Transcript
Brad Glick: What about CSU as a disease? We've talked a lot about it's really not an allergy, it's a chronic condition. What about a little science behind it? Patients are taking antihistamines, hopefully in the right setting where it's those of us that are dermatologists knowingly dose escalate those individuals.
But what about this disease being heterogeneous, a little bit different from allergic diseases? Talk about a little bit more about the targets and exactly what urticaria is, CSU is in terms of those particular targets like mast cells. Your thoughts?
Lawrence Green: I think that's where the education really needs to start with dermatologists. I'll let Laura go into all the specifics. She's a university person. But the understanding of dermatologists, people in general in primary care as if this is an allergy mediated condition, when it's an autoimmune condition, think about it's just like all the other conditions we're starting to treat now, autoimmunity like HS, like psoriasis, like atopic dermatitis, all these things we're now being able to treat, CSU fits in the same boat. It's not an allergist thing. It's really our thing. And I'll let you go from there, Laura.
Laura Ferris: Yeah, I mean, obviously histamine, so the mast cells, the key mediator in urticaria. So antihistamines make a lot of sense. I will routinely tell patients go up to four times the over-the-counter dose of antihistamines. They can tolerate that. And it does actually help a fair number of patients, and that's great if I can get them better on an over-the-counter antihistamine. It's a great outcome for everybody. Oftentimes they end up becoming fatigued, which will happen even with non-sedating antihistamines when you go to those high doses, or it just doesn't work for everybody. So, hitting the histamine pathway, which I like to do, even when I get them on a systemic medication, that's still an adjunct, just maybe not four of them a day to snow them. And then we got to think about, this is IgE-mediated, particularly in type I disease, where you think about the patients who are the activation through Fc epsilon receptor.
So, that's where we could think about patients who may have elevated IgE, may do a little better on omalizumab than the patients who have normal IgE. And then we could think about more IgG-driven disease, and that's where we could think about alternative therapies. Although we know that drugs like remibrutinib and dupilumab actually work well in patients who have normal and high IgE. But thinking about there are different ways to get to mast cell activation and we've got different drugs that can sort of hit that from different angles, whether it's through BTK inhibition, whether it's through the type 2 pathway, type 2 immunity pathway, or whether it's through the Fc epsilon receptor.
Brad Glick: Dr. Ferris just went through the entire science of chronic spontaneous urticaria, but I think it's great, reiterating that there are a couple of different types, autoallergic, not allergic, autoimmune. And I think the other thing too is while we say that we really don't need to do any testing, which I'm in full agreement with, because you want to be able to initiate therapy right away, there are some times when we might want to, particularly in that individual who may have more of that IgG mediated type of CSU, we might get a TPO test. We might look for that thyroid peroxidase antibody in an individual, but I think it's generally uncommon. And I think with the tools in the toolbox, like you just said, we're really not really so concerned about IgE or even IgE mediation because we at least have two, and in some sense, even really all three. Just because someone has a borderline elevated or even slightly low IgE level doesn't mean 100% that they won't respond to omalizumab.
Laura Ferris: No, I think it can be helpful for maybe guiding therapy or explaining things to patients. My only hesitation with the TPO is they're like, "What do I do now? What do I do about my thyroid?"
Brad Glick: Totally agree.
Laura Ferris: And it's not going to really guide necessarily treatments of thyroid disease. And so I always try to caution them when they've come to me with that lab and say, "What do I do?"
Brad Glick: I completely agree, but it's a great opportunity for us to almost make their CSU be a skin sign of systemic disease. At that point, we treat the patient. We maybe unmask something systemically and we send them on back to their primary care physician or to an endocrinologist. Larry, you wanted to say something.
Lawrence Green: I was going to say, I mean, with remibrutinib and dupilumab, we have two great choices that really cover everything. So, working it up further, as someone in private practice, you don't want to necessarily patient get worried or go back to primary care and want to do all these things. We have two treatment options right there and you don't have to worrying about testing in the office first. It's just easy to start one of those two. It's very simple.
Brad Glick: Let's talk a little bit more about new things. We've talked a little bit about IgE-mediated targets and talked a lot about specific target, let's say, where an agent like dupilumab is concerned, which is, as we know, is inhibitor IL-4, IL-13. But what about BTK is newer to us? And I think those of us in dermatology, and maybe some of our colleagues might be a little concerned when we use the word kinase, they might be thinking that it's a different type of kinase. What are your thoughts? What is BTK and what is its role in our toolbox right now for CSU?
Laura Ferris: So BTK or Bruton's tyrosine kinase is a small, it is a signaling molecule, immediate signaling for the Fc epsilon receptor. And so what you're trying to do is if we think about the signals that activate mast cells, you're trying to shut that down. So this is a class of drugs that we've actually seen used across several disease states, but that is sort of what we're thinking about is trying to stop the inflammatory pathway from inside the mast cell.
Brad Glick: It's interesting, I don't want to overstate this, but the particular therapeutic in remibrutinib is kind of a targeted BTK inhibitor because when we start to think about BTK, and I don't want to make this too complex, although you are our resident expert in skin cancer and in cancer in general, BTK and Bruton kinase inhibitors are used in other settings as well, too. Certainly there's a potential impact on platelet aggregation, but there's also, interestingly enough, in addition to the impact on the Fc epsilon receptor and the impact on mast cells as well, which will block the release of histamine, it can also have an impact on another key cell like the basophil, which is also responsible for initiating some of those inflammatory changes and that cutaneous permeability that we see in patients with CSU. Larry?
Lawrence Green: No, I agree. You're stopping histamine release with basophils and mast cells, and it's very simple that it's not an antihistamine remibrutinib, but it's a good basic way, I think, to show how safe it really is that you're making antihistamine even better. So it's not an antihistamine at all by the way it works, but it's doing similar things and that's what we want to tell our patients, make them feel comfortable. And even the dermatologist in private practice, I would say the same thing, to make you feel more comfortable if that's the way you want to think about it. It's a great start because it is a very safe and simple thing.
Brad Glick: I think we may have touched on this already, but maybe we dig a little bit deeper. CSU, CIndU, chronic inducible urticaria. We're starting to get a little bit more flavor for this condition. We're talking about how we bring it back in. I think education is critical. How do we separate out those two a little bit more carefully for our colleagues?
Laura Ferris: So I think this is where taking a good history from the patient is important. So we could think about CSU as being the auto-inflammatory condition. It may be IgE-driven, it may be IgG-driven. If we think about however inducible or CIndU, inducible urticaria, we're thinking about actually physical stimuli that are causing that mast cell activation. And it can be things like we've all learned in residency about cold urticaria where you can put an ice cube on the skin and you can see the cold triggers it, but it can also be things like vibration or pressure. And so if I see somebody who, for example, where they have a tight waistband or bra strap and they get urticaria along there, you want to ask questions about that. Could it be the pressure that's driving that? And then, of course, the scratch test where we can see people who get out of the shower and they've got scratches all across their body.
Lawrence Green: Write their name on themselves.
Laura Ferris: Yeah, to write their name on it.
Brad Glick: I like to do tic-tac-toe. I do tic-tac-toe.
Laura Ferris: That's right.
Brad Glick: What we like to talk about this symptomatic dermatographism or dermatographic urticaria. And of course, recently, I guess we can say this, that remibrutinib actually just got an approval for symptomatic dermatographism, which I think is really a big area for a lot of our patients, and I'll share this privately. My daughter actually suffers from symptomatic dermatographism and she's miserable. She takes antihistamines out the yin-yang, and they really don't help her very much. And so it's nice to know that we'll have some therapeutics in the toolbox that will actually work for that as well.