Ep 55: A spotlight on vasculitis and the kidneys

In this conversation Dr Ashley Elliot talks with Dr Mark McClure, Consultant Nephrologist, based in Belfast. This wide ranging evidenced based conversation spans a comprehensive update in approach to treatment of renal vasculitis to some of the current controversies around avacopan and plasma exchange. A timely discussion! 

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Transcript

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Hi everybody. My name is Ashley Elliott and I am a consultant rheumatologist based in Belfast. I'm delighted today to be joined by my colleague, Dr Mark McClure. So Mark is a consultant nephrologist with significant subspecialty expertise in vasculitis.
 This was gained through six years experience working as a clinical research fellow in the Vasculitis and Lupus Centre in Addenbrookes. So during this time, he's also gained substantial clinical trial experience as a trial physician for many multi-site clinical trials and completed a PhD investigating mechanisms and clinical implications
 of B-cell targeted therapies for the treatment of ANCA-associated vasculitis. So Mark, thanks so much for joining us.

Thank you. Delighted to be here. Thanks for the invitation.

So, look, I suppose to start off in this discussion, from a rheumatology point of view, we're well-versed in sort of going to see people with multi-system disease. And one of the things whenever there's a vast query is we're thinking about renal disease and sometimes we can overcall it, sometimes we can undercall it, hopefully sometimes we get it right. But I suppose it would be just great to get from your point of view, what does ANCA associated vasculitis look like from a day-to-day point of view? How do you see it present? And where do you see where there's more urgent situations from a renal point of view that needs more urgent management?

 Yes, absolutely happy to discuss. I mean, this is a rare disease, obviously, with incidents of around 30 per million per year. So, it's uncommon on the on the medical and renal take, but as you know, when it when it comes, often does dominate the whole week. The renal lesion, the kidney lesion is a necrotizing glomerulonephritis, and that often presents with haematuria, proteinuria, and then a rapid decline in renal function over sort of weeks, so-called nephritic syndrome or RPGN and the rapidly progressed, and essentially that just means AKI with blood on the on the urine dip, and that's often associated with, you know, the constitutional symptoms and other manifestations of vasculitis, but it's important to recognise that while that's the typical presentation that most people are familiar with, there's also a slowly progressive or slow burn phenotype that essentially looks like slowly progressive CKD, and that often is associated with or often seen in older patients and might have little in the way of systemic involvement. We know that the two main factors that influence mortality are how old the patient is, number one, and then the severity of kidney involvement at presentation. So early recognition and then early initiation of it. Effective treatment is crucial when the kidneys are involved to prevent kidney failure and improve survival.

Yeah, of course. I suppose whenever we're screening patients, what are the red flags that you're seeing in a year in depth or the biochemistry that make you want to hear about that patient urgently?

Well, it's just when renal involvement is suspected, so pretty low, low, low, low threshold. We've basically got three, at the moment we've only got 3 biomarkers, got serum creatinine, blood in the urine, protein in the urine. Hopefully we'll have some more coming down the line. But as a nephrologist, if you're suspecting anchor glomerulonephritis and any one of these three things are off, then the nephrologists want to know about them straight away.

Yeah, I suppose, and that's a huge help. I mean, working with you in Belfast, you know, being able to have those open lines of communication, I suppose, because sometimes there's that feeling of, am I overdoing the referrals? Sometimes you're, am I underdoing it? And it's lovely to have that sort of learning and learning from yourself about, yeah, when you should be just getting in touch anyway, just to start that process. I think that the risk is calling it, I think, isn't it? Because you know the damage the damage that can accrue with with under treated vasculitis, especially when there's renal involvement, is significant.

Yeah, yeah, of course. And I think that's where, you know, the role of MDMs and having those open lines of discussion means that even you can start those conversations earlier. And so whenever referring for a biopsy then, or obviously that's going to be something that you're going to be considering, when do you consider renal biopsy and how does that help you in the management of ANCA associated vasculitis?

So, you know, this is a multi-system condition with quite a few potential mimics. So, confirming the diagnosis with a biopsy is still, you know, very, very, very useful, especially before you embark on pretty heavy immunosuppressive therapy. So kidney biopsy is still the gold standard for diagnosis and it's recommended in the guidelines. For example, EULAR, EULAR still recommend kidney biopsy as part of the diagnostic process. It confirms diagnosis, excludes the mimics, it shows you if there's dual pathology, which there sometimes is and it gives you prognostic information. And we've got three validated prognostic tools looking that can predict long-term renal outcome based on the baseline kidney biopsy. So it's useful for all those reasons. However, it sometimes, but it often doesn't change the treatment approach. So, the scoring systems that we have now are prognostic scoring systems rather than rather than designed and validated to make treatment decisions. So, sometimes the biopsy isn't changing the changing the treatment approach, and you know sometimes if there's a patient with a very typical story. They've got positive anca, blood and protein in the urine with AKI and constitutional upset. You know, that's, it sounds like, what is it? Sounds like a duck, quacks like a duck. It probably is a duck. You know, it's reasonable to just get on and treat that patient. Sometimes a biopsy isn't feasible or it's not safe. So it's very reasonable to treat empirically if you're confident that that is the most likely diagnosis. But then bear in mind that if things don't behave as you expect them to, or there are atypical features, then have a biopsy plan for later down the line.

Yeah, and I suppose just thinking about treatment, so it feels like treatment was sort of similar for many years and it started to rapidly change in recent times. But when we think about the question of induction therapy, Ritux versus cyclophosphamide, the trials, how do you think about it from a renal perspective?

 Well, I think, you know, the RAVE trials, one of the most informative anca vasculitis trials that we have, and you know, as you know, compared rituximab and cyclophosphamide head to head in patients with severe AAV and it showed they were non-inferior to each other. And actually, we're talking about superior to cyclophosphamide for people with relapsing disease. And then the post-hoc analysis showed it's better for people with PR3 disease. So when you're trying to limit patient toxicity, especially associated with cyclophosphamide,
 Probably rituximab is preferred for patients with relapsing disease, PR3 disease. The younger patients, of course, have the concern about fertility, frail older patients who often tolerate cyclophosphamide less well. And really it has become the default treatment. I guess the caveat there is for when there's severe, severe renal involvement, rave. The median creatinine was about 150 and they excluded patients with creatinine greater than 350. So there's not robust, we don't have robust data to support rituximab use in patients with the most severe renal involvement.
 And a lot of nephrologists like to use or either include with rituximab or just use cyclophosphamide for the patients with the most severe renal involvement. Well, there's good maybe a thought between for many nephrologists that combining the combining rituximab and cyclophosphamide might result in kind of faster treatment effect. The Ritux fast trial that combined Rituximab and low dose cyclophosphamide with a standard standard cyclophosphamide showed that it was equally effective and safe. And now there's a number of observational studies that have also looked at the combination and reported faster treatment effects, steroid sparing, and possibly more effective, the combination more effective than either on its own. But of course, that's these observational studies. We need actually a head-to-head trial. There is one in the pipeline, I believe called the endurance study, but hasn't reported yet. But I guess a pragmatic message is you pick one as your starting agent, and if you get the desired effect, then that's great and then you can add in the other one if the response is suboptimal.

And Mark, in your practise with stuff you've mentioned there, do you use combination or have you used combination?

 Yeah, we definitely do. I mean, I did my kind of vasculitis training in Cambridge with David Jane and Rachel Jones and the two and two lots of rituximab and two lots of cyclophosphamide was pretty standard treatment actually two and two with a kind of early aggressive steroid taper aiming for withdrawal by kind of three to six months in most patients. But you know, I do use that myself for the patient with most severe disease, but it's not it's not for everyone. And you know, you have to, you know, match the kind of aggressiveness of the treatment with the presentation. You know, people, patients with creatinines of 200, 250, those were patients who were in rave and still did very well on rituximab. So, it's just those with the really with the real severe presentations, really advanced kidney disease at presentation, pulmonary haemorrhage, and real multi-system involvement. I'd advocate the combination, but of course it does, you know, it does result in a in a higher level of immune suppression. So, the patient section is key and best avoided in the frail older adults.

Yeah, and it makes sense and feeling like, especially in those more unwell people, that you're giving something that's going to work a little bit quicker while Rituximab kicks in. But so in terms of then with the rituximab or cyclophosphamide or both, the steroid dosing in light benefit. What do you choose as your as your steroid taper?

 So the PEXVAS and LEVAS, two very complementary studies that really underpin contemporary practise guidelines that advocate minimising steroid exposure in AAV. They're complementary in the fact that Pexivas was patients with severe disease.
 and they used a reduced dose steroid tape, I think 60% of the kind of traditional dose. And then Lovas was non-severe AAV and just patient, just a Japanese cohort who would who were just treated with rituximab. But the message is the same that the efficacy is the same is equivalent for Pexivas that was death and kidney failure and low vas that was remission rate, but the side effects are less with the with the lower dose of steroids with less infections. So, really, that should be the treatment standard now is really for the severe patients is the reduced dose Pexivas style taper. That is if you're not using Avacaban.

Yeah, and I suppose talking about Avacopan, so obviously there's a couple of recent things that have come up Avacopan and just if we talk about the trial data that supports its use, it's placed them in practise and then kind of just talking about recent safety reviews of its treatment. Where do you see Avacopan's place in treatment at the moment?

Yeah, sure. So this is a this is a hot topic, Ash, at the moment, as you know. So now I'll talk about the data and then about the controversies. So I guess just to go back several very convincing pre-clinical studies showing the benefit of targeting that C5A pathway in patients with anca vasculitis and lots of different groups showing benefit. Went on to clinical development, passed through phase one, two very positive phase two studies called clear and classic, and then the phase three advocate trial. That was 330 patients randomised to receive a Avacopan or basically a standard prednisolone taper that looked a lot like the reduced dose Pexivas taper. The clinician could decide whether they gave rituximab or cyclophosphamide. And essentially, they showed no difference in terms of remission at week 26, but then significantly more patients in sustained remission at week 52 in the Avacopan which was a 12.5% point difference. And it was basically because there were more relapses in the standard in the standard steroid arm. So that was the that's the co-primary endpoint, which was remission at week 26 and then sustained remission. At week fifty-two, and that's the main efficacy signal for Avacopan. But the trial also showed better GFR recovery with Avacopan, and that was with greater improvements in GFR with the patients starting with the lowest baseline GFR, so 8 mils recovery versus 13 mils in those with GFR less than 30. It's a pretty impressive renal signal. No differences in adverse events, less glucocorticoids related side effects, and actually a better quality of life, better quality of life scores. So very, very positive results all round. The trial was reported to New England Journal in 2021. Marketing authorization was swiftly approved by FDA and EMA and then recommended by NICE here in 2022. And then you know, we've been we've been we've been using it here. I've been I've been in Belfast now for nearly two years and starting it pretty much on every incident patient that comes through, largely with you know, with good success. We've looked at our cohort and there's other real world cohorts that have been published that largely do reflect that the trial data. However, there has now been as well, there's a safety concern and an efficacy concern, essentially. So, the post the post-trial surveillance has shown a, well, there's always been a liver signal. So, and there's always there's always been a kind of slight liver story, and we know not the recommendation on the label is not to prescribe a avacopan, use avacopan when you know when there is problems with the LFTs and we know to stop it if the if you know if the LFTs if there is an LFT derangement and usually that. You can stop a Avacopan and the LFTs do normalise after kind of after you stop it for a while. But yeah, the post-marketing surveillance has shown that the liver signal is a bit stronger than that. And actually, there was there's quite a few reported serious liver adverse events including worldwide 8 deaths related to liver injury. So you know, you don't really know, I don't know from what's reported what that what the denominator is on that. Presumably it's, you know, 10, 20,000 plus. So it's still sort of a small percentage, but definitely enough for us to pay attention. A lot of the deaths were from the Japanese cohort of patients receiving a Avacopan. And there's a few of the real world studies of reported the similar signal that the liver injuries are perhaps more common in Japanese patients. So suggest a possible pharmacogenetic factors around, you know, cytochrome P450 mediated metabolism. Maybe that may be part of the story. But there's definitely that safety concern that we've seen now. But beyond the safety concern, there's now an accusation of trial misconduct against Chemocentryx, which has now been taken over by Amgen. And it claims, I don't know if you've seen it, but it claims that patient were selected by unblinded trial personnel for a BVAS kind of re-adjudication. And that re-adjudication process resulted in remission status being changed after the database had been locked. And then the P-value for that sustained remission at week 52, it was greater than 0.05, and then after the re-adjudication, it is now less than 0.05. So, sounds a little bit dodgy, doesn't it? Now, It's hard to know what to do really, because you know, I've been part of the BVAS re-adjudication processes before, and you know, the BVAS is a bit of a bit of a blunt instrument, as you know, and you know, for in a multi-site, multi-centre trial. Sometimes the BVAS is wrong, and it does need a adjudication panel to look at it and change things around. So that does happen and that is, you know, all above board. But the real concern is about how the drug company went about it and really didn't do it in a transparent way and didn't say that they were going to do this or say that they did it to the FDA and then went on to get the marketing authorisation based on the re-adjudicated results. So clearly there is some, you know, foul play that that's that that that has happened.

Yes, so there's a couple of issues, I suppose, and it's one of these moving things, isn't it? But yeah, more to be seen about this. So at the moment, in terms of your practice, have you paused its use or how have you responded to all of this?

I mean, well, I think me, and like everyone else in the community, we're in shock because we, you know, I've been singing the praises and I've been encouraging colleagues to start it and encourage them to start it quickly, you know, to get that get that benefit, that renal benefit, and I've had a very good response. And like I said, it's like our experience echoes the trial results. It's, you know, so what do we do now? We speak to patients, speak to my patients about it and I say this is this and try and try and be as open and honest as possible, but it's very hard for a patient to willingly accept a medicine that when they hear about drug-related, you know, drug-related deaths or liver-related deaths, albeit that is rare and you know you can choose patients who don't have any who have got normal LFTs and you can monitor them closely. So I don't see that. I see the benefit being greater than that risk. But you just can't believe you can't trust the data is the is the problem. And you know, and we've got to tell, we've got to sit there and look patients in the eye and tell them that this is this is the drug to take and that the benefits outweigh the risk, but we actually can't say that now. I got to admit I haven't been starting it but you know, now I've got a guy in clinic just last week and his BMI is 32 and he's now on steroids and I'm thinking, you know, I ran through all this data with him and said, what do you think? He said, oh, no, thanks. I don't like the sound of that. So it's a tough one, but I have got patients who, after discussion, have agreed to stay on it. And I'm just going to keep them on it and watch them safely and watch this space. I think, you know, it's hard. You know, I guess the drug company are innocent until proven guilty, aren't they? And I think the good thing is you know, the I think this pathway does work. You know, I think blocking this pathway does work for a patient with vasculitis, and there's another there's another C5A inhibitor monoclonal. I forget the name, Vilobelimab, I think, that's in phase two and it's showing similar steroid sparing efficacy. So I think if we can't, we might not be able to use a Avacopan in the way things are going. I think it is going to be withdrawn. So, we might not be able to use Avacopan, but hopefully there's going to be another molecule that targets the same targets the same pathway and actually has the efficacy profile that that that we that we thought avacopan did.

Sure, yeah. Well, I suppose moving on to a topic that I've seen debated throughout my registrar training and now as a consultant for a number of years, the role of plasma exchange, particularly post-PEXIVAS. When do you use plasma exchange in your own practice?

Yeah, this is another controversial issue, isn't it? And uh, in the world of ANCA vasculitis, and you know the largest anchor trial to date was Pexivas, and it showed no overall reduction in death or ESKD when was added to standard therapy for patients with severe vasculitis, so negative trial which was a big shock because, you know, we've all been we've all been using plasma exchange for many years since the MEPEC study. You know that has basically split the vasculitis community because there's some people that take that as the, you know, a robust and well-run multi-centre, multinational clinical trial that that was negative for its primary endpoint and actually all its secondary endpoints as well. So, people are absolutely not using not using plasma exchange anymore, and you know, you can't actually criticise that at all, because that's what the that's what the RCT evidence shows. You know, however, there is a meta-analysis that's looked at, you know, 9 trials, including Pexivas that does show when you pull them all together, there is a short-term reduction in kidney failure at one year with those with the kind of highest creatinine at presentations, potentially with the most to gain. But it's at the cost of increased infections and then no long-term mortality. So, as a, you know, as a nephrologist who's tried to understand the data and the diseases as best as I can, I do think that, you know, patients with the most severe disease with most severe renal presentations, and we had kind of biopsy data that showed it was the ones with the kind of most acute, and fresh inflammation going on in the in the kidney. Probably those are the patients that would benefit from that aggressive removal of perhaps not just ANCA, but all the other kind of associated inflammatory mediators that the plasma exchange does that does remove. You know, meta-analysis shows a short-term reduction in ESKD. That is as important finding, you know, we do stopping people being on dialysis at one year is a huge thing for a lot for a lot of patients. So I do, you know, I do follow the EULAR and KDIGO guidelines that say if you have a patient that's rising above kind of 350, and they're robust enough to withstand plasma exchange. I am, I am, I am using it. However, if you know if the patient with that I think is, you know, slowly creeping, in over a long time and or we've got the biopsy and it's showing a lot of lot of, you know, more and more kind of sclerosis and scarring or the patient is a lot older and frailer and I know I'm less likely to tolerate plasma exchange. I'm not using it for those patients.

OK, So just in terms of then maintenance, I suppose it's more straightforward if they were commenced on rituximab and there's a lot of evidence in rituximab for maintenance therapy. But how do you think about maintenance regimens for vasculitis and how do you monitor patients in that period?

Well, we got we got we got 22 great maintenance trials, Mainritsan and Ritazeram, and they're complementary again because Mainritsan enrolled patients that had cyclophosphamide and they were kind of all comers, so new and relapsing and gave them a lower dose regimens of 500mg every six months for about 18 months. And then ritazeram was slightly different. That enrolled patients who had had rituximab induction who were relapsing patients and then gave a more intensive regimen of 1 gramme to 1000mg every, every four, every six months for the kind of 16, kind of 16 to 18 months as well. So, so kind of different regimens, different doses, but the message was the same, that ritazeram was more effective than azathioprine at reducing relapse risk. So, rituximab should be considered as the default. And it's quite great to have that range. You know, so main ritazeram is 500mg and ritazeram is more intensive, you know, one gram. So you can use the higher dose for the patients with most refractory and highest relapse risk. But for the standard patient, my standard patient, I'm using the main Ritazeram 500mg every six months.

And how long generally do you treat for, Mark?

For two years, usually two years, and then and then reassess. And that that points that that point is a really important time point to look back and look back at the patient, see what's happened, see how well they've tolerated the the immune suppression assess their relapse risk with by looking at the relapse before, looking at the anca status, PR3 versus MBO, and then what another relapse will mean for them, i.e. do they have enough kidney function to withstand another relapse or would that result in kidney failure, but really just trying to weigh up that infection risk, that risk of hypogammaglobulinemia versus the first versus the relapse risk and making a kind of individualised decision based on that patient.

And you talk there about parameters that would make you go with a slightly higher dose of rituximab. What would those be? 

I think, I think the standard for me is 500mg of rituximab, but if I have tried 500mg with a patient and it hasn't it hasn't induced a solid firm remission, then I know that patient's going to need going to need higher. If they had a very course with a lot of kind of heavy granulomatous involvement, then I might prefer the higher dose of rituximab. And if they've relapsed quite quickly after the 500 milligrams, then I would advocate for the higher dose in that patient. But yeah, my default is to try the main Rituximab lower dose, 500 milligrams. And I find that that is more than enough for the vast majority of patients.

 And that reflects some of the stuff that we do, for instance, in rheumatoid using lower dosing now. So you've talked there about some clinical parameters. Where does, you've mentioned it already, but where does the ANCA status fit in in your monitoring?

So I think I think of ANCA as a risk relapse risk marker rather than a disease activity marker and not as a treatment trigger on its own is the kind of overriding message. But I still pay close attention to it, still measure it and pay close attention to it. I think
 you know, during treatment, especially with rituximab, you can usually get, you know, pretty decent remission and the anchor is often suppressed. It doesn't always go negative. It's nice when it goes negative of course, but it doesn't always. But it's when you stop the treatment that you know, after that two year period, that the, you know, pay close attention to the rising anchor. So on treatment, I think pay less attention off treatment, a rising anchor, especially if it's coming, you know, six months after rituximab, eight months after rituximab usually does suggest that a relapse is just is just around the corner. I don't always treat just on the just on that rising anchor though, because we know that there's lots of patients that can have a can have a rising anchor and actually don't relapse for, you know, 6, 12, 18 months later. So if you've got the right type of patient who you can monitor closely, for example, from a renal perspective can do urine dipstick testing at home or is reliable enough to respond to kind of a change in symptoms, I think it's reasonable to hold off that. We're always trying to give less, aren't we? We're trying to increase the increase the interval. However, you know, you might have a patient who's already shown that they're going to be a relapser, and they've had they had lots of lots of rituximab. You've got a trying to hold off rituximab, but you last gave it 8 months ago, and the ANCAs suddenly doubled and but they don't quite have those symptoms kicking in yet, quite a low threshold for just retreating those patients as well. So it's not a one-size-fits-all approach. It's looking at the patient in front of you.

 Yeah, of course. So what's really been beneficial is, as we've talked about at the start, is that sort of working together on cases. So just in terms of where do you see that MDT working in terms of the management of people with ANCA associated vasculitis?

Yeah, I mean, this is a really, really timely, timely discussion. I think, I think early shared care for any patient with renal involvement is really is important, really important, you know, especially when there's need for biopsy and sometimes need for a more kind of intensified treatment approach compared to patients with, you know, less severe manifestations. So, you know, joint art working, shared care, I think, is really important. However, if you speak to, if you ask patients what they want, and you know, as you know, Rosemary Hollick from Aberdeen has done a huge bit of qualitative work with the voices study, picking up, you know, patient experience and what they want. They care less about who kind of leads their care, but really what they want is, you know, one team with one coherent plan rather than the kind of fragmented messages from the multiple clinics. I find sometimes, you know, you probably feel the same. There can be a bit of a turf war between nephrology and rheumatology. We both are comfortable and, you know, competent at managing patients with vasculitis and with severe manifestations of vasculitis. But I think the interface works best when Rheum and Renal just communicate very well in a low friction, kind of pragmatic way, quick calls, quick emails around kind of cracking in trends, rituximab timing and flares. I think it helps for to have a kind of someone taking the lead, you know, for a patient, just so you know, you know, there's the rituximab scheduling and monitoring and monitoring and follow-up isn't missed, but you know, working together in an open kind of pragmatic way, I think is the way is the way forward. But I know, you know, obviously, I think we work very well together in Belfast, and we're actually in discussions about joining up to provide a combined vasculitis clinic that's kind of led by rheumatology and nephrology. Speaking of Rosemary Hollick's work again, she actually looked at they looked at the key service components that associate with the best outcome in patients with fast colitis, looked at all the different trusts in Scotland, then linked it to national healthcare database. And the key healthcare components for patients for a vasculitis service were services that were organised to give rapid access, nurse-led support, and then cohorted integrated vasculitis clinics with an MDT structure wrapped around that. So, you know, those were the key healthcare components that were associated with outcome in terms of hospital, reduced hospital admissions and infections and mortality in some places, mortality in some cases as well. Those, that paper has been taken up by the British Rheumatology Society in their updated guidelines and there's a whole section on service provision now. So it really does give a blueprint for vasculitis service delivery. And hopefully we can do that here in Belfast and feel like a single joint-up team for the patient.

Absolutely, couldn't agree more. So just in finishing off, where do you see the future going in terms of emerging therapies in vasculitis?

I mean, there is a lots, lots of really interesting emerging therapies for vasculitis. The future is it is definitely bright. You know, Rituximab is the default, of course, but the Rituximab has its limitations. There's still a remission failure rate of about 10 to 20% and a high relapse rate when rituximab has stopped. Some of this is thought to be due to the inability of rituximab to get in the tissue or really deplete the tissue to deplete the B cells at the tissue level you look in the blood, and the B cells have gone but if you look at the in the tissue, and I did some of this work in some in my research and others have shown this as well, if you look in the tissue, there's incomplete B cell depletion. So there's a line of therapies looking at ways to enhance the cell depletion. So firstly, there's a combination trial that we did when I was in Cambridge which is combining rituximab and belimumab, and with the hope that that combination of CD20 depletion and bath antagonism is going to give broader depletion of the B cell compartment, better tissue depletion. And we're about to report that study shortly. There's also a lot of interest in Obinutuzumab. And I know that's recently been approved, NICE approved for lupus, but as often happens with vasculitis, we borrow the drugs from that are working in other B-cell mediated diseases. So OB, as you know, is a type 2 and CD the 20 monoclonal antibody that's been genetically engineered to enhance the mechanism of action and then shown superior B-cell depletion in preclinical trials. There's a head-to-head study going on at Cambridge at the minute in a kind of phase two experimental medicine style of Obinutuzumab versus rituximab. So really interested to hear that, hear the results of that. And then you can't go to a talk on or a conference on anchoring autoimmunity without hearing about CAR T-cell therapies. These days, and you know, I can't help but be excited by them. They really do, really are effective at depleting B cells and helping with refractory disease. There is several case reports.
 sharing efficacy in vasculitis, showing just that, that they get the deep tissue B-cell depletion and clinical trials in kind of phase, phase one, phase two stage, including patients with anchor. So kind of really excited from with the CAR T-cell therapy option. And then on that similar line, we've got the bites, the bispecific T cell engages, which also shown excellent tissue B cell depletion. So some radiation therapies targeting B cells. There are also some other complement therapies, as I alluded to earlier. So Vilobelimab, I believe it's called, is the monoclonal antibody that's targeting C5A. So, if we can't use avacopan, hopefully that will that will that will get through phase three. Then, iptacopan is a small molecule that targets factor B, so it's slightly more higher up in the complement cascade currently in phase two, and then slightly left field, but this drug is really exciting is claudin inhibition. So Claudin-1 is highly expressed in kind of ANCA glomerulonephritis and in health, it is involved in regulating the type junctions, apparently, but in diseases like glomerulonephritis promotes organ fibrosis. So Claudin-1 inhibition has shown in kind of preclinical and an early phase study that it can reduce the transformation of that early kind of cellular inflammation that then lays down the extracellular matrix and progresses to sclerosis. So, really exciting pathway to target for patients with kidney disease, but you can also imagine we create a huge benefit for patients with kind of the upper airway disease, and you know pulmonary fibrosis phenotype that is often quite refractory to the conventional cyclophosphamide rituximab treatments that we use. So that's the horizon and it actually looks very bright.

Yeah, brilliant. No, look, Mark, thank you so much for giving us a whirlwind tour there with your expertise in Vasculitis. That's been hugely informative.

Thanks very much.
 No problem at all.