This transcript was automatically generated from the video recording and may contain inaccuracies, including errors or typographical mistakes.

Overview of Chronic Spontaneous Urticaria

Dr. Benjamin Ungar (Icahn School of Medicine at Mount Sinai): Okay, so overview of CSU. So in this condition, wheals or angioedema, or it can be both, appear spontaneously for at least six weeks, and in particular with no known trigger, which is what characterizes that it is spontaneous, rather than the other entity that is similar, which is inducible urticaria, where there is a clear trigger.

It is due to multiple potential immune dysregulated pathways. The most two common ones are type 1. So this is an auto allergic, and as we are going to discuss, IgE mediated or type 2B or IgG mediated with mast cell activating autoantibodies. The prevalence is upwards of a third of a percent in the US, more likely in women, so twice as likely. And the average duration can be a few years, although some people really can have it for extended periods of time.

It can also develop at any age. In pediatric, which is definitely much less common, 6-9 years old, and then much more commonly in adulthood in the 30-50-year range. But again, it is not limited to those age ranges.

Pathophysiology of CSU

As this diagram shows, the pathophysiology is not straightforward. It is complicated. And ultimately, many of the details are probably not necessary to understand super well, but a few high-level points are worth thinking about because to some extent it can help guide the way we think about treatment ultimately, which we are going to get to later in the presentation. So we talk about different ways of activating mast cells, and mast cells really are at the core of this disease, where, whether it is IgG, IgE, there can be some innate immune activation, a few different ways.

So there is a signaling that has nothing to do with the FC-epsilon receptor, which is one of the primary receptors on the mast cell. So there are other receptors like MRGPRX2. In any case, through a bunch of different mechanisms, mast cells get activated. They release primarily histamine, but a bunch of other mediators as well, prostaglandins, cytokines, and so on. And that produces the characteristic urticaria or wheals. And importantly, many of the substances released then act on cells that feed back into the process. And so, it can be, in a sense, self-perpetuating. And as is very central to the idea of CSU, the S in particular, we do not know what is actually driving the activation of mast cells specifically in terms of triggers.

Endotypes That Drive CSU Pathogenesis

So we are talking about some of the variations or endotypes of CSU, and that is really defined by what is the immune process that is really driving the mast cell activation. As I mentioned, there is a type one IgE-mediated, often associated with comorbid allergic diseases, perhaps not surprisingly, that can also have a concomitant “CindU” or a chronic inducible urticaria. So some people may have urticaria where they can actually identify the trigger and also have urticaria that is not identifiable in terms of triggers. It is important to note that often IgE is elevated in this population of this endotype, but not always the case, despite the fact that it is still mediated by IgE overactivity.

We also have IgG-mediated or type 2B, which is more of an autoimmune version of this. As with many autoimmune diseases, it is increased in females. Often this can be a longer-lasting disease duration. IgE is low because this is not really an issue of IgE at all. And there can be these autoantibodies to the FC-epsilon receptor, which is one of the major activators of mast cells. And we can also see other autoantibodies, which we will touch on in a bit as well.

And then, there are other subtypes as well, or endotypes. So maybe a combination of both type 1, type 2B, other non-FC-epsilon receptor-mediated pathways, as I mentioned. At the end of the day, some of these factors can help guide in treatment decision-making or prognosis, but we still need to treat the underlying disease process that is leading to the clinically relevant symptoms, which is ultimately mast cell activation, and then the subsequent release of various mediators leading to the hives and other symptoms.

Poll 4

So we have a poll here. So how often do you ask patients about the impacts of CSU on daily living?

1. Never;
2. Rarely;
3. Sometimes;
4. Frequently; or
5. Always.

And be honest, if it is more towards never or rarely, it is okay. But we will see.

And then, okay, so a mix. Some people always asking, some people less so, and hopefully, as we discuss further, the relevance of really addressing that.

Real-world Data: CSU Symptom Burden on Quality of Life

So this is really at the key of why we should, in many respects, care about the disease. So this was one multinational cross-sectional survey really highlighting that there is a very large symptom burden that affects quality of life.

So I am going to start off pointing out the blue bars, which are the highest numbers, which is during an exacerbation. We are seeing the majority or a very large proportion of people experiencing a whole host of different physical symptoms: sleep problems, pain, maybe something that is a little less associated, fatigue, decreased concentration. So very multi-system impact, and really in multiple different domains of how they might be interacting with the world.

Now, importantly, those symptoms do not go away in the absence of an exacerbation. So before an exacerbation, afterwards, everything quiets down. They are still experiencing things: migraines, palpitations, all of these are active. And so, this is a chronic condition that is characterized by flares, but that is not the only part of the disease that is worth keeping in mind.

So with that said, I want to just touch base with Dr. Butler and Dr. Hsiao. Dr. Hsiao, what are your experiences with these symptomatology, quality of life? How does that show up when you see patients with CSU?

Dr. Jennifer Hsiao (Keck School of Medicine): Yes, I think that CSU absolutely has one of the greatest burdens on quality of life, that we as dermatologists can help patients with. I think patients oftentimes come in telling us the impact on quality of life. They will say, I am not sleeping. I am not able to focus at school or at work. And I think actually it is not listed here, but I think anxiety is another way that patients will basically feel like they have anxiety about the flare of hives coming. They do not know when it is going to come. And so, even when it is not flaring, I think that baseline anxiety is still there.

What about you, Dan?

Dr. Daniel Butler (University of Arizona College of Medicine): Yes, I mean, I think this list says it all, just the capture of it, of all the experiences that these patients are going through. And I think for those of us who have seen these patients in clinic, we know that sometimes we are seeing the expression of all this in that anxiety, in that how they speak with us, and how frantic they are to get help. And sometimes this is really hard because they do not have a lot on their skin.

And so, I think it is always important, as people are talking about hives or the suggestion of hives or a diagnosis of hives, we are keeping this list of symptoms in our mind, because it really is the true disease. It is not just the visual, it is everything that happens from symptoms to mental health, to quality of life changes.

Dr. Ungar: Yes, so I could not agree more. And in some respect, this is one of the exceptions in dermatology, right? Things show up in the skin, we diagnose visually. And at least in my experience, very often, more often than not even, patients do not have any skin findings, and we have to rely on the history, review of systems, and all of that to really identify this.

Real-World Data: Psychosocial Burden of CSU

Now, beyond the physical symptoms, and this really, I think, is touching, Jenny, what you were talking about, the anxiety, the way people have this psychosocial burden and interact with other people, it really has a tremendous negative effect. People feeling like they were stared at, not having physical contact, or other people, reluctant to have physical contact, impaired social life relationships, being bullied.

I think, a pretty common experience, at least in my case, seeing these patients, and often they have seen other people that maybe have been dismissive of their symptoms because there is nothing visual on the skin. And so they are coming in, again, like you said, really wanting to get that across. And part of that, at least in some cases, is that they have been dismissed, and that can really add up.

So again, this is all to say that it is just so important to put front and center the impact symptomatically, but also just the quality of life that they experience and appreciate just how widespread and through all domains, this really can have that impact. And the flip side of that is we have an opportunity to help these people and really make a tremendous impact, in a positive way, and that is where we go from here.

So let me just move forward here.

Suboptimal Disease Control With Current CSU Therapies

So now that all is how they show up, how they experience, but there is a second part, which is the treatment experience. And it depends. A lot of these patients may see primary doctors first, certainly can then come in to see derms.

Most people with uncontrolled disease, despite antihistamine treatment, which is typically first-line, 50% have resistant CSU, despite taking four times the quote-unquote standard dose of second-generation antihistamines, which really is essentially for practical purposes, a max dose, and that is not controlling things. Patients are experiencing a delay with inadequate response to omalizumab, which we will touch more on as well. And then there are some of these endotypes, that maybe have more difficult-to-treat disease, and some of that may factor into the way we think about mechanisms of treatment as well. And so again, it is not just that they are being dismissed, having this impact, but then they are getting treated, and it is really suboptimal, and that can be quite frustrating as well, which then again feeds into all the symptoms as well and really exacerbates things.

CSU Is Associated With a Wide Range of Comorbidities

CSU is also a systemic disease associated with other comorbidities: autoimmune diseases, cardiovascular, atopic, psychiatric, and so on. And so, basically, when we are treating patients, it is not just to help them feel better, but ultimately this has an impact on their overall health. And also, something to keep in mind potentially, depending on the context, screening questions, maybe referring to certain other specialists as well.

Special Considerations for Persons With Skin of Color

One of the additional considerations that is important, and you can imagine that in a condition where people are dismissed, maybe there are delays to seeking treatment and so on, often there can be a disproportionate burden on patients with a skin of color. So Black patients with CSU experience a longer duration of disease versus Asian and White patients. The presentation can sometimes be more difficult to immediately assess because there may be less visible erythema. And so, you are looking at some of the surface, or not surface changes, but the morphologic features without the color changes being as obvious, and that also may lead to underestimation of disease severity. And guess what? That leads to suboptimal treatments.

Black and Asian patients are less likely to see dermatologists. There is a perceived bias and limitation in access to advanced therapies. So this is all to say, it is important to have that in mind that we really need to have a higher burden of treating, assessing, and really ensuring that we are appropriately treating patients in different populations.

So with that said, Jenny, do you feel like this, again, aligns with your experience? Do you have anything that you want to add to this part of things?

Dr. Hsiao: No, I think you summed it up great. I think all patients coming to us who have CSU, definitely, I feel like most of them probably have been dismissed at one time or another, and it contributes to, I feel that nervous energy that might be in the room, almost like a desperation for the clinician in front of them to provide some relief. And I think just providing validation and supporting is really important.

Dr. Ungar: Yes, I mean, I definitely have had patients almost before we start speaking, trying to convince me that they have these hives, and I do not need to be convinced. I think it is clear when they start discussing history.

Dan, what about you?

Dr. Butler: Yes, I mean, I think the heterogeneity of presentation is key here, and that is not just different skin tones or different presentation styles. It is, even yes or no, do they have them on that day? And being able to wrap your arms around the variety of presentations and the variability in these diseases, they are not like some of dermatologies and allergies flagship diseases where the skin is always going to look the same by nature, urticaria changes within 24 hours. So it is always on the move, and that is a really important thing that we not only know, but we are able to communicate back that we understand to patients. Because that is almost like a pressure release valve when you are in a room with a patient to say, hey, I totally get it. I am here with you. I believe you. I know that this is real for you.

Dr. Ungar: Yes, absolutely. Yes, great. So I think we are going to, with that said, we are going to move on to the next section.

CSU Case Discussions: Diagnosis and Classification

Dr. Hsiao: Great, thanks Benji. So now we are going to focus in really on making that diagnosis of CSU.

Poll 5

And so, we will start with a polling question.

How confident are you in differentiating CSU from similar conditions and identifying CSU lesions in patients with skin of color?

1. Not confident;
2. Somewhat not confident;
3. Somewhat confident;
4. Confident; or
5. Very confident.

Okay, so it looks like it is answers all over, but certainly we have attendees who are not as confident in making the diagnosis. And I really hope that after this webinar, you do feel more confident that a patient walking into your clinic, they have hives that you know the questions to ask, what labs to get or not get to basically clinch that diagnosis for them and be able to start appropriate management.

Patient Case 1: Alex, 36-Yr-Old Man

So let us move on towards our next slide, which is basically we are going to go through two cases where maybe you will notice some similarities between patients who have shown up to your clinic, for example. So the first case is Alex. He is a 36-year-old man. He presents to your derm office with these intermittent wheals or hives that have been appearing for the past 10 weeks. So, key point, it has been over six weeks already. And to be honest with our wait times, by the time these patients come to us, it is probably been over six weeks, right? If they are trying to get in less than six weeks, it is acute urticaria, they are probably in urgent care or ER.

individual wheals resolve within 24 hours. They are not related to identifiable triggers. He has difficulty with sleeping, which we saw with Benji's presentation, significant daytime drowsiness. It is hard for him to work. He did not get a confirmed diagnosis. He saw his PCP multiple times, was told to use basically over-the-counter diphenhydramine or Benadryl, minimally effective. A lot of times patients will say, well, it knocks me out for the night, but it really does not solve the problem with the hives. And sometimes the Benadryl itself can contribute to daytime somnolence as well. And then basically the only other advice he was given was go ahead and try loratadine 10 mg daily, but not surprisingly his symptoms have persisted. I think this is a very presentation that can commonly show up for a patient who has CSU.

Patient Case 2: Kathy, 38-Yr-Old Woman

And so this is a second case, Kathy, a 38-year-old woman presenting with a six-month history. So it has definitely been a longer time for Kathy. Recurrent periodic quote-unquote bumps on her arms, trunks, and thighs. She says the lesions appear suddenly, super itchy, and resolve within 24 hours. So really capturing that transient nature of the lesions, I think, can be really helpful for you in making the diagnosis, right? We are not going to see atopic dermatitis or psoriasis, you know, scaly plaques just disappear within 24 hours, right?

New lesions develop daily. They are often skin color to slightly darker than her surrounding skin. So sometimes it is hard for her to see lesions, but she can feel them, they are palpable.

So she was previously told she has eczema, but when she uses topical steroids, it does not help. And so when we start giving patients treatments that just are not useful, that can also then tie back to that distrust and concerns when they show up to our clinic, right? Again, she has racked her brain, no new exposures that she can think of. And I think that is also a common thing that patients will already have thought about. Is there anything causing this by the time they come to see us? And on exam, basically subtle edematous plaques without prominent erythema.

I think in the photos, we can also see some evidence of those linear plaques suggesting that she is scratched, and maybe there is some dermatographism with pressure induced hives as well. And so let us talk about, you know, when these types of patients come to clinic with hives, what should we do? What should we be looking for? What should we be asking about?

CSU Clinical Presentation Spectrum

So to make the diagnosis of CSU, right? It is chronic spontaneous urticaria. We talked about that really important, the six-week mark. And that is because with things like acute urticaria that might be triggered by a viral infection, typically those hives will resolve within six weeks. So by the time it is over six weeks, they are just getting hives daily or almost daily, it is chronic.

And then spontaneous, because again, there is no identifiable trigger. And urticaria being that, again, the presence of hives and or angioedema. When we talk about hives, it is more of that superficial dermal swelling. You can see that wheal with the flare around it. And then also again, less than 24 hours, it is gone.

So one question I often will ask is, I will point to a hive basically on the patient's body. And I will say like, if I were to draw a circle around this and look tomorrow, would this same exact hive be there or could it have moved somewhere else? And typically patients can tell you that there is that nature where it just disappears and reoccurs elsewhere. So they might have the same burden of disease, but there are new lesions appearing daily.

Angioedema is when it is deeper swelling. And so patients may also tell you, I have some lip swelling, my eyelids get swollen. But one important thing to note is the angioedema of CSU is not the one where it is like, I am concerned for anaphylaxis.

The angioedema for CSU, it stays. They do not complain of throat closing sensations. It is really just maybe one eyelid is swollen or I have some lip swelling. And that also can be helped with our medications that we are using to treat those hives.

Distinguishing CSU From CIndU and Other Diagnoses

How do we distinguish CSU? So we talked about that spontaneous nature versus the inducible nature. And with inducible, when you are talking to patients, you could say, do you feel like the hives come from lower temperatures or cold? Is it induced by heat? Is it when you wear like a backpack and where your straps are, you will notice like that you get hives? Solar urticaria, is it after you have exposure to sunlight?

And then differential diagnosis. There is quite a few conditions where urticaria or urticaria-like lesions can appear on the skin. And I think for a lot of these, if you do a good review of systems just to check off, is there systemic involvement where patients may have like really high fever sometimes with flares or a lot of joint pains or aches.

Yes, I think that those could be reasons to basically look to see if there is some underlying issue. But if their review of systems is stone-cold normal, more likely than not, it is just classic CSU.

The one thing I will bring up is with urticarial vasculitis. That is a condition where, unlike CSU, where basically the hives come and they leave and you would have never known the hive was there, which is why patients get so frustrated sometimes when they come to see us. With urticarial vasculitis, you will see a footprint left behind, oftentimes purpuric or hyperpigmented. And so, if you see a patient where there are hives, but also these footprint-type lesions left behind, that does warrant a workup for urticarial vasculitis. And another sign could be instead of being itchy, it is painful and it burns more. So those are distinguishing features for urticarial vasculitis.

Diagnosing CSU

All right, so history taking for suspected CSU, you want to know when did it start? How long has it been? Again, usually it is been over six weeks. The rash typically erupts suddenly. You want to basically get a sense, is there that footprint left behind, or is it a transient wheal? Less than 24 hours, it is gone. Is it more itchy, which we would think about for classic CSU, or are they like, it does not itch, it hurts, it is tender, there is pain?

Then, I think that leads you towards down a path where it may not be CSU. And then other things to ask about, some patients with CSU may have a family history. So you could try to elicit that. Triggering factors we talked about.

I do think it is important to ask about new medication exposure. Maybe the patient recently started an ACE inhibitor a few months ago. It is probably worth a discussion to switch that ACE inhibitor to something else to see if maybe the hives can improve. So I think that that is a question that could be helpful as well. And then I think it is also helpful to just see what labs does a patient maybe already have in their chart. Maybe it could save you a lab job.

Diagnostic Workup for CSU: 7 Major Aims

So diagnostic workup for CSU listed here. There are international guidelines for CSU basically published earlier this year in 2026. Basically, they have the "seven Cs" to look at. But I think the key takeaway points is you want to basically make sure that you are dealing with CSU. It is true urticaria. It is not urticarial vasculitis. It is more than six weeks. There is no identifiable trigger. And then you basically want to move towards management.

Recommended Diagnostic Tests for CSU

So what are the recommended diagnostic tests for CSU? And different people do different things, but I will say this is what is recommended in the international guidelines, which is supported by multiple dermatologic and also allergy societies and by basically urticaria experts. And basically the key takeaway point is for CSU, the patient otherwise has a negative review of systems, you really do not need to do a million-dollar lab workup. You really do not. And if the patient in fact comes in with a CBC with diff, that is stone-cold normal, their review of systems is totally negative, it would be fine to start a long-term appropriate therapy at that time for patients if they have already failed their trial of antihistamines. And so, I think that messaging of like, it is really important to treat the patient and also not let the patient feel or have this false hope that if I see an allergist, whenever that referral goes through six months later, they are going to find a root cause. The workups, the studies have shown million-dollar workups, they do not find anything. And ultimately the patient has just suffered with their hives for longer.

So looking here, CBC with diff, and that is really just because let us say, they are really anemic or leukopenic, like, yes, maybe there is something driving that, okay? And you could look into it. CRP and or ESR. So that recommendation is more because if the patient is super high CRP or ESR, it does bring the question, especially that they have a positive review of systems. Is there something underlying like autoimmune or something that could be driving it?

IgG, anti-TPO and IgE I will talk about on the next slide, but those two labs actually are not required in order to make the diagnosis of CSU. Again, CSU is a clinical diagnosis, and you do not need to do lab testing to confirm that it is CSU.

I wanted to bring in my fellow panelists here because I feel like we have been taught different things, you know, and when I was a resident, it was like order these 40 lab tests if someone comes in with hives.

So Benji, do you want to comment in on your hive diagnostic workup?

Dr. Ungar: Yes, so 100%, you know, what we learned in training, the lab work, you making sure you are really covering all your bases of what might be driving it. And the reality is you do all of that, and you get to the same place, which is we do not know what is causing it; let us treat it. And so, I just strongly want to echo the same idea that it is a clinical diagnosis, once you assess and identify this as CSU, it really should be focused on treatment.

Now I will just say briefly, patients do often require a little conversation because naturally they want to know what is causing it. And it can be, I think in my experience, part of the conversation is really helping to steer them away from doing the million-dollar workup where that is going to delay their view. And it is not always easy to, I think, internalize the idea that, hey, it is this thing that is happening that I do not know where it is coming from. But once we get an effective treatment and patients feel better, they do not care what is causing it anymore. They are just very happy to feel better. That has been my experience.

Dr. Hsiao: Great, how about you, Dan?

Dr. Butler: Yes, I mean, this is the changing paradigm. You know, I feel like when I was training 15 years ago, it really was a million-dollar workup to try to figure out what else was going on. And I think we all saw that, you know, there was really nothing else from a treatment standpoint, even though you would get some positive lab values rarely, but you would. And then you would be back to square one. And I think that Benji hit it right on the head, which is that there is a colloquial piece to this.

Everybody's seen a movie where someone gets hives. They have seen Hitch where Will Smith gets hives. They have seen My Girl where someone gets, you know, stung by a bee and it has a dangerous reaction. And there seems to always be, you know, hives, and what is the cause, and what is this root cause? And I think it is part of our responsibility in this changing disease schematic to really uncouple that idea of hives meaning singular cause and really helping people understand what we now know about the pathophysiology.

So I try totally to do what you guys are talking about, uncouple the labs from the diagnosis itself and make sure people understand that they can get treated even while we are looking into what else may be involved.

Dr. Hsiao: A 100%. I think that, you know, going off of they are coming in, they are telling you they are miserable. And I am like, it sounds like you are, you know, really suffering from your hives. Like, would you like to try something other than antihistamines that might make you feel better? And I think just moving towards like, let us start trying to get you to feel better. If they still want to, you know, keep thinking about their triggers, etc., that is fine.

But as Benji said, once they are feeling better, that drive to find that cause does sort of, you know, it definitely quiets because they are just feeling overall better and living their lives.

Potential Biomarkers of CSU

Okay. So talking about the potential biomarkers for CSU. So why might you get, for example, IgE, CRP, anti-TPO?

For IgE, as Benji mentioned, when you have basically like that auto allergic versus autoimmune, the auto allergic subtype typically tends to have higher IgE and predicts a better response to one of our three FDA approved therapies, which is omalizumab. However, we have other medications now, which Dan will talk about, remibrutinib, dupilumab, both also approved for CSU, where IgE levels do not matter in terms of whether or not a patient's going to respond or not. And so, again, if it is not going to change management-free, you do not have to get it.

CRP, we talked about in terms of like if it is super highs, or something underlying, and also if you do get it and it is high, it is a signal to us too, that this person with their hives might be suffering with it longer. It is a predictor for longer disease duration.

And then anti-TPO basically is more of a marker for that autoimmune subtype, and it does predict a more prolonged disease course. Again, it does not need to be drawn though. You can make that diagnosed without it.

Challenges in Early Diagnosis of CSU

And so this slide really just emphasizes, again, we want limited testing. If that, to really like figure out and to figure out before going down that, chasing that pathway of all these tests, making patients believe that the tests are then needed, we can basically start to shift the paradigm, even during that first conversation.

Assessing CSU Activity: UAS/UAS7

And really briefly, this will hopefully also help tie into Dan's presentation on treatments for CSU, is how do we assess CSU disease activity?

And so, unlike psoriasis with POSI and atopic dermatitis with the EZ score, which is very clinician-oriented, CSU disease activity, the measurement of severity is completely patient driven. It is just a patient reported outcome. How itchy are you? How many hives do you have? And so, basically the UAS is an urticaria activity score. That is an aggregate of how severe someone's hives are with zero being none, three being more than 50 or a giant confluent area of their bodies affected. And then how severe is their itch? Is it zero, none or three, so intense it is interfering with sleep and daily activities? The aggregate for the day is the UAS, which is again, then 0-6. And then weekly UAS seven, you aggregate you basically add the score through seven days and you get 0-42.

To enter a clinical trial for a moderate to severe CSU, you basically need a UAS seven of 16 or higher.

Assessing CSU Activity: AAS

There is also an angioedema activity score. Just want you guys to be aware of that, that you can capture how the hives are doing. You can also capture how angioedema is doing.

Assessing CSU Control: Urticaria Control Test

And then finally, there is this urticaria control test where it is recommended in the guidelines that we give this out to patients at their visits to assess how well controlled their hives are. And it is basically four questions scored 0-16. 16 means complete disease control.

In my personal clinic, I am not handing this out yet. I think at some point, if I think I have the bandwidth to do so, I might try to implement. But at this point in time, I do feel like being able, having patients tell me, like, I am not having hives or itch anymore. You are at baseline. And so, or like I am better, but I am still having these outbreaks. Like, let us see what else we can do. So I do not think necessarily you have to implement, but it is a tool if you would like to look into it.

Diagnostic Considerations in Persons With Skin of Color

And then finally, I think Benji covered this already, you know, with patients of skin of color, it is just important to recognize that they may have had a longer treatment course or journey before even getting to you. Their disease may last longer. And recognizing that, you know, you may not see as much erythema.

So palpating, and I think part of the things also that we all recognize in our field is we do need resources that just have more skin conditions represented in all diverse skin tones. So just, this is just another reminder for us that when we are looking at patients with skin of color to look carefully and maybe even use lighting to try to see if it helps us to see that palpation.

All right, moving to Dan.

CSU Case Discussions: Guideline-Concordant Care and Emerging Therapies

Dr. Butler: Thanks, Jenny. So I will bring up the caboose of the discussion so that we all feel comfortable treating these patients. But obviously a wealth of knowledge being given over by Benji and Jenny, and I have already learned a bunch from it. So hopefully, this can tie this together.

Poll 6

Let us talk about some of the therapies that are part of the equation now for our urticarial patients. Let us start with a poll.

Rate your comfort level managing patients with CSU who require add-on therapy to second-generation antihistamines.

1. Not comfortable at all;
2. Somewhat not comfortable;
3. Somewhat comfortable;
4. Comfortable;
5. Very comfortable.

All right, we have got a variety, and I think that is pretty apt for this disease.

Patient Case 3: Anna, 42-Yr-Old Woman

So let us go into a case presentation here. This is the case of Anna. She is a 42-year-old woman. So Anna presents with a nine-month history of recurrent hives and intermittent angioedema. She reports pruritic wheals resolving within 24 hours, often recurring in different locations. No consistent triggers related to food, medications, environment. Symptoms continue to disrupt daily life with sleep and daily function. Past medical history, partial relief with standard second-generation antihistamines, hypertension and anxiety are a part of this, are a part of her story, and no active wheals on exam when she is in the room with you.

So let us discuss the therapeutic approach to someone like Anna.

Guideline Recommendations for the Treatment of CSU

So I think it should start with the guideline recommendations. And if you are going to take anything from the treatment portion of this, I want you to focus in on this, which is there are a lot of moving parts when we think about the recommendations for CSU.

Of course, we are talking about when we are saying chronic, we are talking about six weeks in, but these are patients who need immediate relief, and there are a lot of elements to that immediate relief. So there is the idea that a short course of corticosteroids may be used in acute exacerbation. So that is one of the moving parts is getting things under immediate control.

Then another piece to this is the ability to access or refer to a specialist. And so, when should you start to refer to a specialist? That is another piece of the guidelines, which is when you are beyond that first six-week mark and you have given someone second-generation H1 antihistamines and you have increased the dose, which is that big orange, red, burnt orange block up there, once you have reached that point, you should consider referring to a specialist.

And that is first-line therapy is giving a second-generation antihistamine and increasing the dose up to 4x the standard dosing. And then after that, as you can see, you are looking at getting treatments specifically from a specialist, not just saying, hey, let us refer to a specialist, but actually getting these medications from a specialist. And we are looking at what is recommended as strong, which is omalizumab, conditional recommendations of dupilumab and remibrutinib, and we will talk about all of these.

And then you can add onto that some of these possible recommended options, things like cyclosporine, which very recently, as recent as a few years ago, was higher on this list, but has moved down a little bit. And then other alternative therapies, which we will not touch on today, but things that we used to use in the past, like dapsone, colchicine, methatrexate used to be some of the ones that are less in vogue now, but still have been used in the past. So I think steroid possibilities for short term, when to refer and who the specialist is going to be, and then also knowing the strong and conditional recommendations are all those moving parts of these treatment guidelines that have now come out.

Second-Generation H1 Antihistamines

So let us dive into this cascade of options that we have. So we will start right at the beginning with the second-generation antihistamines. And these are things that we probably are all well aware of because we have been taking these for allergies or for a variety of different things throughout our life.

And it is really important that we know that there are certain side effects that can come along with any antihistamine, but those are particularly concentrated with first-generation antihistamines. Lovable medications like Benadryl come with cognitive effects, both short- and long-term, fatigue or sedation, and then potentially exacerbations of memory issues. So we always want to be cautious when we are using those.

So anytime you are first seeing a patient with chronic spontaneous urticaria, you want to start with some of those second-generation antihistamines. Things like cetirizine, desloratadine, loratadine, fexofenadine, levocetirizine. These are pretty standard medications that people can access over the counter. And then ideally, these would be used up to 4x, four times the standard dosing, which we have there. The standard dose, which you will see on the bottle, and then for your CSU patients, you can go up to those 4x doses over 24-hour periods.

Dose Increases for H1 Antihistamines: Levocetirizine vs Desloratadine

So let us look at how these antihistamines actually work.

And here is a study that looks at levocetirizine versus desloratadine. And essentially, the long story short here, I am not going to have time to go over each one of these in as much detail as I would love to give. What you are looking at here is that as you go up in the dosing, you get increased benefit, and you actually do not start to see increased sedation.

This is specifically with second-generation antihistamines. So just keeping in mind that pushing that dose up to 2x, 3x, 4x, that standard dose is going to result in a meaningful change in that discomfort measure from a patient. And you are really not, in most cases, increasing some of those side effects like somnolence.

Now, it is important to remember that second-generation antihistamines can still cause sedation, but for the most part, pushing that dose, as shown here, is just going to benefit the patient and not really overly sedate them.

Pathophysiologic Mechanisms of Approved and Emerging Therapies for CSU

So we can refer back to Benji's expert explanation of some of the pathophysiology, but this brings it back to the view of the medications. And while there are several medications that are on here, both historic and in clinical trials right now, the three that I want to highlight are the ones that we are talking about here, dupilumab, omalizumab, and remibrutinib, all of which work in different ways. Omalizumab, working on the IgE receptor. Dupilumab works in a way that we are still figuring out, but probably through some B-cell regulation by inhibiting that IL-4 receptor alpha subunit. And then remibrutinib, which has a very unique effect by impacting the BTK inhibitor in a way that is different than the omalizumab and dupilumab biologics.

So you are seeing the variety of players here when it comes to CSU. And now it is really exciting that we have the ability to access and target this disease in multiple different ways.

LIBERTY-CSU CUPID Study A: Dupilumab in Patients With Uncontrolled CSU

So let us start talking about some of these medications. So first, I want to bring up the LIBERTY studies for dupilumab. These were Phase III trials that looked at patients with uncontrolled CSU.

And again, I will not be able to detail every single piece of this, but the long story short is what Dr. Hsiao was talking to us with us about, those outcome measures for patients, the UAS7 and the ISS7. The ISS7 really looking more at itch than the HIVE score itself. Long story short, you saw in this study with dupilumab, you saw a pretty remarkable improvement at that week 24 mark. And this was actually in patients who had elevated IgE and those who did not have elevated IgE.

LIBERTY-CSU CUPID Study C: Dupilumab in Patients With Uncontrolled CSU Not Previously Treated With Omalizumab

And this trend continued when you looked at the LIBERTY study C, which was for patients with uncontrolled CSU, but also had not been exposed to omalizumab, and you additionally, again, saw really good impacts on clinical scores for CSU.

You also saw benefits to quality of life indices like DLQI. Long story short is that dupilumab was shown to be really effective in this condition at that 24-week mark. And I would be remiss not to mention that the safety data looked excellent.

Dupilumab is a medication that many allergists and dermatologists are really comfortable giving because of its history and other conditions. And there was no additional safety signal that came out. You saw really comparable AEs in the dupilumab group and the placebo group.

REMIX-1/-2: Remibrutinib in Patients With Uncontrolled CSU

So now that we have talked a little bit about dupilumab, let us look at remibrutinib. So remibrutinib is the BTK inhibitor, and in its pivotal trials, its Phase III trials in REMIX 1 and 2, you saw very similar impressive efficacy data for the UAS scores. And what I will highlight here that is different from what we saw previously was that they were absolutely looking at the speed of onset, and they did not quite do that in the LIBERTY studies, but you actually saw meaningful differences, statistical differences at week one in this study.

REMIX-1/-2: Rapid Symptom Relief With Remibrutinib Within First Wk of Treatment in Patients With CSU

So that was something that we were all pleasantly surprised about, about the speed with which it worked.

And they were able to look at how speedy this actually was. And while truly meaningful differences, statistically meaningful differences came out at day seven, they started to see a difference in the treatment and the placebo group in improvement levels at as early as 12 hours, which is really impressive.

And of course these patients are really frantic and desperate, totally reasonably so. And so it is nice to be able to have a trial that substantiates quick relief. And that is what this REMIX study showed.

REMIX-1/-2: Remibrutinib Safety at Wk 52

And then, of course, the side effects have been really, really wonderful to see. Of course, the side effects are not wonderful, but the dearth of side effects is wonderful to see, with the main ones being COVID-19 in the trial specifically, but nasopharyngitis, URIs and headaches. Those are some of the ones we see.

We also see some risk of bleeding, non-dangerous bleeding in these patients, which is important to mention because patients will often bring it up. So that is another thing that I think is really important to see here. But long story short, a really great side effect profile with remibrutinib that was seen in the clinical trials.

ASTERIA 1: Omalizumab Add-On in Patients With Uncontrolled CIU/CSU

And then the last one, which was actually the first one that was approved, was omalizumab. And it is important that we talk about those pivotal trials because they were really the first ones that started to tackle this disease. And in their pivotal trial, ASTERIA 1, you started to see for these uncontrolled CSU and these trials actually included CIU, chronic inducible urticaria patients, that you saw very quick relief.

You can see the decline in scores as quick as one or two weeks in these trials. And then what is impressive about this is that when you took the medication away, that is further down in that graph, you actually saw the return of patients back to the level of placebo. And that really tells you have an effective medication there.

Long story short, at that endpoint of 12 weeks, you saw a significant reduction in the weekly ISS scores, which is a really meaningful clinical score for these patients.

ASTERIA 1: Change in UAS7 Score and Other Outcomes at Wk 12

And just to further substantiate this, at different doses, that week 12 score, you saw meaningful differences in a decrease of six points in the UAS-7 score. But you also saw a substantial amount of patients with a score of zero, which means that they were completely clear.

And I think that is always a really healthy, but brave endpoint to include in there, because it tells you, hey, what are the chances of actually being completely clear here? And you actually got to see that in this trial, and that is really impressive.

ASTERIA I/II vs GLACIAL: Change in UAS7 Score With Omalizumab vs Placebo in Patients With Uncontrolled CIU/CSU

And it was not just for the ASTERIA 1 and 2 studies here, you also saw it in the GLACIAL study. And the way I like to think of the GLACIAL study is these were the patients who at the time were just on everything. They were like, oh my gosh, we are on anything, everything's failing us. And remember, this was before we had any other treatments out.

But even for those patients, even for not just uncontrolled patients, but patients uncontrolled on standard high-levels of antihistamines and potentially even other therapies, you still, in that GLACIAL trial, you still saw meaningful improvements of UAS-7 score reduction of less than six, and complete zero scores in 33%.

Long story short, again, very impressive data from the clinical trials in these patients.

Poll 7

So let us move over to another poll.

How has your intended approach for management of CSU changed? And if you could put some of your answers in that bar there, that would be great.

While we are waiting, I will ask on Benji and Jenny, if you guys want to comment on this, through these trials, how has your approach changed? And it is been in a cascade where omalizumab was approved, dupilumab was approved, and now remibrutinib was approved. Do you have any short stories of how your practice has changed?

Dr. Ungar: I am happy to just say briefly, to me, when we have multiple effective treatments, and safe also, which is very crucial here, because many of those older treatments did not work as well, and also were not safe. To me, it just raises the bar of what we should be aiming for, and what we think about as a successful treatment.

And you talked about UAS zero. I mean, obviously that is really the goal. Now, not everyone's going to get there, but good enough may not be good enough when there are different options to try. So that is how my perspective has changed a bit.

Dr. Hsiao: Yes, really quickly too, on my end, I think I move more quickly from the antihistamines to one of these safe long-term alternative therapies. And I think one thing to mention is when we are talking about the antihistamines, when you add on that therapy, it is an add-on, right? It is not like you are stripping the patient of the antihistamines. They can stay on it. And you add on your dupilumab, remibrutinib, or omalizumab, and then you can try to taper off the antihistamines, which is also nice because it can decrease pill burden for patients.

And I think it is really nice that we have remibrutinib and dupilumab now because for derms, at least, I think the omalizumab requirement for three in-office monitoring visits was really difficult. But now I think we feel comfortable with these treatments. And I think that expands access for patients.

Dr. Ungar: Yes, I just want to add one point or build on, because I completely agree. You know, we talk about four times a day antihistamines, as if it is not a big deal. It is pretty actually difficult to take a medication four times a day. And there is a big pill burden associated with that. And so, yes, the treatment may be better than the cure, so to speak, or the, but, I butchered that. But the point is, if they are taking something that is difficult to take and they are still not getting that relief, we really should not be settling for that.

So I agree. I am also quicker to go to an effective treatment.

Dr. Butler: Yes, it is an exciting era. And, you know, I think everyone's practice is adjusting a little bit from what we used to do, but boy, is it nice to be able to offer something new to patients.

Emerging Therapies for CSU

And perfect segue to the emerging therapies.

I will not go into all of these, but there is a lot coming down the pike. You know, an additional BTK inhibitor, KID inhibition, TSLP inhibition, and even JAK inhibition. So the cavalry is coming, if it is not already here, but definitely an exciting time for these patients who really have been forgotten.

Key Takeaways

So key takeaways here as we move into the last few questions that are going to come after this, and then questions anyone that has them from the audience can bring them forward. So key takeaways.

Chronic spontaneous urticaria often remains uncontrolled, number one. And then number two is real-world data highlights significant unmet needs. Number three is disease burden extends beyond hives. We talked about the quality of life impact, but sleep specifically is one that hurts us and our patients.

Biologics and small molecule inhibitors have expanded our treatments. We talked about the three FDA-approved ones right now. And then, of course, there is more coming down the pike. So it is exciting for us to be able to explore those with our patients in a safe and effective way.

Posttest 1

So I want to get to these last few questions here. So from a posttest standpoint, we have a 36-year-old woman who presents with a six-month history of daily pruritic wheals and nocturnal symptoms that disrupt sleep. There are no triggers that are identified and examination shows transient urticaria without residual changes. Which of the following best describes the key pathophysiologic mechanism contributing to her symptoms and disease burden?

1. Mast cell activation driven by T-cell-mediated inflammation causing recurrent wheals
2. Mast cell-driven histamine release causing pruritus and sleep disruption;
3. Neutrophil predominant inflammation causing transient lesions; or
4. Dysregulated cytokine signaling causing chronic inflammation and pruritus.

Give you all a minute to vote on that one. Maybe 15 seconds. Awesome, great work.

Yes, so mass cell-driven histamine release. So CSU is driven by mast cells, basophil activation, which is typically IgE mediated or autoimmune leading to persistent histamine and inflammatory mediator release causing pruritus.

Let us go to the next one.

Posttest 2

Posttest two is a 48-year-old with CSU that has persistent symptoms despite high-dose H1 antihistamines and is being considered for omalizumab. Baseline lab evaluation is performed to help guide treatment expectations. Which of the following biomarkers may predict a poor response to omalizumab in this patient? Great question.

Awesome, we still got it right there.

Yes, so IgE is the main one. So omalizumab is an anti-IgE monoclonal antibody, and its efficacy is partly related to baseline IgE levels. Low baseline total IgE has been associated with reduced response to omalizumab, likely reflecting a different underlying disease endotype.

So you can check IgE as Dr. Hsiao was mentioning before starting these patients, and that can help to guide that personalized approach when you are seeing these patients.

Posttest 3

And our last posttest question. A 45-year-old with CSU has persistent symptoms, very high UAS7 score despite high-dose antihistamines in six months of omalizumab with daily wheals, pruritus and angioedema. His doctor is considering a novel oral therapy. Which of the following best characterizes the clinical efficacy of remibrutinib in patients with refractory CSU?

1. Gradual symptom improvement in UAS7 score over 12 to 16 weeks;
2. Limited for patients with elevated IgE levels with minimal benefit post-omalizumab;
3. Significant impact on wheals and itch severity with no impact on angioedema; or
4. Rapid reductions in UAS7 scores with some achieving early disease control.

Awesome, great. We are learning today.

So yes, rapid reductions is the correct answer here. So we saw responses as early as one week that were significant. So great work, everybody.

So I know we have reached the time.

Q&A Session

So, Q&A session, you can put any of your questions in the chat, we are happy to follow up.

Poll 8

But I do want to get to these polls so that our sponsor here has something to make sure that they can take home. Do you plan on changing any of your clinical practice based on what you learned in today's program?

I know I certainly will. So that is a yes for me, even though I am not allowed to vote.

[01:00:52]

Poll 9

And then take a moment to enter one key change you plan to make in your clinical practice based on this.

This is such an evolving area. There are going to be changes that you have now, and there will probably be changes again in another year.