Ep 51: Vasculitic rashes, Vacuoles and VEXAS

Dr Laura Chadwick is joined by Professor Sinisa Savic in this bonus case based episode. What initially seemed like a case of a small vessel vasculitis was not all as it seemed. Listen in to find out more.  

Resource - https://aidanetwork.org/en/register/vexas  

1.Mapping the infectious burden in VEXAS syndrome: a systematic review and rationale for prevention Ribier, Valentine et al. The Lancet Rheumatology, Volume 7, Issue 10, e734 - e744

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Transcript

You're listening to the Talking Rheumatology Spotlight podcast, brought to you by the British Society for Rheumatology. Hello, this is a BSR Talking Rheumatology podcast. My name is Laura Chadwick. I am a consultant rheumatologist working in Cheshire. And it's my pleasure to introduce our guest today, which is Professor Sinisa Savic. He is a professor of clinical immunology in Leeds and he has a variety of specialist interests, but we've invited him to the podcast today due to his clinical and academic interests in autoinflammatory disease. He runs a specialist autoinflammatory disease service in Leeds and is the lead investigator at the UK VEXAS Registry. Welcome, Sinisa

Thank you for inviting me.

Thank you for joining us. Before we start, I was wondering if you could talk to us about how you became interested in autoinflammatory disease.

Well, it's an interesting question. I was lucky enough that way back, for a few years now, we were lucky to have Professor Michael McDermott joining us in Leeds as an academic rheumatologist. He's a gentleman who was involved in discovery of actually one of the first genetically defined with inflammatory disorder, TRAPS syndrome, and he joined Leeds in 2002. Shortly after that, I joined St. James's Hospital Leeds as a trainee in clinical immunology and I was beginning to see some of these really interesting and unusual conditions and I kind of reached out to him, just to talk to him about could any of these be actually one of these new autoinflammatory disorders. And by luck and coincidence, we discovered, we actually identified some of the first TRAPS patients in the region and in the country as well and discovered some new genetic mutations. And my interest really grew from then on and I did some of my postdoctoral, sorry, my PhD was in part in autoinflammatory disorders and then subsequently I set up developing a clinical service for autoinflammatory disorders in Leeds.

Fabulous, thank you. I mean, it is a fascinating area and I think as rheumatologists, our sort of expertise in it is sometimes somewhat limited because it's less common than a lot of the other things we look after. So it's great to have you on board today. So we're going to be talking predominantly about VEXAS today and to help go with the discussion, I'm going to present a case to you. So I'm going to tell you about a gentleman in his late 60s who I met in November of last year. Now, he is usually exceptionally fit and well, so he was regularly running, had no other comorbidities. And when I met him, he had a history of several months, actually, of really significant systemic symptoms. So he'd lost a lot of weight, he was having drenching sweats, he was having recurrent fevers and was really fatigued. And he'd been under investigation by the haematologists who had noted a high ESR and a significant anaemia and also some haematuria. So there was concern here for malignancy. So he had a CT scan, he had a PET scan and they didn't find any significant abnormalities to explain what was going on. So they proceeded to do a bone marrow biopsy. Now at that time, this only showed some reactive change. Because he was noted to have the haematuria, they also asked for a review from urology, but again was given the all clear regarding a malignancy. Now at this stage, his CRP was over 200 and he had no diagnosis. So he was referred urgently to both rheumatology and nephrology, but he was feeling really unwell at this point. So he actually attended hospital because he was getting quite desperate for some answers. So I went to meet him on the ward and he was describing to me a really severe urticarial rash. So he was scratching, he had some palpable lumps under the skin, which were coming and going every 24, 48 hours. And he also described very nicely a sort of flitting tenosynovitis-like picture. And he had some active sinusitis, I think, in one finger when I met him for the first time. And again, it would last 24, 48 hours, disappear and reappear in another joint. At this point, the only real blood abnormalities were his significant anaemia for which he had required a transfusion and his very high inflammatory markers. But the rest of his rheumatology screening was entirely negative, apart from a rheumatoid factor of 20, which I really didn't think was particularly relevant in this case, and a slightly low C4 level. And he also had quite a low albumin, I think, as part of this inflammatory process. So he had really significant pedal oedema. He did also have quite significant haematuria and proteinuria. So we were concerned for a small vessel vasculitis and we did a full vasculitis workup, all of which was negative. And interestingly, he told me about a single episode of inflammation to his ear. So this was the point at which we were really starting to consider VEXAS. And we sent off an autoinflammatory panel to UCL. He also, interestingly, had a repeat bone marrow biopsy at this time, which showed some dyserythropoiesis, but no vacuoles. So he didn't still have a clear diagnosis. So I was wondering if we could open by discussing what exactly is VEXAS?

Well, this is a really beautiful case to open up the discussion because it illustrates a number of salient clinical features that are in keeping with VEXAS, very classical, but also you ask some interesting questions, particularly with, you know, the role of the vacuoles, how much one should be looking for that and how much should we pay attention to that as when we try to think about the condition. So VEXAS is this relatively still newly discovered autoinflammatory disorder. It's, as in your case illustrates, largely affects men over a certain age and from the systematic review that we have done on this condition where we looked through around 700 published cases so far of condition. The most common clinical presentation, it does involve skin rash, so it's present in about 80% of all cases of access and this kind of rash, which is Quick kind of urticarial, but also has got nodular appearance is what you really see in VEXAS syndrome. Most patients will have these systematic manifestations that include fever, malaise, just losing weight is really, really common. Sudden onset weight loss, weight onset, new onset fever is really a common presentation. And then you have all sorts of other multi-system involvement that again was illustrated in this case. There is musculoskeletal involvement in about 40% of cases, although the, for example, joint involvement is not necessarily that well described. So it's kind of hard to know what does, for example, access joint inflammation or tenosynovitis look like in comparing to classical rheumatological disorders. But you also describe brief, brief episode of chondritis, which again is was relatively commonly described to begin with. And we now think that there's about 40% of cases who do develop chondritis as part of this condition. And lastly, which is again another important overlapping feature which makes waxes special is this involvement of the bone marrow and development of anaemia. And again, in about 90% of cases, there's some evidence of macrocytic anaemia to begin with. And eventually that can progress to the point where patients do need bone marrow, sorry, blood transfusion and eventually develop bone marrow failure and some actually develop Frank mild dysplastic syndrome. So the case you've presented really illustrates quite remarkably, really most important sort of differentiating. Well, there are no, we don't have diagnostic or classification criteria for access yet. That's something that we're trying to work on. But these unexplained inflammation, systemic inflammation, anaemia in males over 60 with condition that seem to have multi-system involvement. potentially some degree of bone marrow failure is what you're really looking for to start thinking about VEXAS syndrome.
And I wonder, I suppose the natural question that comes after this, what are the most common mimics that you tend to see in patients referred to you where someone's considered VEXAS syndrome?

Yeah, so the original cohort when it was published of 25 patients Some of the conditions that actually some patients did fulfil actually classification and diagnostic criteria for number of rheumatological disorders, including relapsing polychondritis as well as GCA in one case. However, we've done some work subsequently looking to see how common you can, how commonly you can find vasculitis in uncomplicated GCA and it's not really all that often that you can see, but other conditions that patients have been given labels is Still's disease and surprisingly given that there is this sort of autoinflammatory feel to the condition. But really when you look back at those cases, they all had something more than just Still's disease, the features that you would see in Still's. And the other one from the dermatological point of view is Sweet syndrome. This kind of combination of neutrophilic rash and neutrophilic dermatosis is often that patients were given as a provisional diagnosis. And lastly, from haematological point of view, some were called mild dysplastic syndrome, this kind of mild dysplastic syndrome with inflammatory complications. But now if you ask haematologist and if the patients only have mutations that are in keeping with waxes, it's debatable whether that bone marrow change is really in keeping with classical mild dysplastic syndrome.
How interesting. Okay, so I'll give you a little update on what happened next, and then we might move on to some of the genetic, actually, if that's okay. So I started this gentleman on 40 milligrams of prednisolone when he was an inpatient, when we'd got a huge number of negative investigations back, just to try and get him feeling better while we waited for his autoinflammatory screen results to come back. And I was also liaising with the renal about a biopsy at this point, given the unexplained diagnosis. He responded brilliantly to the steroids and he came back to see me quite quickly in clinic. And interestingly, at this point, a lot of his pedal oedema had settled and he'd started to be more mobile and he'd noticed a right-sided foot drop. So renal at this point, we're feeling this probably would be a sort of ANCA-negative small vessel vasculitis. However, I then received his genetic results panel. So this confirmed that he had a positive UBA1 gene. And if anyone hasn't had this report yet, it comes with a whole load of information that I didn't really understand. So in brackets, it told me there was MET 41 THR and I was given a variant allele frequency of 61%. So this positive UBA1 gene obviously confirmed the diagnosis, but I was wondering if you could tell me a bit about the alleles and the variant allele frequency. What do these actually mean from a clinical perspective?

Absolutely. So the obviously the genetic cause of X's syndrome is the mutation in the gene, as you mentioned, the UBA1. Why it mainly affects man is because it's found on X chromosome. So you really need just one hit. to cause a mutation. And we know there are women who can also develop access, but they're largely protected because they've got two copies of X chromosome. So if you develop mutation on one chromosome, then you protect it because you have a, you have a healthy copy of the gene on the other chromosome. And this is something that you're not born with, which is important point to make. It's a mutation that you acquire during lifetime, like mutations that you would get if you're developing haematological malignancies. So this is something that arises within the bone marrow in progenitor cells that give rise to all the peripheral cell types, red blood cells, white blood cells, platelets and so on. And this is where this value allele variant alien frequency comes into. It gives you an idea how many cells in the periphery that you have tested carry the mutation. So if you have buff so-called of 60% means the 60% of cells in the periphery carry the mutated genes and the 40% of those cells don't. Now, we weren't quite sure to begin with whether or not the level of mutation actually was directly proportional to the severity of the disease. But with subsequent work that she's been done recently, there is certainly evidence to suggest that the greater the amount of the mutated cells that you can detect in the periphery, you're more likely to have more severe disease and potentially more wider systematic involvement. There is also some so-called genotype and phenotype correlation. So there are different type of mutations which can happen at this specific position 41 that you have mentioned on the UBA1 gene. And I'm not sure that that we necessarily need to go into details of that, but this position is critical because it affects how this gene, the mutation causes the disease. But just simply to say there are three different amino acids that can be changed from the methionine, which is what you would found in a healthy copy, to three different other ones. So you can either have a change in threonine, leucine or valine amino acid at this position. And depending on which amino acid is changed to, you may get some clinical manifestations and maybe disease outcomes that may be slightly different. So we think the valine change is probably the most severe and sometimes associated with slightly worse prognosis than the other two.
Yeah, it is absolutely fascinating, isn't it? And you wonder when we come back in 10, 15 years, how relevant these things will be to our treatment pathways. when we have a better idea of the condition. Okay, thank you. And as a sort of practical question, do you now do the UBA1 testing as part of your standard autoinflammatory screen or do we have to request that as an extra?
No, the UBA1, so obviously in terms of the autoinflammatory task, this is provided in England. centrally by the lab in the UCL and they've included the UB1 gene as part of the standard panel. So you'll get that screened even if you're not necessarily specifically asking for it. But a lot of these patients are now being picked up via haematology route. So if you've been investigated for anaemia, the UB1 gene is part of the so-called myeloid panel. So the genes that you look to test for mutations that might cause mild dysplastic syndrome, acute myeloid leukaemia, things like that, the UBL1 gene is part of that panel. So if you have unexplained anaemia and you're having genetic tests, this is how many patients are actually now being picked up from the haematology side of things.
Yeah, and I think it's interesting how patients either end up under haematology or rheumatology, and we might come on to that a little bit in the treatment section. And before we move on to that, I actually have a question from my patient, if that's okay. So he is aware of the podcast and I think he's looking forward to listening. So he specifically wanted to ask about ocular manifestations of VEXAS. So he was known to already have macular degeneration, but he noticed quite a deterioration in his eyesight at the time. And ophthalmology felt that there was some evidence of some inflammation at the back of his eye. Now in the literature, this is reported, but I don't know how commonly you see this in clinical practice or what that tends to look like.
So that would that's not really a common manifestation in in in in Vexes. I mean there is there are other eye manifestations, but in particular periorbital oedema. That's in something that's seen quite relatively frequently in Vexes. So I'm not sure to what degree this is necessarily highly linked. I mean there is systemic inflammation which could have made the underlying condition worse. I think it's worthwhile just whilst we at that point. the renal manifestations is something that I haven't necessarily reflected on when you presented the case, but we do know that there are actually now, you know, interstitial nephritis is seen in VEXAS and it may be directly related to VEXAS itself. So it's something that's seen in some patients. Again, not the most common manifestation, but certainly recognised.
Yeah, brilliant. Thank you. So if I talk to you about the treatment options. So for this gentleman, I took him to our regional MDT. So it's a sort of specialist commissioning meeting. And I was hoping to get some sort of local experience of what patients had done. And I was relatively surprised to find we actually had very few cases in the region. However, we did discuss the few treatments that do have some evidence. And I had been spending quite a bit of time trying to look through the available options. The evidence is obviously very limited as it stands, but in the end, I made a decision to apply for local funding for IV tocilizumab earlier this year, which he's currently having and is doing really well on. I was just wondering about the different treatments that are currently used for VEXAS and the evidence that's available for those. How do you approach that in clinic?
Just, yeah, absolutely. Just to say, we do have also a national multidisciplinary team meeting set up for access. So just in case for those of you who are listening and you want you have difficult cases you want to discuss, you can maybe we have that set up. These are monthly meetings and we usually discuss four or five cases at a time and we collecting this information and people are more than welcome to come and join if they just want to listen. In terms of treatment, this is still something that's evolving as you obviously described with your patient. Response to steroid is great in this condition. This is a very steroid responsive condition and that may be actually the mainstay treatment for some patients. So in some cases, and particularly if individuals are elderly and have many comorbidities and you can potentially manage inflammatory complications with relatively small amount of prednisolone, you know, with the doses of 10 milligrams and less daily. If you so obviously people have used empirical treatments in the past before we knew what this was. And after the discovery, again, you know, based on the basic principles, but targeted therapies, as you suggested, could be anti IL-6 or JAK inhibitors have been shown to have some good efficacy. We have published the retrospective data from the UK not that long ago in Lancet dermatology, and prior to that there was a French retrospective study which showed that, I mean, you know, none of these treatments are great. They're OK. You may get a complete response defined by controlling clinical symptoms and managing to reduce the steroids below 10 milligrams daily and controlling CRP in about 30% of patients. either by using a JAK inhibitor and I would say that's probably most the best one for that. So far evidence is emerging to be ruxolitinib and anti-IL-6 therapy tocilizumab seem to be doing is a good choice. Anti-TNF treatments have not really shown to be that useful. Now IL-1 inhibition is complicated. Some patients can respond, but often they're complicated by quite severe injection site reactions. And a traditional classical DMAS really have very little or no role in really treatment of access. And you know, so beyond that, I don't know whether you want to. There are other options to consider, which is so the treatment, the targeted options that I mentioned now are really about managing the inflammatory complications. But the other way of thinking about vexes is actually, you know, targeting the clone, you know, targeting the mutated cells. And here there are two potential options to consider. And in my clinical practice, all newly diagnosed patients depending on the stage of the disease and the comorbidities and their age, I think they should be considered at least for the possibility of bone marrow transplant as a treatment option, which could potentially be curative. So there is now increasing experience of using that. What we don't know for sure yet is who are the best candidates, how best to choose patients, at what stage of the disease to intervene and so on. And this is an emerging evidence. In that same respect, terms of targeting the clone, there is a treatment that I wasn't familiar with until not that long ago and it's something that we all learning about. It's something called azacitidine and this is something that haematologists have used a lot in treatment of aggressive forms of mild dysplastic syndrome. So these are high risk MDS. subtypes which have great, there's a greater risk of them progressing to acute myeloid leukaemia. Now, Azacitidine, as it turns out, can be very, very effective in vexes. And actually, overall, the evidence as it stands at the moment, and still this is all based on retrospective data, would suggest that the treatment response is around 60% in terms of complete response. But one thing to say that azacitidine is a little bit complicated treatment to give. So right now it's an intravenous treatment. So it's a subcutaneous treatment, but you need to come into hospital for it. It's given in a cycles and you know, it's not something that is being used outside haematology.
Yeah, I think this is where the haematology rheumatology split is really interesting because I think we always like to use things we're familiar with. So although we are familiar in rheumatology with JAK inhibitors, the ruxolitinib isn't one that we use. So I've had a lot of conversations, as you can imagine, with haematology and they are currently our backup options if for any reason the tocilizumab becomes less effective. And my gentleman is actually in consultation with the haematology team about bone marrow transplant. But I think it's quite a difficult decision to make when you're currently feeling so well. So that is something that we are exploring as a potentially curative option, but obviously with the risk involved with bone marrow transplantation when your treatment is working is not an easy decision to make. On the back of that, I was just wondering if you could tell us a little bit more about the National VEXAS Registry. So you've mentioned the MDT, but I was actually made aware of you because of the registry and I was recommended to submit my patient.
Yeah, thank you very much for asking me about that. It's a registry that we had set up few years ago. It's available. So it's the to the MDT as patients are coming through to the MDT. We use that opportunity to get them into registry. We currently have around 80 cases in the registry, which is nice number to start being able to build up a bit better picture about what's going on. We are linked in with other national registries around Europe and world, so there's a lot of discussions going on about coordinating the registries, making sure that we collect the same data, and actually also there is conversation about developing an international registry where maybe all of us. put the data together rather than actually all of us doing it separately. So, but that's an evolving conversation and we don't have the, the, the agreement yet. But as far as the UK is concerned for sure, we would be delighted to hear from people who have patients who want to provide the data and, and you know, we are quite happy to share the data and outcomes of what work comes out of any of, of this registry. It's really important in terms of understanding the natural disease progression, how the vexes behaves so that we can try, you know, have a better way of planning, you know, future clinical trials. And we currently have one which is just opened up not that long ago. So the first proper randomised controlled trial in vexes is currently ongoing. There are four centres in the UK, including my centre in Leeds. which are recruiting patients for the trial. But actually what we realized when we were trying to develop the trial inclusion exclusion criteria, various outcome measures for the trial, how it will be new in terms of what are the best outcome measures to collect, how best to design trial. And for all of that, really what's needed is this kind of understanding the natural progression of the disease. Because if you know that for, you know, some complications are likely to occur two years’ time, how long does the trial need to go on to show some benefit and some. So these are all still evolving picture pictures that in vex us.
Yeah, OK. I mean, it's great to know that there's a trial ongoing and I suppose if anyone was interested in that, are they? Are we OK to just contact you to get details about exclusion criteria, etc?
Yeah, absolutely. And this is one of. you know, two, three, hopefully another trial that are coming on the back of the one that is currently, as I say, it's opened and we expecting that we know that there's at least another one plant from a different company entirely next year going to be opening up and hopefully we'll again have similar number of centres available in the UK to recruit.
Brilliant. Okay. I suppose that leads us on to the issue with the lack of funding in the UK for treatment at the moment. So I applied locally for funding. Are there any upcoming plans for sort of a national commissioning model for VEXAS? Because at the moment obviously it's a little bit of a postcode lottery independent on your local trust what you can get through.
That's a great question and it's a really difficult one to answer. I mean I did on behalf of so that I forgot to say that we do have so something called VexNet UK, which is basically Vax's interest group UK. And again, it's a very open and group, you know, it's group of us who are interested in Vax's. It has rheumatologist, haematologist, other ologies, dermatology and so on. And actually we having have a second VexNet UK meeting shortly in end of November in York. And hoping, we're hoping that over time this becomes a bigger group of people and so on. But aside of that, on that basis, on that kind of interest group, I applied to at the time when NHS England was still was in existence to ask about commissioning several different drugs for vaccines, including tocilizumab, JAK inhibitor and azacitidine. And unfortunately, the commissioning body at the time decided that there wasn't enough evidence for us to progress with formal process in terms of commissioning. Now, I understand there are some other conversations currently going on to try and readdress this because as you say, It's really difficult and you know, we only can, you know, only access prednisolone really steroids. Everything else is a little bit of a lottery and depending on local availability, but that's something that we are trying to address.
Yeah, and I suppose that's where the clinical trials are essential, aren't they? So we'll have to see where things progress in the next sort of five to 10 years. Okay, as a sort of aside from that on treatment, so to update you on my gentleman, so currently he is down to 9 milligrams of prednisolone. It's been a slightly slower wean than planned because he's had a couple of different things happen in between. He is doing really well, so he's had no return of symptoms at all on his tocilizumab. Now, he did have some issues with recurrent neutropenia and we did have to drop his dose from 8 milligrams per kilogram down to 4 milligrams per kilogram. We've been liaising closely with haematology and they're happy that there's no evidence of myelodysplasia at the moment. However, it did increase my risk of concern for infection for him because he has a condition which is likely to increase his risk of infection alongside the neutropenia and the tocilizumab. So in rheumatology, we don't use a huge amount of sort of prophylaxis. We do for some of our more extreme cases, but haematology do this all the time. So I actually sought their advice and I was wondering if you usually recommend sort of prophylactic treatments for your VEXAS patients?
That's a great question and it really leads into these other concerns in terms of managing the patients. And you alluded to one problem, which is increased risk of infections. And, you know, sadly, that's often the case. The reason why people end up in hospital with vaccines or suddenly die from because there is overwhelming infection that is part of what this condition causes. So this condition, as you alluded, causes both primary and secondary immune deficiency. And we know that primary immune deficiency is due to the mutation actually affecting the immune system in a way that it's unable to respond to infection challenge appropriately. But then also we use all these other drugs that suppress the immune system. So it's a double whammy in terms of infection risk. And often, you know, the degree of neutropenia, which we wouldn't tolerate in other conditions when using biologics, we suddenly have to in vaccines because we got really nothing else to use at this point in time. Now, be honest, there is a paper that's been published in Lance and Rheumatology looking at, It was a systematic review looking at the burden of infection in waxes and there are some recommendations in that paper in terms of how and when maybe you should consider using some of the prophylaxis for both common bacterial and some opportunistic infections which can be described in condition. So that's in the last month or so that that that the paper has been published. So if rather than going through the details, people can look it up. There's also a consensus guidance that's been published in arthritis and rheumatology again around similar time. Again, this is from a group of experts that have come together to, you know, we haven't got enough evidence to provide formal guideline. So that's why it's called guidance to differentiate it. But again, there is some suggestions in terms of. how to support the patients really in addition to targeted therapy. And one other feature of access which is important to just highlight is this propensity towards thromboembolic events. Many patients may have had PE, some have had DVTs and so on. Now, there isn't an agreement, there is no consensus at the moment how and when to use prophylaxis for this purpose. Clearly, if somebody has already had an event, then I think we all in agreement that they should just remain on lifelong prophylaxis. But you know, that could be complicated by thrombocytopenia later on. So again, it's not necessarily all that clear. Then as you know yourself, if you put patients on JAK inhibitors, there is, you know, inherent problem then with increased risk of thromboembolic events due to the treatment. But we haven't come up with suggestion yet or recommendation to necessarily put everybody on anticoagulation if you start JAK inhibitors. So this is something where the registry, for example, the registry data longer term follow up, hopefully might give us a better idea of how and when some of these supporting measures should be put in place.

Yeah, absolutely. I'm going to have to add that Lancet paper to my reading list. Thank you for the signposting towards that. Okay, so a slightly different question here. So when I first told my gentleman that we'd had confirmation about VEXAS, so he's very well educated as is his wife, they'd been away and looked into this and it was the one diagnosis that they didn't really want this to be. And they had obviously looked into this and had seen some of the really quite concerning mortality data. So we had a sort of real open and honest discussion about this. So what I found tricky about this really is obviously it's a new disease. And what I was saying is obviously we would expect mortality to be higher in a newly emerging disease because we have to try and figure out the treatment options. And also the commonly affected patient group here, which is obviously normally older men, are likely to be co-morbid, which will increase their mortality risk. And then on top of that, a lot of these patients end up getting myelodysplasia. So for me, this is part and parcel of why the mortality is so high. But for my gentleman, he's normally completely fit and well, you know, he's back out walking his dog 4 hours a day at the moment and he doesn't have any bone marrow involvement. So really, I didn't feel I could give him a firm answer other than to say, we've got you on some treatment, we'll monitor you closely. And I don't think you fit into the same group as everybody else. And I was just wondering how you approach this sort of discussion with your patients in clinic?

That's a great question and unfortunately not one that can be easily answered. And again, this is just simply due to the lack of longer term data that we have on this condition. So yes, overall, you're right. The condition is associated with reduced survival. But then again, you know, the length of the condition can vary massively between different patients and depending on their comorbidities and the stage of life when they got it and so on. So, you know, we have individuals who are in their 80s, they're newly diagnosed with access. And I guess, you know, some of these questions are less. concerning for somebody at that stage rather than somebody who's diagnosed at 50, you know, what's going to happen over the next several decades of can I, you know, can I expect next several decades of life with this condition? The one thing I can probably, I think I'm in in patients who are relatively younger or who don't have any comorbidities, I think it's important to really consider a lot of potentially curative options such as bone marrow transplant. And as you said, it isn't an easy conversation, but it's better to be prepared for this alternate, you know, for this treatment option early because it takes several months to get everything in place. Do all the investigations, of course, find the donors and everything else. And if that's something that you, you know, if you start struggling in terms of treatment options, infections, then you can plug that in much, much easier. I'm also hoping that they will be, you know, coming in some of the new treatment options like azacitidine might be something that we use more readily. As I said, it's not something that we are used to use in other disciplines other than haematology, but again, that might be an option that become available to some patients like the gentleman you described that maybe is an option for not necessarily right now, but some later stage in the in the disease. where again is going to produce a good response that that is lasting. And you know, new trials are ongoing. We are there's interest, which is great because initially it was very hard to engage some of the pharmaceutical companies. But there is quite an interest from a number of different pharmaceutical companies to get involved in this space. And that's. promising in terms of them being able to do formal trials and actually hopefully come up with something that we can use with a great efficacy for access in the long term.

Yeah, and the stem cell transplant I found really interesting because I had to go away and look into this because in my mind, for the patients who have sort of bone marrow involvement to the extent of myelodysplasia, then I was like, well, of course, yes, then transplant makes sense. But I was interested to try and find the data for the patients with the inflammatory phenotype, but it does look as though although they don't necessarily pull them out separately in the studies. My impression is it is still really quite effective for that. I don't know if you can elaborate more.

Yeah, no, absolutely. I mean, this is the difficulty with VEXAS because obviously, you know, the bone marrow transplant initially idea was based and actually the selection criteria, the risk assessment and everything else is based on a different disease, mild dysplastic syndrome, not VEXAS, which is, there is an overlap, but it's not the same disease. And for sure, patients like this have been transplanted, including patients from my centre who have actually done extremely well. So I think it's an option that I would be increasingly consider for, you know, again, we're talking about all the relative terms, but if you are in your late 50s, 60s and so on, these are, and we currently don't necessarily know how, you know, some of these treatments that we use in vaccines, they all have potentially time span whilst they're working and then we don't really know what is would be the next option in in in case these things stop working. But there's really nothing to be lost to be prepared for this option. And actually, ultimately, you know, whoever you don't necessarily need to proceed, but it's better to be prepared and have this discussion because, you know, I'm not in a position to really give genuine risk assessment and title necessarily patients, you know, what's the. mortality related to bone marrow transplant and this is why we have colleagues in haematology with much greater experience and they're much more now readily seeing inflammatory vaccines without necessarily significant bone marrow involvement as a disease that is transplantable.

Yeah and I think what we agreed is it's probably worth at least just going to the consultation with the transplant team and then he can get a proper idea of what that would entail and what those risks would be. OK, I suppose that leads nicely onto my sort of last question, which is it's obviously very difficult for patients with a condition like this to find useful information. I just wondered what sort of support organisations or literature you usually recommend for your patient group.

There will be more in this space. You're right. Right now there is a little bit kind of vacuum in particular in the UK. We don't have one particular patient organisations that patients can turn to, but I'm involved with the global Access Foundation, which is being run from the states, but this foundation will be available to patients in all other countries. And actually, one idea behind this global foundation is that it will also run a registry, which is going to be patient-led registry, where patients themselves will be able to input their data into that foundation. Again, you're not obliged to do that, but if you want to, you'll have that opportunity. And that also will provide and hopefully much more information about the condition that that is verified and then useful contacts and so on. So this should be coming online quite soon. And beyond that, really, as I say, you know, for clinicians in the UK, we have this national MDT and again. people are more than welcome to come and join and if they just want to come and they want to present the case or they want to be just listening to conversation, it's open to everybody. And lastly, the VexNet UK again is this sort of not formal organisation, but maybe something that will grow into a bit bigger and more formal grouping that will be able to engage with the patient community more formally in time to come.

Brilliant. I love the idea of a patient initiated registry entry. I think that's a great initiative to be part of. OK, before we close, I was just wondering if you had any final thoughts or anything else you wanted to share with us that I haven't asked you about?

No, look, no, thank first of all, thank you for inviting me. It's really thank you for helping to increase the awareness of access. I think it's a fascinating disorder. I mean, it's one that we still have to there's quite a lot to learn about how best to manage the patients, and I think this is where we need to pull our resources and heads together to really speed up the process, because, as you say, people have quite significant symptoms. We, you know, there is a risk of... reduce life expectancy and all of that. So we do need to work harder and faster to come up with the treatments that will actually make change in long term.

Yeah, so essentially watch this space. Yeah, no, thank you ever so much. I'm sure our listeners will have gained a huge amount from this. So thank you for your time and your answers.

Thank you and thank you again for inviting me.
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