Activity Transcript

Adam Friedman, MD: Hi. I'm Adam Friedman, professor and chair of dermatology at GW [George Washington] School of Medicine and Health Sciences in Washington, DC. Welcome to this program titled: "Chronic Spontaneous Urticaria: Tag, You're It!"

Joining me for a fun game of tag today is David Lang, who is professor of medicine at the Cleveland Clinic Lerner College of Medicine in Cleveland, Ohio. Welcome, Dr Lang.

David Lang, MD: Thanks, Adam. Great to be here with you.

Dr Friedman: So, today, we're going to keep things pretty fast, which as [an] expat New Yorker, I really like that, as we go through a series of questions taking 60 to 90 seconds to answer and see if we can beat the clock as we talk about the diagnosis and management of patients with chronic spontaneous urticaria (CSU). Let's get this party started.

First off, Dr Lang, we know that CSU, it can have a profound impact on patient quality of life. What does the physical and psychosocial impact of CSU look like in your clinic?

Dr Lang: Chronic urticaria is a condition, as many of you know, that typically affects women more than men, about 2 to 1. The typical patient with chronic urticaria is a woman about the age of 40, and this condition is associated or can be associated with a huge hit in terms of quality of life. Patients with this condition frequently, at least [with] chronic spontaneous urticaria, have episodes seemingly on a random basis.

This is associated with anxiety; frustration; can impair social interactions, work performance in terms of not only absenteeism but also what we call presenteeism, meaning that individuals are impaired at work typically because this condition can be associated with intense pruritus that can impair sleep quality, similar to other conditions such as atopic dermatitis and other conditions associated with chronic pruritus, which I imagine you also see frequently, Adam.

Dr Friedman: Absolutely. Yeah, I would have to agree with everything you've said. I think in dermatology we are inundated with patient-reported outcome data and experience. We pretty much end of the day, we all know all dermatologic diseases, especially chronic ones, are profoundly impactful. I think the end all be all is very impactful, very disabling, which means we got to do something about it, no question.

Dr Lang: From your perspective, Adam, what would you say is the most significant burden of chronic spontaneous urticaria on daily living?

Dr Friedman: I would have to say the spontaneity of it. Not knowing when the next shoe is going to drop creates tons of anxiety in terms of how someone goes about their day, whether it be [their] professional or social life. But from a physical perspective, the pruritus, this both burning and itchy pruritus, which is somewhat unique to chronic spontaneous urticaria, drives these patients crazy because they want to scratch, but they get a negative feedback, as opposed to atopic dermatitis, and it hurts to scratch. They don't want to scratch, but they do want to scratch, and that just adds [to] the burden in terms of how it affects what they do on a daily basis.

Dr Lang: I would encourage all who are listening to make it a point to ask your patients about the quality of their sleep and how it's impaired by itching. I mean, again, the patients who come in to see you have typically taken a huge hit in terms of their quality of life. The validated quality of life instruments indicate that the impairment and quality of life [for CSU] is at the level of patients with other chronic conditions, including psoriasis or rheumatoid arthritis.

Dr Friedman: Absolutely. I think sleep we take for granted. We choose not to sleep in our professions; these patients don't get to choose their lack of sleep, which then percolates into every facet of life. In thinking about that, the societal burden of CSU, what's your take on that?

Dr Lang: These patients are not similar to patients we manage in allergy immunology who have asthma, for instance, a severe, persistent asthma that's poorly controlled. They may be in and out of the emergency department or even hospitalized with flares of their asthma. These patients [with CSU] are typically not in the hospital, but, yet, there is an indirect burden, and indirect medical expenditures can be quite substantial with this condition, including missed school days, missed workdays, and, as was mentioned, what's called presenteeism, which means that even though they're present at work or present at school their performance is impaired.

Dr Friedman: I think cost has so many different meanings. I love that you bring up presenteeism. That's almost worse than absenteeism because showing up and not being able to perform at the expected level is even more impactful and harmful, especially on the psychosocial burden in terms of beating oneself up because they weren't able to perform and, of course, the negative feedback that comes from that.

Dr Lang: Adam, we've talked about chronic spontaneous urticaria. How would you define it?

Dr Friedman: I guess it depends on the audience. If I'm talking to a patient, I really want to define it as a bump or a rash that each individual rash lasts, at most, maybe one day to two days if we're really pushing it because that's going to really define this from urticaria versus something that's urticarial. The other piece that we're talking about, CSU, is that this has been ongoing for 6 weeks. Now, that doesn't have to be continuous. It can be on and off, on and off, but the overall duration of those flares should be going on longer than 6 weeks. If I'm talking to a colleague, I would describe it as dermal papules and plaques that have no surface change that, once again, each individual one lasts less than 24 hours, but the overall duration of disease should be longer than 6 weeks.

Dr Lang: I think our approach is consistent. If it's less than 6 weeks, you're in a category of acute urticaria, which is a different ball game. Frequently, these patients have had reactions to a virus, to a drug, and testing is more appropriate. We'll get to the workup, but testing is more appropriate in that setting than in the setting of chronic urticaria in which the overwhelming majority of cases we don't identify a cause.

Dr Friedman: When I say acute urticaria, my mantra is food, drug, or bug, that's the way to remember it. Tons of things in each category, but usually you can probably find something in those 3. How are you assessing your patients that come in if you're thinking about CSU or other?

Dr Lang: Clearly, if I had a dollar to spend on everything I could do, probably 90 cents are in the history. Frequently, patients come to us, and they don't have urticaria on the day they present. Now that everybody has cell phones, I'm looking at pictures on the cell phone, which could be helpful, but, typically, I want to ask patients about the sensation of their lesions. Is it pruritic? Does it have a burning quality, or is it painful? The burning or painful are [in] a different category. What is the appearance of the lesions? Are they circular? Are they linear? Linear lesions is more dermatographia.

Is there a residual bruise? Do the lesions -- as you said, Adam -- last longer than a day, 2 days, et cetera? Are there provoking factors? In other words, one of the questions I have for you, can you bring on an episode? Is there something you can do that makes an episode more likely, whether it's running and exercise, which would imply a chronic inducible urticaria syndrome, such as cholinergic urticaria. I mentioned dermatographia, a condition that occurs in about 3[%] to 5% of the general population, where individuals have lesions based on trauma or stroking or pressure. Cold urticaria. There are a number of chronic inducible urticaria syndromes. Different category would imply that certain avoidance strategies can be helpful. Is there associated fever, arthralgias, recent exposure, travel, which would direct more laboratory investigation and perhaps put us in a bit of a different category?

Dr Friedman: Could not have said it better myself. It's all in the history. You covered the gamut; that was perfect. I have nothing else to add.

Dr Lang: Laboratory testing, here we are. What do you do?

Dr Friedman: I am a, not even just "less is more" but pretty much "nothing is more." I think you let the patient guide you. I think if it's urticaria plus, you mentioned arthritis, other systemic features, things in the review of systems, that's where a really good dialogue with the patient is important, but, in general, I try to do none. But I think if a patient has other symptoms along with their urticaria, I think it is worth going down. We know with the chronic urticaria, it's not even CSU. A subset of patients have been associated with autoimmune diseases. If there's something in the history that's suggestive, maybe [I would perform] a workup, but I really try not to.

When it comes to biopsies, absolutely no. This is an invisible dermatosis on pathology. You'll probably see nothing, maybe a few neutrophils, which could be useful for some off-label therapies but, at end of the day, less or nothing is absolutely more.

Dr Lang: Yeah, I would agree. I think the consensus is . . . it's more than a consensus. It's evidence-based that routine, extensive testing is not indicated for people with this condition. That is for individuals with an unremarkable history and physical exam. Otherwise unremarkable, I should say. Targeted testing may be appropriate, depending on what's identified in the history and the physical. Limited testing may be appropriate, and that provides what I call the reassurance value for the patient.

Routine tests like complete blood count, complete metabolic panel, sedimentation rate, or C-reactive protein [may be appropriate], but routine, extensive testing is not warranted, and, in the overwhelming majority of cases, no laboratory testing is appropriate.

Adam, when you assess a patient with chronic urticaria, what differential diagnoses are you striving to rule out?

Dr Friedman: First, in the world of urticarias, I want to define acute versus chronic based on that 6-week mark, then the world of chronic [urticarias], if that's where we are. I also want to know, is there a history of angioedema? Certainly that can be present with CSU, but I want to know is it CSU, is it urticaria associated with autoimmune disease, or is it inducible urticaria? Patients are allowed to have both. I have many patients with CSU and inducible urticarias. Now, if we're beyond that 24-hour mark in terms of a single lesion lasting longer, then we're in the urticarial differential diagnosis, which is massive.

This is arthropod assault, Well syndrome. This could be the urticarial stage of bullous pemphigoid. This could be infection, cellulitis, erysipelas. It could be a drug reaction; it could be erythema multiforme, fixed drug eruption. There's a very long list, and it's important to stay organized based on the depth of the process, but also you can think about what cell type could be making up that clinical picture to keep those buckets in check. But the urticarial differential is much, much broader than your urticaria differential diagnosis.

Dr Lang: Let me return the comment to you: [I] couldn't have said it any better. Yeah, and a lot of this is based on the history, the duration of the lesions, their morphology, their sensation, and that's really what can put you in a different category.

Dr Friedman: Absolutely. And, back to you, how are you treating [this condition]? What is your approach in terms of the maybe climb or sprint up the therapeutic ladder?

Dr Lang: Yeah, I think that the guidelines in our 2 specialties are pretty similar. Basically, to boil it down, we are treating with 3 drugs, second-generation antihistamine monotherapy. And then, about more than half the time, patients[' symptoms] are not well controlled, so they're candidates for second-generation antihistamine dose advancement. When that doesn't work, we go on to the second drug, which is omalizumab, and when that doesn't work, we go on to the third drug, which is cyclosporine. The H2 antihistamines and antileukotrienes, which used to be prescribed rather frequently, now I think are being prescribed less often and have been discouraged, in more recent guidelines, based on evidence indicating that the quality of evidence supporting their therapeutic utility is weak.

Dr Friedman: Certainly, I rev up that therapeutic ladder from the standard dosing of antihistamines to fourfold the recommended dosing. That's going to happen probably in 3 to 4 weeks from that first point of contact, and if that doesn't cut it, which is roughly 50% of the time, we're going to be moving on to omalizumab, and then we have a whole host of off-label therapies. Cyclosporine has the most evidence, but there is evidence supporting methotrexate, narrowband ultraviolet B, dapsone, [hydroxychloroquine], mycophenolate mofetil. Not a ton of data but certainly something we can pull to if we're having difficulty managing our patients.

Dr Lang: There are a whole bunch of drugs that are out there, and there are a few randomized control[led] trials supporting some of those, but, yeah, the evidence is not as solid as it is with cyclosporine as well as omalizumab. What do you avoid?

Dr Friedman: First and foremost, I'm avoiding systemic steroids. I think the one caveat to that is if I use systemic steroids in a patient who is absolutely miserable and we're bridging that patient on to the recommended therapies, though I find I'm more using intramuscular kenalog, which is a safer way to give systemic steroids. It kind of releases over time from a depot effect in the fat of the buttocks rather than oral steroids, which often, when you come off [them], results in a rebound worsening effect, which we want to avoid. We talked about our lost friends, the anti-H2s and the leukotriene receptor antagonists. I try to avoid other immunosuppressants just because of the baggage that comes with them, but, when needed, I'm with you. I will turn to cyclosporine first, maybe then followed by mycophenolate mofetil, thanks to Nick Soter's work at NYU [New York University]. Then, I try to avoid food restrictions, especially in kids. [There's no] evidence to support their utility, and [it] actually could cause more harm if you're restricting dietary things, especially at younger ages. What about you?

Dr Lang: Yeah, I would second that. I would say foods are commonly suspected but rarely confirmed as culprits, particularly for chronic urticaria. Acute urticaria is a different story, as we've mentioned, but for chronic urticaria, there's no evidence supporting the therapeutic utility of food avoidance.

Dr Friedman: Completely agree. How do you decide? You mentioned you start with your first-line [therapies], you move to your second line. What metrics or what about the patient pushes you to go to that second line, to go to omalizumab as you said?

Dr Lang: In all recent guidelines, the use of what are called PROMs, which is patient-reported outcome measures, has been encouraged. There are a number of validated instruments now. There's the urticaria activity score, the urticaria control test, which is the one I tend to use. The urticaria control test and the urticaria activity score, UCTUAS, track together when patients worsen or when they improve, but, to me, control is more important than activity. There are a number of others, including the angioedema activity score, and there are quality-of-life instruments that have been validated for both urticaria and angioedema, so the use of objective and validated measures, these instruments, has been encouraged, and when patients don't achieve the goals of management, when they continue to have episodes and active lesions, whatever instrument you're using, then it's time to step up. The majority of patients that I see, and I imagine it's the same for you, they're not going to be controlled on monotherapy with a second-generation antihistamine, and you're going to need to dose advance to 4 times the FDA-approved dose, whichever one you select. And then, when patients don't achieve the goals of management, they graduate to a level of having antihistamine-resistant chronic urticaria, and they're candidates for either omalizumab and cyclosporine. The evidence is much stronger supporting the therapeutic utility of omalizumab in multiple randomized controlled trials.

Dr Friedman: The only thing I would add to what you said, which was perfect, is sleep. I like using sleep as a metric of success. Just like so many other areas of dermatology, where our goal now is treat to clearance, not treat to 75% clearance, that's the same goal here. We want to get them 100% clear, and, aside from using those great tools you mentioned, I use sleep as a good metric for success as well.

Dr Lang: Years after omalizumab, almost a decade, Adam, we finally have a pipeline of drugs in development, so let's talk about these drugs. First, dupilumab. What do you think about dupilumab?

Dr Friedman: Dupilumab is certainly no stranger to either of us, with multiple indications spanning both allergy and dermatology in a very short time period. I think what I'm most excited about [regarding] dupilumab is that it will hopefully open the door for more dermatologists welcoming these patients. I think, in the US especially, there is an imbalance, and there's more of a burden on allergists, immunologists to manage CSU patients. I think part of it is, I would say, maybe the burden or the baggage that comes with omalizumab originally, with having to mix it up in the office, keeping patients there for 2 hours. That's become easier with the at-home injection and the limitation on needing to keep patients in the office for that period to ensure there's no anaphylaxis, which, of course, is so extremely rare.

I think dermatologists don't shy away from a black box warning, but the burden of that in a very busy practice setting can be difficult. Now you have something that won't have that, and it's also a drug that is certainly very familiar to the majority of us, so I think this will bring CSU back into our wheelhouse, and we can join hands and forces and take care of these patients together. The phase 3 data is certainly supportive of that, and I foresee an indication, hopefully coming soon, and I think our patients will certainly benefit from that.

Dr Lang: It's interesting that you raised this issue. I think that if you go back to the 3 drugs I mentioned, which [are] second-generation antihistamine[s], which clearly everybody's comfortable with, I think allergists are more comfortable with omalizumab. We deal with the threat of anaphylaxis all the time, giving allergen immunotherapy. Omalizumab is associated with anaphylaxis in 1 to 2 [patients] per 1000, and that was in pivotal trials of patients with asthma, and these are people getting omalizumab for allergic asthma. They've got the machinery to make allergic responses to drugs much more than the general population. And, really, the anaphylaxis, I don't know that there's data on this, what the clinical experience is. I've seen a few patients who've had anaphylaxis from omalizumab who got it for severe, persistent asthma but not for chronic urticaria.

Dr Friedman: Yep, absolutely. And, to that point, in terms of a comparison to omalizumab, what are your thoughts about ligelizumab?

Dr Lang: Ligelizumab is a second-generation anti-immunoglobulin E (IgE) monoclonal antibody, [which] has a higher affinity for IgE and a slower offloading time. It led to better responses than placebo and omalizumab in a phase 2 trial, but a phase 3 trial showed that while ligelizumab was superior to placebo, it was not superior to omalizumab. As a result, it's my understanding that further development of ligelizumab for chronic spontaneous urticaria has been halted.

Dr Friedman: It will fall into the TBD [to be determined] category, no question, but having something comparable to omalizumab is not necessarily a bad thing. I think more options are better, certainly, for our patients. Everyone responds a little bit differently, and I think there's some other things coming down on the horizon. Actually, just this week it was announced that there was top-line data that will be presented soon on remibrutinib, a BTK [Bruton tyrosine kinase] inhibitor, so we'll have some oral therapies as well, but I guess we're waiting with bated breath to see what that data showed. They like to give us . . .

Dr Lang: Right. There are several BTK inhibitors, remibrutinib, fenebrutinib, rilzabrutinib, and they're undergoing clinical trials for patients with chronic spontaneous urticaria who are antihistamine-resistant. There were some limitations, in terms of safety, associated with previously developed BTK inhibitors, but the novel agents under study now have improved safety profiles and could be a major therapeutic class for patients with more refractory urticaria.

Dr Friedman: Absolutely. As we wrap up, Dr Lang, it's been an absolute pleasure. What are the 3 key take-home points you hope our learners walk away with today?

Dr Lang: Number 1 is that patients come to us having taken a big hit in their quality of life, and, although we can't answer the question that most of them come to us with, which is what is the cause of this condition, nonetheless, we can do a lot to help these patients. Number 2, our understanding of this condition has grown over time, and we have more effective medications with which to treat it, yet there are still unmet needs. However, now I'm on number 3, there are a number of promising agents on the horizon, and there's also work that will show that a number of so-called biomarkers can be used to more specifically target patients to direct therapy more precisely. I think, for those of us who manage patients with chronic urticaria frequently, this is an exciting time.

Dr Friedman: Yep, completely agree. I think my points are, CSU psychosocially stinks. Speed up the therapeutic ladder when managing CSU. I think many of us are used to taking our time or expecting drugs to take a while to work, but we'll know pretty quickly if antihistamines are effective, in a matter of weeks, so do not take your sweet time. Get them as therapeutic[ally] optimized as possible. I think the future is very bright, finally, for CSU. I'm very excited to expand my therapeutic armament to address these patients.

Well, thank you so much, Dr Lang. This has been a pleasure; it's been insightful. It's always great to partner with colleagues from across the aisle, and I hope all of you had a wonderful time learning from us, and I had a great time learning from you, Dr Lang.

Dr Lang: Thank you, Dr Friedman; I would say the same. It was a pleasure to participate with you, and I also learned from you.

Dr Friedman: Absolutely. And everyone who's joined us, please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.