In targeting CD 19 and being able to get that deep tissue penetration as opposed to, you know, a attacking circulating B cells, um, through rituximab, we've seen dramatic, dramatic responses in lupus and in various autoimmune diseases. Um. It's not without its risk. Um, so there are different ways of making these CAR T-cells.

So there's autologous or allogeneic. So autologous is a patient comes, they get a, uh, potentially get a central catheter put in. Um, they donate their own T-cells, those will be sent out. To, uh, the sponsor, the pharmaceutical company. They will then process and create those T-cells, do all the safety checks, ensure those T-cells can actually reproduce in vivo, and then send them back.

Patients will then be admitted into the hospital. They get a preconditioning regimen because we don't want their immune system to attack their, be these T-cells that we so meticulously created. But also we don't want these T-cells to be, um, potentially set off an autoimmune cascade within the patient.

So patients will then get a chemotherapy regimen. Um. Depending on the trial, it may vary on doses or what they actually get. Most, um, regimens give a combination of cyclophosphamide and fludarabine. Patients will get that for three days and then they will get their infusion of CAR T, um, as standard protocol at Northwestern.

Our patients are actually admitted for then observation, for any side effects for two weeks. It. Depends on the institution and the protocol, but that's what we do here at Northwestern. For the allogeneic healthy donors donate their T-cells and then the pharmaceutical company then, um, does potential magic.

And there's many, many of these off the shelf for allogeneic, um, CAR Ts that have been genetically modified in different ways. Um, and then subsequently they insert the car. And really the patients then don't necessarily need to donate their cells and go through that process, but they would still get their, um, preconditioning regimen and then they would get admitted for their, their CAR T use.

Um. Um, it's an incredibly exciting time. The data so far in lupus, scleroderma, and myositis has been incredible. Um, you know, slowly but surely the car ts have been onboarding also for vasculitis. Um, we see also, um, there's different trials for ms, for example, so other B-cell targeted. Um. Other diseases where we target B cells.

Um, and so I think we are at a revolution point where potentially for our very, very sick patients that have been refractory to so many diseases, we actually have this option for them that didn't necessarily exist in the past.

Dr. Richardson, we talked about scleroderma. It sounds like we're just.

Beginning there, but does that, how, how, how much promise does that show in your disease?

Carrie Richardson, MD: I think it's very promising. I think, um, the, the data still needs to, um, we need to see the data, but I think some of the things that we thought weren't possible in scleroderma, I think it, it's, it's possible with CAR T-cells.

So I think one of the things that we see is that the autoantibodies, so the immune response that people with scleroderma make has been thought. Traditionally to be very, very stable, that once you have these autoantibodies, they persist and really you could recheck them 20 years into the disease. They will still exist.

You could treat the disease as, as well as you could. The antibodies will still be there. Some of the conditions like lupus, so the antibodies may be a biomarker of the treatment response, but not in scleroderma, but that just may reflect that our, our therapies are just not that potent. And so I, I think there's, you know, again, some of the, the first case report on CAR T-cell therapy.

You see this reduction in the RA polymerase three autoantibodies, and the question is, is that, is that an isolated, is that a fluke or is that something that we're going to see that once you deplete these B cells, you actually do have a true change in the immune response, or you're not producing these autoantibodies or you're producing them as.

At a lower level, maybe autoantibodies will be a biomarker. The other thing is there's certain tenets of scleroderma, right? That this is a fibrotic disease, that the damage that is done has been done, and if the heart muscles involved and the lung is involved, well, it's that you're just going to have to live with that.

But with CAR T-cell therapy, I think there is the question of can some of these fibrotic processes or these processes that we thought were irreversible. Could there be reversal once we restore normal immune function? Could the body somehow heal in a more normal way? And we certainly see that, you know, again, people get COVID and their lungs get, you know, terribly scarred and people do have recovery down the line.

And it is, if your immune system is, is, is in a more normal state, there can be remodeling of scar tissue. So could you see the same remodeling in someone with scleroderma once you restore more normal immune function? Okay.

Eric Ruderman, MD (Moderator): And Dr. Dla, I think in vasculitis, I mean, the challenge there is do we know the cells we're targeting?

In other words, are there are, are there B cells making anca antibodies? Is that the problem or is it, is there something else? And, and where are we going to go with this? In, in, in. That world?

Anisha Dua, MD: Well, we know that B cells are involved, and of course there's always the question of whether, you know, are they specifically pathogenic?

And there's good, you know, historical mouse data with MPO being specifically pathogenic and creating, you know, glomerulonephritis in, in kidneys. So we know that they do play a role, um, in perpetuating the disease. And we haven't had the, you know, multiple biomarkers. And so we have been basically dosing our rituximab and watching the B cells replete and watching for our ANCA titers to either become positive or double and then.

Deciding when to dose again. And so, um, I think we have options, which is great and they've been effective, but there's always better and more targeted options. I know Dr was mentioning, you know, potent, our, our drugs are potent, but they're just not potent in the right direction, you know, so I think it's, it's trying to find the, those specific targets.

And so, um, at least with the anca vasculitis, we, we know that there is an important role for B cells, and we do have some, some. At least Okay. Biomarkers that we can, we can try to follow to see how, how this works.

Eric Ruderman, MD (Moderator): Okay. And I, and I can't help but add in here that, um, as someone who treats a lot of rheumatoid arthritis there, the, the promise of changing T-cells actually has a role there.

Mm-hmm. because it doesn't have to be just T-cell that target B cells, there are modified T regulatory cells mm-hmm. That are being developed now. That may change the immune process in a positive way. Mm-hmm. As opposed to knocking out the cells you don't want. So there's just so much promise here with this, um, cellular therapy world, so.

Mm-hmm. Well, I want to thank everybody for being here today. I think this has been a tremendous conversation and it's just, um, just seeing what's come along the last few years is so exciting and, um. You know, if, if we think about where we are from my world in rheumatology and, and rheumatoid arthritis and psoriatic arthritis compared to 20 years ago, it's, it's a whole different world.

And I think the promise of doing that in these other diseases is just incredible and really exciting. So thank you all very much for. For being here.

Anisha Dua, MD: Thank

Melanie Cole (Host): you. Thank you. Thanks for having us. Thank you all so much for that enlightening discussion. And to refer your patient or for more information, please visit our website at Breakthroughs for physicians.nm.org/rheumatology to get connected with one of our providers.

That concludes this episode of Better Edge a Northwestern Medicine Podcast for physicians. I'm Melanie Cole.