New Rules for Old Hives

“We have to keep in mind that urticaria has to be treated until it's completely gone. So, absolute control of the disease.” 

— Dr. Herminio Lima

Chronic spontaneous urticaria has long been managed with the goal of complete symptom control. But for many patients, that goal remains elusive. In this episode of The Allergist, Dr. Mariam Hanna talks with dermatologist and clinical immunologist Dr. Herminio Lima about the updated urticaria guidelines—and how new treatment options are giving clinicians more ways to act, and more hope for getting patients all the way to control.

On this episode:

• What’s new in the 2025 guideline—including additional second-line options beyond antihistamines
  
  
• Why nearly 40% of patients may need to escalate to biologics
  
  
• How remibrutinib compares to omalizumab and what its trials revealed
  
  
• What the CUPID studies say about dupilumab, especially in biologic-naive patients
  
  
• Key safety signals and clinical considerations for the new treatment options
  
  
• How to move toward full disease control—and why suboptimal outcomes are no longer acceptable

Complete control is still the destination, but the path to get there is about to get a lot more flexible.

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The Allergist is produced for CSACI by PodCraft Productions

Transcript

Dr. Mariam Hanna:

Hello, I'm Dr. Mariam Hanna, and this is The Allergist, a show that separates myth from medicine, deciphering allergies and understanding the immune system. When you hear clinical practice guidelines, what do you envision about that giant meeting that led to this? Or the flurry of emails sent back and forth? And what about the manuscript revisions with those impassioned comments on the margins? I don't know, given the recent times I've likened it in my mind to the whole process of a conclave. Will it be black or will it be white smoke? A handful of times a year, I meet a patient with stubborn urticaria. 

A trial of high-dose antihistamines and a long explanation to the pharmacist, explaining dispense as per these guidelines. And for some, that's not enough. They're perhaps drowsy, still itchy, and then some can have a huge impact on their mental health because they're itchy and they're not sleeping and they're frustrated. 

I've often had good luck with starting omelizumab for this indication. The patients are extremely grateful. It's left this perplexing disease, one that typically has a happy ending, often full of patients that finally find relief and burst into tears.

So from my story, you'll see why the new guidelines left me initially surprised. Aren't we really awesome at managing chronic urticaria in allergy and immunology? Why do we have room to improve on? What more is there? And please don't tell me this is just a longer discussion on first-generation antihistamines and that we should stop using them. Well, rest assured, from my understanding, it's actually very exciting of an update, and I found just the right speaker to discuss this with us today. 

Allow me to introduce today's guest, Dr. Herminio Lima. Dr. Lima is a clinical immunologist and a dermatologist. He earned his MD from Brazil and completed his PhD in immunology at Harvard University. 

He was a professor at multiple academic institutions in Brazil until he returned to Harvard for a fellowship in clinical trials. He came to Canada in 2010 and is now an associate clinical professor of dermatology and clinical immunology at McMaster University in Hamilton, Ontario. He has authored over 100 scientific publications and has been principal investigator of over 60 clinical trials, focused on numerous skin conditions from atopic dermatitis to psoriasis to vitiligo and, you guessed it, urticaria. 

Today's topic. It's my absolute pleasure to welcome you. Thank you so much for joining us and welcome to the podcast. 

Dr. Herminio Lima:

Thank you very much, Miriam. It's a pleasure to be here. Thank you for the invitation. 

Dr. Mariam Hanna:

Okay, Dr. Lima, so was it just time to do another urticaria guideline or what prompted this update for this time around? 

Dr. Herminio Lima:

So in the last four years, there are many studies, new medications that come specifically for chronic spontaneous urticaria and that's the reason that it triggers the advance of this guideline. One thing that I have to point to you, Mariam, is the fact that there is not only an initial revision but also they are adding the data that has a high level of evidence on the guidelines. 

Dr. Mariam Hanna

So there's high level of evidence that are adding what our algorithm is going to look like once these guidelines are released. 

What are the major changes that we can look towards in this updated urticaria guideline? At the time of our recording, nothing's been officially released or fully released, but this will be soon. Tell us what we can look forward to. 

Dr. Herminio Lima:

So the most important change is going to be the presence of two new treatments that is going to be used after the patient has failed antihistaminic of second generation. 

So it's going to be in the second line, which basically,  spoil alert here, but basically we are going to have three new medications, three new options that we are going to be kind of option after the patient fails the treatment with antihistaminics. 

Dr. Mariam Hanna:

Okay, perfect. And like, what's not new in terms of this stepwise approach? The antihistamine route hasn't changed. 

This is all second generation antihistamines. This part is not new. And specifically what will be new sounds like that second line or when you introduce biologics in this process.  Did I catch that correctly? 

Dr. Herminio Lima

Yes, there is the introduction of a biologic and a small molecule simultaneously in the guideline. The reason is because although Remibrutinib is going to be one of the medications that's going to be side by side in the guideline with Omalizumab as the second line to be adjuvant therapy after the fail of the antihistaminics is not present in any other parts of the world, but Dupilumab, as we know really well in allergy and dermatology, this molecule has been approved in a few countries already that actually last week was approved in USA as well. So right now we have four countries that has approved to be used for chronic spontaneous urticaria. 

So it starts in Japan, then we have the Emirates, and after we had Brazil and now USA. 

Dr. Mariam Hanna

And what about the footprint for Remibrutinib? Like where is that currently being used? 

Dr. Herminio Lima:

So right now the Remibrutinib is still in the end phases of the phase 3. Remix 1 and Remix 2 are the pivotal studies that have been finalized and that's going to be the one that's going to be used for approval in different parts of the world. But there's still some data, for instance, there are data on making a direct study compared with Omalizumab. 

The studies are being done right now. The process of approval should start already by this second semester and many countries are going to start to have the approval by the late 2025 or early 2026. So for this what is going to come in the guidelines is going to come with the print that when is available in the country kind of thing. 

But it's going to be in the same level of the Omalizumab. So basically it gives us more opportunities to decide for the patient and customize the treatment for the patient. 

Dr. Mariam Hanna:

And it's fantastic that it's being incorporated in the guidelines even knowing that you know the phase 3 trials are still underway or wrapping up. 

And we will go through the trial information or kind of their efficacy and what they were able to show. But first let's talk about like treatment failures with the traditional algorithm that we've had. How often do we find that patients need to move on to biologics with CSU? 

So how often are we just using Omalizumab or any biologic? 

Dr. Herminio Lima

Yeah it's very interesting that question because when we go to the literature and we find that it's about 40 percent in many of these studies of the patients that have to evolve to advanced therapies. 

And if we see the data of Omalizumab alone, we are going to find that 30 percent of the patients do not respond to Omalizumab, do not have control. And if you, it's completely fair, if you see the absence of control there is a study that showing that 70 percent of the patients do not achieve completely control with Omalizumab. 

Dr. Mariam Hanna:

I think I am totally floored by some of these numbers like 40 percent needing to move on to biologics. 

This is much higher than I think I anticipated in my mind. And even saying treatment failure on Omalizumab, I don't think I'm the only allergist who's like, why do we need anything beyond Omalizumab? Because we're doing well. But just to recognize that even our patients could be okay with suboptimal control or targeting really zero symptoms, zero lesions on them. 

Okay so at what point, and again this is a spoiler alert, but at what point do the guidelines in this like second tier recommend introducing like a different molecule other than Omalizumab? Would this replace first line therapy being Omalizumab or is it after failure with that? 

Dr. Herminio Lima:

And it's interesting we go back to the first point that you made when you compare with the conclave kind of thing. So it was a lot of discussion on that. So to make sure that we are going to be open to the opportunity for the physician to choose any of these three in any moment. 

So there is no order like you have to go on Omalizumab first now. No, you can choose any of the three. That's what the guideline is going to say. 

And of course you are going to find specific reasons why you are going to use one or the other. And we can discuss that over time. 

Dr. Mariam Hanna

Absolutely.

There's the white smoke. I am very into this whole timely manner. Okay let's talk about Remibrutinib.

This represents a new molecule that we may not all be as familiar with. Let's talk about mechanism of action first if you don't mind. 

Dr. Herminio Lima

Perfect. This is a molecule that targets and blocks a very common molecule. I remember that when I was doing my training in allergy immunology. We have to about the immunodeficiencies. 

And we know the BTK protein is if it is absent. If we do not have that in development of the fetal development, it means that we are not going to be able to produce B cells. However, outside of the body, one of the cells that uses the most of this BTK protein to transmit this signal from the external to the internal is exactly the mast cell and basal fields. 

So it's very interesting if you block that, you block the function of the transmission of the information from the extracellular environment to the activation of the cells. So basically what's that big discover is the ability to do that without affecting the B cells per se. So there is no interaction of the BTK on the B cells kind of component.

So it's basically the mast cell. So the molecule basically blocks that activation of the mast cell. So basically that's the idea of the molecule to create a kind of a situation where you froze the mast cell. 

As a result of that, we know that urticaria is a mast cell disease derived mainly by the mast cell activation. So when we block this cell, basically the urticaria disappear. But more than that, we know that every time that we activate the mast cells, we create a feedback positive. 

So that creates a more active mast cell and very easy to degranulate. So when we block this whole process, we block also this feedback positive. And eventually this disease can enter in a completely control. 

We can eventually remove the medication and the patient is cured. 

Dr. Mariam Hanna:

OK, so let's go back to remibutinib in phase two and phase three trials. So these are the remix one and two. 

Let's talk about what those trials were able to show us in regards to efficacy for chronic urticaria.

Dr. Herminio Lima:

So the most important finding is kind of to find finally a molecule that we can give by mouth for the patient. So it's something that we move away from the biological like large molecules to a small molecule. 

And that it's very pleasant for some patients that have needle phobia, for instance. And the second point is that the aspect of being efficacious, as efficacious, or although we do not have the data yet with the Omalizumab that's going on, but it's also we can say that from the results, if we compare the results is as efficacious as Omalizumab, but much, much faster. We have results in two weeks, the patient's kind of active points that we can reduce the UAS in more than 20 points from the initial baseline on the patient in only two weeks. 

As you know, on Omalizumab, sometimes we have to expect this happening in three doses and many times it doesn't occur. 

Dr. Mariam Hanna:

OK, and when we talk about oral small molecules, I mean, one of the first things that jumps out to us in our mind is the JAKs and like just being able to monitor and safety signals. Are there any current like or concerning safety signals that we see for this small molecule? 

Dr. Herminio Lima:

Yeah, and I want to point it out. I also work a lot with the JAK inhibitors in many aspects, like not only as a topical, as oral medication. So let's separate to make clear to the listeners here. So when we think about these small molecules, they are going in different pathways.

So, for instance, the T cells do not have as much BTK dependence as the B cells or even better, in this case, the mast cell. So the first thing that we separate is this kind of aspect. The second aspect that is very interesting with remibutinib is the aspect that like not only target specific cell, in this case, the mast cell and the basal fields, it also it seems to be easily metabolized by the liver. 

So we do not see some elevation of liver enzymes or alteration of the CK or alteration of the lipids, as we see with the JAK inhibitors, or even a little bit of increase of the risk of F. simplex. So what we see is kind of a very interesting phenomenon. And the main phenomenon that we see that call attention to the doctors that initially in the phase two study was considered kind of call attention because nobody was really expecting was the presence of petechiae being developed in different parts of the body. 

But interesting kind of aspect is that this is not associated with increase of the time of coagulation. So there is no alteration of that aspect. So the platelets is still working the same way. 

But basically, other than that, we are going to have the natural kind of data that we have for any of these molecules. We have a little bit of gastrointestinal discomfort, and we are going to have a little bit of headaches and a little bit more infections kind of thing, respiratory infection, but it's still a very clean kind of molecule. If I compare with the data that we have with the JAK inhibitors, this molecule is much cleaner in the sense of side effects. 

And the platelets occurs in about three to four percent of the patients. And it's very interesting that this is a discussion among the researchers is that it seems that was observed in specific parts of the world, but not in many parts of the world, kind of thing. It seems that is not as prevalent as was observed in Europe as has been in North America. 

So there is a lot of things for us to understand about this phenomenon.

Dr. Mariam Hanna:

 And those patients that develop petechiae, did they discontinue therapy? 

Dr. Herminio Lima:

They continue the treatment and the platelets naturally spontaneously disappear over time.

Dr. Mariam Hanna:

Perfect.  Okay, now we're going to go to a molecule that we are a little bit more comfortable with. Dupilumab also shows up as the second line treatments after antihistamines, and it's been making waves in other allergic diseases. So we've definitely heard about mechanism of action of Dupilumab. 

And I think when we get another indication for them, I'm never that surprised. But what do we know about its role in urticaria now? How does this molecule help with urticaria? 

Dr. Herminio Lima:

So that's a fantastic question as well, because if you ask me like many, many times before, we always say that this is a mast cell disease. And I still believe that this is a mast cell disease, not a type two kind of response kind of disease. 

And we are aware that the mast cell produce IL-4 or IL-13 as well. And the most interesting kind of aspect is that like we know now that using this medication, because it starts with the presence of patients being used this molecule for other kind of diseases. And eventually some people observe that, oh, they also treat the urticaria kind of phenomenon, right? So there was that observation that drove this attention to have the clinical trials done. 

So now we know that the IL-4 participate on the activation of the mast cell as well. So in this kind of component, so if we will block that molecule, we are also blocking in a certain way the activation of the mast cell. That's basically the mechanism of the medication work. 

So there is this CUPID study. So there is the CUPID-A, was done with patients that has been biologically naive, so they never had omalizumab. And in that numbers, we achieve similar control that with around reduction of the UAS-7, about 20 points as well in the CUPID-A kind of study. 

So at the same time, we are doing the CUPID-B study, which was designed for patients that were biological experienced. So patients that have been in treatment with omalizumab. However, in that study, the molecule didn't achieve a difference, significant difference of the placebo. 

So that called the attention that maybe the mechanism of action is going to be very similar to the mechanism of omalizumab as in other biologics. So we know when we are treating patients with omalizumab, if they have very low levels of IgE or very high levels of G-dimer, for instance, that are kind of very pro-inflammatory patients. So we know that they probably are not going to respond the same. 

And it seems that this is going to be the same characteristics that we are going to have for the dupilumab. So it's going to be a molecule that's going to be probably designed for first line. That's one of the things that we defend during the guidelines to maintain the omalizumab, dupilumab, and remibrutinib in the same level as an option for the patient to have.

And so we are going to be more reluctant to put patients that already have omalizumab to go on dupilumab because of that result on cupid B. Then we had a third study that was the cupid C. In the cupid C, what we had then is basically reproducing the cupid A. And in that study, just was released recently some of the data. And actually, there is a little bit of reduction when we compared with the cupid A. It didn't actually have as much effect on the UAS7 as we had in the cupid A. But it doesn't mean that it didn't actually have a statistical difference kind of thing. But still, what we are going to see in the guidelines is that, as you mentioned in the beginning, because we know so well this molecule, we have been working with this molecule. 

So it is going to be a very good molecule, especially for patients that have other atopic diseases. So it is not uncommon. And you know that we have patients with atopic dermatitis in hives as well. 

So maybe that's the big indication of these patients. 

Dr, Mariam Hanna:

Perfect. And is there any CSU-specific dupilumab safety signals? 

Dr. Herminio Lima:

No.  One of the things that we concern a lot is on AD and with the kind of ocular conjunctivitis or the red face kind of response. And that was like in the study with asthma, it was not seen as much. It was reduced even in half or even less. 

And the same with urticaria. Rarely we see a case that develops conjunctivitis. And in this case, we look back and we are going to find probably the patient has atopic dermatitis as well. 

Otherwise, it's a very safe medication. 

Dr. Mariam Hanna:

Yeah, no, fair enough. OK, as we look at this new data, are there any red flags or misconceptions that you're worried that clinicians might develop or they should be aware of when they go through this? 

Dr. Herminio Lima:

So usually in the mindset of the clinician and in the general clinic is basically when the patient disappears, it doesn't mean necessarily that the patient disappears because it was better. 

It was many times because there is a failure and they look for another center, especially outside of Canada, that you can go to different doctors and eventually you find a center that we are going to find these kind of patients with failure. So maybe there is an inflation on these numbers of failure, but because we are talking about really long registries that we have nowadays, just to give you an idea, we are participating on a global urticaria registry called CURE and we have in this study 14,000 patients all over the world. And that's where the numbers of 30% of failure is coming from. 

Dr. Mariam Hanna:

OK, what's still unknown in the urticaria space? Where are we going to see the guidelines moving in the next four years?

Dr. Herminio Lima:

 I think one of the things that we still don't know is the origin of this disease and we need studies on biomarkers. So we are doing a little bit of the reverse kind of story. Instead of finding the biomarker directly, we treat the patients and we try to find the biomarker that was affected by the treatment kind of thing. 

So we still have a difficult to find biomarkers, but we have an idea now, like if we measure the IgE levels, if we have measurements of CRP and D-dimer, maybe we can have an idea where we should be using a specific kind of molecule. And I have to call attention that remibrutinib, it doesn't matter if you have bio experience or bio naivety, you respond the same way. Another point is that there is new molecules that are coming. 

Can you imagine, Mariam, that we can completely abolish your mast cells and we can have a treatment like that? So we can destroy the mast cells and treat the urticaria. That's the new wave of coming of treatments as well. 

Dr. Mariam Hanna:

That's exciting.  Now that's exciting. All right. All right.  So we'll stay tuned in four years to hear the next set of guidelines and what happens between now and then. Many exciting things. All right. 

Time to wrap up and ask today's immunologist slash dermatologist, Dr. Lima, for his top three key messages to impart to patients and physicians on today's topic, the new urticaria guidelines. Dr. Lima, over to you. 

Dr. Herminio Lima:

OK, thank you. 

I think one thing that I always to repeat in any time that I have opportunity to mention, we have to keep the mind that urticaria has to be treated until it's completely gone. So absolute control of the disease. So this is something that everyone that works in the U-Care centers is objective. 

It's not a partial improvement or something that the patients are happy. We have to actively completely control. So that's the most important. 

Keep in mind that our main objective on these guidelines is to active completely control of the disease. So for my colleagues, clinicians, so never get satisfied if we have just an improvement in the quality of life of the patient, but they still see hives and still affect many of the aspects of the life of the patient. And the second point is that don't give up on the kind of never say to our patients that there is no treatment, that we active the last point. 

We have still evolving and we still new medications to come. And finally, I really think that another point is that let's put urticaria as an important disease because there is no deaths in general on chronic spontaneous urticaria. It doesn't mean necessarily that this disease should not get attention because there is a recent study that was published and it shows that urticaria, it is a serious disease. 

And to the point that believe it or not, the survival rate of the patients with urticaria is smaller than the rest of the population. And unfortunately, the main cause of this increase of mortality is associated with the mental health of the patients as well, because that disease affects the mental health of the patients. So, and keep in tune, like October 1st is coming, 2025. 

We want to make a lot of noise. So, it's the Urticaria Day. It's coming. 

Dr. Mariam Hanna:

Oh, very nice. October 1st, Urticaria Day. Thank you, Dr. Lima, for joining us on today's episode of The Allergist.

Dr. Herminio Lima:

Thank you very much, Miriam, for the opportunity to talk about this field that I love the most. 

Dr. Mariam Hanna:

This podcast is brought to you by the Canadian Society of Allergy and Clinical Immunology and produced in collaboration with PodCraft Productions. The opinions shared by our guests are theirs alone and do not necessarily reflect the views of the CSACI. 

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