Chronic Spontaneous Urticaria Learning Zone
Transcript: CSU symposium at EAACI 2023
Clive Grattan, MD; Emek Kocatürk Göncü, 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.
- Good afternoon and welcome to this session on chronic urticaria, chronic spontaneous urticaria, the past, the present, and future. And this symposium is being filmed and it's available for those online. And welcome to you as well. My name's Clive Grattan. I'm the chair and I'm also going to give the first talk. The co-presenters will be presented in a minute, and you'll be shown how to use your iPads to answer questions and also give questions to us to answer for you. So my background is that I'm a dermatologist at St. John's London in United Kingdom. My colleague over there is Dr. Emek Kocaturk. She's at the Koc University School of Medicine and also currently a clinical fellow at the Charite in Berlin. And on her right is Professor Martin Metz, who is the head of translational medicine in the allergology and immunology department in Berlin. So we have a great faculty and I'm sure that they will give you a great afternoon. So the agenda will be exploring the past and that's me. Current guidelines in CSU management, that's Emek. And what's new in management, and that's Martin. And then there will be a Q&A and panel discussion and then a wrap up. And you will receive your certificate post event and please complete a feedback form on your iPad.
Thank you for that. This symposium has been accredited and photography is allowed if you want to, but the whole symposium is filmed and will be available on the Medthority website afterwards. So the interactivity with your iPad is that to answer a question, you tap your answer and then submit. And to ask a question, you use the icon which has got the question mark, top right, and that will submit the question and we'll do our best to answer it. So this is your first question. Which best describes your current occupation? Allergologist, paediatrician, allied healthcare professional, dermatologist, general practitioner, scientist, psychologist, other clinical specialist. So the poll is running. So we've got a spread of audience specialties, particularly allergologists and everybody here is welcome. So we'll move on to the next question. Which country do you practise in? Please type in your country. So the cloud is growing and changing, and I can see Germany is heavily represented, Brazil, Switzerland, United Kingdom. In fact, this is a worldwide symposium. Thank you for attending.
Now this is a question for you in relation to chronic urticaria control. Does a patient with an Urticaria Control Test score of three have a good disease control, yes or no? The answer is no, because zero means zero control. And if you have a high score, it means good control. It's just the reverse of what you might think. This is a slightly tricky question, but can you ask yourselves what percentage of patients are thought to have IgG autoantibodies against the high affinity IgE receptor? Is it 25 to 30%, 50 to 65, 70 to 85, or nearly everybody? And the majority of people think 25 to 30%. And I agree with you. This is the test that we can use to define autoimmune urticaria. In fact, it measures functional factors in the serum and we assume that they are functional antibodies, many against the high affinity IgE receptor. Well done. So I'm going to move on to my presentation. But the background to the symposium is that chronic spontaneous urticaria is common and it can be a cause of considerable unhappiness, morbidity, and disadvantage to patients. And that's why we need to understand it and treat it better. Exploring the past. I have these conflicts of interest. But let's start with a definition of urticaria. This is the subject of our symposium. Itchy wheals, angioedema, or both. Acute if it resolves completely within six weeks, but chronic if the disease is continuous, i.e., most days of the week for six weeks or more. And remember that this definition applies to all types of urticaria, not just spontaneous. And this is what wheals will look like. They're itchy, they're superficial, they're pink, and they can look different in different skin types. And these are examples of angioedema, often affecting soft tissues, the lips, the eyelids, but could be anywhere and usually no colour and often not itchy. They may be painful if they're big. And let's classify urticaria into spontaneous or inducible.
And inducible can be physical, symptomatic demographic, delayed pressure, cold, heat, sun induced, vibratory angioedema, or the maybe other types of the inducible urticarias, including the cholinergic, aquagenic, and contact. But today we're going to focus on spontaneous, chronic spontaneous urticaria. Now the consequences of having CSU are to have problems with costs, cost to the patient, cost to society, comorbidities for the patient, maybe psychiatric disturbance, associated autoimmune disease, underlying infections and metabolic syndrome, unpredictability. The patient never knows when they're going to look good, feel good, and that is a big burden. Impaired family relationships, high impact on quality of life, impaired work performance. And they're often resistant to standard treatment. And by that I mean antihistamines predominantly. Long duration, maybe one for months or years. Associated angioedema of the face, very disadvantaging And patients hate to go into work with swelling of their mouth, for instance, sexual dysfunction. And a study, a retrospective case note review published in 2017 looked at the cost of urticaria, the annual direct cost per patient using a formula called purchasing power. Parity ranged from $907 in Italy or to almost 3000 in France.
And there were indirect costs. And this is patient reported total work productivity loss over four weeks due to presenteeism, which means that they're present but not functioning properly. And this ranged from over 6,000 in France to over 15,000 in Germany. And the overall productivity impairment was 27%. So how does the mast cell relate to other cellular inflammatory events in the skin? This is a slide of urticaria lesional biopsy with a fairly sparse inflammatory infiltrate and edoema of the dermis, but the epidermis is not affected and the cells are mainly around the small capillary venules where the mast cells also reside. And the eosinophil may be one of the first cells to migrate into the inflammatory wheal and crosstalk with the mast cell. And the basophils may come in later and the lymphocytes, particularly the TH2 subset of lymphocytes, appear to predominant in spontaneous urticaria. And you may also see some neutrophils, but this won't be a big feature of the histology. And if it is, you have to think of neutrophilic urticarial dermatosis and also urticaria vasculitis, neither of which are the subject of this talk. Histamine is a major mediator of urticaria. We all recognise that. And it's worth going back to basics with histamine to say that if it binds the H1 receptor with poly modal nerve fibres up to the central nervous system, it will trigger itch. Or if it triggers the C-fibers, the small C-fibers, it can result in an axon reflex, initiates it, but the actual mediator of the reflex is probably neuropeptides. And there are H2 receptors in skin as well. And both H1 and H2 receptors will lead to vasodilation with redness and vasopermeability with swelling.
So histamine is a very important mediator. And if we look at the timeline of treatments developed for urticaria, we see that back in the 1940s, the classical antihistamines were developed. In their day, they must have been wonderful because up to that point, there were no specific treatments. And then corticosteroids in the 1950s and then second generation antihistamines, which we use today mainly for long-term management of chronic spontaneous urticaria. Then immunosuppressants in the 1990s when it became clear that functional antibodies were an important driver for some patients with CSU and now anti IgE, everybody's familiar with that. It has been a breakthrough in the treatment of difficult urticaria. And at the bottom are low evidence-based interventions, not reported with big clinical trials, but clinicians have been using them for all these years to help patients and they still have utility today. I will discuss those. It's worth also going back to the H1 antihistamine development, the first generation, second generation and what was for a period of time called third generation. But that term has now gone. And the first generation would derive from different chemical groups, the alkylamines, ethanolamines, piperazines, piperidine and the phenothiazines.
And you'll recognise some of these antihistamines in use today. And then second generation, which derived from again these chemical groups, cetirizine, loratadine, terfenadine, bilastine and then the derivatives of these, levocetirizine, the levo enantiomer of cetirizine, desloratadine, the active metabolite of loratadine and fexofenadine, which is the metabolite of terfenadine. So these are the antihistamines that we use in our daily practise and we need to understand the difference between them because not all antihistamines are the same. So I've illustrated some of the differences in pharmacokinetic properties with this slide. So Tmax is the time to maximum drug level after a single dose in a healthy volunteer. Then there's Thalf, which is the elimination of half of the concentration of the drug. And if you take five Thalfs, then you get to elimination from the body in effect. So let's look at the nine different second generation antihistamines. We can see cetirizine and levocetirizine are rapidly absorbed and is so is rupatadine. And then we look at desloratadine, it's slow to be absorbed. It takes three hours for to achieve maximum concentration in the blood. And then we look at the elimination from the body. Acrivastine is the quickest, it's gone within a day. Cetirizine, levocetirizine take about two days and desloratadine can take up to six days to leave the body. So there are differences between a antihistamines and also the root of elimination may be renal, hepatic, biliary. And therefore you have to factor in if someone has severe renal impairment that you should avoid certain antihistamines, acrivastine or reduce the dose. So know your antihistamines for good prescribing, particularly if you're going to up dose them. Ciclosporin has been used now for a long time and the evidence for using ciclosporin is not so strong. But this was one of the first studies.
It was a small double blind placebo control study which shows a separation between the patients who were randomised to placebo at the top and those randomised to ciclosporin at the bottom. So they were given four milligramme per kilogramme. And you can see within just a week that there was a response that was sustained in the patients on ciclosporin. With both itch and wheals. And the basophil histamine release assay was checked before and after ciclosporin. And you can see in nearly every case, it fell. So we have proof that ciclosporin can work and we have a mechanism by which ciclosporin may be effective. And then here are the low dose evidence, low evidence interventions for CSU. And you can see that there are many different classes, antidepressants, H2, antihistamines, anticoagulants, immunosuppressives, immunomodulators, leukotriene receptor antagonists, miscellaneous and the cell phones. All of these have been used at different times by clinicians to help patients who don't respond to H1 antihistamines and they can be of value, but the evidence for them is not strong. So they tend not to get into guidelines because guidelines are evidence based. But what you can consider is targeting these for the particular situations that you want to use.
The low evidence based treatments, corticosteroids, severe urticaria exacerbations, I think we would all consider them. But just for the short term, dapsone for delayed pressure urticaria, urticaria vasculitis, H2 antihistamines can be used for all urticaria, especially when the patient has high vasculitis. Hydroxychloroquine may be more useful for autoimmune urticaria and for urticaria vasculitis, which is not the subject of this symposium. Doxepin is a tricyclic antidepressant but is also a very potent H1 and H2 antihistamine and can be a useful add-on. Montelukast probably finds its best role in aspirin sensitive and pressure urticaria, but can be used for all types. Sulphasalazine, particularly valuable, I think, for delayed pressure urticaria and tranexamic acid for idiopathic nonhistaminergic angioedema. So I'm going to close with the British Association of Guidelines for the Management of chronic urticaria published recently. And it's a little bit different from the international guidelines which Emek will probably present and they're more pragmatic and they use these drugs that are low evidence if they're going to be helpful outside the the high evidence drugs. So to start with, make the diagnosis, get it right because urticaria is not so easy a diagnosis and sometimes people have other conditions including eczema, maybe other urticaria problems. Give general management advice and then use validated scoring systems. DLQI, UAS, AAS, and urticaria control test, give educational material, access support for anxiety and depression and psychological impact, tropical antipyretics and avoid triggers and stop ACE inhibitors in people with angioedema without wheals. And here's the pathway for people with chronic spontaneous urticaria, first line, second generation antihistamines, licenced doses, then up doses to four fulfilled if you wish. And then not in the international guidelines, you can switch antihistamines if you wish because there may be difference in absorption and tolerance. You can add montelukast acid to the antihistamine and at this stage, worth measuring total IgE and the basophil histamine release assay if you have access to it 'cause that will inform you as to whether omalizumab or ciclosporin is more likely to be the most effective of the second line treatments. So omalizumab, high IgE, low or negative basal assay, ciclosporin, high basophil assay, low IgE. So you can target your treatments at this stage.
And then if the patient is not responding, we've got all these other treatments included here as third line, the low evidence-based treatments that I've already run through and of course, rescue treatment, short courses of steroid. And we've got the inducible urticaria pathway which follows a similar principle, but here you see at the bottom, the different types of inducible urticaria possibly responding better to the selected targeted treatments in this guideline. So I'm going to close at this stage and I'm gonna hand over to Emek who's going to talk about current guidelines in CSU management, which will go beyond what I've said. And Emek do come to the podium. - Thank you. Is, can you hear me? Yes, I guess so. I'm a bit away from the microphone, but thanks for coming. I see a full room and it makes me really happy to see this interest in urticaria, welcome all.
So I'm going to speak about an individualised approach to treatment of chronic spontaneous urticaria and here is my, okay, so yes, so thank you Clive. And I'd like to start with a case presentation and I need your help to manage this patient. So there will be some questions and I want you to vote for these questions. So this patient is a 35 year old woman experiencing recurrent wheals and angioedema attacks for two years and she has been doing well with levocetirizine once daily. But her urticaria aggravated when she had COVID-19 infection one year ago, she was then prescribed two times daily rupatadine. But she states that she has to visit emergency department for getting steroid injections every two weeks. So what would you be your next step in managing this patient in your clinic if she came to you for her chronic spontaneous urticaria? So you can start voting, send her for allergy workup, up the rupatadine up to fourfold, combine rupatadine with hydroxyzine, prednisolone, 30 milligramme daily for three weeks, add H2 blocker. So yes, yes. And 80% of our colleagues choose to up those rupatadine up to fourfold, now I continue my presentation. So the EAACI urticaria guidelines suggests to follow an individualised management approach for CSU patients, especially to assess patients for diagnostic procedures, comorbidities as Clive has already mentioned, and severity and assess disease severity with respect to disease control and with patient reported outcome measures.
And the basic laboratory workup that is recommended by the EAACI guideline is for every patient to check for complete blood count, CSR and CRP and ESR testing, anti-TPO IgG and total IgE levels. In a nice review by Martin, the the paper suggests to focus on seven Cs while managing the patients. And now I will go one by one these seven Cs for the management of CSU. First of all, we have to confirm if we are really dealing with a chronic urticaria patient. So we have to check if the lesions are disappearing within 24 hours. If not disappearing, then it's probably most probably not urticaria, it can be a picky reaction, it can be an allergic contact dermatitis, exfoliative like as other things. And we have to also ask the patient are the lesions are itching because if there is burning sensation and pain, pronounced pain or there are post-inflammatory hyperpigmentation or purpura, then we need to consider the probability of urticaria vasculitis. And if the patients complain about systemic complaints such as fever coming in the evenings, the patient may have an autoinflammatory syndrome.
So we need to consider these. And the cause of urticaria is urticaria now is considered as an autoimmune disease. And autoimmunity has two mechanistic pathways in urticaria, chronic spontaneous urticaria. The most common type is type one autoallergic CSU where we have IgE type auto antibodies against patient's own autoantigens. And these patients have high comorbid atopic diseases, they have higher normal total IgG levels and they have good response to omalizumab, while the type two B one is a rarer type. Approximately consisting 10% of the patients, these patients have high comorbid autoimmune diseases, low total IgE levels and they show a poor response to omalizumab treatment. And we also have to warn the patients for cofactors, some aggravating factors such as NSAIDs, aspirin, opioids, some histamine rich foods may also aggravate patients' symptoms and after infections or stressful events, they may have aggravation of their urticaria. So we have to tell the patients to keep the disease under control in these situations or warn against taking and sets for the treatment of infections. And comorbidities are an important part of chronic spontaneous urticaria management because chronic spontaneous urticaria coexist with especially autoimmune diseases, especially Hashimoto diseases in one fourth of the patients. And mental disorders are also present in one third of the patients. So focusing in the management of these comorbid conditions is also important to have a complete control of the disease. And as Clive already mentioned, we need to assess patient's disease severity and treatment control with patient reported outcome tools.
There are very nice, specific tools that are generated for CSU and also for CIndU. But here the most important ones are urticaria activity score, weekly score, which shows if over 27, it shows severe disease activity, urticaria control test, when it is over equal 12, then it shows that the disease is under control and we have a sufficient treatment and the chronic urticaria quality of life questionnaire, when it is over 50, then this means that the patient is really very much burdened and has a impaired quality of life because of chronic urticaria. So now we have the patient's laboratory test results and her complete blood count and routine chemistry tests are in normal ranges, but anti-TPO is positive. While thyroid function tests are normal, total IgE seems low because we consider levels below 40 as low total IgE levels. She has an elevated CRP her, she doesn't have seem to have any infections, mp psychiatric comorbidity and her thyroid ultrasound was normal. And we also checked her severity and control and the urticaria weekly activity score, UAS score was 33, which shows a severe disease. And her urticaria control test score was two, which shows a poorly controlled disease and her CUQoL score was 61, which shows an impaired disease, impaired quality of life.
So as Clive already mentioned, the guideline has three steps for the treatment of chronic spontaneous urticaria. We start with standard doses of second generation H1 antihistamines and increase the dose up to fourfold when we don't have control. And if we don't have enough control in one, two to four weeks, then we add on to omalizumab treatment. And the guideline stresses the importance of staying on omalizumab at least for six months because there can be late responders. So before deciding that omalizumab is not working, we need to wait for six months, we can increase the dose of omalizumab up to 1,200 milligrammes or we can decrease dosing intervals. We can manage according to the needs of the patients. And if omalizumab is not working, then we switch omalizumab to cyclosporine treatment, add onto antihistamines, and we have to modify the treatment. The guidelines suggests us to modify the treatment according to urticaria control test results. If UCT is below 12, then it is uncontrolled disease and we need to step up treatment. If we are on antihistamine treatment for one to four weeks, then it's time to step up, up to fourfold. If we are on omalizumab treatment for three months and if we have a UCT below 12, then we need to step up omalizumab, we can increase the dosage of omalizumab. If we have a UCT score between 12 and 15, then the patient is under good control and we continue with our treatment. And if UCT score is 16, then it means that we are good with the treatment and the patient is completely controlled, then we can start stepping down treatment, for example, if we are on omalizumab treatment after three to six months, we can start stepping down treatment. So let's come back to our case study. Her rupatadine dose was increased as you suggested, to four times daily. And when she came back after two weeks, her UCT score was still two, then she was started on omalizumab, 300 milligrammes four-weekly, and after three injections, her UCT score was still four. So what would you be your next step in the management of CSU in this patient? You can start voting, would you up those omalizumab up to 600 milligrammes? Ooh, I already got the answers, very quick. Okay, let's continue then, maybe we have less time or.
Or was it, did I see it wrong or, oh, okay. So yeah, up dosing omalizumab up to 600 milligrammes, but some of our colleagues also up dose it to 1,200 and some combine omalizumab with cyclosporine. Thank you for the answers. So sorry, what happened? Okay, so what we did, we increased the dose of omalizumab up to 600 milligrammes and we stayed in this dose for six months. But after six injections, her UCT score was still eight and she was getting steroid injections still, then omalizumab was seized and ciclosporin treatment was started and she was starting to get good response to treatment and her UCT increased to 11. But she says she wants to seize the treatment because she's very afraid of the side effects, although she didn't have any. So that then now we have to think about another treatment option. So let's look at dosing data of omalizumab. So the real life studies were combined in a paper and it shows that complete response was achieved in 60% of the patient whose omalizumab dose was increased and it's still showed effect in complete non-responders to 300 milligrammes and patients who has high BMI, low total IgE levels and who used previous ciclosporin previously are candidates for opting of omalizumab treatment.
So there are different endotypes and clusters of chronic spontaneous urticaria and we see these patients, very different ranges, different response to treatment. There is a nice study from Turkey that shows four clusters of chronic urticaria patients, which can also show different responses to treatment. The biomarkers for treatment. We are still searching for good biomarkers as Clive already mentioned. We have two biomarkers now that we can trust. Low total IgE is a good predictor of treatment of omalizumab, if there is low IgE, then omalizumab may have a poor response or very slow response. And if the basophil tests are positive, the patient can respond better to cyclosporine treatment. So what shall we do in this patient? What would you do in this patient in your clinical practise now that she didn't respond to up dosing omalizumab and she doesn't want ciclosporin treatment, what would you give to this treatment? Stop ciclosporin and switch to dapsone. Stop ciclosporin and switch to colchicine. Insist on ciclosporin, prednisolone for 30 milligrammes daily for three months. Stop ciclosporin and enrol the patient to a clinical trial. Yes. So then we need to send the patient to Martin. Martin do you have good studies for this patient? Okay, I invite you then. Thank you very much. - [Clive] Well done Emek, that's a nice transition because we're going to hear about the future from Martin and it is a bright future. Thank you very much.
- Yeah, thank you. And this is an interesting start of my presentation here. I will check for this one here, this is the better one. So wonderful that you are all planning to enrol this patient into clinical trial, that's excellent. I hope you have enough trials, otherwise send them to Berlin. We are happy to to enrol them because there is a lot happening and I'm briefly talking about why there is the need and you heard from Emek what we have at the moment. I mean on the one hand this is beautiful because it's super clean, right? So this is very straightforward. I mean if you look at atopic dermatitis or asthma, I mean it's just far too confusing, here, it's very straightforward, so this is the good bit and it's also good that we can treat these patients efficiently with omalizumab. But what we see from this already old data also is that we do have patients that are not under control. And you know, at the time we were super happy that we get so many patients completely controlled, but now we look at these 60% up here that are not completely controlled. So even though the guidelines do look nice, they are lacking other drugs, they're lacking other options for our patients. They're just lacking more treatment opportunities in our patients. And I'm showing you here the data also for the chronic inducible urticaria for omalizumab, this is all real world, real life data and you see excellent response for omalizumab in most of the of almost all of the ClndUs but it's not approved.
We don't have a single approved drug in chronic inducible urticaria. So, apart from antihistamines, so, we definitely need also drugs in this disease and we need more drugs in chronic spontaneous urticaria and there are so many possibilities. So I will just mention the principles that we have in urticaria treatment, you know, by targeting mast cells because mast cell is the crucial cell in urticaria. And then I will present some of the data that we already have. So what can we do? Well first of all, the most straightforward one inhibit mast cell mediators and we have mainly antihistamines of course for that. For the others, evidence is, I would say lower. Most promising at the moment. Direct inhibition of mast cell activation because we do have FcεRI or anti IgE in here. But there are other receptors that are expressed on mast cells and these are actually not all of them.
And for all of these, there are programmes planned or ongoing to target them in chronic spontaneous or chronic induced urticaria. Another approach, very interesting approach is something that we haven't had so far and this is the direct activation of mast cell inhibition and there's one receptor, specifically interesting cyclic eight. So this is an inhibitory receptor and I will come back to this a little bit later. We have indirect inhibition of mast cell activation. We have modulation of mast cell activation by different receptors expressed by other cells that affect the outcome or affect the severity of the disease. And we have to learn a lot about that, how much this contributes also to the disease. But we will learn about this because the trials are running and ongoing. And then finally, we now have the possibility to deplete mast cells, get rid of mast cells at all. And I will present a little bit of the data here as well. So I really show only for the lack of time but also for the lack of available data. Some of the clinical results of the studies that have used some of these molecules. And I wanna start with maybe the most promising one if we look at the near future. And this is BTK inhibition, Bruton tyrosine kinase inhibitor, there are various drugs, three of them have been used in chronic spontaneous urticaria, fenebrutinib has been stopped. There's only used in multiple sclerosis now, but we have two ongoing in clinical trials. But why BTK inhibition? Something that we haven't, you know, used in the past really as allergologist, dermatologist. And it makes so much sense to go for this in urticaria because if we look at where BTK, Bruton's tyrosine kinase works, this is downstream of the FcεRI receptor and therefore, it works both for the type one autoimmune patients where we have auto IgE that crosslinks FcεRI and leads to the release of mast cell mediators.
But it also works on the type two B where we have IgG antibodies that are directed for example against the FcεRI. So again, cross-linking of the FcεRI. So everything that works downstream of the receptor is again, blocked. So it would work for both aspects. And then there's an additional interesting aspect, the BTK is also downstream of the B-cell receptor and here, it seems to be involved in the production of auto antibodies. So we may have a long term effect by using BTK inhibitors, by reducing auto antibodies, which are the crucial factors in the autoimmune urticaria. And this is not new data. So this is phase two, the phase three is very close to be shown, but here I can only show you the data on the phase two. So bear in mind numbers are of course lower. This is dose ranging study. So per arm, we haven't that many but the message we get here is clear. We have throughout all of the doses used in this study, a super fast reduction in signs and symptoms of these patients. And this goes down, look at the change in the UAS. So this is minus 20, so this is really nice and it stays down through the time of the study. But what's more important or similarly important, I would say, it also works in those patients where oma did not work. So you see in red, these are patients that did not have anti IgE treatment before, but in blue, these are patients who had oma before and of course they would've stayed on omalizumab if it would've worked. So these are non-responders or bad responders to omalizumab and you see that they basically respond similarly in both populations. So we possibly have a drug with the BTK inhibition in patients for both type two one, type one and type two B.
So also in those where we have problems with omalizumab. Depletion of mast cells. So this is for a mast cell biologist, super interesting to get rid of mast cells in humans. So far we only had patients, mice, but we were able to do this. Now we have patients and this is by targeting KIT. So KIT antibody that blocks binding of SCF to the mast cell and the mast cell needs SCF to survive. So what it does is it induces the apoptosis of mast cells and therefore in the end, the depletion of mast cells, we get rid of mast cells and there is ongoing, well ongoing phase two studies, but there are also studies in chronic spontaneous urticaria that Marcos Malva will present at this meeting later, I think Saturday or maybe Sunday. So look out for this. But this is the first data in clinical use of this drug in patients with cold urticaria and symptomatic dermographism. And look at the serum tryptase, which we use as a marker for mast cell numbers. This goes down super fast. This is a one-time application of this drug and tryptase is basically gone and this can, we can also see and we look at skin mast cell numbers in these patients, so it's not only the tryptase goes down, it totally reflects also the number of mast cell that goes down. Here you can see a tryptase staining. So mast cells are the only cells in the skin that have tryptase so you see these, all of these red dots are mast cells after 12 weeks. This is an empty skin, mast cell empty skin. So we have a must cell depleted. Well, this is over exaggerating the data, at least in the skin, we have no more mast cells that we see. It does not mean that there are no more mast cells at all in the patient. But what does it mean for the disease? Well urticaria is a mast cell mediated disease.
So no more mast cells, no more symptoms. This is provocation in cold urticaria patients. So this is a critical temperature threshold. And you see after four, six weeks you can't provoke the skin anymore with cold. So they're completely free of symptoms. Same is for symptomatic dermographism, no more mast cells, no more signs of the disease. You may ask what does it mean, you know, in terms of adverse events, is this a problem? Well of course we have to wait for larger trials and longer duration but this is blocking KIT. So we have KIT associated side effects or adverse events and this mainly is hair colour changes, melanocytes express KIT and apparently the melanocytes in the hair follicle, they need the SCF signalling, so the patients do get white hair. Some of the taste buds, express KIT receptor, especially the umami ones. So there is taste changes in these patients. This is completely reversible, but this is something that we have to be aware of. So interesting new aspects that we learn also about KIT biology through this drug. But it's certainly something for us super complicated and difficult to treat patients. And finally, the one target that I mentioned, which is also super interesting, the activation of inhibitory receptors and here the siglec, THE siglec, they're more than siglec-8 but these are inhibitory receptors expressed on mast cells, not only mast cells, also eosinophils, but nothing else than that and this is early data. Again, there's an ongoing phase two study, so please enrol your patients in these studies, but this is very promising the data that we had here. So this is, we have data for chronic inducible, this is for chronic spontaneous urticaria.
This is an open label study, but you see improvement in the symptoms, quite a good improvement in both omalizumab naive but also in the oma refractory patients, so again, in our difficult to treat patients. So really hopefully, we will have one or the other drug coming up soon to help our patients because we do need this. We do need new opportunities, new possibilities for our patients either to have a fast treatment in all of our patients or to have a treatment at all in these patients. Furthermore, something that we cannot address at the moment, even though Emek was referring to this already, that we have a different, you know, phenotypes in our patients. We have different biomarkers that we still have to learn more about. But this opens the possibility to have a personalised treatment also for these patients in the future. And there seems to be some heterogeneity and we should be able to address this. And there is something that can help here to address this individual, you know, a more personalised approach and please use this if you don't do this already. This is the CRUSE Control app. Actually, you can get more information by going to this QR code, using the CRUSE Control app, this can help your patients in understanding more about his or her disease and it could help you better understand the disease of your patient and then in the future, also guide you to a more precise and better treatment. And also, something that we hadn't really addressed.
You know, getting more information on aspects where your patient needs maybe interdisciplinary approach apart from just getting a better treatment for the chronic urticaria. All of this information is required and can help your patients. And with that I'd like to thank you very much for your attention and we are happy to take questions. I think. - Well done. Thank you so much. And you've stuck to time. We have about eight minutes left for questions and we already have a few coming in through your iPads and those people who want to go to the microphones, there would be an opportunity. But one of the questions you've already answered, Martin, and it's about using the digital tools like CRUSE. The answer is you would encourage everybody. - Oh yeah, a hundred percent. And how many countries do we have Sophia for the CRUSE app translation languages? 14. So 14 languages. There's high likelihood that your country is in there as well. - Perfect, right, from floor, Ivan. - [Ivan] One question, in the real life when you have your patient, this could be possible to combine two type of antihistamine, H2 for example, I don't know, cetirizine and loratadine, is possible to this mix before or after increase for four doses? - Okay, I'll answer that.
The answer is yes. I would be very happy to combine an H1 and an H2. I do it for many patients and you can split the dose and have two different antihistamines. There isn't one way of prescribing antihistamines, you have to try and optimise it. - [Ivan] Levocetirizine In the next guideline, it's possible to put this? - The next guideline will be beyond guidelines. Okay Louis? - [Louis] So Martin, do you think it'll be possible to combine two different- - Yeah. - [Louis] Immuno biologics for? - Yeah, very good point, Louis. Yes, I do think so, first of all, we know by now that it's safe to combine it from different diseases. You can combine so, safety aspect but you can use possibly more than one mechanism of action. So will be interesting to understand for example, the future of some of the biologics are disease modifying. So maybe there's something where you have acute treatment for six months, very effective one and in peril, use a different one where you hope that you have a disease modification. But this is just pure hypothesis but in general, yes I do think that it may makes sense but we have to learn a lot more where it makes sense. - There's a question here for Emek. Do you ever combine omalizumab with ciclosporin?
- Yes, I had some experience with combining these two medications and indeed in the beginning I was thinking that why would I combine these two treatments? Because if it's not responding to omalizumab, then I would go onto ciclosporin. But there is a nice paper from Sanchez at all, I guess, they compare the patients, they give both omalizumab and also they give ciclosporin to all the patients and they are not responding to any of the drugs. But when they gave the patients the two drugs together, then they had response to treatment. So this really makes sense. I think these patients have both type one and type two be autoimmunity so that they have a complete response when you give these medications together. So yes, I had some experience. I also had experience when I gave and omalizumab was somehow, when patients lost response to omalizumab, then I give for a short period ciclosporin. And then when the disease is under control then I keep on with omalizumab treatment again. - And I agree. Now there's an insightful question for Martin here.
Have BTK inhibitors ever been associated with hypoglobulinemia? - So BTK inhibitors with hypoglobulinemia? No, no. - Simple answer. - And I mean the inhibition of BTK will, you know rather cause, oh, hypo, you're talking - [Clive] Hypo. Yeah. - Oh, okay. So there's limited data and so we did this for example with fenebrutinib and looked at IgG levels and the general IgG levels did not go down, only the auto antibody levels. So probably the response to something will be potentially reduced, but there's not a general hypoglobulinemia by BTK inhibition. - Excellent. Yes, please. From the front. - [Audience Member] Yes, that is a question for Martin as well. Do you have any experience about isolated angio mast cell, angioedema using this new drugs, BTK and? - Wonderful question because we do need this clinical data. We have personal data, so individual experience, but there is, as of yet no clinical trial looking specifically at these patients and this is something that we definitely need to answer this question profoundly, but from, you know, from clinical experience, yes, it seems to be at least, you know, from these patients that have both angioedema and wheals, it looks at the response is similar but it may be something special to those with angioedema only and we have to get this data.
- [Clive] Yeah, because maybe in future we will have to classify the angioedema due to baricitinib, we have to exclude first. - 100%. - [Audience Member] And not responding to antihistamines, corticosteroids and- - Yeah. Yeah. Thank you. - [Audience Member] Thank you. - [Clive] Another question from the floor. - [Audience Member] I have only remark if possible, I'm from Georgia, we are doing clinical trial with barzolvolimab. First of all, thanks for great session and we are so happy. Just I'm sharing the same that was just discussed before by Marcos Malva that we had before, I mean 10 week, one week ago as I remember. So the trial is excellent and so the patients who were not responding to omalizumab before and who were very severe with a very, very, not, it was impossible to control the asthma even with steroids. So there were a lot of problems. So barzolvolimab is working, I think of course we are ongoing in a clinical trial and about there is, we had no problems with taste but of course it's going on and only I think very small, only neutropenia. But it's a not, very slow, very low, mild let's say. So I'm just want to thank to these clinical trials because they give another possibility, so thank you. Just this, okay, thank you very much.
- Yeah, thank you. Yes, I think it's a very interesting antibody and may have a role in sort of mast cell disease generally beyond urticaria. Now we have got to the end of the session. There is one question again to answer because it's relevant to me. What about hydroxychloroquine? Can it be useful for CSU? The answer is I don't prescribe it unless I have no alternatives because I think it's a weak treatment. It may be helpful, but I do prescribe it for vasculitis, particularly hypercomplementemic vasculitis when I think it does have a major role. Would you agree Emek? - Yes. - Okay, so your participation has been very welcome. Thank you so much. And I think there's just a wrap up slide with a QR code for those who want Medthority website so that you can look at this symposium and think about it in your own time. So once again, thank you so much for coming and it's great to see so many people interested.
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