Transcription
Today, we have a lecture by Professor Marcus Mora on chronic urticaria: an update. Welcome, Professor Marcus Mora. Professor Marcus Mora is the Professor and Director of Research of the Department of Dermatology and Allergology at the University of Charité in Berlin. Professor Marcus Mora has an excellent career with a lot of publications, over 540 in peer-reviewed journals, and over 40 book chapters. He is a leader in the field of mastocytosis, autoimmunity, neuroimmunology, and on the clinical side, on urticaria, pleuritis, psoriasis, atopic dermatitis. Professor Marcus Mora has received several awards and recognition over the years. He is also the lead of the global guidelines on chronic urticaria and, in fact, led this as early as 2011-2012. We, as APACHE, are extremely privileged and happy to be part of that global guideline from this update onwards and will look forward to working together on various aspects of this area. So, Professor Marcus Mora, welcome, and please start your lecture.
Hello and welcome to this APACHE web lecture. My name is Marcus Maura, and we will be talking today about chronic urticaria. I will update you and provide some tips and tricks, really practical things for when you see your next patients with chronic urticaria. Let's start at the beginning. We all know that chronic urticaria can be a challenging disease for us as the treating physicians, but more importantly, for our patients. This is a horrible disease, really, with the itch that comes from the wheals, with the anxiety and fear that comes from the swellings, the angioedema, with this "I don't know what this is" and "how to deal with this." Patients need help, and we can give them help.
And here is my approach to a new patient with chronic urticaria. Patients come to you, but rarely do you see a picture like this. When was the last time that you, in your consultation hour, really saw wheals that looked like this? This usually happens in the afternoons, at night. Patients tell me, "Doctor, I'm so frustrated because I can't show you what this normally looks like." We all know that the wheals are fleeting, transient. So, I always ask my patients to show me pictures. And sure, they do have pictures from the last time that they had wheals, from the last swelling that they had. This is so important to get an understanding and to make the patients realize that we know what this is, even though we cannot right now, when the patient is with us, see the signs and symptoms, the lesions of chronic urticaria.
Now, once I've made sure that this is chronic urticaria, longer than six weeks of wheals and angioedema, or both, my next question really is, what type of chronic urticaria are we dealing with? Is this spontaneous, where there's no trigger, or is it inducible, or is it both? Because we know that 20% of patients have chronic spontaneous urticaria and cholinergic urticaria or symptomatic dermographism or another form of inducible urticaria. I ask the patients, "Can you make your wheals come?" even when I'm already sure that they have chronic spontaneous urticaria, so that I know what I am dealing with. And I always ask about both wheals and angioedema. Why? Well, I want patients to understand that I realize how bad wheals and angioedema are, and I want to know in patients who like to talk about their wheals if they also have angioedema, and in patients who like to talk about their angioedema if they also have wheals. This is the most common presentation: wheals and angioedema. But you and I, we know that there are patients who only have wheals, there are patients who only have angioedema, and all of this is chronic urticaria.
Does it happen in children? Just a quick yes, it does. Of course, you all know that. Actually, we know now that in Asia, children are more likely to have chronic urticaria as compared to adults. And we have learned quite a bit about children with chronic urticaria. We've learned that this goes away, just like in the adults, but that it may take years for this to happen. And we've also learned that if it starts out bad, with a high disease activity, then chances are that the duration will be longer. So, this helps us to guide our approach in children and to talk to parents about what to expect from this disease.
Back to the adults. "Doctor, is this dangerous?" I get this question a lot. Look, these patients come, and they've experienced swellings of the lips, swellings of the tongue, and this is why they think that this may go deeper, this may go to the upper airways and make them suffocate. And yes, we know there are types of angioedema that do that, that kill our patients: bradykinin-mediated angioedema, hereditary angioedema. In chronic urticaria, this does not happen. And it is very important for our patients to realize that. I tell them, "I know exactly how much fear such a swelling can induce, how this makes your appearance impaired, how this is really bad for your quality of life, but it will not lead to suffocation."
Seventy percent of patients with chronic spontaneous urticaria have angioedema. So, it's an important and underestimated and underdiagnosed component, and it is something that's very important to our patients. When you ask them about their angioedema, then, well, four out of five patients will say that this is at least moderate, and every third patient will say this is severe. So, don't underestimate, don't underdiagnose, and don't undertreat angioedema in chronic spontaneous urticaria. It is a very important component.
Communication with our patients is so important. What do we want to convey? We want to let patients know that we know what this is, we know where it comes from, and we know how to treat it. We are there to help them. And when I get questions like, "Doctor, how long will I have this?" the first thing that I say is, "This is a disease that will go away. We don't know for the individual patient, for you, when this will happen, but we know that after a couple of years' duration, it will go away by itself." That's an important and positive message. And so much in urticaria, with all the consequences and psychological burden that comes with this disease, so much is about good communication. Of course, good treatment also, but good communication with our patients.
So, I talk about what we know. I talk about what we want to achieve, and I tell them, "Look, we will work with you to treat your disease until it is gone." That means until you have no longer wheals, no longer angioedema, and until this whole thing goes away by itself. That's my goal for you. And if we work together with measuring and treating and compliant management, then we will achieve this goal. We will not give up until we do.
And of course, you all know the current algorithm for the treatment with three treatment options, really: antihistamines at standard or higher than standard dose, followed by omalizumab if the antihistamines do not work, followed by cyclosporine if the omalizumab doesn't work. And in our recent consensus conference on the update and revision of this guideline, this stays the same, except for we put in more information on how to apply this algorithm. These three treatment options are really what should make us and our patients confident that we will get this under control.
Patients have lots of questions, so it is important to address these questions and to let them know what is relevant and what is not. Now, one of the things that patients say is, "Doctor, I don't know why this comes and goes. Sometimes it's better, and sometimes it's really bad." And I think, "Maybe, no, no, no, no, no." What we want our patients to achieve is control of their disease, obviously, but also a handle on their disease. They shouldn't be guessing if it's better or not better. They should know, and we should provide them with the tools to do so. And this is why I'm telling you, be a pro, use the PROMs, the Patient Reported Outcome Measures. What are they? These are validated, good, and free tools that we provide our patients with.
Now, in chronic spontaneous urticaria, the Urticaria Activity Score for those with wheals, the Angioedema Activity Score for those with angioedema. And when you have patients with a chronic inducible urticaria, CIU, well, you can measure disease activity by provocation. Disease control is even easier to assess, and I recommend that you use the UCT, the Urticaria Control Test, across all of your urticaria patients. Very simple. I'll show you this test in a minute. And if you are interested in exploring the quality of life impairment in your patients, well, then you use the quality of life tools that are given on the bottom. The UCT is the way to go, believe me. I've used this tool for the last years, and it is so helpful. It makes me a better urticaria treater. Why? These four questions that you see here, and the four answers that come with it, provide you with point numbers on the level of control. Patients who have full points on all four questions, 16, well, they are completely controlled. And if you bring them to 12 points, that means you have already shifted the disease. It is no longer in control. Now, the patient is in control. It's well controlled, not perfectly controlled, you need 16 for that, but you're on the right track. So, use that tool. It's everywhere on the internet, and if you can't find it, do send me an email. I'll be happy to guide you to where you can get this.
One of the most important questions that patients have for us is, "Doctor, why do I have this?" In fact, some patients are so driven by this question that they will go from one doctor to the next doctor, to the third doctor, sometimes then being subjected to useless tests that cost time, cost money, and delay treatment. So, it is important that we have a question, uh, that we have an answer to their question, "Why do I have this?" My approach to this is to talk about the things we know. Don't go to what we don't know. Instill confidence in your patient that you know what this is, because you do. You know a lot about this disease. You know that it is a mast cell-driven disease. You know that it is because mast cells get activated and release their mediators, including histamine. You know that these mediators are responsible for the signs and symptoms: the itch, the wheals, the angioedema. You also know that this mast cell degranulation is the major driver. And we also know why mast cells get activated in patients with chronic spontaneous urticaria. Out of all the different receptors and ways of activation that mast cells have, it is the high-affinity IgE receptor, FcεRI, that drives mast cell degranulation in patients with chronic spontaneous urticaria. How? Well, we know that there are two ways that mast cells get activated by this receptor. The first one is, well, here's the receptor on a mast cell, binding IgE. IgE that is not to allergens. Urticaria is not an allergy. Chronic spontaneous urticaria is not an allergy. No, this is IgE to autoallergens, to thyroid peroxidase, for example, or interleukin, interleukin-24. And this makes for a common cause of chronic spontaneous urticaria: autoallergy.
And then there are these patients who have true autoimmunity, type 2b. No autoallergy, we call type 1, and autoimmunity, type 2b, is driven by these IgG antibodies to the IgE receptor that go directly to the mast cell and activate it. This is the bad type of chronic spontaneous urticaria, the hard to treat. Look, these are patients with autoallergic chronic spontaneous urticaria. If you give them omalizumab, 70% of them will be complete responders. This is what this first randomized control trial showed. And these are patients who, when you take their serum and transfer it to a healthy person, makes the healthy person have chronic spontaneous urticaria. Look, this is skin prick testing, not with allergens, but with autoallergens, TPO. Beautiful wheals in chronic spontaneous urticaria patients. And then taking their serum, injecting it into healthy skin, makes that skin responsive to skin prick testing with an autoallergen. So, we're very certain that autoallergy is a main cause. IgE drives IgE receptor-mediated activation. And we're also fairly certain that the other type, the autoimmunity type 2, is diagnosable by basophil activation tests, a tolerance serum skin test, or immunoassays for these autoantibodies. Now, we don't have these immunoassays in our routine clinical practice, that's true. But we can diagnose these patients by looking at their low IgE levels and their expression of IgG on TPO. You will find that 10% and 20% in this study, only one in 12 patients have this autoimmunity type 2b. And it is so important to gauge who is who, who is a type 1, who is a type 2b, who is an autoallergic, who is a true autoimmune patient. Why? Because this gives us information on how these patients will do. Those with the type 2b will have a long duration, severe disease, will have comorbidities, autoimmune comorbidities, will have problems in responding to antihistamine and omalizumab treatment, and in turn, have good response to cyclosporine and to Bruton's tyrosine kinase inhibitors. The type 1 autoallergic patients, they are the ones with high omalizumab responder rate, fast onset of omalizumab, and they don't have a high rate of autoimmune comorbidity, if at all. They have a higher rate of allergy comorbidity.
So, the short summary of this is: yes, we know what this is. No further tests are needed. You have an autoimmune disease. This is inside of you, but this will go away, and we will treat it.
"But doctor, I think it's what I eat." Don't ignore that. It is possible. In fact, we know that it's true that there are circumstances, conditions, and triggers that act on mast cells and on chronic spontaneous urticaria. But we have to distinguish between true causes, causes that lead to degranulation of mast cells, and these are the autoantibodies that we just talked about, and cofactors, conditions that are relevant for the disease activity by modulating mast cell responses. Look, many of my patients tell me, "When I have an infection, things are worse. I have more wheals. When I eat aspirin, then things are worse. When I eat this or that. When I'm stressed, things are worse." This is not nonsense, this is real, because all of these conditions can translate into signals that act on mast cells to make them more susceptible, more ready to respond to degranulation by the underlying autoimmune and autoallergic mechanism. So, do take that serious. But no need for systemic comprehensive testing of these things. They will not improve a therapeutic approach to chronic spontaneous urticaria.
The therapeutic approach to this disease is this algorithm. And by applying this algorithm and really sticking to the times that we put into the algorithm, we come to effective treatment fast. Look, there's no use in switching from one antihistamine to the next to the third. There's no use in cortisone. Please don't do that. There is use in giving a good second-generation antihistamine a chance, two weeks. And if this doesn't work, patients still have wheals or angioedema or both, and go up in the dose, up to fourfold. And again, two to four weeks. Whatever doesn't happen within those two to four weeks will not happen later on. And no, no need, no use to switch to another antihistamine or to combine with an H2 or leukotriene antagonist, things that we did in the past. No, move to omalizumab when you can. And in the new guideline, that is now also co-sponsored as a title society by APACHE, we recommend that updosing of omalizumab is what should happen in patients who do not respond to the standard dose of omalizumab.
Look, I don't want to let you go without putting some hope and vision into your heads, because yes, my patients do ask me, "Doctor, when is there something that will cure this disease? When is there something that really helps, because everything I've tried so far hasn't really worked?" We're working on several, four, actually, very potent treatment approaches for chronic spontaneous urticaria. We're working on, let's start at mast cells, inhibitors of their mediators, for example, H4 receptor antagonists. So far, we only block H1 receptor, but of course, histamine also binds to the H4 receptor in the skin. And let's block it. Let's see what happens. We work on the inhibition of activation. Okay, we already do that with omalizumab, with ligelizumab, blocking IgE and the IgE receptor. But there are other targets, other receptors on mast cells that contribute to mast cell activation. Let's block those too. And we're working on mast cell silencing. This is a very powerful approach. Why? Well, if I push a button on my cells that shuts my cells up, well, that would mean that they can no longer degranulate, can no longer make wheals. And we have two different approaches that use this mast cell silencing technique. And the most powerful approach is to deplete mast cells. If I reduce numbers of mast cells, well, how can the skin make wheals if there are no more mast cells in the skin? So, we're also pursuing the approach of depleting the skin of urticaria patients of mast cells, so that the disease stops.
Today, the future of urticaria treatment is looking brighter than ever. Look at all these targets. What makes them targets? The knowledge that we know that all of these things on this slide contribute to the pathogenesis of urticaria. Mast cells are in the focus. Well, we talked about this, but we can target different mast cell receptors, including silencing receptors. We can target what's inside of the mast cell that translates the activation of mast cells into the release of mediators, BTK, for example, and Syk. And of course, we can target what comes out of the mast cells, and that's more than just histamine. We can target other cells that contribute to this mast cell-driven disease, either by making IgE or autoantibodies, or by being recruited by mast cells downstream of activation. Well, if you take a biopsy of a wheal in chronic spontaneous urticaria, what will you see? You will see eosinophils, T cells, B cells, and basophils. So, these cells come to the skin and cause more havoc. They go up on the initial inflammation that was induced by the mast cells.
So, looking at just some examples now, um, of these four treatment approaches, and maybe zooming in only on antibodies and not on small molecules, we really have very nice treatment options under development. Look on the top right, where B cells make IgE and send them to the mast cells. We can already block this by omalizumab, but we will be even better with ligelizumab, and hopefully other anti-IgE targeting treatments. TSLP is a primer, inactivator, and growth factor for mast cells. So, it's a tezepelumab, which is going into clinical trials right now, is a valuable approach to hit that target. And on the left, we have lyrentelemap, a silencing antibody. We have anti-KIT, cdx159, an antibody that blocks SCF action on KIT and thereby kills mast cells. And we have afarelimab, an anti-C5a receptor antibody that would block autoimmune activation in chronic spontaneous urticaria. And on the bottom, you see a couple of examples of already licensed biologics, all of which are currently being tested, um, and have been shown in individual patients to be effective in chronic urticaria. Two examples: omalizumab works. We know that it's in the guideline. It has improved the treatment of chronic spontaneous urticaria patients tremendously, but not everyone responds to omalizumab. We also know that. So, here is ligelizumab, the big brother of omalizumab. Just concluded its phase III trials. Red is oma, and you see that there are two curves here that cause disease reduction that's bigger than omalizumab. Two doses of ligelizumab. And let me make this easier to see. In the same study, omalizumab had a treatment response rate, patients with no wheals, of 26%, the red bar. And ligelizumab at 72 mg had more than 50% responders. So, this is something to look forward to. Novel treatment options that learn from our current treatment options and improve it, and treatment options that use different approaches, different techniques, and different strategies. All of this will help us to be even better in chronic spontaneous urticaria management in the future. And all of these treatment options are ones that we are want to pursue for us.
Now, it is important to show our patients that, okay, we are much better today in our understanding of this disease, in our treatment, and we will be getting better, even more so in the future. So, the future is bright, and so is our take on chronic spontaneous urticaria.
I want to, at the end, give a big shout-out and thank you to APACHE. APACHE, who this time, for the first time, joins the founder and title societies, the European Academy of Allergy and Clinical Immunology, GA2LEN, the EDF, EuroDerm, as a powerhouse of urticaria and a motor of the update and revision of the international urticaria guideline. This is so important because it unifies our approach globally, it harmonizes it, provides best practice, so that all patients anywhere can be in benefit of our insights, our tools, and the new management options for chronic urticaria. And in line with this, a big shout-out to the Asian and Asia-Pacific Ucares, the Urticaria Centers of Reference and Excellence in your region. Thank you very much for your contribution to this global network of urticaria specialists. If you want to learn about this network, please go to www.galen-ucare.org and check out what we do. And if you are at a urticaria center that specializes on this disease, well, please consider to become a member of the UCARE network. And for all of us who see patients with chronic urticaria, please let's donate our data to CURE, the Global Chronic Urticaria Registry. Check it out at www.urticaria-registry.com. More than 4,000 patients already included, a valuable resource, a valuable platform for us to learn about urticaria across different countries and regions. So, please help with Asian, Asia-Pacific data on chronic urticaria by using CURE, the Chronic Urticaria Registry.
And with that, thank you again for inviting me. Thank you, Ruby, for making this happen. Um, I'm very much looking forward to your questions, and I want to thank you for your attention. Greetings from the UCARE at Dermatological Allergology at Charité in Berlin. This is my team. I put my email address on the bottom right. So, if you have questions that come to you later, or a difficult patient that you want to share, or you want to become a member of the UCARE network, please do reach out. I'm looking forward to that. Thank you very much.
Ruby: Thank you very much, Professor Marcus Mora. It was a brilliant talk, as always. We, we've always enjoyed your really energetic and powerful talks, and with so much of content that is really, really beneficial to our community and our membership. So, I'd like to start by asking you a few questions. And before that, thank you very much for having us as part of your, uh, update of the guideline. We're very happy to be part of the urticaria guideline as the title society, and we will do our best to contribute as much as we can, including to the registry. So, my first question to you is, when, when you look at the burden of chronic spontaneous urticaria globally, what precise data do we have? Do we have some specific regional data, country-based data? Are there big pockets, um, in certain parts of the world where we have no information at all? Where are the gaps, and where is the understanding?
Ruby: That's a very important question. Thank you very much. Uh, we do understand that this is in allergology, in dermatology, both of these disciplines see chronic urticaria patients. One of the most devastating diseases. The burden goes across all the different domains. There's a psychological burden, there's a functional burden, um, there is a burden in terms of the consequences of the disease and the comorbidities. There's also a financial burden. And some of these aspects are well understood, others are not explored fully yet. In fact, we have to say that when it comes to global data, and that is insights on different urticaria populations and different geographies, very little is known about urticaria in Asia. We need more information on the differences and the similarities in the prevalence, but mostly in the burden. What are the unmet needs that patients have? What do we need to address with our treatment options? And yes, urticaria can be different, you know, someone with wheals has a different impact of the disease than someone with angioedema. Someone who's had this for 10, 15 years will have a different burden than someone who has it fresh. So, let's explore that. And I want to point again to the value of CURE, the Chronic Urticaria Registry, because burden in the sense of comorbidities, consequences, psychological burden, is within the scope of this registry. We do collect information on these aspects. And I think that once we have 10,000 patients in the registry, we're almost halfway there, then we can also compare different patient populations. So, it's so important that our colleagues in Asia contribute to this collection of data. And I want to thank those centers who are already on board with the registry. Thank you very much.
Ruby: That's a wonderful, um, explanation. And, um, we certainly will do our best by reaching out to our many, many, uh, centers across Asia and try to get more and more, um, uh, centers to actually collaborate because I, I sincerely and, um, very much agree with you that it's so important to have that data for our region. We, we don't have that. And without that data, it's very, very difficult to actually even reach out to the governments to get licensing and approvals for products that are, especially the monoclonal antibodies that are expensive. And I think the burden is, is, is key to that. So, we will do our best. And, um, I can assure you that, um, coming to the diagnosis and classification, um, of urticaria, I mean, this global guideline has been a miracle. It's really been a big, big initiative that has done a lot, I would say. And I can say that I, I start this association with the time I was, uh, president-elect and president of WAO. So, yeah, you know, so I know the story right from then. I know the passion with which you actually initiated this whole guideline movement to bring together so many people from around the world to have a voice, to give recommendations, to give their input, so that the guideline is not just Europe-centered or the US-centered. So, it's just fantastic. But when we look at the evolution of the diagnosis and classification criteria, like 15 years back, and what is it now? What would you just like to say the key factor that's really different now, and how do we stand now with a better understanding?
Ruby: First of all, thank you for your kind words. I truly believe that only as a global community and together can we change the way we treat chronic spontaneous urticaria. And this is so needed. And I do agree with you, the guidelines have helped to unify and harmonize our approach, bringing us together as a community. And they do make things easier because of the classification, because of the recommendations that they provide. Now, what I'm very happy about is that we're finally no longer using chronic idiopathic urticaria. This didn't make us look good because it conveyed to patients that we don't know what this is. The contrary is true. We know what this is. We know many things about urticaria. And, and so I'm happy that this is gone and was replaced by a very stringent, um, classification as chronic spontaneous, the more common type, and the chronic inducible urticarias. And the inducible urticarias, they really live by the definition that you need to have this trigger present for wheals to come, and wheals will only come when the trigger is present. This is the way to think about these chronic inducible urticarias. And this is why we now know that one person can have more than one chronic urticaria. Look, this was a mess in the past. No, we thought about chronic urticarias, everything is just a big mess and mix of everything. And you know, I, I learned urticaria when I first was introduced to the disease as a disease where you have spontaneous wheals and you have an artificial component, where some of these chronic spontaneous urticaria patients, when they scratch themselves, they get wheals. Well, today we know they have two forms of chronic urticaria. They have spontaneous urticaria and, in addition, they have symptomatic dermographism. So, this approach to a patient has changed because of the classification. We have good tools to identify these subforms. And well, this classification also is the basis for investigating the underlying causes, which we've done very successfully in chronic spontaneous urticaria. But we still have our work cut out for cold urticaria, where we know exactly what it is, but we're not so sure what causes mast cell degranulation by the cold exposure in these patients.
Ruby: Thank you very much, uh, uh, Marcus. I'd like to ask you, like, if you put children versus adults, what would you say are the most important key factors in these two groups?
Ruby: I think what is important is to realize that chronic urticaria is not rare in children. I think this is still a misconception. Um, and, of course, we know that children get acute urticaria, probably more often than, um, than adults. But we now know also that the rate at which children get chronic urticaria, spontaneous and inducible, by the way, is very similar, if not higher, than in adults. We also know that most of the things that we find in adults in terms of the underlying causes, the duration, the comorbidities, are similar in children, although we don't have as much data as we would like to have. I think what we need to understand is what the specific burden is for the kids. Not, it will be different for a preschooler to have angioedema and and and wheals than for a teenager. And right now, we do not have tools like we have in the adults. Now, we don't have a Urticaria Control Test for preschoolers. We don't have a quality of life instrument like CU-Q2oL for the for the kids. So, this is something that I would like to see us move to, to better understand, to better measure, and thereby also to better manage chronic urticaria in the pediatric population.
Ruby: Thank you very much. And I think, I mean, I would even go to say that if, if with this tool, if we had like a mobile technology where people can actually, um, record their day-to-day, uh, changes in their symptoms and then act, you know, convey it, um, electronically to the doctor, I think that's also a very, very good way of having a better way of management and assessment. My other question, sorry, my other question is also about the autoantibodies to the IgE receptor, because we've had lots of, uh, studies on that, as well as on the Staphylococcus aureus. And so, what's your take on that?
Ruby: Ruby, I think this is the most interesting thing about urticaria. I know this is where the scientists really get excited because understanding and characterizing mechanisms and then being able to identify them in individual patients to guide our treatment decisions. Well, you know, this is what we get up for in the morning. Um, we have some way to go, but we're on a good track. We have in certain laboratories, certain UCAREs, we have the assays established, and we can measure that. The next step must be to make this available to the global urticariologist community, actually to all physicians who treat urticaria patients. How can it be that we can only truly identify type 2b autoimmune chronic spontaneous urticaria or autoallergic, uh, urticaria at these specialist centers? These are tests that should be available everywhere now. These should be routine diagnostic tests. So, I think, you know, now that we have completed this, uh, research phase of things, let's move to the development part of things, and let's make these assays commercially available. You know, let's start by us as urticariologists in sharing our assays, validating our assays, harmonizing them, improving them, so that we have good assays that can then be disseminated throughout our global community and be brought to the laboratories of our hospitals, of our clinics, and our consultations. I think this is so important. IgE to self, we need to be able to measure that. IgE to Staphylococcus aureus, we need to be able to measure that. IgG to IgE or IgG to the alpha chain of the IgE receptor. This is an ELISA. This is not rocket science. This is basic diagnostic approach and technology that must be made available to all physicians who treat patients with chronic urticaria. That's the next big goal.
Ruby: Yes, absolutely. I fully agree with you. I mean, this is really truly an important aspect for getting better control of the disease. Also, another aspect is the psychological, or the psychological impact of chronic urticaria, because, you know, just having a rash is bad enough. And, you know, people who have this chronic urticaria, we see patients who have such terrible, you know, cr wheals and, uh, uh, you know, they just, uh, can't sleep at night. And, uh, even with, um, for antihistamines, they don't get sleep. I mean, it's, it's really, um, a painful, um, I wouldn't think that chronic urticaria, nobody says chronic urticaria is like cancer, but it can be even worse from a psychological point of view. What is your take on that?
Ruby: Look, Ruby, I think we are still underestimating this. I also think it is difficult for us to imagine what it feels like to be an urticaria patient. Okay, I'm a dermatologist, allergologist, so I see patients with different skin diseases. I look at someone with psoriasis, I see the plaque. No, I see the lesions. And it is easy for me to understand that that's not a nice disease to have. I treat patients with atopic dermatitis, and I see the lesions, I see the inflammation, and I understand. But most of my urticaria patients, I don't see their wheals. I don't see their angioedema. It's an invisible devil that we're fighting, and that makes it difficult to understand the psychological burden that comes with this disease. In fact, it increases it, because our patients feel that we don't truly understand them, because we don't see what we are going against. Look, these people don't sleep well. I just had an email yesterday from a patient who says, "For three months, those were the worst three months in my life." It's a 36-year-old male. "I don't sleep longer than three hours per night. I get up four or five times at night to take a cold shower to, to actually survive this." So, this is these are the stories we hear. Um, that bad sleep leads to bad mood, the inability to fight this disease, and not finding someone who wants to can help you increases the bad mood. And it's not just bad mood. Thirty percent of patients with this disease become depressed, manifest depression that requires antidepressant treatment. Thirty percent have anxiety, anxiety to the point where they need medical help for an anxiety disorder. The longer you have, and this is actually data from Korea, we're very happy about this for data. Every year that you have chronic spontaneous urticaria adds to your risk of suffering depression and anxiety. And it doesn't stop there. Sexual health is diminished. Up to 70% of women with chronic spontaneous urticaria have severely impaired sexual health. Sleep performance, no, it is all linked. If you don't sleep, you don't perform well. If you don't perform well, well, that has serious consequences for you at school, at your job, which again adds to this. And then you spend a lot of time trying to find help, buying medicines here and there, that adds to the financial burden. Ruby, we could go on for quite some time and still wouldn't capture the spectrum and the intensity of the burden that this disease poses on our patients. It is so important for us to understand that and to realize that this is a bad disease. No, we're still, um, hearing, "Oh, yeah, you know, everyone has some wheals everywhere." It's no, no, no, no, no. This is a devastating disease that is on par with many diseases. You talked about cancer, uh, cardiac disease, severe asthma. You know, think of a disease that you feel is really bad. You can be sure that urticaria, chronic, chronic urticaria, is on par with the impact that these diseases have on patients.
Ruby: Yeah, fully agree with you. And I think that's why, I mean, we should move forward in the direction that you are taking. And I think try to do this, uh, for the sake of our patients globally. And my final question to you is, like, when we talk about the different types of the heterogeneity of treatment, which starts from, of course, as you rightly said, start with double the dose of second-generation antihistamine, go up to fourfold. While in Japan, it's still only double the dose. We don't, it's four times is not approved here. So, it's double the dose. And then some places, people just mix two antihistamines and think that's better, which really isn't the true story. But I'm particularly interested in these new monoclonal antibodies. We know that omalizumab works, and dupilumab. But I'm particularly interested in TSLP. So, could you just highlight a little bit on TSLP?
Ruby: Ruby, I share your excitement. Urticaria treatment has never been more exciting than now. Don't forget, we're, we're moving to more better, novel treatments for our patients. But these, these monoclonal antibodies, they're also instruments, surgical instruments that help us to understand the pathogenesis of the disease. We have learned so much about chronic urticaria from omalizumab. So, it's give and take. Now, developing new treatments and understanding the mechanisms help us also to understand how the disease works. TSLP is fascinating. Um, TSLP is an alarmine, um, and it comes from keratinocytes and other cells in the skin. And it has three major effects on mast cells. Don't forget, urticaria is a mast cell-driven disease. It's all about mast cells. So, if we understand what makes mast cells go crazy in the skin and what increases their numbers, we are on a good track to understanding urticaria. What does TSLP do? Well, first of all, TSLP activates mast cells, which is exactly the problem that we see in chronic spontaneous urticaria patients. So, there is priming, activating, modulating effects directly on mast cells. By the way, TSLP is also produced by mast cells. So, it may be a feedback loop where mast cells recognize it, get activated, release it, and stimulate the next mast cells or itself. Now, mast cells, um, uh, also are increased in chronic spontaneous urticaria. This is not massive, this is not ten times more mast cells than in the skin, but it is there. It is 50%, 100% more than in normal conditions. And you can probably well understand that the more mast cells you have, well, the bigger the problem may be in chronic spontaneous urticaria. Now, TSLP acts on mast cell numbers. So, um, it is a cytokine that prevents apoptosis. Apoptosis is a cell death that occurs, uh, in, in other words, if you go against TSLP, which is what tezepelumab does now in clinical trials in chronic spontaneous urticaria, you take away a mast cell mediator, you take away a mast cell activator, and you take away a survival factor for mast cells, which will, that's the prediction, result in downregulation of mast cell activation, downregulation of mast cell numbers, and in consequence, make mast cells become quiet and, um, urticaria to stop. This is the one mechanism. The other mechanism is that TSLP is a driver of Th2. Th2 is what's underlying many chronic inflammatory, allergic, and inflammatory diseases of the skin and otherwise. Th2 is IgE, big role in chronic spontaneous urticaria, itch, mast cells, the whole spectrum of Th2 features is driven by TSLP. And if you turn it around, that means that inhibition of TSLP with tezepelumab will stop that motor of Th2-driven inflammation in urticaria and in other Th2 diseases.
Ruby: Thank you very much, Marcus. This was just brilliant. Thank you for the wonderful lecture and for all the questions that you answered so beautifully. I'm truly, truly sure that our membership is going to be very much benefited, uh, with this talk of yours. And we look forward to continued collaboration, continued information, and sharing of knowledge from you, participation in the guideline, as well as in the registry. So, thank you very much.
Ruby: Thank you for inviting me. Thank you for your wonderful questions. Thank you for everyone's attention. I was very happy to be here and hope we can do it again sometime.
Ruby: Yes, we will. Thank you.