Transcript
Walter Liszewski: Hello everyone. Thank you for listening to today's podcast. My name is Walter Liszewski. I am a dermatologist at Northwestern University in Chicago. And today, I am joined by my good colleague, Dr. Naiem Issa. Dr. Issa, how are you doing today?
Naiem Issa: Hey, Dr. Liszewski. It's really great to see you. Thanks for having us today, and it's a pleasure to be here.
Walter Liszewski: All right. Well, let's kind of get into it. So today we're going to talk about CSU or chronic spontaneous urticaria, or if you're as old as I am, what I was taught was chronic idiopathic urticaria. And, although chronic spontaneous urticaria is something that dermatologists see and it's in our textbook, many dermatologists don't feel comfortable managing it. They don't really know what it is, and they don't actually know what's available out there in terms of disease management.
And so, I have a couple questions for you today and hopefully you can educate our listeners, but I want to start with some real basic, really simple things first. And the first question I'm going to ask you is what is chronic spontaneous urticaria?
Naiem Issa: Way to put me on the spot, Walter, because back in the day when I first learned about this, I used to tell my patients and colleagues that I was a, quote, unquote, "idiot," because we used to call this, as you said, chronic idiopathic urticaria because half the time we didn't know what the heck caused it.
So we are actually still kind of in the same boat, but we have refined the actual definition. So first and foremost, it's important to kind of level set on what the heck urticaria is into two major classes. So cornerstone, you got a mast cell and the mast cell is what degranulates when it gets quote, unquote, "turned on."
And then, the mast cell, when it degranulates or releases histamines as well as other pro-inflammatory mediators, that's what causes you to swell up, make hives, wheals, angioedema, swollen lips, swollen around the eyes, and so on and so forth.
Now, the first thing that we try to do is to separate acute versus chronic, because sometimes you can have a mixture of the two, depending on the types of urticaria that come in. But the most basic level is when you have the patient, you ask them, "All right, well, how long have you had this urticaria, or these hives?" And so, we usually demarcate it based on six weeks. If it's less than six weeks, it's acute. If it's longer than six weeks, we call it chronic.
And if you were to ask me why on earth do we say six weeks? Well, probably somebody who was doing a dissertation had to call it six weeks, and then basically we drew the line in the sand.
But the more important part here is that we have this delineation between acute and chronic. Acute, we have potentially known triggers. That's where we frequently do the testing for those triggers, such as food allergies and other exposures, viruses, and so on and so forth.
And then for chronic, we separate chronic urticaria into two other major classes. We have your inducible urticarias and you have your spontaneous urticarias. And for those who are still following at this point, when we have chronic inducible urticarias, these are typically things such as being nervous, we call it cholinergic urticaria, or when you exercise, or sometimes heat will cause you to have urticaria, sometimes vibration. Imagine you're a construction worker on a drill that can cause a vibratory urticaria, for example, solar urticaria, so on and so forth. There are inducible triggers or dermatographisms should you stroke one's skin and cause the mast cells to pop.
But if you go down the line of thinking for inducible urticarias and you rule those out, then you end up with the spontaneous, which is this kind of grab bag, this class where we just don't know why it comes and goes. We don't know when it's going to come, we don't know how long it's going to last, and so on and so forth.
So, we put us in a spontaneous category. And typically the good thing about the spontaneous category of CSU is that it does not lead to anaphylaxis. So this is actually not scary. We don't need to have an EpiPen on hand and so on.
But the long and short for this really long answer has been that acute versus chronic urticaria, based on six weeks, in the chronic you have inducible, and you have your spontaneous.
Walter Liszewski: Yeah. And there's a couple of things that I just want to kind of tease out for our listeners. So the first thing is that although chronic spontaneous urticaria is defined by six weeks of involvement, you don't have to have daily involvement. So it can be daily hives, or almost every day having hives, or a couple of times per week.
The second thing is this concept of angioedema. And so, when you have hives, when you have the wheals, that's inflammation of the papillary dermis. When you have inflammation of the reticular dermis, that's the deeper part of the dermis, that's when you get angioedema. And that can be on the eyelids, the lips, the hands, the feet. And we know about one third of all patients with CSU will have both hives and angioedema. And notably the angioedema we see in CSU is due to an internal process, unlike the angioedema we see in say a food allergy or bee sting, which is an external process. So, although they're both similar, they both do not convey the same risk of anaphylaxis. So in CSU, not to worry about that.
And then, finally with the physical urticarias, the inducible urticarias, I learned them as physical urticarias in residence, although we oftentimes now call them CindU, which is chronic inducible urticarias. And notably about a third of all patients will have both CSU and CindU. So those are things like, well, you have CSU plus you have dermatographism or you have CSU plus you have cholinergic urticaria.
So, that's really helpful to know about these differences. Now, next question is, what tests do you need to do for CSU? Do you need to do food testing? Do you need to send someone to an allergist? Do you have to order a bunch of lab tests? If someone comes in with CSU, and there's not an identifiable trigger, what testing should be done?
Naiem Issa: Well, Walter, I'm so glad that you asked me this question when we don't have any allergists in the room, because I would be afraid to get mobbed by our colleagues. Because what we have found, actually I say this jokingly, because actually this has been an evolving concept in terms of laboratory testing, when it comes to CSU specifically. We actually don't have any recommendations, actually, in terms of testing. In fact, there are no gold standard testing strategies for CSU.
The concept behind this is that, because it's spontaneous, for lack of a better word, and without any known triggers, testing for triggers does two things. One, it utilizes resources when we know that there are no known triggers for CSU if you're going to have a clean delineation, but it's not to say that you won't get a positive if you have an overlap condition. So it gets a little bit muddied, but if you're going to be doing strict didactics on this, we don't necessarily need to test for any triggers.
However, testing for triggers is one bucket, but what I do, specifically, is test for any autoimmune association. And typically what I test for is for thyroiditis. I call it the four Ts, the TSH, free T4, thyroglobulin, thyroid peroxidase. Now, why on earth am I even testing this as an adjacent workup? It is because we know that CSU, in part, is an autoimmune condition. In fact, we separate CSU pathophysiologically into two major camps. One, we call it the autoallergic, which is about 85, 90%, which is IgE mediated, that goes through and causes degranulation.
And then, we have the IgG version, which is the autoimmune, about 10% give or take. And that IgG version of CSU from pathophys is actually highly associated with thyroiditis such as Hashimoto's. So sometimes if I have a CSU patient, I may catch their comorbid thyroid condition. I'm not testing for what causes triggers. I'm looking for an associated comorbid disease with that specific testing.
Walter Liszewski: And I think one thing to really emphasize here is when patients have CSU, we know that CSU tends to happen most often in people between the ages of 20 and 40. These are people who've never had any health problems. They're like, "What the heck is going on? Why am I having rash all of a sudden?"
And the reality is is that it's an autoimmune process or an autoallergic process. It's not due to something external, it's your body making autoantibodies that are activating the mast cell. And those can be IgE, IgG, or anti-IgE, IgG. That's a mouthful to say. But the point of it is that the body's making these wonky antibodies and that is what's driving CSU. It's this autoimmune internal process.
You know what? I agree with you. I definitely check thyroid function in patients. And then in terms of other things to test, it's really dependent on what you think is medically important or medically necessary.
One thing that's not necessary is to do routine allergy testing. Again, CSU is not an external cause, it's an internal autoimmune process. And if you refer someone to an allergist, think about your own clinic. How long does it take to get in? It can take months. So if someone's miserable, they're itchy, they're uncomfortable, instead of taking the bull by the horns and actually managing their disease, if you just kick the can down the road and refer them to an allergist, you're going to be prolonging someone's suffering with a highly unpredictable, random, itchy, debilitating rash. There is really not additional benefit from doing allergy testing.
Now, patients may ask for it, and that's challenging because patients want us to look. So if you think it is medically appropriate to do a limited amount of blood work that is relevant to CSU, that is OK to do, but categorically recommending extensive testing for all patients with CSU is really without merit. It just adds to healthcare costs and it delays diagnosis and management.
And actually that's a really good segue to my next question is, how is CSU treated, and can you talk to me about the international guidelines that came out earlier this year?
Naiem Issa: Sure. So the needle on how to treat CSU hasn't moved in a really long time until this year. And classically, from what I even remember back from medical school, let alone residency, has been that CSU, or CIU at the time, was a mast cell problem, and so you treat it in kind with antihistamines.
OK, that makes sense at first, right? Then once you have a degranulation of the mast cell, you're going to have histamines. So why not block the histamines? That made sense until it didn't.
And so, you have patients who are not under control with second generation non-sedating H1 antihistamines or H1 blockers. You start them off at a regular dose, and then since you are not getting the care that we are expecting, those results, we are going to elevate and increase the dose two times, three times, four times, for X number of weeks.
Typically, once we escalate, we do it for a month, or give or take, before we reassess. But because degranulation is beyond just histamines, we have other pro-inflammatory mediators, usually antihistamines don't cut it. And so, then we start to add, back at the time before the new guidelines, we would add a H2 blocker, thinking maybe we'll cover more histamine receptors. If that didn't work, then we'll add leukotriene inhibitors such as montelukast because leukotriene was also part of the granules, but still that's not covering the whole gamut.
And then, after we started using cyclosporine, which is a big gun at the time, it's more of an immunosuppressant, then we had omalizumab, and the omalizumab was an anti-IgE and it worked for a great number of patients, but that was the only advanced therapeutic that was FDA approved at the time.
Then there was a lull for a while, and now we have two additional advanced systemic therapeutics, one which is remibrutinib, which is an oral small molecule that targets Bruton tyrosine kinase.
And we also have dupilumab, which is a interleukin-4 receptor blocker. Both of them now FDA approved. Now, these were not recommended prior in the older guidelines. Now in the new 2026 international guidelines, these are recommended as the next step after failing second generation H1 antihistamines, and that is recommended about two to four weeks, give or take, of failure on the antihistamines.
And when you are going to escalate care to that advanced systemic, these three medications, omalizumab, remibrutinib, as well as dupilumab, are all recommended equally as the next stage of therapy. And that is the new update here.
Walter Liszewski: Yeah. And again, these guidelines are literally four steps. These guidelines, which were the consensus guidelines of multiple chronic urticaria organizations from all over the world. And just to go through them again, step one, someone has hives daily or almost daily for more than six weeks, you know they have CSU, you're going to start them on second generation antihistamines. So those are things like cetirizine, levocetirizine, fexofenadine, or loratadine, and you can go up to four of them per day.
What happens if you take more than four? You reach a saturation point. So you don't have to push a patient all the way up to four total per day, but you have that availability.
Now, the guidelines are very clear. If someone is not improving in two to six weeks, so as little as two weeks on scheduled antihistamines, then you bump them up to a systemic agent. And again, that could be omalizumab, remibrutinib, or dupilumab. And if that doesn't work, you can change the agent, or consider moving to something like cyclosporine if needed. But fortunately with three great options available, we almost rarely, if ever, have to do that.
And one of the cool things though, is not only do we have three agents that are advanced agents now, they all have different mechanisms of action. So it's not like we have redundancies here. So we have a lot of options available for patients if they fail to improve.
Now we talked about these newer agents that are available as well, as are older agents like omalizumab, but do you have any thoughts why CSU is undertreated in dermatology, and why maybe dermatologists aren't as aggressive at managing poorly controlled disease the way they are for say psoriasis or atopic dermatitis?
Naiem Issa: Yeah, absolutely. And it's a great question, and we're kind of at a pivot point now in the field, and trying to bring CSU back into the house of dermatologic medicine.
So I see this problem as twofold. So one is, are we diagnosing it? And number two, are we just punting it because we didn't have the available therapeutics to us?
So for the latter, now we have therapeutics. I think that's already changing the game. So we have access, we understand the mechanisms and so on. It's a lot easier for us to treat. But I think the bigger issue is problem number one, are we diagnosing it correctly? And these patients take time in order for us to spend with them, in order to get to the proper diagnosis because they've been suffering for a number of years, they're needy patients, and we need to have a good thorough history.
Now in that history, and this is where the problem lies, is that have we figured out a way to ask the appropriate questions in a streamlined way, in order to find out whether somebody has inducible urticarias or not and how to basically streamline the patient's care and to make the patient happy, all at once?
And so, now I think we're getting better at finessing the review of systems and so on so that we are better able to identify CSU patients earlier in their journey, and get them through antihistamines and ultimately to advanced therapeutics that are FDA approved.
So I think we're still learning, but as we do the messaging like this and we go to conferences and so on, I think we are getting better at doing this portion of it.
Walter Liszewski: Absolutely. And I think part of it is that we know based on retrospective studies that patients oftentimes will suffer with CSU for years, years before they get a diagnosis. And we know over 50% of patients who do get a diagnosis of CSU are inadequately controlled on antihistamines, and the majority of them do not get moved to advanced agents.
I don't think any of us in 2026 would see a patient with say 20% body surface area of atopic derm and not think to ourselves: maybe they should be on a systemic agent. We wouldn't see a patient with psoriasis and psoriatic arthritis and think to ourself: maybe they don't need a biologic. We are really good at recognizing AD and psoriasis patients who need to be escalated, but in CSU, we're still kind of struggling with it.
But really just remember the guidelines. Daily or almost daily hives for a minimum of six weeks. You try second generation antihistamines, and if there's a lack of response to that within two to six weeks, then it's medically appropriate to move them to an advanced therapy. And that could be omalizumab, remibrutinib, or dupilumab.
So with that, Dr. Issa, thank you so much for taking time to chat with me today. I really appreciate your insights, and to all the listeners who tuned in for this. Hopefully you'll learn from some of these pearls, and hopefully it will change the way that you diagnose and manage chronic spontaneous urticaria.
Naiem Issa: Thank you all very much, and we're itching for you to listen to our episode. See you next time.
