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CME / CE

Chronic Spontaneous Urticaria: Frequently Asked Questions

  • Authors: Brian Kim, MD, MTR; Jonathan A. Bernstein, MD
  • CME / CE Released: 8/19/2022
  • Valid for credit through: 8/19/2023
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  • Credits Available

    Physicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

    Pharmacists - 0.50 Knowledge-based ACPE (0.050 CEUs)

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Target Audience and Goal Statement

This activity is intended for dermatologists, allergists/clinical immunologists, pharmacists, nurse practitioners (NPs), and physician assistants (PAs) who specialize in dermatology or allergy/immunology.

The goal of this activity is that learners will improve knowledge and competence of the diagnosis, treatment, and understanding of the etiology of chronic spontaneous urticaria (CSU).

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Disease burden and impact on patients with CSU
    • Role of immune cell signaling in the pathophysiology of CSU
  • Have greater competence related to
    • Implementing evidence-based diagnostic criteria for CSU


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Faculty

  • Brian Kim, MD, MTR

    Professor and Vice Chair of Research in Dermatology
    Director
    Mark Lebwohl Center for Neuroinflammation and Sensation
    Icahn School of Medicine at Mount Sinai
    New York, New York

    Disclosures

    Brian Kim, MD, MTR, has no relevant financial relationships.

  • Jonathan A. Bernstein, MD

    Professor of Clinical Medicine
    Department of Internal Medicine
    Division of Immunology/Allergy Section
    University of Cincinnati Medical Center
    Partner
    Bernstein Allergy Group and Clinical Research Center
    Cincinnati, Ohio

    Disclosures

    Jonathan A. Bernstein, MD, has the following relevant financial relationships:
    Consultant or advisor for: Allakos; Amgen, Inc.; AstraZeneca Pharmaceuticals LP; Celldex Therapeutics, Inc.; Genentech; Novartis; Sanofi-Regeneron; TEVA; TLL
    Speaker or member of speakers bureau for: AstraZeneca Pharmaceuticals LP; Genentech; Novartis; Sanofi-Regeneron
    Research funding from: Allakos; Amgen, Inc.; AstraZeneca Pharmaceuticals LP; Celldex Therapeutics, Inc.; Genentech; Novartis; Sanofi-Regeneron; TEVA; TLL
    Contracted researcher for: Allakos; Amgen, Inc.; AstraZeneca Pharmaceuticals LP; Celldex Therapeutics, Inc.; Genentech; Novartis; Sanofi-Regeneron; TEVA; TLL

Editors

  • Faisal Islam, MD, MBA

    Medical Education Director, Medscape, LLC

    Disclosures

    Faisal Islam, MD, MBA, has no relevant financial relationships.

  • Grace O’Malley, PhD

    Medical Education Director, WebMD Global, LLC

    Disclosures

    Grace O’Malley, PhD, has no relevant financial relationships.

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  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC

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    Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

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This activity has been peer reviewed and the reviewer has no relevant financial relationships.


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CME / CE

Chronic Spontaneous Urticaria: Frequently Asked Questions

Authors: Brian Kim, MD, MTR; Jonathan A. Bernstein, MDFaculty and Disclosures

CME / CE Released: 8/19/2022

Valid for credit through: 8/19/2023

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Activity Transcript

Brian Kim, MD, MTR: I'm Dr Brian Kim, professor and vice chair research and dermatology director of the Mark Lebwohl Center for Neuroinflammation and Sensation​ at the Icahn School of Medicine at Mount Sinai in New York, New York. Welcome to this Medscape program on Chronic Spontaneous Urticaria. Joining me today is Dr Jonathan Bernstein, professor of clinical medicine in the department of internal medicine, division of immunology allergy section at the University of Cincinnati Medical Center and partner of the Bernstein Allergy Group and Clinical Research Center. Welcome. Jonathan, to get us started, could you give us an introduction to chronic urticaria and how it impacts patients' lives?

Jonathan A. Bernstein, MD Well, thank you for that introduction. Yes, let's start by trying to understand what chronic spontaneous urticaria is. It's a skin disease that is characterized by the recurrence of wheals, angioedema, or both that lasts at least 6 weeks or longer. And wheals are described as pruritus with burning sensation and pain. They're fleeting and nature. In other words, they're evanescent. They can travel from one part of the body to the other. The swelling of these lesions are variable size, surrounded by reflex erythema.

Angioedema is often associated with wheals and itching, and it is described as sudden erythematous swelling. It affects the deeper dermis and it can be painful and take up to 72 hours to resolve. Chronis spontaneous urticaria can be further subdivided into spontaneous and inducible forms. The spontaneous forms being the development of wheals and angioedema in unprompted unpredictable fashion, whereas inducible forms, responds to specific triggers, either physical stimuli, such as cold, heat, friction, UV light, or urticarigens which would refer to things like cholinergic urticaria, exercise, passive warming, contact urticaria, or even aquagenic urticaria.

It's important to recognize that urticaria, chronic urticaria specifically, is not a trivial disease. It does have a significant impact on a patient's wellbeing. In fact, the AWARE study was performed in antihistamine refractory patients with chronic spontaneous urticaria, and they found that a significant percentage up to 50% of patients with chronic spontaneous urticaria display high rates of angioedema. And patients with chronic spontaneous urticaria are generally undertreated. In fact, up to 80% had an urticaria control test score less than 12, baseline showing uncontrolled disease. And they also found that patients with chronic spontaneous urticaria have significantly impaired health related quality of life and report frequent use of healthcare resources. So the AWARE data highlights the need for improved patient care and the significant burden this condition has on patients.

Now, this slide illustrates the significant impact that angioedema has in chronic spontaneous urticaria. This is again from the ASSURE study. This is looking at the chronic urticaria quality of life total and domain scores. And one can see that as, on the Y-axis going from zero to 100, low impairment to zero and high impairment is 100. And we can see that in patients who have angioedema compared to those who don't have angioedema, their overall quality of life is significantly more impaired.

And this also translates to all of the domains of this questionnaire, pruritus swelling, impact on life activities, sleep, overall limitations and appearance. So chronic spontaneous urticaria patients with angioedema experience greater negative impact on health related quality of life, specifically sleep, daily activities, compared with patients who do not report angioedema. Now, this slide illustrates what impact complete control of wheals and itch can have in patients with chronic spontaneous urticaria on sleep quality. And it shows that the controlling the symptoms of urticaria leads to improved health related quality of life and sleep. And there's a direct positive correlation observed between symptom control and sleep independent of patients' angioedema baseline status.

So Brian, we can see that chronic urticaria really is very burdensome for patients. Before we think about how we can diagnose and treat this condition, could you tell us a little bit about the underlying pathophysiology of this chronic disease?

Dr Kim: Absolutely. Thank you, Jonathan. And I think the other interesting point is that whenever, as a dermatologist, whenever I talk to our allergy colleagues, a big difference for me, and I just want to speak to a little bit of experience, is the angioedema. I think that we tend to see much less as dermatologists patients with the angioedema component compared to the urticaria. And I think that's something to heavily consider in terms of referral bias and also just selection of who we tend to see within these different specialties as well. We'll talk a little bit here about the fundamental pathophysiology of urticaria. There's a lot known, but there's also a lot not known. It's largely considered a predominantly mast cell driven disease. That's not to say that other cells are not involved.

But the basic mechanism centers on the mast cell. And the mast cell is a granulocyte and contains a whole host of different granules that contain a variety of different molecules, such as histamine, proteases, cytokines, and even other pro-inflammatory biolipid mediators. And it's really the degranulation of this mast cell that essentially is releasing all these factors all at once that really drives a variety of different processes, such as the dilation of blood vessels, plasma extravasation, resulting in edema and influx of other immune cells, as well as activation of sensory nerve fibers within the skin that mediate itch along a spectrum, all the way to pain, as described by Dr Bernstein already.

Histamine itself, acting upon the H1 receptor, is a key mediator in the development of a variety of these symptoms. It's not exclusively histamine, as we know, based on therapeutic response, but we know a lot about what histamine does in this condition. And it's certainly a molecule that we block in urticaria. But although the detailed pathogenesis is not completely understood, activation of mast cells and as well as basophils in patients is thought to occur via a variety of different mechanisms. There are, we know high affinity IgE receptors on these cells. These cells very tightly bind IgE and the crosslinking of IgE results into activation of a whole host of intracellular signaling cascades that results in the activation or degranulation of the cells.

And additionally, there's also a commonly accepted theory of autoimmunity whereby not only do these mast cells or basophils become spontaneously activated, but in fact that there are autoantibodies that either bind IgE itself or the high affinity Fc epsilon receptor, and this results in essentially what we can think of as auto activation by our immune system of these mast cells, his mast cells.

So now that we know a bit more about how urticaria actually develops in terms of the physiology and what we don't know, we can look at how we diagnose and treat this disorder. Dr Bernstein, can you start us off here by going over the diagnostic criteria tests and what we use?

Dr Bernstein: Yeah, certainly. Thank you for that overview on the pathophysiology. The diagnostic workup includes a thorough history, a thorough physical exam, basic testing, and an assessment of disease activity, impact and control. And basic tests, it's really recommended to do limited testing initially in patients who present with chronic urticaria, as the critical part of the evaluation is the history. And this is where you can glean a lot of the actual information, what associations, what patients believe are triggering their hives, are there any inducible components and so forth.

So guidelines generally recommend limited testing unless there's something in the history that suggests otherwise. So a differential blood count, a C-reactive protein, with or without a sedimentation rate, would be something advocated in all patients. And certainly, there is value with the differential blood count, looking for low eosinophils and low basophils, as these are emerging as defined phenotypes for certain types of urticaria subsets. A total IgE and a IgG against thyroid peroxidase would also be reasonable to obtain in patients, especially if they're presenting after trying over the counter antihistamines that have not demonstrated significant response. Again, low total IgE and the presence of auto antigens also seem to point towards a more difficult to manage a patient with chronic spontaneous urticaria.

The guidelines, international guidelines, really list 7 major aims for the diagnostic workup in chronic spontaneous urticaria. And these are listed here, and they're all interestingly, starting with Cs, confirm, cause, co-factors, comorbidities, consequences, components, and course. And what is this specifically referred to? Well, confirming the diagnosis and excluding other causes that could be causing hives, the cause, identify the underlying cause. And unfortunately, in chronic spontaneous urticaria, we often don't find a specific cause. In fact, it is not typically related to an underlying food and therefore, it's not recommended to routinely do large panels of testing against foods. It's not typically caused by aeroallergens. So testing for aeroallergens is not recommended in these patients unless these patients have concomitant disease such as allergies or a well-defined food allergy, that would be appropriate.

And if one were to test, one should probably do serologic testing, given the fact that they're having diffused hives and the skin is already very reactive. So skin testing itself would not be as appropriate. Co-factors investigate co-factors that modify the disease activity and looking at underlying comorbidities. And it's important to recognize that chronic spontaneous urticaria is associated with a higher incidence of autoimmunity as was discussed. And also, the effects it has on mental health. What are the consequences? Check for the consequences of this disease. We've talked about quality of life and the effects on sleep. And recent studies shown it has a significant effect on sexual health, as well as on work productivity. Monitor components that may predict the disease course in response to treatment. As we talked about, certain biomarkers may be appropriate to determine response or lack of response to certain medications. And then monitor the course of disease. And this really involves using patient reported outcome measures that can look at activity or urticaria control and the impact it's having on the patient's daily life.

So patients should be assessed for disease activity, their impact and control at the first in every follow-up visit. And I don't think that's really routinely done in many clinical centers, at least in the United States, to my knowledge. There are some very nice validated tools, the urticaria activity score. It's a score that one measures the number of hives and the severity of itch on a daily basis over 7 days. So it does have a very nice composite assessment of hives over a week period of time. Certainly, when the UAS7 is zero, that means there's no hives. But the scale goes up to 42, and that's the most severe, where there's diffuse hives with severe itching.

And again, there's also the angioedema activity score in those patients who also present with hives associated with angioedema. It's important to mention that up to 20% of patients might present with isolated angioedema without hives and not all of these cases are bradykinin mediated. They may be histaminergic and we should not forget that these patients may be treated in a similar fashion the way we treat chronic urticaria.

The quality of life forms have been validated for chronic urticaria. There's the CU-Q2oL, and this is for all chronic spontaneous urticaria patients with wheals. And there's also an angioedema quality of life questionnaire for patients with angioedema, with or without wheals. Now, disease control should be monitored and this is the simplest test I think that all clinicians could incorporate into their daily practice. This helps us assess whether patients are well controlled or not. It assesses 4 questions about the impact it's having on the patient's daily life. And this can be used in patient with wheals with, or without angioedema. Similarly, there's another test called the angioedema control test for patients. And for patients with wheals and angioedema, one could use both tests.

Dr Kim: Yeah. Thank you, Dr Bernstein. I think it's very insightful and I think you're highlighting that there are a lot of factors to consider when making a diagnosis of CSU, but also how we can quantify the severity of the condition over time in these individuals who have it. Now, can you tell us a little bit more, once CSU is diagnosed, what do we do? How do we treat this and how do we think about these different treatment options?

Dr Bernstein: Well, the goal of treatment, as you know, is to treat the disease until it's gone as efficiently, as safely as possible. So that's the objective of the international guidelines. So one who wants to aim for this continuous UAS7 score of zero, meaning no hives and no itch. And this is complete control with a normalization of the patient's quality of life. So our approach to treat should be to find and eliminate an underlying cause. And again, sometimes there may be an inducible trigger. We want to avoid these triggers, induce tolerance, and then to use pharmacotherapy to prevent release of inflammatory mediators. Now, this figure really looks at disease activity in CSU and how it can vary. So treatment may need to be intensified or reduce at different time points. So we want to follow the principle of assessing, adjusting, acting, and reassessing.

And so we can look at the urticaria control score and look at the control level. And if patients have a UCT score of less than 12, then we recognize that they're uncontrolled and we want to step up treatment. And the guidelines would advocate using initially 1 to 4 times the FDA recommended dose of second-generation antihistamines, for at least 7 to 28 days, to see if this is effective. And if not, again, then one would need to step up. And this would involve using omalizumab, which is now recommended as step 2 therapy in the most recent guidelines. And would want to try this for at least 3 months to see if there's an effect. Now, if the urticaria control test is between 12 and 15, and this would indicate the patient's well controlled and one would want to continue therapy and maybe even try to optimize it to see if we could get that urticaria control test higher up to 16, where the patient is completely controlled. And once they've been controlled for at least 3 to 6 months, no hives, no itching, then we would start to step down based on individual factors and so forth. But it is important to establish that control and maintain that control for a period of time before stepping down.

So this is a nice algorithm. This is the most recent guideline, the international guideline published. And the only real major difference between the previous version is that step 1 and step 2 have been condensed into 1 step. So it says start with standardized second generation H1 antihistamine, and if needed, increased the dose up to 4 times the recommended dose. So instead of having 2 separate doses. And then if there's inadequate control on high dose antihistamines and after 2 to 4 weeks or earlier, depending on the clinical situation, then one would consider stepping up, and the step 3 would be adding on omalizumab. And again, in this scenario, one could increase the dose or shorten the dose interval depending on how well patient is controlled.

Now I recognize that omalizumab is the only other licensed treatment for patients who don't benefit sufficiently from H1 antihistamines. And this therapy is a recombinant humanized monoclonal antibody that targets peripheral IgE. But it not only reduces the levels of free IgE, but also down regulates high affinity IgE receptors on mast cells, both of which are essential in mast cell and basophil activation. So stabilizing the mast cell membrane is critical, is thought to be a critical mechanism for omalizumab.

Now, if this is not effective, then one would need to and move on to step 3, which in this case, is cyclosporine, as there is evidence in the literature to support cyclosporine in the treatment of chronic urticaria, albeit it's not an approved therapy. Now, I think when we look at this algorithm, it looks okay, this is very straightforward. We go from 1, 2 to 3, but there are nuances in how we might manage patients with chronic urticaria. And part of that may involve utilizing biomarkers, which have now been demonstrated to predict response or lack of response to omalizumab in the management of more difficult to treat patients.

So this sums up the current standard of care we have, but there is lots of research going on, looking into novel therapies. Brian, could you tell us more about these emerging agents for chronic spontaneous urticaria?

Dr Kim: Absolutely. As we said, from the very beginning, we really put mast cells at the center or the pathogenesis of CSU. The question is how central are mast cells? That still remains to be determined. But not withstanding that, as we've already discussed our number of strategies that are known. There are ways to inhibit products that are derived from the mast cells, like histamine.

We of course, want to inhibit the IgE histamine axis. But in addition to, for instance, omalizumab, there have been other drugs that have been developed to target IgE. There's also Bruton Tyrosine Kinase inhibitors, which actually targets downstream of the IgE pathway. So you're also inhibiting mast cells in response to stimulation of IgE, but also inhibits the B-cell pathway as well. So we think actually, the production of IgE as well, could be targeted by these BTK inhibitors. There are other things that activate mast cells, for instance, such as TSLP. So another way is to actually block TSLP using monoclonal antibodies.

But now, another major target is the IL-4, IL-13; these 2 cytokines either at once or perhaps even independently. And then there are other ways that you can actually also get at the activation of the mast cells as well, not just the production, but calming them down through other pathways, that have nothing to do with IgE or even cytokine for that matter by way of molecules that block, for instance, Siglec-8. And then perhaps the most extreme is to just completely try to target the mast cells entirely and perhaps even try to deplete them using C-Kit. We know that mast cells express C-Kit. So there are a number of different therapeutic strategies we can bin into different mechanisms of action. There are probably more, but this is coming from a mast cell centered kind of universe.

When we think about a lot of the factors that I talked about or cytokines, and I've already alluded to some of these B-cells. We know that a lot of the shared mediators are also produced by basophils. T-cells produce a lot of these type 2 cytokines that can amplify mast cell responses, but it still remains to be determined how much these other cells can do directly. Eosinophils are also granulocytes that have a lot of similar effect on molecules as well. So at both the molecular and cellular level, there is a lot more in the pipeline. But of course, in the interest of time, we can't cover all of these different agents.

We'll now look at some examples of emerging treatments from these groups, starting with inhibition of signals leading to mast cell activation. Two groups in the category are IgE targeting therapies and BTK inhibitors, Ligelizumab is a humanized recombinant monoclonal antibody that targets IgE with actually higher affinity of omalizumab. IgE bound to ligelizumab is no longer able to bind high affinity IgE receptors on mast cells or basophils, inhibiting activation of these cells. Fenebrutinib is actually a potent, highly selective reversible BTK inhibitor. So Bruton Tyrosine Kinase, as I mentioned, plays a key role downstream of the IgE receptor. But also with regard to the B-cell receptor as well. So we think, again, with this molecule, you can both block the signaling of IgE as well as some level of production of IgE as well.

And dupilumab is certainly in this group. It's a human monoclonal antibody that binds the IL-4 receptor alpha subunit. And it actually disrupts both IL-4 and 13 signaling on target cells by blocking this receptor pathway. So dupilumab inhibits IL-4, 13 mediated responses, including a release of a whole host of other pro-inflammatory cytokines, chemokines, and even potentially production of IgE as well.

As we know, omalizumab is already approved. Ligelizumab demonstrated efficacy in phase 2B study and demonstrated very strong safety and efficacy in a 1-year extension. It was well tolerated with no newly identified safety signals.

In terms of BTK targeted therapies in CSU, fenebrutinib as I mentioned, a double-blind placebo controlled phase 2 trial with 93 adults with antihistamine refractory CSU, the primary endpoint was changed from baseline in the UAS7 at week 8. The primary endpoint was indeed met. Dose dependent improvements at UAS7 were seen at week 8, occurring at 200 mg, twice daily and 150 mg daily, but not at 50 mg daily of fenebrutinib vs placebo.

However, asymptomatic reversible grade 2 and 3 LFT elevations were observed in the fenebrutinib, 150 mg and 250 mg groups. So there were some AEs. This drug does have some AEs associated with it so that is one of the potential downsides. But nonetheless, efficacy was seen.

So, in terms of dupilumab, we've seen already, in both case studies, the patients with CSU improve. In the case studies were actually really hinted that perhaps patients who received dupilumab would actually benefit even if they actually failed to respond to omalizumab. In the phase 3 LIBERTY-CSU CUPID Study, in the study A, there was certainly clinically meaningful and statistically significant improvements in patients who were antihistamine, H1 antihistamine resistant. And certainly, this was well tolerated.

So now that we've looked at emerging therapies that inhibit signals leading to mast activation, Dr Bernstein, can you talk us through the next 2 groups of agents being investigated for use in CSU?

Dr Bernstein: Yeah. Thank you, Brian. That was a very good overview of some of the therapies that are further along in the pipeline for development

So the next category. And these are silencers of mast cells, and these are therapeutics that activate inhibitory receptors on mast cells. And one example is lirentelimab, and this was also referred to as AK002. And this is a humanized non-fucosylated IgG1 antibody against Siglec-8. And Siglec-8 is an inhibitory receptor that is selectively expressed on mature eosinophils and mast cells and has low expression on basophils. And by binding Siglec-8, lirentelimab inhibits mast cell activation, thereby reduces granulation and release of inflammatory mediators. Then there was one study, it was a phase 2A study that enrolled patients with chronic urticaria that was refractory up to 4 times the recommended non-sedating antihistamine dose. Patients received 6 monthly IV doses of lirentelimab. And this was 0.3 mg, 1 mg, and up to 3 mg per kg. And the primary efficacy endpoint was change in the urticaria control test at week 22.

Now, this was an open label study, so it wasn't placebo controlled. But what it told us was, and we can see that a significant percentage of patients from each of these groups responded to lirentelimab, which was clinically meaningful. So quite encouraging, which would lend to the further investigation of this therapy and more double-blind placebo control trials to determine its true effect in the treatment of patients with chronic spontaneous urticaria.

Finally, we have the agents that caused depletion of mast cells, as you alluded to earlier, and this is the CDX-0159. It's a drug that falls into this category. It's a humanized IgG1/κ monoclonal anti-KIT antibody. The KIT receptor, tyrosine kinase and its ligand stem cell factor, are master regulators of mast cell biology. In fact, stem cell factor is an essential factor for mast cell differentiation, activation, proliferation and survival. This compound inhibits stem cell factor dependent kit and mast cell activation. Now, these trials are also underway, are ongoing as we speak. But in some of the preliminary data that shows that there was a rapid and durable response observed, and this was in response to provocation tests, looking at patients with cold urticaria and symptomatic dermatographia. So in this case, we see that there were 10 patients with cold urticaria and 10 with symptomatic dermatographia. But 10 out of 10 actually had complete response to CDX-0159, illustrating a decline in the cold temperature threshold illustrated in blue on the left.

And 9 out of 10 in the symptomatic dermatographia patients experienced a reduction in the severity of their dermatographia.

So there are rapid and durable responses observed for both of these inducible forms of hives. And it was generally well tolerated with mild adverse effects, the most common being hair color changes, infusion reactions and taste disorders, which generally improved over time as the drug was used for longer periods of time.

Dr Kim: Thank you, Jonathan. Lots of interesting and potentially very dramatic options for targeting mast cells in CSU and treating our patients. So overall, what do you think are some of the important clinical lessons we can take away from all of this that we've discussed here today?

Dr Bernstein: Well, I think to improve the management of our patient with the chronic spontaneous urticaria, we need better diagnostic approaches. And I think we've outlined that in the context of patient reported outcome measures that have now been validated for chronic spontaneous urticaria, for angioedema and now for even some forms of chronic inducible urticaria. So we need to use these more in our clinical practice to assess and monitor patients' response.

I think we also need to recognize the value of emerging biomarkers that will allow us to personalize our care of patient with chronic urticaria. So it's not just a rote exercise to go from steps 1, 2 and 3, but there are definitely differences in patient phenotypes that correspond with different patient endotypes. So in general, it's not one size fits all as we've seen in some of the earlier clinical trials that we've outlined. We want to treat until urticaria is gone, and we can do this in the majority of patients that we see with the existing therapies. But there's still a gap in treatment. There's still patients who are resistant or refractory to the treatments that we have available to us today.

Once we do achieve control, we want to... Well, until we achieve control, we want to step up on therapies. We want to optimize therapy. And then once we achieve control, we want to step down and to use the least amount of medicine necessary. And also, it's the only way to know if patients have actually gone into remission, is you step down and off therapy. So we also want to address unmet needs, such as quality of life and assess other comorbid conditions that urticaria can impact, such as depression, work impairment and so forth. So we really need to have a holistic approach to these patients who present in our office because as we've can see from this discussion today, this is anything but a trivial disease.

Dr Kim: Thank you very much. And I think it also tells us that we do know a lot and a lot of what we have known is being validated through some of these therapeutics. But there's also a lot we don't know, as you said, in terms of gaps in clinical unmet need. But the positive is that there are many, many therapeutics in the pipeline. We've only actually covered a handful of them here today. So thank you so much, Dr Bernstein, for this great discussion and thank you all for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This is a verbatim transcript and has not been copyedited.

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