Ep 47: A spotlight on relapsing polychondritis

Dr Yik Man speaks with Dr Marcela Ferrada about relapsing polychondritis. She brings a unique perspective to the discussion as both expert patient and rheumatologist. Typical clinical presentations to the future research agenda are covered and they even touch on VEXAS - a must listen.

Reference - https://www.nature.com/articles/s41584-024-01113-9 

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Transcript

YM - Welcome to this BSR talking rheumatology spotlight podcast. I'm Yik Mann. I'm a consultant rheumatologist at Lewisham and Greenwich NHS Trust in London, and I'm very pleased, to welcome doctor Marcela Ferrada with us. She's joining from The States today. She's a clinical associate professor at the University of Maryland, and she completed her rheumatology fellowship at the NIH, National Institute of Arthritis and Musculoskeletal and Skin Diseases. She, has been certified in internal medicine, critical care, infectious diseases, and rheumatology, and she's the current director of relapsing polychondritis and the Vexas Programme at the University of Maryland. So welcome Marce 

MF - Hi. Thank you so much, for this opportunity. This is amazing.

YM - We're very lucky to have you on board and actually I thought it would be very interesting for our listeners to start by hearing about your journey into rheumatology because obviously you were training in, critical care and infectious diseases before that. 

MF - Right. Yes. I know. It was just that is what I chose to do from my heart initially but you know things change. You just need to adjust. I was sick before but, you know, I think that we just all try to, as physicians, we just try to pretend that nothing is happening or, like, normalize what your life is. But I had a lot of joint pains, a lot of other symptoms, but I used to be a runner. The problem is that I will get sick after a run but I was like yeah whatever I just put tape, you know and then so I finished my critical care fellowship or my infectious diseases fellowship and actually before I was diagnosed I have decided that I didn't want to do research anymore. So I decided that I wanted to be a clinician and I wanted to do critical care and I wanted to evaluate like patient safety and, you know, fixing things. And when I finished my fellowship and, I was working as an attending, at NIH and doing ID at Hopkins, I got very sick. I mean I got worse because I was I was initially very sick after having my daughter, so I started with respiratory symptoms and worsening of the musculoskeletal symptoms, but initially I thought that I mean you always I don't know why, you know, it's like all the physicians that I took that have any medical condition and many patients as well, but I think that the patients is are having those thoughts because we, as doctors, are maybe making them feel like that. But as a physician, I think that the initial thought is like, I am just imagining everything. You know? Like, this is not happening. So that was very challenging. 

YM - And then a few years ago, wasn't it, that you were diagnosed with relapsing polychondritis and that sparked your interest in the condition? 

MF - I was diagnosed in 02/2015. Yep. And then, I was diagnosed because I had a dalton's asthma, but it didn't go away, and I knew it was an asthma. And they gave me steroids. And that's so great. Really, really, yeah, I mean, it fixes it's amazing. I mean, I just didn't even know that I had been in so many places because I had been living like that for so long. And then, and then I couldn't taper, the steroids, you know. So I finished my time as an attending, but, I couldn't taper the steroids because I started having worsening and worsening symptoms. So I had a lot of joint, you know, swelling and pain and, and the joke I mean, I just keep believing that they we were joking about this at the beginning because I was coughing so much that I had to, like, get out of meetings. Right? And everybody will look at me like I was, like, having a contagious infection. Right? And it will be like and I was like, hey I'm just having allergies. So, anyway, so I got diagnosed and then, and then after that, I was very, very I mean, I was very sick actually until, like, about a year and a half ago. So I am so so lucky. Yes. I'm so pleased so pleased to hear that you're better.

YM - I know. And it's such a rare diagnosis. I mean, and just listening to your story, there was clearly quite a long time, to diagnosis, and how long was the journey for you? 

MF - Oh my goodness. Well, I think that, I think that there are a few stages. Right? So I think the first stage was I don't have anything, but you know that you have something, but you just don't want to believe it. Right? Because it's like it's not normal to have this and then have that and then have that, but you're like, yeah, whatever. So it goes away. And then there is the stage of like, uh-oh. I really have a problem. So between the I have nothing but I'm really sick it was about at the end of medical school. So this was 2004 when I still had repetitive symptoms and then when I couldn't, stop, like, when I got very sick, that was, 2014 because my baby was born December 2015. It was ten years, wasn't it?

YM - A decade. Mhmm. Yeah. Yeah. I mean yeah.

MF - That's good. I was very lucky, that I met this doctor. Amazing clinician. Super kind. Yeah.

YM - So we're gonna talk about relapsing polychondritis in a bit more detail. You've obviously already elucidated on some of the symptoms but what is RP? 

MF - So okay. So this is I have a different ideas. Right? So the, what people learn in medical school is that relapsing polychondritis is a disease that will affect the ear and you need to have the ear swelling and some people confuse that with ear damage. So like you need to have ear damage, you need to have the form. If not, you don't have relapsing polychondritis. That is the first challenge because that is the minority, minority, minority, minority. Right? Certainly, when I would think about relapsing polychondritis is when there is, perichondritis and typically it spares the earlobe because that's not cartilage. But yeah. Yeah. Yeah. But it's not, like, it spared the lobe. Right? So I have been learning so much about the ear. I have a very, interesting relationship with the ear. So I hate the ear for a long time because it's very upsetting that patients will stick with so the respiratory, type of herpes sometimes will affect the lower airway, only the lower airway. And then or the lower airway and a few other things. And the type three, which is the one that has all of these weird things that we didn't know it happened, it is, it's like all over. So it is very challenging, right, you know, to, to tell you what I what is RP. So but to make it simple, like, very simple. So RP is an inflammatory disease. It is not I don't think that this is an autoimmune disease. I think that I suspect that this is more on the spectrum of autoinflammatory disease Okay. Yep. That, that affects, patients with a specific pattern of organ involvement that can provide you the clinical diagnosis. Right? And then what is that? So that is, that you have, signs of inflammation in the ear in the ear, in the nose, in the eyes, the joints. Yeah. You know, and then hearing loss and, an airway. We don't have definitions of organ involvement, so that is our challenge. How would you define ear chondritis? What is your definition? 

YM - So inflammation in, the cartilage in the ear which is very in the lab which is non cartilaginous. With relapsing polychondritis it typically comes and goes, hence relapsing, so that's probably what I would think about. And I have one patient in my cohort so it's a very rare condition. 

MF - Fascinating honestly. Yeah but okay so we said like if you have inflammation on the ear that comes and goes and what would be the definition of inflammation?

YM - So so what we'd expect as rheumatologists, so you know you'll get the redness, swelling, pain, you may see some changes in the blood test in terms of raised inflammatory markers and usually often have a very good response to steroids. 

MF - Okay so I like a few things that is actually you this is one of the most comprehensive clear explanations that that I heard from someone so but it is challenging right because then there are many patients that we have a ER redness and swelling or ER a little bit of tiny redness but a lot of pain and the timing of the symptoms is also all over the place. So it's like if you have it for one day, two days, half an hour, it comes and goes within a day, it lasts seven days, what is it? You can you sleep on it?

YM - Does it get triggered by any particular trauma or situation? 

MF – Right, So it is it is challenging. And then, the second point that you made, which is the elevated inflammatory markers Yeah. That is also very tricky because many of the patients will have normal inflammatory markers, and I think that plus this I mean, who decided that these are the inflammatory markers that we need to use?

Yes. There are so many others. I mean, there is LDH. There is factor eight. There is, like, so many other things. Why everybody's like, let's keep doing CRP. I mean, where was this just, you know, like, validated? We validated this. Anyway. So, you can have other markers of inflammation that are not the conventional ones. So we talk about ESR and CRP. Yes. Many patients won't have elevated ESR and CRP. And so the patient that I have has always had normal inflammation markers when she has had chondritis, perichondritis. We can talk about that and then I can but so then the then, then that is the one of the main issues. Right? Because I think rheumatologists have the knowledge, the compassion, empathy, and capability to relate to patients that are having pain and the blood test will not show inflammation. However, many other physicians cannot because they do not have the experience and have, less understanding, you know, and knowledge that that can actually happen. But it can happen, because there are different pathways. Not all the pathways will give you this and sometimes we also forget that the patients are taking steroids when you're doing the blood test. So are the inflammatory markers numbered because of what you're giving them? Of course. Or, you know, so many other things like obesity can give you that. I mean, there is very, different, situations that can alter that, those blood tests. Yeah. 

YM - So you've kind of touched a bit about lung involvement already, and we know that's probably one of the most significant organs to be involved. Can you talk a little bit about that in terms of the diagnostic workup, how you would manage it? 

MF - So, you have a patient that comes to clinic, and the patient is like, oh, you know, I have this pain all over, then everybody's going to say like, this patient has fibromyalgia. Right? That is one of the diagnosis that actually is going to delay the diagnosis in relapsing polychondritis. And then, the patient, you know, is telling you, oh, you know what? By the way, I have been having these voice changes, this hoarseness, and I was just diagnosed with adult onset asthma. That should trigger. Okay. Show me the pulmonary contact going on. Exactly. Yeah. Because like, adult onset asthma is not I am not a pulmonologist. I am critical care but I have been spending a lot of time reading about this, and I think that in many, many, many cases, the adult onset asthma diagnosis sometimes is something else and in many occasions, this diagnosis is given by the patients by the primary care without pulmonary function test just because of the symptoms. And I think that that is, a disservice to your patient because you are exposing the patient to medications, you know. Long beta agonists and short, alpha beta agonists are medications, are drugs that can have side effects. So I think that this is this is an important, point. So thank you so much for asking about that. And then what is the workup pulmonary function test, they're not to diagnose relapsing polychondritis. That is wrong. You know, that question's on the boards, that's wrong. They need to delete it. Because if you take a look at the loop, right, I mean, what they're telling you is that. Hey, I have a patient. I have and then you take a look at the loop and then it's flattened. That happens when there is damage. If you diagnose a patient with relapsing polychondritis with those PFTs, you make the diagnosis too late. Yeah. You wanna make the diagnosis before there is damage, before there is significant obstruction. And how can you do that? You can do, a dynamic CT scan. So and then all the CT scans, the majority of the new CT scans that exist in the world is, are capable to do this. Right? So they can take an image when you're taking a deep breath Expiration and expiration. Yeah. And then you will see and then the other beautiful thing about the CT scans is that you could see air trapping, you could see bronchiectasis, you could see tracheal thickening, you could calcifications, you could see a lot get a lot of information without having to do an invasive procedure. And the reason to do PFTs is because I don't look at the first of all the pulmonary function test reading and numbers, the guidelines are new, There is a new guidance, so no. We have to rule out the guidelines. But if you wanna go for the old ones, we don't look at the FEV one, right, on the FEC. You look at the I'll look at the FEVF twenty five seventy five. Why? Because there is a surrogate of distal airway disease.

YM - That's very interesting to know. It's always very challenging to study rare diseases, and I know that you're making good progress with this. And I think it's important for us to improve our understanding about the pathogenesis, and that will help us in terms of treatment. At the moment, when you recruit, patients with relapsing polychondritis into clinical studies, are you using any classification criteria? 

MF - Yes. So, the inclusion criteria that that we usually, that we use to say this patient has simple chondritis or not is, meeting the macadam's, a pattern of organ involvement. But unfortunately we do not have clear definitions. However, if you have someone that is, you know, waking up at night ten times because the ear is painful, I will call that chondritis, right? And then we try to have witness like ear chondritis, but many of the patients are going to come with pictures. And, and there is a different interpretation of patients coming with pictures because everybody has their opinions. So it's like and I heard it right here and they're like, oh, this patient came with the pictures. Right? It doesn't mean that it doesn't, like, immediately has to, you know, represent that the patient is having, you know, is a neurotic person. It could be. Right? It's not an exclusion criteria. But what happened to these patients is that they get dismissed a lot. You know? I was told that I had syncopal episodes because I was working too much. And I was like, do you work too much? Do you have syncopal episodes? I don't think so. So then I think pictures are extremely important, especially with a condition like this where it comes and goes. And the other kind of situation I ask the patients to take pictures is with palindromic rheumatism where, again, they might be having inflammatory episodes in their joints when they're not in the, clinic with you, and then it becomes very helpful. So I think that's a very good point to make. You can document it. You should document it. You should ask the patients to send you pictures of the ear. They will, and they that is why they come for with pictures because nobody believed them before. Yep. Yep. Yeah. So that's why. So look at the pictures. 

YM - Yeah. Very good tip. Right. So we've we talked about the McAdams criteria in terms of kind of classification criteria. Once the patient's done Clinical criteria. 

MF - Right So this is not is not classification. We we submitted long time ago a classification, product for ACR and Euler, but it didn't get accepted for endorsement. And since then, things have changed Yeah. Because of new discovery. So we have to do that again. So there is no classification criteria, but there is a clinical criteria which is the McAdams. 

YM - Thank you for correcting me, I think that's very important for our listeners. So we've now got a patient who has been diagnosed with relapsing polychondritis, how do you typically manage a patient? 

MF - Oh my goodness. Where can I start? So that is, you start by having an understanding of what is the level of organ involvement. The level of organ involvement, if there is any organ damage, and how the disease is affecting the patient's quality of life. Those are the three main things that you should use to decide how to treat the patient. Because, going by like, oh, because he has the ear, oh, because he has the nose, oh, because it doesn't that is it's not like that. Because the disease, in many occasions can go to multiple places and it travels. It's very funny. It's like today I'm going to the nose, tomorrow I'm going to the hands, right? So it's just like counting and then Laurent Arnold, he developed a relapsing polychondritis disease activity and then we were in the process of trying to validate that before I left NIH so there is a lot of things that are still in the air, you know, while I'm settling. And then there was a discovery, right, of Vexas so it was like, explosion. So then there is a lot of things that we need to do. But, yes, there are there is a, disease activity that is complex and and it should be complex because these patients are complex.However, when they give you only twenty minutes to see a patient in the clinic, what you need to do is just, evaluate those three things, which is the primary points that you should target. Yeah. 

YM - We get even slightly less in the NHS. Yeah. Really wrong.

MF - So but the treatment, anti inflammatory drugs, but say, you know, still having ongoing symptoms and you're thinking of adding a conventional DMARD. So methotrexate, azathioprine, any thoughts? If you have a patient that has a scleritis, right, and the eyes, that patient treatment immediately. Why? Because it's the eye. And I have seen people, like, having like, it's horrible. So then you give them, post steroids.

That patient needs to be treated aggressively. Give them post steroids. And in that patient, depending on the rest of the organ involvement, because usually patients that have severe eye disease, they may have nose and an upper airway that is the type one. Those patients, respond well to, IL-6 in combination. The majority of these patients won't, usually won't respond to monotherapy, because this is not and that is also something that I have been thinking about. You know, the immune system is just not one pathway. I mean, it's not like IL6, It's IL6 and all these other things. Yeah. So, RP, I think that that is why it's challenging. So that will be what I will do for patient that is having that is having scleritis, that is having, airway disease. So a patient is having upper airway disease. Lower airway, you have a little bit of time, but upper airway, that is an emergency because then you will have sclerotic stenosis. And then they will need to have emergent intubation because they cannot be intubated. Right? Because the tube won't go through. And then if you have a patient that is having acute hearing loss, very rare in in relapsing polyconductor. You don't have that. You don't have the neurological things of, like, GPA, you know, like a food handler, like a like a food drop and neurological things or acute hearing loss, not happening. It's very, very, very subtle. If you have someone with acute hearing loss and dizziness and, eye disease, then we think about COGANs. That can happen with ear chondritis. Yep. But in those patients, any organ involvement that it is going to, generate significant consequences on the patient. You do high doses of steroids and you have to do a biologic. Yeah. Rituximab, has not been I mean, none of these medications have been well studied on this disease. Right? But rituximab, was evaluated long time ago in in, in the French cohort, and they found that it didn't work. And then with so many patients that they were treated by, with rituximab for, like negative, serologically negative GPA, and it didn't work. So that wouldn't be my first choice. Yeah. So the first choice in order will be severe. You can do tocilizumab or a TNF. Tocilizumab works very like, faster when you do IV in combination with methotrexate or as a thyroid. Right then? If you have, only lower airway disease, so you have a little bit of time, the patient is having, you know, thickening and he has joint pain, tocilizumab and methotrexate, can work as well. Yeah. But at the same time you have to see what are the other, issues that each patient will have independently, right, or diseases. And then for patients that have, the type three, which are these ones that you just that is so hard, you know, to find out what is the disease activity because then they're like I'm having joint pain and you're like when do you have joint pain? Well I don't know every day and you're like but is every day a lot or is every day a little or you know that is so like difficult. And do you have ear pain? Oh yes I have ear pain. How often? Almost every day, right? So it's just so hard you know to calculate what is how is this affecting the patient. Those are the patients that I think that are the most challenging and those patients actually I will try to don't use a super high dose of steroids. And I don't know if you have experienced this but there is a subgroup of patients that when they have higher doses of steroids, initially they get better, but then they get worse. And they will come and say, like, I don't know what is happening, doctor. These steroids aren't working anymore. And when I take them, I actually feel terrible, and it's not taking away the inflammation. Have you ever seen a patient like that? 

YM - Mhmm. Tell me a bit more. Yeah. I know. What what is going on?

MF - Right. So, the type three okay. So the reason that we, that I decided to do these different three types is because by knowing the clinical close to random that it makes sense, that that is the way that I was going to go after you read and see a patient, was to try to find out the mechanism. And then so we're saying that for relapsing polychondritis, as I understand, that there are now three different distinct patient clusters. So yeah do tell us about the different clusters and then what it means. Right. Yeah. So the type one is the one that is, the more severe. And these are the patients that have, sudden nose that will end up with sudden nose deformity, cauliflower ear, subglottic stenosis, and saccharides. They have inflammatory markers that are elevated. This is the minority. This, analysis was done with, variables that demonstrated damage. So this is late disease. So you know that will happen. The idea will be to try find out how you recognize that earlier. And one of the things that, we evaluated was the time to the symptoms. If you have someone that has nose pain, redness, and swelling for more than five to six days Yep. That patient has something that is not good, you know, that is going to be very severe. And it happens very quickly. And then the same thing with the ear. I mean, if you see someone that comes with the ear that looks like a giant tomato and I mean, I have patients that that are like, they have, like, told me they want to have the ear, like, cut off. So, like, just cut it off. You have someone telling you that and elevating inflammatory markers, you need to watch out that person very, very, very closely. So surveillance. Right? So what we said at the beginning is make sure what is the organ damage. And I just want to say this before I forget, which is doing a dynamic CT scan, doing a hearing test, doing a echocardiogram because sometimes very rarely you can have valvulitis Yeah. But you can also have pericarditis and then do a very complete review of systems and I'll talk about that a little bit when I talk about the type three. Now the type two is the group of patients that are going to come with a little bit of joint pain, maybe this like ear that is like a little bit bothersome. They may have oral ulcers because you know there's magic, right, like, magic syndrome, yes. And then they tend to have a little bit more oral ulcers, the people that have airway disease, and then they have the diagnosis of adult onset asthma. So they will have adult onset asthma or this ongoing very difficult to treat dry cough for years and we don't know what it is, then ten years later you do a dynamic CT scan and then you find like oh it was actually tregium. Those patients respond well to tocilizumab and then and the type three is like the mix of all of this. Right? So it's like patients that meet criteria based on the pattern of organ involvement. So they will say and they will show you pictures. And I said like my ear I'm sitting I'm sitting in the kitchen and then all of a sudden I feel that my ear started hurting and kind of burning, and then it gets very red and very hot and it hurts a lot, and it would last for one hour. And then it would happen again multiple times during the day. And then at night when I'm having this then I can't sleep because it hurts, right? Those are like usually not constant like the other one. Same thing with the nose and it will show you and these are the patients that are going to have additional complaints. So it's gastroparesis, POTS, tachycardia, you know, other symptoms that that you will never think that could be related to this disease, but I think it is. So then, they have pain everywhere. Right? So that's why they have fibromyalgia because they will say, doctor, my body hurts everywhere. I mean, I think that if you ask them, they hear it hurts. They will say, like, yes, my hair also, it hurts when I put it. Okay. This patient has tender points that would have this patient is for myalgia because the inflammatory markers are neck. And their inflammatory markers are normal. Yeah. You got there before me. Yes. And then it's everything is normal, but she hurts so much. And then and then she said that that sometimes her legs are swollen, but I can never really see it. Those patients yeah. Go ahead. Go ahead. This highlights the importance of taking a good history.

YM - Yeah. It's back to our bread and butter. Yeah. Yeah. Absolutely. I just also wanted to mention just for our UK listeners because obviously you've talked about IL-six Toclizumab quite a lot, we will obviously have difficulties getting access to biologics to treat this condition, but there are sometimes ways around it just in case people are listening to us and thinking well, how are we going to get tocilizumab for relapsing polychondritis in The UK? 

MF - Well, I have a list I have a list of candies. 

YM - Yeah. Excellent. Right. So I know you've been keen to talk about this from the beginning, and I think it's very difficult to not talk about VEXAS in the context of relapsing polychondritis. And you were obviously involved in the pivotal study, which identifies somatic mutations in the UBA one gene published in the New England Journal of Medicine, about VEXAS Syndrome. So can you give us a brief summary of the findings and the implications?

MF -  I can, but I have to finish something else about RP. Oh. I'm sorry. I have to say. So so when they complain of pain everywhere, check an aldolase because these patients can have fasciitis without myositis. And I have seen this in MRIs, and it goes away very quickly with steroids. So, if you check a CPK, it's gonna be normal. If you check an aldolase, it could be very elevated. So it is fasciitis, but it's giving them pain. So that is disease activity. And also look for CPK and all these other things. And if anybody's interested to talk about more, I will be happy to talk to you. But now we're gonna talk about Vexas. So Vexas. is so then it's v for vacuoles that are in the Balmoral. Right? They're very pretty, but we just don't know what they are, but they're pretty. These little things. I mean, we should make like a like a t shirt. Right? Like purple. And then we have, and then a v for vacuoles, e because the mutation on the UBA1 gene would lead to the malfunctioning of the e one enzyme, which is the first enzyme for the ubiquitin pathway process. And then, so that is e one x, is because it is x link a, due to auto inflammatory and s because it's a somatic mutation. So these are mutations that are located in exon three. Initially, the position was p 41 and the main, changes were, methionine for threonine, methionine for valine, and methionine for, leucine, right, at position p, 41. But since then there have been many other splice mutations that have been discovered that have been also associated with malfunctioning the ubiquitin pathway and disease. And then we have, look at the first main, you know, variants and then and then we found an association with the clinical manifestations. And what these patients are going to have is inflammatory disease associated with hematologic abnormalities. So this is the hematologic subgroup of relapsing polychondritis. Those were the patients that I identified the hematologic subgroup, which is where patients that have microcytosis and ear and nose chondritis only. I didn't see any airway disease, but we didn't find airway disease. 

YM - And why is it important that we identify these cases of excess? 

MF - It's a horrible disease. So one, because you can recognize the symptoms. You can make a diagnosis with a blood test. Access to the blood test the diagnosis is not available in all the countries, but in your country, there is someone that is very involved in VEXAS. His name is Sinisa, Sinisa Savic. So we work together. And then, so then he will do it, right, in his institute. 

YM - And certainly for those of us I was gonna say certainly for us, for those of us in London, we would typically send a rule free National Amyloid Data Center to Helen Lackman, who would also be able to do those tests for us.

MF - Yes. Yes. I know. She's also she was also involved in the in the initial description. She shared cases, from The UK with us that were included in there, four cases. And then the way that you recognize this disease is by, putting all the pieces together. That's why it's very interesting and that's why you need to talk to the patients and then learn about, the previous manifestations and examine the patients Because these are guys. Just a first thing, most of them are guys, which means that they are not going to tell you everything, and they're going to minimize. They're all like grandpas. You know? You go and talk to them and they're like, no I'm fine. And then you go and look at their legs and they're giant. And they're like, this doesn't hurt? And then you start asking and asking and then you find a bunch of stuff. I mean, I have someone that I saw actually at University of Maryland and I was like, have you ever had any skin lesions? And he's like, no. No. Excuse me. And then I examined him and he had a and I was like, so what is this? And I'm like, oh, this is normal for me. They come and go. And I was like, yes these are skin issues. Yes. So it's super important. This looks like Vexas. Yes. So if you have a male that is having an elevated MCV and the primary care, continues to send, you know, vitamin b twelve DSH and trying to find out why the MCV is elevated and there is no reason and the patient has inflammatory markers elevated, that patient is someone that I will do because, what I've seen I mean I look at records and records and records and then I didn't have all the records to be able to like put this together, but one of the main initial changes that I saw is the MCV, like even before the anemia. All of these patients were doing vitamin b12 because they're trying to correct something. And then on specific symptoms because it can go anywhere, mainly the lungs. They can go into respiratory failure, and they are risk of opportunistic infections. So the, I think that the reason so many opportunistic infections are intracellular. And then what I saw at the beginning in these patients was micro bacterium, a typical micro bacterium. Okay. Guess what? That is an intracellular organism. And then when I start reviewing the other stuff, then I saw that they have Legionella, Salmonella, and I was like, So intracellular organisms, they are at risk for this. The NTM is very important. Why? Because one of the main most common symptoms in VEXAS is skin disease. Skin disease, super important. What do they have? Neutrophilic, infiltrates, they cause acroclastic vascularis. They have many other things. And it can resemble sweet syndrome, can't it? Absolutely. That too. Now when you do, if you have a patient that has excess and you do not do a biopsy and you treat only with steroids, you could be missing an NTM. Why? Because you need a special test for NTM, and the vasculitis can happen at the same time. So if you do a biopsy and you see vasculitis, not enough. You need to do AFV. Why? Because your patient can have an NTM and you're giving them steroids, and that's no good. Yeah. They need PJP prophylaxis because it happens, and then they don't die from alpha herpes viruses, but they have horrible complications. So I also recommend prophylaxis for that.

YM - Great. Thank you very much. I think it would be good to finish where we began, and it sounds like there's still a lot that we don't know about relapsing polychondritis. So what is the current research agenda? Because I'm sure lots of rheumatologists that haven't worked with you in The UK would like to collaborate with you.

MF - So what is current research agenda for MRP? So there are different we can divide them into clinical projects and more translational, projects based on, different, you know, ideas and and things that I keep seeing, you know, after I left an age. So one of the, clinical important projects that are very close to be finished, we just need to let me need to do it, is the classification criteria that we need to finish because we started that with a very nice, group of people and the disease activity that needs to be done. And then and then clinically there is a lot of things that need to be explored, translationally I mean, I was telling you So these patients can have, not ESR and CRP elevated, but LDH. So looking for inflammatory markers that are already that already exist that are out there, and we just never look for them. And there is less understanding of how they are implemented in the market. Excellent. Thank you very much, and thank you for being so enthusiastic. And I think it's you know, you're a great advocate for the condition, obviously.

YM - And just for our listeners as well, there's an excellent nature review article that you've been involved with, in 2024 which gives a good summary of what we've spoken about today. Any final remarks? 

MF - That I think that all of you guys are amazing, and all of you are very smart, so you can diagnose these patients. Thank you so much for listening. This is a great opportunity. Thank you so much. Thank you very much.