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This is an ACR 20 '20 five podcast coming to you from Chicago. Hope you enjoy it.

Hi. My name is Akhil Sood reporting for RheumNow. When it comes to cell therapies, the landmark study published by the Erlang Group really set the stage. The case series showed a remarkable efficacy and safety of CAR T therapy across several autoimmune conditions. But there's a catch.

The process is intense, it requires harvesting a patient's own T cells, engineering them to target CD19B cells, and giving conditioning chemotherapy to make room for the CAR T cells. And this is followed by prolonged hospitalization to monitor side effects. But not every patient has the time, resources, or ability to undergo that kind of intensive treatment, especially when you factor in time away from work or travel to a specialized site. So what if there's a faster, less labor intensive approach? That's exactly what abstract o six sixty three did.

They looked at an off the shelf approach for CAR T. Instead of extracting T cells from each individual, researchers are developing CAR T from a bank of pluripotent stem cells, essentially mass producing them for broader use. And to make things even simpler, they're testing whether one of the conditioning drugs can be eliminated altogether. And so what do they find? Patients experienced fewer side effects with this less intensive regimen and most showed improvement in these activity as measured by the Selenite two ks, though a few did have some rebound in activity by the nine month mark.

As for B cells, there's significant CD19 B cell depletion followed by repopulation of naive B cells. So the bottom line? This off the shelf approach looks promising. While it may be effective, it's unclear whether non response in some of these patients may be driven by the limited conditioning chemotherapy or the off the shelf approach. So we're still early in terms of CAR T and there's ongoing enrollment and longer term follow-up that's needed.

But this could be a major step toward making cellular therapies more accessible and convenient for our patients with autoimmune disease. This is Akhil Sudh reporting for RheumNow. Thank you.

Hi, my name is Al Kim from Washington University School of Medicine in St. Louis, Missouri and welcome to day two of the ACR Convergence twenty twenty five meeting. We've been covering the cellular therapy and t cell engager abstracts here, which there are over several dozen. I thought I'd be covering a lot more of the clinical trial data, but what's been really striking in my eye has been a lot of the innovation, the preclinical work. And so I wanted to highlight one of these abstracts, it's abstract nine eighty one called a GNTI three fifty, a CAR Treg therapy offering durable immune reset with improved safety in the B cell driven autoimmune disease.

The title is a little bit overstating since all of this work is preclinical. But nevertheless, this is actually a really interesting compound created by a biotech company called Genta Bio Bio in collaboration with the University of Washington. And what this is is a c d 19 CAR T cell that has been polarized upon after activation to also become a Treg. So this combines two really of the newer concepts in, again, CAR T cells. The first is the killing of B cells vis a vis inter interaction with CD 19, but also then functionally creating a that CAR T cell to become a Treg and provide an immunosuppressive mu wherever that Treg is.

So as I mentioned before, this is all preclinical work. And so they start off with in vitro work demonstrating that yes, their CAR T cell can kill CD 19 positive B cells. That's not a problem. When you co culture GNTI three fifty with B cells, they upregulate their Treg markers and then they can suppress other T cells that are also within that culture, again consistent with the product. On top of that, when you combine that with inflammatory conditions that can create a cytokine release syndrome, those conditions are attenuated.

And I think this is the really interesting and important point of this compound, why you would want to combine Treg function with a killing function in the CAR T cell. The main direct effect that the company thinks is its advantage is that it will abrogate cytokine release syndrome issues because a lot of that is gonna be coming from the dying B cells within that tissue. So it'll be interesting to see whether or not this actually pans out in humans. They do have in vivo data such as this is true. So they do see reduction in cytokines such as IL-six that are responsible for cytokine release syndrome in mice when it depletes B cells and then they show efficacy data in a mouse model of lupus, the SLE one two three mouse model strongly attenuated disease progression.

So, you know, it's interesting. Innovation is everywhere right now at ACR in terms of CAR T cells and T cell engagers. And this is just one example. There are other companies that are trying to alter the signaling of the CAR construct in order to reduce cytokine release syndrome. Here, what they're doing in this particular example is going to give that CAR T cell an additional function.

You could argue this may be over engineering. Right? There are other solutions to be able to get around cytokine release syndrome. And there's also additional questions long term. How long does the Treg actually last for after they differentiate into these Tregs following CD nineteen stimulation?

And the other issue here too is what happens if these CAR T cells that are now Tregs go into irrelevant tissue? Does it immunosuppress? A lot of questions that need to be answered in long term, you know, preclinical studies or in first in human studies. But again, innovation's everywhere here and this is just another example.

Hi everyone, Mike Putman from the Medical College of Wisconsin reporting from ACR Convergence. Now I wanted to talk about abstract eight ninety five. This is a subset or a post hoc analysis of the Select GCA trial. So a quick reminder, Select GCA was a large double blind randomized placebo controlled trial that compared upadacitinib, a Janus kinase inhibitor, a JAK1 selective Janus kinase inhibitor to placebo. People in the JAK group got a twenty six week steroid taper.

People in the placebo group got a fifty two week steroid taper. We've already heard the results of that study. It was successful and it has been FDA approved. But what I wanted to talk about was a post hoc analysis that looked at the infectious adverse events from that study. It's always interesting when you have a randomized controlled trial to try and get a better sense of what things your patients should look for.

There's a couple of really interesting findings that I want to highlight here. The first one is that they looked at Herpes Zoster. We know that JAK inhibitors cause Herpes Zoster. That's been a relatively well replicated finding across the literature and they saw that here. Patients who got a JAK inhibitor, about seven cases per 100 person years compared to four per 100 person years among people who got prednisone.

It's not that different. If you see 100 people and you treat them, three extra over a year would develop zoster, But that's enough that I strongly advocate for vaccinating folks with the Shingrix vaccine before initiating treatment with a JAK inhibitor. Interestingly, during the oral abstract session today, they asked the lead author if the patients who developed herpes zoster had been vaccinated and none of them were vaccinated against herpes zoster. So you imagine that maybe a little vaccination could attenuate that. Now, importantly is the risk of serious infections.

These are the kind of scary infections that you really don't want your patients to get and that was actually the opposite. Patients who got the placebo fifty two weeks SteraTaper, about thirteen per one hundred years got infection compared to eight per one hundred person years who got a JAK inhibitor. This is one of those things that I always bump up against. You're in clinic, you're talking to a patient, you say, Yeah, may want to start you on this JAK inhibitor, this TNF inhibitor, and you say, Increase the risk of infection, and the patients say, Oh, don't want that. Well, if you just go with a steroid taper, you're actually signing up for more infections.

My second teaching point here really is that steroids are the problem. When you give people high doses of steroids, they get infections. Giving a DMARD and less steroids is actually a way to reduce the risk of infections. I always try to emphasize this point when I'm talking to my patients in clinic. We saw the same thing for tocilizumab and giant cell arteritis and we see it across the board in a lot of our disease.

Any DMARG you can give or steroid spray therapy you can give that reduces steroid exposure has a good chance of actually improving the risk of infections. Final teaching point, don't do both. A lot of people are adding these therapies to already long steroid tapers. Great way to get all the adverse events and there's no real data that that's any better. I recommend going with a shorter steroid taper and a steroid steroid therapy upfront for all patients with giant sideditis.

Hope that was interesting. Thanks for tuning in and I hope you all enjoy the meeting.

Hey, everyone. I'm Brian Jaros, and I'm coming to you live from ACR 2025. Today, I'll be talking to you about abstract seventeen thirteen. This was a group that looked at delayed diagnosis in psoriatic arthritis and how that affected patients' imaging outcomes. As we all know as rheumatologists, it's never easy to diagnose our patients.

They present in a lot of different ways and it's always keeping us on our toes with a high level of suspicion, in order to make the correct diagnosis and get our patients started on treatments. Psoriatic arthritis is no stranger to this compared to something like rheumatoid arthritis which has biomarkers that can aid in our diagnostic armamentarium, psoriatic arthritis may require a higher level of clinical suspicion in order to make that diagnosis. And of course there's concerns that if we're not making the correct efficiently enough patients of course are suffering from a clinical standpoint and there's also been concern from a radiographic standpoint that patients may have crew damage over time that will have trouble reversing. This has been shown in other disease states like spondyloarthritis and this group wanted to explore this question in psoriatic arthritis specifically. So they searched, the PubMed and other research databases for any observational study of psoriatic arthritis that included the terms diagnostic delay and performed a meta analysis ultimately capturing 15 studies, that were included in this analysis.

Patients had to be diagnosed with psoriatic arthritis based on either criteria or a physician determined diagnosis and ultimately throughout these 15 studies that were included they captured a patient population of over 22,000 psoriatic arthritis patients. Now when we get to the actual results, this is pretty interesting, the pooled mean diagnostic delay of these patients was nearly thirty one months. So that's patients taking over two half years on average to get a diagnosis when all of these studies were looked at. And we can imagine just from a patient perspective how challenging that must be to be searching for a diagnosis for all of that time. They actually stratified by country of study, and so we saw actually quite a big range geographically where rates varied from being lowest reported in India with a mean of about six and a half months, then increasing for The US, The Netherlands, Singapore to around one year, and then highest reported rates of diagnostic delay from Spain at forty eight months, China at fifty months, and Italy at sixty two months.

Of course, this may partially owe to the timing of the studies, the different ways diagnosis was determined in each study, and the specific methodology. But I think the takeaway here is that we're seeing a vastly different range of diagnostic time when looking at different studies around the globe. They also didn't just look at diagnostic delay, but also referral delays finding that it took a long time for patients to even get to rheumatology, the mean being either fifteen or twenty one months depending on the specific statistical analysis used. So it's taking these patients a long time to see rheumatology to get a diagnosis. How does that affect their outcomes?

When they looked at radiographic changes or damage they saw that delays were associated with an odds ratio of either 2.8 or 2.5 depending on which effect model was used, but the takeaway being that these diagnostic delays were associated with increased odds of a patient presenting with radiographic damage by the time they got their diagnosis. So overall, I think this is a really important takeaway for us as a rheumatology community to keep our eyes vigilant for these patients, to keep educating, other specialties, dermatology, primary care physicians to get them into our clinics more quickly, to decrease that referral delay, and then increase our clinical suspicion to decrease delay. Certainly, we also need better biomarkers, better tools to diagnose psoriatic arthritis, if the diagnostic time is taking this long as well. So that's what I have for today. I'll be signing off, and I'll see you tomorrow.

Bye.

Hi. Welcome, everyone. It's, doctor Janet Pope. I'm tweeting for AtRoomNow at ACR twenty twenty five in Chicago. I want to talk about head to head or, for us, joint to joint or even toe to toe.

I wanted to talk about two comparative, head to head RCTs that are late breaking abstracts. The first is l b zero nine. This is the question that is always on our mind. A patient has axial SpA, so what we think of as ankylosing spondylitis, and they are TNF inadequate responders. Most in general are a secondary loss of effect.

Now what's going what are we going to use next? It's a great clinical question. So this was an RCT randomizing patients to the next TNF inhibitor or an IL seventeen inhibitor. So the bottom line is it doesn't really matter. There was no superiority.

They could both do well. So I think the take home on this head to head is if your patient isn't doing well enough on a TNF inhibitor, an Axial SpA, you can try another TNF inhibitor, a second line advanced therapy, or you could go to an I o seventeen. No superiority. What about the next one? I've got a patient with psoriatic arthritis, and they've been TNF, inhibitor exposed.

This was a randomized controlled trial of moving on out of class. Psoriatic arthritis, TNF exposed. Now they are randomized to secukinumab, so an IL seventeen a inhibitor, or eusukinumab, an IL twelve twenty three inhibitor. So it's a big question to know because the derms in general seem to like, IL, 20 threes, but also IL twelve twenty threes on skin and IL seventeens do very well on skin as well. The winner is, drum roll, please, Cosentyx.

Why? It was both an ACR 50 and a PASI score superiority. I think the other questions would be, what if I tried a different IL seventeen? What if I tried just an IL twenty three inhibitor as opposed to a twelve twenty three? However, superiority with clinically relevant differences in tender and swollen joint counts as well as I as I mentioned, the ACR 50 and the PASI score.

So bottom line is head to head trials in real world situations really do help me to choose the next treatment for my patients with seronegative, various types of, seronegative arthritis. Thank you. Please follow me at Janet Bourdeaux. Thank you.

Hi. It's doctor Arti Kavanagh, University of California, San Diego here at the ACR twenty twenty five convergence in Chicago. So a lot of things happening across fields, a of lot things happening in psoriatic arthritis, and that's what I wanted to talk about a little bit this morning. One of the real exciting aspects is novel approaches to therapy. Now, we have many mechanisms of action.

We've had the biologic agents, the TNF inhibitors are fantastic, then we had the twelve twenty three inhibitor. Now we have IL-seventeen inhibitors, and we have several of them and more to come. We've had the IL-twenty three inhibitors, and then the JAK inhibitors, and a lot of things that are in development, and the PDE4 inhibitors. Now, we also have some conventional synthetic DMARDs, which I mentioned partly because the older medicines, methotrexate, the sulfasalazine, leflunomide, the cyclosporine, they're oral, and the route of administration is something that affects patient choice of therapy. Some of the newer medications, your primal ostipedi4 inhibitor, the JAK inhibitors, the tofacitinib and the upadacitinib, they're oral as well.

But I think an exciting new approach is that we're starting to see some development in oral versions of the same mechanisms of action that we're used to seeing in parenteral, in subcutaneous or intravenous medications. So there are a number of those that are in development. Now, sometimes happens in psoriatic arthritis. Our colleagues in psoriasis are ahead of us. They get to see these new therapies first, and there have been several that have been tried in psoriasis and show promise.

So there's an inhibitor of tumor necrosis factor, and it blocks binding through receptor. We know that the TNF inhibitors really change the whole approach to psoriatic arthritis and psoriasis. So is it possible to get that in a pill? Most recently, IL-twenty three inhibitor, I. Kotrokinra, has been looked at.

Interesting data in skin psoriasis. Mechanistically, it looks as if it may well be a IL-twenty three inhibitor. One of the things we see when we have newer versions of medicines for which we already know the mechanism of action, for the TNF inhibitor, when the fourth and fifth TNF inhibitors came along, we kind of treated them as, well, we know what to expect from this class of therapy. With these oral agents, that's going to be a question. Are they really just oral versions of the parenteral medications?

I think we would think that, and we would hope that, but of course we have to see. It's just absolutely fascinating. We had thought for many years as fantastic as the parenteral medications were. Were proteins, and protein's not really susceptible to oral therapy because their body treats them like food and digests them, but with progress in pharmaceutical technology, now able to have inhibitors that are oral. It's interesting.

It raises some issues for discussion. If something is oral and you have to, say, wait a while when you first get up in the morning, if you take a pill then you can't have any food, things we've been used to if you think of it with the bisphosphonates for osteoporosis. You absorb very, very little of each individual pill, so you really can't take it with things that have calcium because you'll go right through. You won't absorb any of it. These medicines might have some of those same considerations.

What time of day do you have to take it? What are the rules as far as what else you can take? And with oral medicines, we know the other condition or the other factor that we consider is the frequency. If something once a day, That gives much better compliance. If it's twice a day, you lose a little bit.

The kind of issues that we've thought about when thinking about oral medications for the conventional synthetic DMARDs, for the JAK inhibitors and the PDE4 inhibitor, Now, we may be on the verge of having oral versions of our other biologic agents, and of course, another aspect of this is, does that lend itself better, perhaps, to combination therapy, to induction, and then consolidation approaches to therapy. So a lot of interesting things that will be coming. So a lot of new information here, a lot of excitement, a lot of buzz at the ACR twenty twenty five convergence, and the best place to keep up with that is RheumNow. This is Doctor. Arti Kavanaugh.

Thanks for watching.

Hi, this is Doctor. Ji He Lee reporting from RheumNow from Chicago, And I have here with me Doctor. Shivani Garg here to talk about going from prescribing from abstract to realism in the management of prednisone as we're increasingly learning about its risks. So Doctor. Garg, you have an abstract on October where you developed a shared decision guide for communicating the risk about prednisone.

What motivated you to study and how did you get to something that is very visually easy to understand? Yeah, thank you.

That's a great question. So during my clinical practice, prednisone has been an issue in the regards that a lot of times patients symptomatically feel better, but there has been a lot of side effects that comes with prednisone and explaining all the side effects during a clinic visit can be a lot for a clinician. So that kind of was the genesis of trying to develop simpler tools that patients can understand as well as it does not take too much time. Using some of the work that we had already done for hydroxychloroquine at CQ Safe, we thought that the next topic that we could address is chronic prednisone use because there is more and more data that shows that even lower doses of prednisone such as ten milligrams, seven and a half or five milligrams are associated with bad outcomes and our patients are younger and they're going to live longer with the DMARDs, biologics that are there. So they might have a higher risk of having a fracture or getting hospitalized, having a stroke.

So how can we prevent that and how can we make our patients understand understand that there are some harms that are associated even if you symptomatically feel better? And how much do you symptomatically feel better in regards of numbers? So that's the genesis of PREDSafe.

I see, and I think that's the important part. Translating numbers into information that patients can understand. Like you said, for us, we're very used to thinking about odds ratios, hazard ratios, but that's not how patients think necessarily. So I believe for this tool you actually have patients informed or involved in the process to design and communicate how they want information conveyed. How did that impact the design of the tool itself?

Yeah, that's a great question again. It's interesting, there's a lot of literature on health literacy and numeracy particularly. So a lot of times, even me included, early on when I was practicing, I used to bring up, hey, the chance of having a fracture is twenty two percent. So patients were like, What does that mean in regards of me or people like me? So that gave me, got me thinking that while percentages, odds ratio, how we interpret science as clinician scientists is not the way patients understand, so we need to give them an easier way to understand.

So we went back to our patients because they are the ones who are experiencing all these things and want better guidance and want to be involved in decision making, which is very interesting that they want to partner with their healthcare team and be involved at every step. So they told us that we don't understand percentages. Don't show us graphs. Bar graphs, I don't know what it means. And they told us, so we modeled multiple ways of showing data.

And then we showed some existing tools which have been created in rheumatoid arthritis, for statins and osteoporosis. And they were like, this data does make sense because we can see that red is bad, green is good. It's easy to understand. And I understand it's like one hundred people. And out of that, the risk, the chances I can have it is fifty.

So that is big to me. So we went back and forth showing different ways of doing it, and that's how our patients felt even motivated to share their feedback because they knew it will help them, as well as help several other patients who are living with it. We had like sequential, iterative interviews. We used to show them one version, get their feedback, edit it, show them another version, and then find the best version where they felt most comfortable and had a higher likelihood to recommend to a family member to appear that would you use it.

Yeah. I think one of the striking thing was the visual simplicity of the tool, like you said. You use consistent units to show risk per 100 people and use a very clear color of the red being bad and green. I think for one like osteoporosis, you could clearly see out of one hundred be forty. In addition to osteoporosis, what other domains or components of risks did you as physicians or patients find that it was important to communicate?

Yeah, so we looked at several domains. So we went back to literature. There's a lot of literature on prednisone. So we wanted to identify what areas harms are classified into and then what areas benefits are classified into. So we started listing down using a systematic review meta analysis approach the different domains and started pooling data for each domain.

So the domains that we came across besides bone fracture risk were damage, any organ damage. We came across cardiovascular disease event risk. Infections was a big that we came across. And then we came across some other domains such as pregnancy concerns or issues that can come during pregnancy, diabetes, adrenal insufficiency, but the literature was not enough to pool the data. So then we tried to go back to our patients that we have listed, say, 10 domains of benefits and maybe three domains of harms, or like 10 domains of harms because we're talking about prednisone here, and three domains of benefits with lower or higher doses of prednisone, what resonates more?

Like, what have you experienced? And I

think the important thing is, like you said, is the communication about the benefits versus the harms. So, you've communicated the harms, and what the benefits, what was really nice is to communicate, is the perceived benefit about preventing flares or disease activity worth it? And I think you show that very well for combined data between two diseases, RA and SLE. Yes. So is this tool something that can be used across rheumatic diseases or currently specific only for RA or in lupus?

Yeah, excellent question. We do pull data from RA and lupus. The reason being a lot of the FLAIR data comes from RA where there were randomized controlled trials and there are observational cohort studies where they tried to, several Canadian groups tried to reduce prednisone and see how many flares happened. So we did pool data, we did run sensitivity analysis and tried to identify that rate that we can show our patients. Right now, when tested, more patients were lupus or had lupus or were living with lupus and we had a smaller subset for rheumatoid arthritis.

How I envision this tool will move forward is that we, because nobody likes paper these days and we are going electronic, it might be the opportunity to create a web based version which lives there and patients can access it themselves as well, though we encourage to go over or a clinician, nurse or a pharmacist to go over the tool. And then it becomes more disease specific. So it has the opportunity to click RA, if you have RA. I'm living with RA. And it clicks RA and it opens everything about RA.

And it switches to another disease scenario. As we get more data on other disease scenarios, it could just translate to other diseases because chronic prednisone use, honestly, it's not just a rheumatology problem. It is problem of pulmonologists, asthmatic patients, ILD patients, so on. So that's how we envision the tool will go. But that's the next step for this project.

I think that's wonderful and ambitious because the prednisone, I think what you called it a necessary evil. It's helpful but there are harms, but the communication is important, and this is a patient informed tool that can be real time, interactive for use as patients' priorities change or their expectations change. And one of the things about raising awareness is then what then next? It's about getting off the prednisone. Yes.

And I think your tool also communicates about that as well.

Yes, yes, that's a great point. So what next is always the question. So we do have a taper guide, which is an optional material in the current tool because clinicians who were participants as end user or stakeholder feedback, they felt that sometimes giving guidance to maybe a very experienced clinician could be taken plus or minus. So some people need guidance, some people don't need guidance. So we created this optional material which has validated information from European guidelines on steroid taper, particularly led by the endocrinology group.

And it shares key details like your dose of prednisone is forty milligrams, then you should taper by X dose every two weeks. And these are the symptoms that you should look out for. This is when you should test for cortisol levels and this is when you should stop the taper, hug the taper, and go slower. So it gives us guidance. And I think as we were discussing, maybe the next step would be also to start thinking about how we can add the existing shared decision making tools around biologics, DMARDs, because at the end, the goal is not to just reduce prednisone, but is to control their disease better.

Absolutely. And disease better, controlling disease is where DMARDs or newer medicines come into play. What is the right medicine for you when we get off prednisone?

So we as a rheumatology community have, over the past couple of years, really gotten to understand and become aware of the risk about low dose prednisone and chronic use. And now the next step is to communicate that back to our patients, and we may have a tool to make that very visually easy, interpretable, real time. So thank you for sharing the work. This is Jiha Lee RheumNow in Chicago.

Hi, my name is Akhil Sood reporting for RheumNow. In psoriatic arthritis, we often think about disease control across several domains, including the skin, the tendons, and the joints. Over the last few decades, we've seen an explosion of biologic and targeted therapies, including many that have been highlighted here at ACR25. But what about brain fog, a symptom many of our patients often complain of, in psoriatic arthritis? Abstract fourteen twenty one takes a closer look at this approach.

Using data from a large national registry of patients with psoriatic arthritis or spondyloarthritis, investigators examined the relationship between disease activity and brain fog. They focused on a known target treatment called minimal disease activity. This includes number of tender or swollen joints, limited skin involvement, and tendon involvement, And it looks at patient reported outcomes including their assessment of disease activity, functional status, and pain. So what do they find? Patients who did not achieve minimal disease activity had a significantly higher odds of brain fog.

This relationship seemed to be partly explained by fatigue, depression, and anxiety. So what's the takeaway? While brain fog is a patient reported outcome, it may be linked to disease activity and mental health factors. So next time you're assessing a patient with psoriatic arthritis and active disease, consider asking about their brain fog. It may give clues to the underlying disease activity.

This is Eccles, Cush, reporting for RheumNow. Thank you.

Hi everyone, Professor Peter Nash reporting for RheumNow from ACR Convergence in Chicago in The US. And I thought we would summarize a dozen abstracts and the numbers will be given to you that are looking at CAR T therapy, the flavor of the month here for autoimmune rheumatic diseases. There was a lovely presentation by Anka Akenazi who summarized the information we have today. She talked about 16 studies of CAR T therapy up to one hundred and forty five lupus patients, but also patients with myositis, scleroderma and, a number of other autoimmune diseases, IG4 disease for example. And these patients, the targets have been CD19 which takes out the plasma blast, which makes lots of the autoantibodies we're interested in.

Double stranded DNA, SSA, JO1. Also, like BCMA, which takes out the plasma blocks, plasma cell. Now that's where STL70 comes from, but unfortunately if you take out the plasma cell, the downside is infection and that's something that has to be considered. 12 of them were autologous, where there's expansion of these T cells externally, the CAR Ts externally, then put into the patient. Four of them are allergenic, which is much more convenient because it's an off the shelf product with a fast turnaround.

There's a number now looking at in vivo expansion rather than expansion in the laboratory. The efficacy has been quite amazing. Seventy percent of these patients are in doris remission, is quite hard to get. Eighty nine percent in LLDAS, which is also hard to get. Eighty four percent in drug free remission.

Now the downside of safety, fifty six percent of these patients have CRS, but it's been relatively easily managed with paracetamol and subsequently tocilizumab. Only one has been grade three, none have been grade four compared to the oncology experience. Four patients have had ICANS, one grade three and one grade four, it's a neurotoxicity. Eleven out of a hundred and forty five have had severe infections and there's been one death from pneumococcal meningitis. There has been no deaths as far as known from other issues.

And there's been one successful pregnancy. There's been a couple of recurrences that have allowed retreatment. So there's a number of long term follow ups with drug free admission after four to five years now in significant numbers of pay people. If you want, there's a very nice review in July's edition of seminars arthritis and rheumatism twenty twenty five by Nordmann, and that summarizes the experience to date with CAR T. So what are the problems and the take home messages from my point of view?

If you're gonna have CAR T, you need to set up a center of excellence model where you can go to a academic center or a private center, it doesn't matter, but you need collaboration between Rheum, HemOnc, Nephrology who have stolen all our lupus patients and the infectious diseases group who are set up to do this kind of treatment for the and there are a number of issues. One is finding the appropriate patient. As I said, the nephrologists have stolen our lupus nephritis. We only see these patients when they have extra renal issues they want sorted out. Number two is the question of lymphodepletion.

Lymphodepletion means eight days in hospital, and we all know how difficult it is to get public beds and they would have to pay for private beds and they're neutropenic so they need hem onc to collaborate and look after these patients for those eight days. Then you need access to filgastrum, you need access to tocilizumab, neither on simple easy label for these kinds of things. And so there's a number of practical feasibility issues for the average Rheumatologist to do this kind of involved, treatment. So cost is the next issue. I'm sure it'll come down over time.

The oncologists are used to using it for lymphoma and myeloma and I think those kinds of costs can will will come down, but they're very country dependent. In some countries, half €1,000,000 in Germany, In America, expensive. In ours, we can do it much cheaper. QM QIMR quoted something like 40,000 US dollars to develop the CAR T, but they still weren't able to collaborate and do it for us. So there are a number of issues, excellent efficacy, if it's your daughter with lupus nephritis and bad prognostic features and the option is a life of low dose prednisone, mycophenolate, hydroxychloroquine, belimumab, in and out of hospital, issues of pregnancy and fertility or, a therapy with ups and with upsides and downsides that are manageable, four to five years of drug free remission, I think it can be an easy sell.

So, complicated, I suspect it needs a, excellent center of excellence model, appropriate patients will be the ones that will be the trick And now with T cell engagers coming along, we'll discuss another time, there might be a more feasible alternative that the rheumatologist could do in his own office compared to what's involved with CAR T therapy. So I hope you found this discussion of interest, and I look forward to the next one. Thank you.