EULAR 2024 SLE Topic Panel Save

Hello, everyone. Welcome to RheumNow's coverage of UR twenty twenty four. I've convened our panel on lupus to discuss, the abstracts that we thought were of interest at UR twenty twenty four last week in Vienna. We had a number of people, we had others that were going to join us but are out sick. So it's going to be just the three of us.

And we're going to talk about all the cool stuff in lupus that happened at the meeting and there was a lot of it. So our format is we'll introduce ourselves, we'll present a few abstracts each, discuss those, and then we'll do this again all this week at this at the same time 5PM Eastern Time. We're going to have today lupus and then after this is going to be a panel on psoriatic arthritis and then on rheumatoid arthritis. Then finally, we're going to have a rheumatology roundup with Doctor. Arti Cavanaugh and I on Thursday.

So I'm Jack Cush in Dallas, Texas. I'll ask, my discussants introduce themselves. Yusuf.

Everyone. My name is Yusuf. I'm from Leeds.

And Andre.

And I'm Antoine Fava. I'm a physician scientist from Baltimore.

And part of the Hopkins Lupus Center. So, I want to I think I began when we were off camera talking about what I thought were some themes from the meeting. I think you nodded when I said one of the themes was lupus and minimizing the dose of steroids and the other one was CAR T cell. Do either of you have another overarching theme from the meeting? Andrea?

I think I agree with you. Were a few clinical abstracts that were quite interesting to see, but not as explosive as in previous meetings.

And Yus?

Yeah, so there were some abstract pertaining to some potential new therapies. So there were a presentation about ayanalumab, There were open label of anti CD38 monoclonal antibody, daratumumab. So yeah, there's quite a few novel promising therapies as well.

Okay. Yeah, there certainly are. It is a hot therapeutic area in drug development and no better place to see those. I get the first glimpse of those is at ACR and UR. And while that's exciting, that's also very early and things tend to look really good early not especially in phase two.

And then as I said before, phase three is where the rubber meets the road and we find out how, what the real long term potential of these drugs is going to be. But let's get into it and hear what our experts think about what they like most in the meeting. We'll start with Doctor. Fowler. Let's start with Yuz.

Yuz, why don't you give us your first favorite abstract?

Okay, so I'll start with the low dose use of glucocorticoid in lupus. So essentially, there's a lot of flavour in this because since the EULA recommendation last year, set a target of oral prednisolone equals to less than milligram per day. So there's a beautiful study done by cohort inception cohort in Italy. So the abstract number is OP0180. So this was a retrospective study of a prospective data collection.

So they look into patients who achieve remission. So define remission by Slidai2K equals to zero, and also prednisolone equals or less than five milligram per day. And also they had to be on a stable dose of immunosuppressant, including hydroxychloroquine. So what they found, they then follow these people up who met this definition of remission criteria for over seven years. And also after when they hit that criteria, there were seventy four percent people managed to completely discontinue steroid, whereas twenty six percent people still remain equal to less than five milligram per day.

So they look into the flare rate and interestingly, the flare rate was much lower than those who completely discontinued steroids compared to those who remained on the less than five mg per day. So essentially the take home message from the study was that after remission criteria was met, proper steroid tapering until completion appeared to be safe and was not associated with increased risk of flare.

Yeah and again on lower dose steroids, I think we talked about this offline before that the other study was the voclosporin study on this, right? Where the patients were treated with, in one study, the arm study, they were treated with IV cytotoxin or up to three grams of mycophenolate and higher doses of steroids that was weaned down. And then they compared that to the AURORA two study and another study they put together where they were using lower dose steroids and the background was Michael family two grams and also voclosporin. And while the regimens were different, it turns out that the voclosporin regimen that use less steroids got to the renal endpoint faster and had less toxicity. So just another one of the abstracts kind of making the same point.

So I'd like to know what Doctor. Fava thinks because I once heard his colleague, Doctor. Petrie, say at a meeting that we may well be able to manage lupus without steroids. I thought, oh my god, I think I've had a stroke. Really, should we be going that hard after lowering steroids or you're always gonna need some steroids?

Yeah, I was very impressed by abstract. I mean, also because we do not have an explanation as to why people flare more on prednisone. Think that one of the striking findings is, I mean, as expected, is the damage accrual they showed at two years, where they showed that basically there was a 17 percent damage accrual in people who remained on prednisone versus seven percent of people who tapered. But the damage accrual that the group of prednisone had was for a large part from prednisone, but there was also a part that was independent of prednisone, was quite interesting. So I think that there is a nice way to come off prednisone and then we should always strive for it.

I think that eventually we will get it done. There's a beautiful study that was highlighted in one of the sessions about the What's on the Horizon and one of the initial plenaries coming from Mayo, from Aliduarte, where they basically did a meta regression of multiple trials of all the different kinds of steroids in lupus nephritis plus or minus the pulses. And one of the major findings is that, well, if you pulse ahead, you have a higher chance of response in any way. So I think this resonates with some of the practices that we tend to have at least here, where if there is a bad flare, we'd rather like hit hard with the pulse and then put patients on a very low zopranosone right after instead of starting this very long regimens with sixty, eighty milligrams and going down over a month. I think that a steroid, at least a low, if not free future is coming.

Yeah, I've done

a

lot of lupus over the years where I treat, but I'm known more for RA. But in RA, steroids are what? They're the drug that gives you rapid control of your situation while you're waiting for disease modification. And Right? Steroids don't really play a role in disease modification, really at all.

I mean, you have to work hard to find these studies where you can make that point. But there's a greater reliance on steroids and lupus because the inflammation is different, the organ damage is different and much scarier, and hence the reliance. And so this shift as we have more therapeutic targets that, we can effectively engage with means that we should be using less steroids. I like this progression. I think it is going to make rheumatologists better at what they do and patients have safer outcomes in the long run.

Usually get final say on this.

Yeah. So, can you just add something? So, I've just got some important, point as well. It was a steroid, was, initially used, in, the field of lupus, exactly seventy five years ago. So it's nice to see, you know, we're taking a long time to reach here and hopefully we're nearly there.

Right. When we talk about steroids, we should make the important distinction between oral steroids from parenteral steroids, because most of these studies showing the damage coming from steroids come from oral prednisone, so oral steroids. Whereas usually we see much less of an effect with IV or even intramuscular tramsinolone, for example, that we tend to use more frequently to treat mild to moderate flares.

Yeah, I agree. All right, Doctor. Fowler, you give us your first favorite of the meeting on lupus.

Yeah, I mean, really liked the abstract OP 89. There was a phase two, the data on the phase two trial on enalumab. This is a monoclonal that targets BAF receptor and is engineered to be basically B cell depleting, which is quite interesting to see because we think of B cell depletion when we think about targeting CD20, CD19, and this is like targeting B cell from a different receptor, which is basically the same family that's been targeted by belimumab. But this is done in a way that really depletes B cells as opposed to belimumab. And so basically this is an extension.

Did a first twenty eight weeks was a placebo controlled and then there was an open extension where the patients who got placebo eventually got the drug. And the curves were very nice. Primary endpoint was a combination of SRI4 and the ability to tapering steroids below a certain threshold. And there was a very nice response at week twenty eight. But what was nice to see is that the patient eventually got the enalumab in the open extension by week fifty two caught up with the patient who'd been getting the drug the whole time.

So it seems that it's going toward a medication that is targeting a meaningful pathway, is showing an effect. And so it will be very nice to see another, basically another medication will help us targeting these B cells that now we're getting from multiple lines of evidence, the idea that these are truly driving part of the disease, because when we target them, the disease gets better and sometimes it can even cured if you see the data on CAR T.

What is the extent of depletion that we see and for how long would this-

forgot. It was not on the abstract. They showed in the slides. Will have to think about that. I think they achieved basically the same depletion you will get with rituximab with by flow cytometry.

They showed that the cells went down to zero. I forgot the longitudinal data, but they didn't really show patient which was quite impressive.

Yeah, think I do agree. I think they showed that data in the ACR twenty twenty three last year that they had a profound depletion in the inalumab group. And it's quite profound because they have a dual mode of action, so they kill the B cell through the antibody dependent cellular cytotoxicity, as well as the BAF receptor inhibition, so inhibition B cell survival. So this dual mode of action is quite potent in terms of B cell therapy mode.

Theoretically, the advantage over rituximab, which you know that has a different MOA and it may have different kinetics as well. And that gives it maybe potentially more hope than what we saw with rituximab. Again, I always like to remind everybody, you may love rituximab, in the condition that it's not approved for where it failed, and yet you are loathe to use it where it actually has been approved in rheumatoid arthritis because you have many other choices in rheumatoid arthritis. But yeah, I mean, rituximab does work in hematologic indications. Mean, ITP and, autoimmune in my experience and maybe some select, but there's still a heavy reliance by rheumatologists on rituximab.

So these newer molecules, belimumab certainly and now inalumab obentuzumab as well. If you were happy with rituximab and what it may do for a little bit patients, you'll really be happy with these in the future. But again, we've got to get over some major phase three data before it's going to be FDA approved. But it's certainly everyone that I know that's looking at this data is really encouraged.

And also with the positive data on Sjogren's, right? So this is one of the few biologic that targeting the immune system in Sjogren's showed like a positive trial also on Sika symptoms, which is quite impressive.

Right, very hard to do. Sjogren's is where all biologics have failed thus far until this most recently. That's also encouraging. I'll bring up the sub analysis of the Paisley study using the TYK2 inhibitor, Dupuisitinib. That study was previously presented in November 2022.

And they're rolling out sub analyses of that and they have a larger phase three that's in progress in this study. In this study, OP0448. They looked at one hundred and one patients with chronic cutaneous lupus and looked at the dupravacitinib responses, as measured by the class C50 and the class C60, response criteria and using what looks to be the right dose, which is three milligrams or six milligrams BID, about a sixty percent, sixty five percent class C 50 response and a class C 70 response, at the three milligram BID versus placebo was sixty five percent versus eight percent. They were mainly treating, a variety of different skin disorders. It was not only acute LE skin disease, but also discoid and subacute and that's, think ill defined variant of chronic cutaneous LE.

And of course there was nothing else about this study. What I find interesting about this is number one, I think this is the way lupus trials should be going, which is having a specific end organ primary endpoint as opposed to an SRI four, SRI six, which is really hard to get an FDA approval on. But the problem I think is with the regulatory agencies and their acceptance of a skin endpoint. I don't think that that's been worked out with the FDA. So using what most researchers are saying is the best, most validated tool, the classy response criteria that the FDA hasn't quite given its stamp of approval to that.

And that's why you're not going to see lupus approved initially for a cutaneous indication. I think that's a shame. Either of you have any impressions about this sub analysis?

Yeah. Thanks for bringing this abstract, Jack. I find it really interesting as well because as we know, cutaneous lupus is variable and also can be very difficult to treat. We've used a lot of rituximab in The UK and we found that in terms of skin response is also variable, particularly people with chronic discoid lupus. None of them responded to the rituximab that we gave.

So we are stuck, and they usually have anti Ro antibody and no low complement, so we can't use belimumab. So we did publish before a case series using an ifrolumab, and it did work really tremendously in a variety range of cutaneous lupus. So it's good, like, you know, if we see the same signals again for ducravacitinib, so we got this option as well for those patients because these are all disabling features of lupus.

Yeah, one other comment. I think that this is another piece of evidence that when you target type one interferon in lupus, skin responds beautifully. The rest of the systems, it's not always the case, but in all trials that did not complete the monoclonal blockers of type one interferon, and now we see with anifrolumab and then now with the small molecules like docobacitinib, the target type one interferon signaling, we do see the skin response beautifully. I think that that's gonna be the thing that we're gonna be seeing. Then to get back to your comments about the outcome measures, this is absolutely true and is one of the major issues in lupus trials.

And I wanted to give a shout out to the major effort that Eric Morand is taking on redefining the clinical outcomes in lupus, starting basically with what's needed from regulatory agencies in order to approve drugs and then working with patients also to combine what's important to them and combining basically new ways to establish a response that are tailored to accelerate the approval processes. It truly is a massive and beautiful work, but I think it will have a tremendous impact.

I can tell you I was on the FDA advisory panel I think the very first advisory panel they had trying to look at endpoint measures in lupus, and they had all the big lupus mavens around the table. It was a difficult time back then. This was like maybe fifteen plus years ago that they did this. And it still is a challenge, you know, I mean, once the FDA has, its teeth into, endpoints that a drug can be judged sufficiently, then drug development proceeds. The FDA had to go through a number of these meetings, with the advisory panel and then experts and then the companies themselves before they got around to actually, understanding, how to best do the trials that we're going to get approval.

But I think, you know, renal endpoint is pretty easy. You know, it's, you know, I think that's already been decided upon. It's going to be harder when you start looking at you know, non renal or not in the general lupus. So, you know, hematologic lupus or neuropsychiatric lupus, pulmonary lupus, articular lupus should be easy with an ACR twenty would probably applicable here. But anyway, this is what we need to further develop better therapies to manage our patients in lupus.

All right, our next Go

ahead, Anand.

If I can add one

quick thing, we can go to an abstract actually, forgot the name of the abstract, but it was a post hoc analysis of the phase two nifrolumab study in lupus nephritis, which was a failed trial by proteinuria. And this was about checking the CD163 in the urine level, so urinary biomarker. And this is a biomarker that correlates with histological activity. And what was found is that if you look at the responders, both the placebo and onifrolumab, well, they all had a decline into D163, which usually reflecting resolution of inflammation in the kidney. But it was interesting that when you looked at the non responders by proteinuria, you would see that the patients who got a placebo had the flat line of CD163, and the patients who got anifrolumab, despite being non responders by proteinuria, had a decline of CD163, at least early, which is telling us that perhaps, yes, you give a drug that is attacking the immune system, is an anti inflammatory generally, and then you do see an immunological response that perhaps is meaningful.

We should know if it's meaningful or not if you don't resolve proteinuria, but I think it's a SAR to tell us that if we have a better treatment endpoint and outcome, perhaps we could capture these better responses.

Yeah, and this is where your biomarker work has been really, really important. And I think it's going to be not only clinically applicable, but will be important endpoints in clinical trials going forward. Okay, Yus.

So think we've got to talk about CAR T cells, because they're everywhere at EULA twenty twenty four. So I think if you don't talk about it, you you might have not attended the EULA. But they're all early phase trial and all open label in a phase one, so it's not randomized yet. So the one that is striking a little bit, which was presented at the abstract session, was about compound CAR T cells. So the abstract title OP0017.

So as we all know, CAR T cells took centre stage two years ago when Professor George Shetz presented the data on five patients with refractory lupus. So now two years forward, rather than just CD19 CAR T cells, they presented data on compound CAR T cells. Essentially what happened during the apheresis, so the T cells were then re engineered not just for CD19 but they also add one more receptor which is the BCMA. BCMA attaches on the surface of cells including the plasma cells, so basically it will be effective to remove the autoantibodies. So what happened?

So this was open label Phase one studies in China of 12 patients with refractory lupus nephritis and this patient had a biopsy positive prior to starting the CAR T cells and they failed treatment including cyclophosphamide as well. So of all the 12 patients that were treated with this compound CAR T cells, most of them achieved a complete renal response. I think there's one or two that didn't hit the spot of a complete renal response. And in terms of general safety, because people are concerned that if you, you know, with a risk of infection particularly, I think there was one urinary tract infection recorded mild COVID cases as well. So the only thing was the follow-up was quite short, it was only twelve months follow-up.

We do need in a longer follow-up, you know, for these kind of kind of studies to see, you know, once the B cell have repopulated, whether do you, you know, have a disease relapse, and so forth. And what else would you do if they do relapse? I mean, would you want to give another compound called T cell was potentially going to be, you know, have a high degree of toxicity and also be expensive? Or there are also other alternatives because, you know, one of the main principles of CAR T cell is profound lymphodepletion. So, you know, we do have other alternatives, for example, a better rituximab like you were saying, Jack, you know, if the obinutuzumab might be licensed in the future, ayanolumab going for phase three and potentially daratumumab which is like NTCD38 monoclonal antibodies.

So there are quite a few other alternatives there. And also potentially something that we're going to look out in the next maybe ACR or next year, just to be aware of another strategy called BiTE, which is bispecific T cell engagers, for which there was data that shown for refractory rheumatoid arthritis in this conference, but I heard they've already done it in lupus, so we might get a result of that in the next two conference probably.

Andre, what's your view of this new wrinkle to CAR T cell therapy?

It's very exciting. I really look forward to seeing the results on BiTE because they really capture the same mechanisms with CAR T. And also I think that with CAR T, the gamble is to see how low we can get in terms of complexity and cost and being off the shelf and having a low risk to the point that we can make it available for more patients. Truly becomes a curative treatment. And so the more effort that we get to get these new compounds that are being prepared, are getting closer and closer, I mean closer, there are already trials on off the shelf products.

I think this is going to be incredibly exciting.

The one So I heard Gheeraj Shet talk about two or three weeks ago at Yale. He gave a great overview of his 15 patients, nine lupus patients, and that experience. And talked about the B cell depletion and how it comes back and how it comes back as more, I don't know, a kinder, gentler B cell and not quite so angry. And makes me rethink, you know, the pathogenesis of lupus, especially since, CD 19 is not found on plasma cells and CD 19 is not found on plasmacytoid dendritic cells, a major source of type one interferon. Up until this CAR T cell story, I would have said most of the damage in lupus is plasmacytoid dendritic cells and what's going on at the plasma cell level, not the pre B cell in the marrow and not circulating B cells.

This whole, know, his therapy blows that out of the water. Now, this compound that Doctor. Youssef is talking about, that's BCMA targeting as well. BCMA is targeting plasma cells and plasmacytoid dendritic cells. So it'll be interesting to see what the contrast is going to be, not just in the short term where it looks like there's some benefit, but also in the long term as far as benefits, but also as far as safety.

This is exciting area. There's a whole bunch of brand new companies getting into this all making their version of the same, using autologous and allogeneic CAR Ts as well. So it's going to get real complex real quick in the next two years. And I think it's going to be an exciting area. All right.

Doctor. Favre, you have one more to go to that you want to review?

I do. Let me put it up here. It is so this is not about treatment. This is diagnostic. It's after the OP two fifty five and was printed by Melissa Monroe from OMRF.

And this is, I mean, we often see this, this newer diagnostics in lupus. This was a serum based assay where basically they measured in the, I think it was serum. Anyway, it was in the peripheral blood, multiple biomarkers. And they wanted to find a panel of biomarkers that could predict active lupus as defined by SLEDA. And then they drilled it down to 10 of them and they validated it.

And basically the bottom line is that they had a panel that with a decent amount of reproducibility could predict in a validation cohort, patients who have active lupus as to patients who are quiescent, but also with several of these biomarkers that could identify renal lupus from non renal lupus. Now, I'm usually very skeptical of these biomarkers that predict something that I could get for myself at the same time, right? I mean, why would I need a biomarker to tell me the current zli di if it's something that I can calculate myself? I mean, I want a biomarker that could predict if the patient is going to respond or can predict if something is gonna happen in the future. But I think that if we look at this into the broader context, for example, not everyone, especially in an area where there's not a rheumatologist available or with a storage of rheumatology, arming other providers with the ability of differentiating a lupus activity from something else and perhaps catching these patients or just more accurately identifying lupus activity as defined by a lupus expert.

The Dyslea is seems easy, but it's not that trivial. I think it can provide some use in the future as this biomarkers are getting validated.

The biomarkers are a very hot area and I like it. I think rheumatologists have become very, comfortable with the biomarkers they use. And you guys being lupus experts tell me about the biomarkers that we really hang our hats on and why we shouldn't be so comfortable with proteinuria and complement levels and lymphopenia as my targets for therapy?

You want to start, Jus?

Jus, what do you think?

Yeah, so I think sometimes there is, some, discordant between the clinical pictures. For example, do see some people with high anti double stranded DNA titer more than 300, but clinically they're quiescent. So sometimes the biomarkers in this all this current immunology tests are good for diagnosis and not necessarily for assessment of disease activity or of lab prevention. Hence, we do need better biomarkers in order to better personalize and stratify our patients. So there's quite a few other blood biomarkers.

For example, we've been working on interferon biomarkers in Leeds. And also, when we try to talk about interferon biomarkers, it's still not being used in a clinical practice because when someone says, oh, I have a high interferon gene signature, what do they mean? What do they measure? How many interferon genes in nature that you captured? Are you measuring protein or gene expression?

So there's quite a lot of this variability that needs to be harmonised. And certainly Andrea will agree. I mean, I think Andrea has been measuring quite a lot of urinary biomarkers. So I think, there's quite a lot of validation that's needed. And also once the process validation is happening, I think we really need to focus into bringing these biomarkers into clinical practice.

As we all know, there's quite a lot of multiple hurdles to get that into practice.

Yeah, I agree. To get to your point, Jack, about the biomarkers that we have, especially thinking about extravenal lupus, where perhaps it's a little bit more challenging. There is much heterogeneity in lupus patients to the point that, sure, if we have a patient with symptoms that have a rising double stranded DNA titers and a dropping C3 and C4, well, that's, in a way it's easier, right? But if we have the patient who never had the DNA antibodies or the patient who never like drops compliment, we have these patients and identifying flares in this patient may be quite challenging. And so if you are in a lupus center where we get to see the variety and the volume of patients to make us more confident, that's one setting.

But in other setting, when that becomes more challenging, sometimes doctors are left with no biomarkers to go by and yet the patient have lupus. So having something comprehensive that can help us understanding the underlying inflammation that is more specific to lupus, could help. It could help when have it's not perfect.

Yeah. Think I think it's I'm I'm looking forward to this with a great deal of of hope because all all the data on the newer biomarkers, the c d one sixty three nineteen, the one that you reviewed here. I think this is an exciting time for lupus management. I think as I said before, it's going to change clinical trials as well. I want to ask both of you to comment on one.

I think there was two abstracts on open entuzumab, the anti CD20 monoclonal antibody and the re analysis, the phase two nobility trial, the one that I saw looked at subset analyses. Again, this is the preferred B cell depleting antibody in lymphoma, mainly because of its characteristics and safety profile and kinetics on it, and that it is superior to rituximab. And that's the feeling going forward in the lupus trials that have been thus far done. In this study, they showed that again, the B cells are depleted for a year, but that when they reconstitute, it's the naive cells that come back and the memories I think stay depleted longer. But what's your view of the data so far?

What was presented at the meeting on obinutuzumab?

Yeah, so I did interview Doctor. Vital, which is my colleague in during the conference. So he presented this work. So it is a P. So P0.0529.

So that's the abstract number. So essentially this was looking in terms of longitudinal biomarker assessment and as what you said Jack earlier, so they found that people who achieve complete B cell depletion had a better renal response than those who had incomplete depletion. So when they mentioned this, so the degree of the B cell depletion was measured using highly sensitive flow cytometry technique. So this is different than the conventional cytometry technique. So the difference between the two essentially is the enumeration of the plasma blast cells because using the conventional cytometric technique, so usually the gating started on the CD19.

However, you know, as we know, the plasma cell, not all exclusively come from CD19. So you you have to start your gating from monocyte and multiple gating strategies. Basically this showing in terms of the property of the type two anti CD20 monoclonal antibodies through a DCC mechanism of action that they're able to result in complete depletion. But also not just that's the first phase of it, but secondly also they were looking in terms of those who had this sustained depletion, they also had had a better response as well. And then clinically, well, I did a lot of this work during my PhD.

We did see some patients who developed anti rituximab antibody in the subsequent cycle of rituximab. So what happened back then, we did manage to get some compassionate use of Ocrelizumab. Ocrelizumab was promising initially in the trial but then it had to be terminated because there's quite a lot of fatal infection in Asia. And so what happened when we used these in the five hour patients, so most of patients really had complete B cell depletion and these patients also would come off medication, they'll come off mycophenolate and stay on hydroxychloroquine only. And when I checked serial B cells, the plasma cell still has not come back after four years, you know, and then they relapse after four and a half years.

So, you know, it will go really astounding amount of depletion that we can achieve it back then. But, you know, it's showing to say that, you know, the importance of achieving this deep B cell depletion to get a good and prolonged response.

Yeah, mean it's hard to top that since there was a few PhD use. I think it's quite concerning too. We often like rituximab, but we always prescribe it with the concern that, okay, I'm giving something that is going to immunosuppress this patient for six months and I can't hold it if something goes wrong. And then if we think about obinutuzumab, but now you can deplete B cell for as long as four years, well, that's quite concerning. We do know that from clinical experience, these patients are The rates of developing hypogammaglobulinemia, it's there.

So I think that is a powerful new drug, but as we get to understand it better, we should really think about the long term implications of removing an important part of the immune system.

Okay. I want to ask you your opinions also about this abstract. I think it comes from Toronto about responses in patients with membranous lupus nephritis versus proliferative lupus nephritis. It was an retrospective study from their lupus cohort, two hundred patients and fifty with membranous disease, one hundred and sixty four with proliferative disease. The bottom line was that, it looked like patients with membranous disease deserve aggressive treatment.

Were you guys familiar with this abstract?

I'm pulling it up.

Was POS0732. And, again, I thought it was interesting in that, you know, its conclusion that Membris is not just proteinuria, only that, it's not a benign disease and may be associated with significant deterioration and even death rates. And on that basis, it really was the outcomes, I think comparison from a single center. And they have a pretty aggressive, lupus clinic at the Western Hospital in Toronto. If you look at show Kaplan Meier plots on all kinds of outcomes.

Boy, they're very overlapping between membranous disease and GN and proliferative GN. And that kind of goes against my training that membranous doesn't always need to be, don't give them cytotoxin, nobody does that, whatever. And that you're only going to treat them if their renal disease progresses or if their proteinuria is out of control. And so anyway, I thought this would challenge the conventional wisdom in lupus management.

I agree. It's very interesting. We published from the Hopkins lupus cohort a paper a few years ago in general rheumatology, where we looked at the outcomes of patients who had pure membranous on the second biopsy. So meaning you have a patient treated and then you have a re biopsy for cause, and then you find pure membranous and then you say, Well, sure, it's just membranous so I can get reassured. And then what we've seen is that actually there is a significant rate of CKD progression to ESRD and including death.

And so what we found is that one of the predictors of poor outcomes was having had a history of proliferative lupus nephritis in one of the previous biopsies. Which is with the notion that these patients So it's very well known that lupus nephritis patients, if you biopsy multiple times, they can go all over the place. They start at five, they go to four, then they go to two and then back to four. But they can do whatever they please. And so yes, these patients may be membranous at the time of biopsy, but there may be a kinetic problem as it was describing in one of the talks, that risks this kinetic chaos, that maybe this patient is turning to proliferative after a while.

And we don't know because we can't just re biopsy patients every few months. And this is also an area where urinary biomarker can really help. So I think that it is good to see that these patients with non class three or non class four lupus nephritis are getting more attention because things may change. The other thing I would like to add is that when we studied pure membranous lupus nephritis in terms of their proteomic profiles, we found surprisingly that a lot of these patients had signature of inflammations such as neutrophil degranulation and also extracellular matrix degradation. What?

They say, oh, this is reassuring, it's classified and we see active degradation of the matrix. It's not something that we have in mind with that phenotype. So there's an abundance of new data also coming from class two lupus nephritis that is showing that that perhaps is the gateway and is to then class three and class four showing that perhaps is more aggressive than we thought. And so I think that seeing lupus nephritis is kind of like a more heterogeneous group of diseases that is also like kinetically diverse, should be in our mind when we treat these patients.

Yuzhua, do you have a different view on this?

Yeah, so I think there's also been some presented in ACR. I think last year, I think we're looking into post hoc analysis of the voclosporin trial. So although it was not powered to answer question, but one of the questions was asking whether it is effective in people with Class five membranous lupus nephritis. And what they found, the response using voclosporin was as good as treating the Class III and IV as well. But this is likely because of the preservation of the proteinuria because that's where the voclosporin works.

And I do find in my clinical practice as well, and when I do see a biopsy of class five active membranous polyneuropathy, membranous lupus nephritis, what we found, I tend to use the voclosporin first, or cyclosporine first just to conserve the heavy leakage of proteinuria before I start using different immunosuppressants. Because prior to the advance in cyclosporine development, When we use a lot of rituximab, we found that potentially nothing happened. It might have been like you give rituximab and it just peed it off after the infusion. So I think that's what how we to say as well.

Okay. All right. I think that's plenty to digest, in lupus world. I want to thank, Doctor. Falwa and Doctor.

Youssef for, contributing their time and spending and focusing on lupus at ULA twenty twenty four. And, we'll be doing it again at ACR in a few months. So, thanks everyone. Have a good night.

Bye bye. Thank you. Good night.