Chronic Spontaneous Urticaria Learning Zone
Transcript: CSU symposium at EADV 2023
Emek Kocatürk Göncü, MD; Marcus Maurer, MD; and Martin Metz, MD
All transcripts are created from symposium footage and directly reflect the content of the interview at the time. The content is that of the speakers and is not adjusted by Medthority.
- Welcome to Berlin again. My name is Marcus. I'm from here, and I'm very happy to have you here. You came to the right session to conclude your day. This is all and everything you ever wanted to know about urticaria, an interactive session from the past to the present. Welcome, welcome, welcome. We have a stellar faculty, Emek, right next to me. - I'm Emek Kocaturk from Istanbul, Turkey, and also Berlin, Charité University. Welcome all. We will be having fun and learning a lot about urticaria today. And you will be voting. So I will give the instructions for you a few minutes later. - Super. And welcome, Martin. - I have my own microphone here. Yeah, so also hello from my end. Let's start. My name is here, so that's fine.
- You're ready. Then I'm ready too. All right, these are just practise questions. No right or wrong here. You can click whatever you want. We just want to see that you have a laptop on your knee and know how to work it. Which is best describing your occupation or specialty? You can read it. Please type now, and we will see how many people are in the room. Who of you has a laptop, has an iPad on? All right, let's work it so that we know who you are, that we know that you know how to take part in the polls. Good! All right, that looks good. We have lots of dermatologists, big surprise at the EADV. That's good. And we will be talking about a disease that we own as dermatologists. Now, let me know where you're from. Where are you from? And you can type planet, city, street, country, whatever you want to do. We can go to the next one. So the next question is, where are you from?
Super, UK. UK taking the lead here, but we also have Jordan, France, Nepal. Hello, Nepal. Excellent. - [Emek] USA. - France, Norway, USA. New Jersey. Excellent. And a lot of Germans, as is to be expected. All right, you guys know how to work this. Thank you very much. There will be questions from us to you, and we're looking forward to many questions from you to us. Let's make this interactive. Let's make this address what you want to know about all the questions you ever wanted to get answered on chronic urticaria. - Okay, so. And now you will be speaking about the past, Marcus. Aren't you young to speak about the past? - Oh. Emek. Thank you very much. Look, I wanted this because I wanted to remind all of us that where we stand today is entirely different to where we stood when this all started. And I don't mean in the 1800s or 1000 years ago, I mean 20 years ago, 15 years ago, where our knowledge, our tools, our treatments, our understanding, and our expectations were very different from what they are today. These are my disclosures. Now, the disease has always been the same, ever since there are humans, they've had wheals, they have angioedema. This did not change. Of course, the prevalence changed tremendously. And from our past understanding to today, a lot of things have happened in our view of this disease. We used to have limited understanding. And when I first got into urticariology, this was a psychosomatic disease.
You had this disease because there was something wrong with your head. Imagine, that's not 20 years ago. So this thinking has changed entirely. Of course today we know that your head suffers too when you have chronic spontaneous urticaria, but that is the consequence of having this stupid disease, not the reason for it. We didn't really know about the burden. We didn't really see what it does to our patients. We had no tools to measure disease activity, impact, or control, or to do provocation testing in a way that allowed us to assess disease activity in chronic inducible urticaria. There were no guideline, there was lots of eminence-based medicine, but no evidence-based medicine because there was no evidence. We had no registries, we had no app, we had very little, including very few treatment options. And in the heads of many physicians, urticaria made this happen. All of these thoughts come up, "Oh, it must be an infection, we better use antibiotics. Oh, this must be something with the gut. There may be helicobacter, this may be autoimmune, this may be what you eat, this may be what you breathe, or I think my people are all crazy, they have this because they are psychosomatically sick." All of this was going on in the heads of physicians and patients 20 years ago before we finally found the common denominator of this disease. It's a mast cell driven disease. It is one cell in the human body, in the skin of these patients, that make them sick. And to understand that all of the factors that have previously been speculated to contribute, that they all come down to muscle activation, was an essential step forward in our understanding, in our communication, in the development of drugs that work. So this really is a breaking point in the development from bringing past to present the understanding that mast cells are key players in making people sick because of what they do in the skin, because of what they do to people and the clinical signs and symptoms. Today we know that people are sick with chronic spontaneous urticaria because they have an autoimmune disease, an IgE autoantibody or IgG autoantibody-mediated disease. We did not know that. We did not know that for the longest time. And this is really something that is reflected. I pulled this up.
This is a slide I used my 20 years ago when I tried to explain to myself and others what chronic spontaneous urticaria is. What a mess! What a mess! Bringing everything on board that anyone had ever said could be linked to chronic spontaneous urticaria. Yet it is simple if we understand that mast cells driven by autoantibodies are the key player in driving the disease, driving the disease in different ways. We now understand that these two ways of being sick with chronic spontaneous urticaria really mean two somewhat different diseases. A very bad chronic spontaneous urticaria when you're autoimmune, and a much more easy to treat, short-lived disease when you are autoallergic. We also have emerged our thinking on the classification of chronic spontaneous urticaria. Now we call it chronic spontaneous urticaria. You know what it's called? You're all too young to know that. It was called chronic idiopathic urticaria. Ugh! As if we didn't know. Well, back then we didn't know, right? But today we know. So it's not idiopathic. It is spontaneous in nature and known in its underlying causes. And so important to let people know that inducible urticaria really is distinct. Yes, one patient can have more than one urticaria, no question about it. But it's not what we used to call it, a factitial component in chronic spontaneous urticaria, or this patient has chronic idiopathic urticaria but also responds to the cold. Ugh, no! Patients can have chronic spontaneous urticaria and cold urticaria, or cold urticaria and symptomatic dermographism.
Yes, but let's go and look in each patient what urticaria is present, because we know. So from all of these shortcomings in the past, we have emerged understanding of how bad this disease is. Why? Because we measured, we asked, we went to patients, and now understand that this is a severely troubling disease. You think psoriasis is bad? Chronic spontaneous urticaria is just as bad or worse. You think that asthma is bad? Chronic spontaneous urticaria is just as bad or worse to have. Just ask patients what it does to their lives, to their friendships, to their partnerships, to their work performance, to them being parents or kids. It ruins lives. And we as their treaters need to understand that, the need to treat and provide that treatment. And this knowledge we have today, we didn't have that before. We also make it very clear today that an angioedema is not a big wheal and a wheal is not a small angioedema.
No, these are two different ways of how mast cells make these people sick. They can coincide, and that's what they do in many patients. But we do have patients with exclusively angioedema, no wheals, and exclusively wheals, never have angioedema. And today, and this is evolution over the past, not 10 years, 8 years, we have tools to measure disease activity. We still don't have a marker. We still can't take blood and say, "Oh, this level is here, so the disease activity is," no. But we have tools that educate patients and ourselves on how bad the disease is. We started with the Urticaria Activity Score. Then came the quality of life instrument, the CU-Q2oL. And today everyone is using the UCT. How many of you treat patients with chronic urticaria? Hands in the air. That's almost everyone. Of those of you who treat chronic urticaria, who of you uses the UCT? Bam, those are the same hands. If your hands didn't go up twice, you're doing something wrong. Start tomorrow. UCT is a must in the treatment of chronic urticaria. For those patients who have angioedema, we had nothing. We could ask, "Did you have angioedema?" But today we have the Angioedema Activity Score, the Angioedema Quality of Life Questionnaire, the Angioedema Control Test. And if you're not using one of these tools to assess your patients with recurrent angioedema, you're making a mistake, and you can be a better treater if you bring that on board. Plus, it saves you time. In the CindUAS, chronic inducible urticaria, we used to put ice cubes on the skin of our patients. We are much better today. We know that the trigger strength that is needed to induce the wheal in chronic inducible urticaria is reflective of the disease activity.
And just to review with you briefly how easy these tools are for our patients and for us to understand, with the UAS7, all you need to do as a patient is tick one box for each one box for wheals every day to give you a point value, which times seven days a week will give you a weekly Urticaria Activity Score. And I copied this straight from what we had in mind 20 years ago, where we handed out sheets of paper where patients mark this down every day or in the bus ride to their next visit with us. Then we moved it to web forms, for example, this website here. And today everyone is using CRUSE, the chronic urticaria self-evaluation app. If you're not using CRUSE, start on Monday. This is the tool to bring on board with your patients. Available in 21 countries in the national version with the national medication list. Easy to do for patients, free to download, saves them time, saves us time. I'm a much better urticaria treater since I've been using this tool. In fact, I don't treat patients anymore if they don't use CRUSE. So, see how we've emerged? This was what we used to do 20 years ago when we suspected patients to have cold urticaria. No, mamma mia. You can see the cold water running down the skin, leaving the marks, the whealing marks.
We don't do that anymore. We've developed TempTest, a sophisticated, validated, robust, and reproducible device in different steps. This is version 2.0. And here you can see the 12 spots that this device made with different temperatures. Today, it's all about a gradient of temperatures that we expose the skin of patients to let them know, let us know how bad the disease is. So true evolution in a lifetime. This is 20 years of development, and today we stand with tools that are readily available and provide good answers. For example, what is cold to you? When does your skin reach a temperature that will make it have a wheal? Is it 15 degrees Celsius? Is it 40 degrees Celsius? Is it 30 degrees Celsius? We can tell patients what temperatures are risky for them, what lakes they shouldn't swim in. So here we have true evolution. Same with symptomatic dermographism. This is a disease that is very common, and we used to just take our pens and scratch patients up and down. But today we use dermographometer. How many of you have a dermographometer? Not enough! I suggest you get one. This is the way to assess disease activity in symptomatic dermographism. With FricTest, for example, four pins, four stripes, four wheals means high disease activity. And of course, our thinking has emerged tremendously because of the data that are now there. For example, from CURE, the Chronic Urticaria Registry. This is eight years of work where we now have 60 countries, no, centres in 27 countries, contributing more than 5,000 patients. This is the present. This was not the past, where everyone had their own little data bank, their own little knowledge, the same as others, different than others. Today we merge our data, we work as a global network, we collect data. So we come from limited understanding, underestimation of this disease, limited knowledge, no guideline, no networks, few treatments, to a very strong community with strong tools and a great guideline, which will be my last point here. Treat the disease until it's gone.
Ever since the first version of the guideline 20 years ago, this was the mantra. You see young Thorsten Suvaby here, young Clive Grattan and Carsten Bindslev-Jensen. This is 20 years ago. And then we had nothing. We had antihistamines, old antihistamines, and we had to say, "Non-sedating," to distinguish them from what everyone was using. And then over time, every four years, we made the guideline better, we got new tools. This is 2016. And then 2020, the pandemic years, moving us to more sophisticated treatment. Now also including up dosing of antihistamines and omalizumab. And of course, five years ago, UCARE came on board. UCARE was born. A global network of centres with now 167 UCAREs around the world, in 43 countries. This is what modern urticariology looks like. This is where we get the knowledge. This is also where we distribute the knowledge. For example, on Urticaria Day, for example, via our programmes. Level up for us as physicians, or for you, for the patients. All right, I'm done preaching. All I wanted to say is we come from horrible times, especially for our patients, and we're moving to a disease that is easy to treat, well understood, and should be, because it is still as troublesome as it was 20, 200, or 2000 years ago, only today we can do something about it. And if you want to learn more or share your own experience and are free the first week of December, by all means come to Sao Paulo, join us for the world's UCARE conference and share with us the evolution in our understanding, treatment, and progress in chronic spontaneous urticaria management. This is the UCARE in Berlin. I see many of its members in the room.
Thank you very much for your continued support. I put my email address on the bottom right, so any questions we don't have the time or you don't have yet to answer today, send them to me. Share your difficult patience with me, ask me your questions, share your interest. Thank you very much for your attention. And with that, Emek, it's your turn. Do bring us to the future. Where do we stand with the current guidelines in chronic spontaneous urticaria management? - Okay, so I'm going to speak about a patient-oriented approach in chronic spontaneous urticaria. So yes, but I'd like to start with a case study, and I need your help to solve this patient. So this is a 35-year-old woman who has been experiencing recurrent wheals and angioedema attacks for two years, and she has been doing well with levocetirizine 5 milligramme daily. But her urticaria aggravated when she had COVID-19 infection as we all physicians experienced similar cases. And then she was prescribed rupatadine two times daily by a dermatologist. But she says that she is visiting emergency department every two weeks for steroid injections. So my question is, what would be your next step in the management of CSU in this patient? Please vote for your answers. Send her for allergy workup. Updose rupatadine up to 4-folds. Combine rupatadine with hydroxyzine. Prednisolone 30 milligramme daily for 3 weeks. Add H2 blocker. Please vote. Start voting. So 75% updose rupatadine up to 4-folds, while some give prednisolone and some add H2 blocker, while some combine, and some send to allergy workup. Thanks for the answers. So now it's closing, I guess.
- [Marcus] Was it right? - Ooh, we will see. Time will show. So let's come to our international urticaria guidelines. So the guidelines suggest a patient-oriented approach, and we should assess every patient differently. And first of all we have to make the diagnostic procedures the guidelines suggest us and we should take care about comorbidities the patient has. And also we should assess the disease activity and disease control and also consider patient preferences when deciding the treatment. And then we can modify the treatment or decide on the treatment and educate the patient. And we have to see the patients in routine controls to decide if she or he is under control and change, step up, or step down the treatment with deciding on their UCT scores. So we have the 7Cs provided by Martin Metz, a great article, you should definitely read it. So we have the 7Cs, and first of all, the basic laboratory work-up that the guideline suggests us to do is making the CBC, CRP/ESR, anti-TPO IgG, and total IgE levels for every patient. And then we start with the 7Cs.
Let's go one by one very shortly. So the first 7C is the confirm. Of course we need to confirm the diagnosis of urticaria in this patient. Are we dealing really with urticaria, chronic spontaneous urticaria? So first of all the patient should have itchy lesions. If the burning sensation or pain is dominating rather than itch, then we should think about urticarial vasculitis for example or the wheals are lasting longer than 24 wheals, then it could be another disease, it could be eosinophilic cellulitis, it could be a PQ reaction or low sphingolipids. If the patient has post-inflammatory hyperpigmentation or post-inflammatory purpura, then we may be dealing with urticarial vasculitis. And if the patient tells us, "I'm having my rash with fever in the evenings," then maybe we are dealing with an autoinflammatory syndrome. So we should be thoughtful about these possibilities. And the cause, as Marcus already mentioned, urticaria is an autoimmune disease, and we take the autoimmune pathomechanism as two underlying mechanisms. First is type I autoallergic CSU where we have the IgE type autoantibodies against self, and these patients have more comorbid allergic diseases and they show good response to omalizumab. The autoimmune type IIb type has low total IgE levels, and they show poor response to omalizumab treatment, and they have more comorbid autoimmune diseases, but this is a rarer type. Most of the patients have autoallergic type. And the co-factors, we shouldn't be forgetting about this, and we should also tell our patients that NSAIDs and aspirin can aggravate their diseases, and they can use paracetamol instead. And stress and infections can also exacerbate their diseases. And it's important to keep their disease under control when they are facing such events or occasions. And comorbidities is also very important, especially autoimmune comorbidities really have a high prevalence in CSU patients especially. Hashimoto thyroiditis is one of these. And there can be atopic disorders, there can be mental disorders especially in one third of the patients. Metabolic syndrome and other chronic inducible urticarias may coexist in chronic spontaneous urticaria patients. And of course patient-reported outcome tools which are now merged in CRUSE app.
So it's a really very convenient tool to use. But if you like papers and want to print out and give to the patients, then the most commonly used ones are Urticaria Activity Score, Urticaria Control Test, and Chronic Urticaria Quality of Life Questionnaire. If the UAS7 score is higher than 27, then we are dealing with a severe urticaria. And if the Urticaria Control Test is below 12, then it's a patient who is not responding enough to the treatment, so it's not under control. And if the patient has Chronic Urticaria Quality of Life score over 50, then she or he is impacted substantially by the disease, severely impacted patient. So let's come back to our case. And so we checked her laboratory values, and her CBC and routine chemistry tests are in normal ranges. But she has elevated anti-TPO levels, but the thyroid functions are normal. Total IgE seems to be bit low, 34. And CRP is elevated. No Helicobacter pylori. Urine analysis normal. No chronic infections, no psychiatric comorbidity, and thyroid ultrasound is normal. So then we give her, we didn't have CRUSE at this time, tests. So and her Urticaria Activity Score weekly was 33, so it's a severe disease activity. And her Urticaria Control Test with rupatadine 2-times daily was UCT, 2. Sorry.
And Chronic Urticaria Quality of Life Questionnaire score was 61, so she is severely disabled by urticaria. So what shall we do? How does international guidelines tell us to treat the disease? So we start with standard doses of H1, second generation H1 antihistamines, and we up those up to 4-folds, and if not responding then we are adding omalizumab to the treatment. And the guidelines suggest to stay in omalizumab treatment at least six months before deciding that it's not working. And if omalizumab is not working then we are switching to cyclosporine treatment. And UCT is very important in deciding how to manage the disease. So if it's below 12, then we need to step up treatment. For antihistamines, we need to updose. For omalizumab, after three months we can shorten the intervals of the injections or we can increase the dose up to 600 milligrammes. And if we have the UCT 16, we are very well, and we can start stepping down the treatment. So in this case we increased the dosage up to 4-folds rupatadine, and when she came back after two weeks, her UCT score was still two. Then she was started on omalizumab treatment, but after three doses of omalizumab, she still has UCT score of four. Now please help me. What shall we do in this patient? What would you do in this patient? Please start voting. It's a bit stressful. Are you voting? Okay. Oh, 80% is updosing omalizumab. So you're listening to me. Okay, so let's see what we did in this patient.
So her omalizumab was first increased to 450 milligrammes and then to 600 milligrammes. But after six months of 600 milligrammes of omalizumab, she still has UCT 8. And she says she's still getting steroid injections. And then we cease omalizumab treatment and give her ciclosporine treatment. And she started finally to get better, but now she says that I want to cease this medication. It's a lot of side effects. I don't want this drug. So it can happen, you know. I want to briefly speak about how to updose omalizumab or a little bit information on it. It can be updosed. We made this review and in this review we found out that omalizumab updosing can be beneficial in patients even if they are non-responders after three or six doses. And there can be a complete response in 60% of the patients when we updose omalizumab. In patients with high BMI, previous cyclosporine users, or low total IgE levels, this seems to require higher doses of omalizumab treatment. So there are some predictors of treatment response. For example, low IgE levels means that the patient may not respond omalizumab that good, but can respond to cyclosporine better. And there are also different clusters and different endotypes of patients. And so what's your next step in this patient? So she says, "I want to cease cyclosporine now." What would you suggest this patient to do? Has used omalizumab, updosed, no response. And we gave cyclosporine. She was responding, but she says she wants to cease. Did you what? - [Marcus] I voted. - So, stop cyclosporine and enrol the patient to a clinical trial. Oh, Martin, it's your turn now. Then please tell us about the clinical trials.
What do you think? Are there clinical trials that we can send this patient to? - Yes, of course there are. And about some I will talk about, and there are more to come that I won't be talking about. But I love the, I love the response rate. 76%. - How many in the room work at a urticaria centre? Let me see the hands. And how many of you with your hands up, leave your hands up if you offer clinical trials. All of you have clinical trials? Super. Okay, that's what we need. Perfect. Let's send patients to participate, benefit. - And if you don't have them, send them to the next centre that provides them, because as we heard from these types of patients that Emek we're just talking about, but also, I mean many others, they need additional medication. And this is actually what I will be talking about here. So you saw this one before. This is the current guideline that we have for the treatment of our patients. And I don't want to go into detail, but I want to stress that there is room for improvement. And I think Emek's patient was the best example for this. I mean, and this is not, I mean luckily this is not the everyday patient nowadays. Yeah, for us, of course, more commonly so. But these patients are out there, and they need something else beyond OMA. And let's be honest, who wants to go back to cyclosporine? This is I think treatment of the past. So Marcus can talk about this for keep talking about it is passive urticaria treatment, hopefully.
So I will be talking about the future, hopefully what will come, what will be around. But what I want to start with is what we have at the moment. So at least one slide for omalizumab, and actually today I received an email celebrating 20 years of omalizumab in asthma apparently was approved 20 years ago. So this is a drug that we know quite well now, and we know that it's an excellent drug, it works well. So these are the results from the pivotal trials that led to the approval in chronic spontaneous urticaria. And this is excellent. And at that time we were totally excited and said, "Finally we can deal with urticaria. And we're so happy." And now we realise that, well, there's 60% left that are not sufficiently treated. And then we have the other side, the chronic inducible urticaria, where we have tones of evidence that omalizumab also does work in quite a large amount of patients, but we don't have it approved. So we don't have an approved drug apart from antihistamines in chronic inducible urticaria. So for sure we do need new drugs, we do need new targets to offer other possibilities. So here I come to the clinical trials, and I want to introduce the general therapeutic principles for any mast cell disease. So not necessarily only urticaria, but urticaria is the most best known and most prominent mast cell driven disease. So of course we can inhibit mast cell mediators. We have done this for ages with antihistamines. But you see maybe here on the side, there's also cytokines, something that we have to reconsider. Mast cells make tones of cytokines, and we have cytokine antibodies, dupilumab, the AL5 antibodies, and so on and so forth.
These are all cytokines that are also released by muscles and may play a role. Direct inhibition of mast cell activation is the one thing that we're doing at the moment quite efficiently by getting rid of anti-IgE. But there are other receptors that activate the mast cells. And I will talk about some in a bit. Something very interesting. Direct activation of mast cell inhibition. So we also have receptors on the surface of mast cells that do not activate but silence a mast cell. And there's also something happening, something that we call indirect inhibition or the modulation of mast cell activation. We know that other cells are involved, again, cytokines largely involved here. And then finally we can get rid of mast cells, deplete mast cells. And as mentioned before, I will talk about a few of them where we do have data. And I want to start with direct inhibition of mast cell activation by blocking BTK. Actually something that marks this, 20 years ago we didn't even know that it exists, basically. Now we know, and we know why it is so good in urticaria, why it's such a good idea to come into this disease with the bruton tyrosine kinase inhibitor. This kinase, the BTK, is downstream of the FcεRI. And of course we know now IgE, auto IgE is important.
This is why omalizumab works so well. And this is downstream of the FcεRI because you have cross-linking of the receptor. So if you block this, patients are happy. And then we have these other group of patients, these type IIb or classical autoimmune patients. And here we mostly have IgG antibodies that are directed either against IgE or against the IgE receptor. So again it's downstream of the FcεRI and again it needs to go through BTK. So it makes perfect sense here. We have an added benefit. BTK is also downstream of the B-cell receptor, so it also reduces the auto antibody production which over time may extra benefit for these patients. So it makes perfect sense to use this drug in urticaria. And it has been done. And Marcus published the phase two study. I can tell you already, the phase 3 study is also already out there. And there was a press release basically confirming the excellent results that we've seen for this phase two study. But what you can see here is that you have a very rapid effect. This works perfect here. You have a very rapid effect. So already after one week a dramatic reduction in the Urticaria Activity Score, and then you reach plateau already after two weeks, and then it stays down. And this is quite a dramatic effect.
What is of crucial importance for us is that we have an alternative to omalizumab. So because these are at the moment our most problematic patients, those patients that do not respond at all to omalizumab or where it takes too long for them to respond to omalizumab. And these are the patients with Emek was talking about, where we just we go back to cyclosporine and something that we really do not want to do. So here in the phase 2 trial, they looked at how do omalizumab-naive patients improve as compared to those that previously had omalizumab and were not full responders to omalizumab. And without going into details on all of these bars, you see that there's basically no difference in between them, regardless of which dose you were looking at, telling us that the efficacy for the BTK inhibitor seems to be similar for those patients that before did not respond to Xolair as compared to those that are omalizumab-naive. Giving us really hope we have something in the hopefully near future. As I said, phase 3 trials will be presented later this year.
So hopefully this is around the corner. Now I come to something, I would say completely different, special for mast cell enthusiasts and of course also urticariologists. And this is a drug called barzolvolimab that is able to deplete mast cells. So it blocks the binding of SCF to KIT, and the mast cell requires KIT and signalling through KIT by SCF to survive. So if we can't do that or the patient can't do that, then presumably there are no more mast cells. This was done in chronic inducible urticaria patients. A single application of an IV drug, and within no time tryptase levels were down. Tryptase is a marker for mast cell burden. We know this from mastocytosis patients. But not only that, it's not only the tryptase serum can be found, but indeed, when we looked into the skin, we also saw that the mast cells were disappearing. So you see here, this is a tryptase staining. So all of these red cells are tryptase, and the shadow, the red shadow, around the cells is the tryptase that is a little bit released from the cell. So this is how it looks like normally. Four weeks later, only around the blood vessels, some mast cells left. After 12 weeks, we have a mast cell deficient skin at least. Now what does this do to the patients? All of the patients with inducible urticaria here, with cold urticaria and with symptomatic dermographism, lost their signs and symptoms, 100%. Okay, it's only 10 patients, but it's clear it's a mast cell driven disease. And no mast cells, no more disease.
So at some point, a single application, there were no more signs and symptoms in these patients. Now this was for inducible urticaria and this is the most, I would say, straightforward urticaria disease when it comes to mast cells. And the chronic spontaneous urticaria appears to be a bit more complex. So it was really interesting to see the first data that were reported by Marcus earlier this year at the EAACI in Hamburg, not yet published here. And what you see in the end is almost the same. So if we look only at the two highest doses that were used here, down here, the red and the violet, this goes down to almost zero in the Urticaria Activity Score. It does take longer. So we find out what's happening here, what's the difference? There probably are the cells also involved here. Note that there's not a single dose, but a multiple application of the drug. What is most important, all of these patients in the two higher doses achieved control. So the UCT that we learned is so important is above 12 in all of these patients at some point, and stay up. You know, this is also something that you see here. So last treatment, and it stays up. So you would say that, "Okay, is it a good idea to get rid of mast cells?" And at the moment I would say, "Apparently it doesn't matter."
Of course this is early times, so we have to follow this up. But getting rid of mast cells doesn't make obvious problems, apart from maybe also losing allergy. But getting rid of KIT does cause a few problems, because KIT is also expressed by melanocytes, for example, and the melanocytes in the hair follicle, they require the SCF. And therefore you do see hair colour changes in some of the patients. This seems to be dose dependent, so you need to figure out the best dose that is used. But at some point at a certain dose, all of your of the patients or most of the patients will get a hair colour change. We learn from Our patients actually that they don't mind that much because some think that, hey, it's cool, look like George Clooney with the beard. And others, we thought especially the younger women would have a problem and they say, "I dye my hair anyway." So we have to see how this is dealt with, but at least it's something where we can treat basically almost all patients. And then finally at the end, also very interesting approach. I mentioned this, the silencing of the mast cell. So we have these inhibitory receptors, and there's a drug called lirentelimab. Now, this is data from an open label trial. So we have to still be careful.
The phase two placebo-controlled trial is ongoing, and we're very much looking forward to these results. But what we do see here is that it shows efficacy in this open label trial, and it shows, again, similar efficacy also in the omalizumab refractory patients. And that would of course also be a cool and neat treatment if we silence the mast cell, because then it doesn't matter what other activator comes along, and the mast cell would be calm. Okay, my last slide. A few words on other things that we, yeah, the title was "What's new in management?" And for management, there's more to look at than just the treatment. I mean, I think you are all convinced, you all know that we need novel treatment, novel targeted treatment options, but also because we need to have a personalised treatment. This is true for so many diseases. But this is also and will be true for urticaria. At the moment we just don't have it, because we only have OMA, and we would love to be able to say that, "Okay, you will be the best for omalizumab, Please stay with this, because you will respond within a day." "For you, BTK may be the best." "For you, we completely deplete your mast cells." So we need that. But we also have to, and this was mentioned before, and I'll mention it again and again and again, your patients should use the CRUSE control app, because here you also find a personalised approach to the disease, because there are different aspects to the disease.
For some it's the wheal, for others it's the angioedema. And we need to get this information. And since you know, you saw the list from Marcus, if you all do this on paper, it's a long. I don't know how many are doing this in private practise. So this app takes control of this. And then finally, still there are patients there that are different in their comorbidities. And some, Emek mentioned it, sometimes you have cofactors that worsen the disease and it may make sense to send them to an ENT. There are still these patients that require some other specialists, and you should think about that. And with that, I'd like to thank you very much. - Thanks, Martin. Brilliant overview. The future is bright. My iPad is exploding with your questions. That's great. But I will give priority to anyone who wants to step up to the microphones and ask a question live. If we could only pick one of the patient-reported outcome tools. So we talked about the UAS7, UCT, CU-Q2oL, when time is limited in a busy clinic, which one would you choose? Martin, this one goes to you.
- So I was following here. I have to read up. If we could only pick one of the, well, the UCT. - UCT. That's clear, clear-cut answer. - I second that. Four questions, less than a minute. You can do it. There's a UCT7 if you're interested. - And it covers everything, right? - Covers everything. - So you get the patients with inducible urticaria, those with angioedema. So you have the one tool that, you know, broadly. - Super. Please. - [Audience Member] Do you really envision in the coming two, three years that type I will be still more dependent on omalizumab and type IIb will be more on the BTK inhibitor? Something like that? - Well, this is really dependent on what we have as biomarkers. And as you heard from Marcus, we are not there yet. We don't really have them. We have some biomarkers that indicate that this is more this and that. But what would be nice is, especially for the type one, we don't really have that. So if we have a simple blood test that shows you here's auto IgE relevant in this patient. Well, if I have this, if I know this is the, and no other autoimmune, this type IIb part, then I will know this is a patient who will respond within hours, maybe, even one or two days to omalizumab. And yes, this would be a patient where I would go for omalizumab first. This is one example, but we're definitely not there yet. But hopefully we will have this possibility then to choose. - Second part of my question is, Are BTK inhibitors actually disease modifying? - Well, it's too early to say that, but yes, it could be, because I mean at least for a certain amount of time, because it interferes. And we have shown this for another one for fenebrutinib, another BTK inhibitor, we've seen that there is indeed a reduction in autoantibody levels. And this is also seen in other diseases like rheumatoid arthritis and MS. But whether this is sustained, we just do not know yet whether it's truly disease modifying.
- Good one. Hello. - [Audience Member] Hello. I have a patient, a child. He is seven years old, and he has albinism and chronic spontaneous urticaria. He's using omalizumab for about one year. And now I opened the weeks for four weeks, five weeks. But after six week, again the urticaria occurs, so I get back again. But how long can I use it, and what is waiting for him in the future? - Very good. Super question, because that happens a lot. Emek, you want to take it away? - Yes. So with kids, I don't have long-term usage of omalizumab, but it seems there are many case series about it, and it seems safe to use in children, and for long-term, we are not aware of any bad stories about omalizumab treatment. I have patients on omalizumab for 10 years almost, and I didn't really see any long-term side effects. - Treat the disease until it is gone. That's for kids and adults. So as long as the disease is there and you have treatment that controls it completely, that's the way to do it. You can space the intervals. If you have someone who can do it every five weeks without having problems, all right, that's okay. But not let them come back to having the signs and symptoms. Sophia. - [Sophia] Do you think JAK inhibitors will play a role in the treatment? - JAK? - [Sophia] Yeah.
- Which one do you want, one, two, three? - [Sophia] That's the question. - All of them, okay. JAK inhibitors, people, what do you say? - Well, there are some questions that you also have to answer. - No, I only take the easy ones. - Since it was my part, I'll try to get this. I mean we have IIb, already some trials, and we know that some of the, where we think that it shows effect goes via JAK. So at least it's definitely worthwhile testing it. And for sure there will be patients who respond to JAK. Whether it will be, I don't foresee it as this fantastic drug, as in AD, but for sure there will be some where it makes sense to use it. - Very good. We're coming to the five-minute marks, and that means rapid fire from now on. Short questions, short answers please. - [Audience Member] Why is rituximab not well investigated as a treatment option for chronic autoimmune urticaria?
- I don't know. - Yeah, the clinical trial was stopped. There was a CSU clinical trial, but it was stopped. - Yeah, I mean there are probably various reasons, but I mean one is of course also safety. I mean you completely get rid of the B cell and your infection risk is high. This is something that you don't want to see in CSU. - But when it is used, it often works. So that's that. Please. - [Audience Member] Does it need to do a tuberculosis before using omalizumab? And what is the most important lab investigation for follow-up in the patient for one year? - You are asking if there is a laboratory work-up needed. - [Audience Member] A baseline. - The baseline laboratory work-up is, as I showed you, hemogram, CRP, ESR, anti-TPO and total IgE. Total IgE levels work for foreseeing, for predicting if omalizumab may work or may work later in this patient. So if the total IgE level is below 40, then maybe this patient may respond later or may not respond at all. So total IgE is important. - [Audience Member] No need for tuberculosis as like other? - No, no, no, you don't need it. - No questions from the room right now, so we can take some from online. Is it still worth sending all patients with CSU to ENT dentist focus search exclude H. Pylori?
- No. - You see two experts shaking their heads no, that's not what we do anymore. When to de-escalate omalizumab. So when to stop omalizumab? How do you proceed? All right, I'll take this one. So the Berlin clock is one year, my clock. I have my patients document for one year, no signs and symptoms, no breakthrough wheals, no breakthrough angioedema, that's when we talk about stopping the treatment and we don't do it cold turkey. I used to do that, just stop and see what happens. Now I space it five weeks, then six weeks. And if it holds, if there's no breakthrough, if there's no signs and symptoms coming back after nine weeks, after reaching a nine-week interval, we stop altogether. And I'm still cautious, and tell them, "If it comes back, you come back, because then we need to treat again. Then antihistamines will not do the job. They didn't do it last time, they will not do it now. And we will start re-treatment, or we'll start treatment with omalizumab again." That's how we do this. What's the more useful endpoint? This is from clinical trials, UAS7 or ISS7? The ISS itch severity score is a part of the UAS. The UAS7 is the gold standard. Please use the gold standard if you're planning to do a trial. Question here for Emek. On the guideline it says, "Add on omalizumab." Do you stop the antihistamines when the omalizumab kicks in and there are no more signs and symptoms, what do you do? - No, we need to add on omalizumab treatment over antihistamines, because if we interrupt antihistamines suddenly and start omalizumab, then we can have aggravation of the disease, so we should keep on the antihistamines.
And if we have good response to omalizumab, then we can de-escalate the doses of antihistamines, and we may also quit them if not needed by the patient, but after three to six omalizumab injections. - People want to know a little bit more about the problems with muscle depletion. Martin, you want to go into more detail? You talked about the hair. - Yeah. So I can tell that we worked a lot, actually, both Marcus and I worked a lot with mice that are muscle efficient or KIT deficient, that is. And we saw a couple of problems like wound healing problem, for example. That's why we looked in our patients. And this does not occur in patients. So there's no change in wound healing whatsoever. So therefore I cannot predict if there will be anything really. I mean, if you're an animal and get bitten by a snake, then this might be a problem, but since this is not relevant for us, I don't see really anything.
- I agree with you, but we should say that other KIT-positive cells like the melanocytes do also get hit by this treatment. So some people lose or get impaired sensation of umami, because the umami taste beta cells are also KIT positive. Men need to expect that they become infertile transiently, but sperm cells also carry KIT. There's a bit of neutropenia which never got to clinically meaningful levels. But essentially you're hitting every cell that has KIT. And the mast cell is not the only cell that is KIT positive. - Marcus, there is a question for you. Why is urticaria? - I saw that one. We ignore that one. No, hit me. - It comes to you. Why is a acute urticaria in some people but chronic urticaria in others?
- Well, we're trying to find out. You have to know that up to 30% in some studies and as little as 1% in other studies of patients with acute spontaneous urticaria go on to have this for longer than six weeks. And by definition, they now have six-week chronic spontaneous urticaria, and the two CHAPEAU projects at Charité, in Berlin, they are trying to figure out is it the evolution of autoantibodies, is it autoantibodies there from the beginning, or then losing autoantibodies when spontaneous remission occurs that is responsible for this change? As far as today, we do not know. That's not a good way to conclude a symposium on urticaria, because we know a lot. So one more question here from the feed. If I updose the antihistamines, do I give them all in the morning or do I split the dose? - Emek, this one is for you. - We split the dose two times two daily. - Super. - For psychological reasons. - There's a couple of more questions here. If they come from you, send us an email. We'll be happy to answer them offline. Thank you so much for coming to the symposium. Thank you to our marvellous speakers for their presentation. I wish you a wonderful night in Berlin, and a great rest of the congress.
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