Latest / The Science of Skin / Chronic Urticaria Explained: BTK Inhibitors & Remibrutinib

Transcript

Chronic Urticaria Explained: BTK Inhibitors & Remibrutinib · The Science of Skin

• 0:00
  SPEAKER_01: This episode is sponsored by Navartist with content independently created by the Science of Skin Podcast.
• 0:14
  SPEAKER_00: Hello and welcome to the Science of Skin Podcast.
• 0:16
  SPEAKER_00: My name is Dr.
• 0:17
  SPEAKER_00: Ted Lane.
• 0:17
  SPEAKER_00: I'm a board-certified dermatologist practicing in Austin, Texas, and I have got a very special guest today.
• 0:23
  SPEAKER_00: Her name is Dr.
• 0:24
  SPEAKER_00: Serena Elmeria.
• 0:25
  SPEAKER_00: She is an MV PhD professor of dermatology at UC San Francisco.
• 0:30
  SPEAKER_00: She's also the director of the UCSF Center for Itch and Neurosensory Disorders.
• 0:36
  SPEAKER_00: Serena, how are you?
• 0:37
  SPEAKER_02: I'm doing well.
• 0:38
  SPEAKER_02: Ted, thanks so much for having me, and honestly, for saying my name correctly.
• 0:43
  SPEAKER_02: That's a feat in and of itself.
• 0:46
  SPEAKER_00: A win for Gryffindor.
• 0:47
  SPEAKER_00: So, um, Serena, we are going to be talking about CSU.
• 0:51
  SPEAKER_00: This episode is sponsored by Novartis, by the way.
• 0:53
  SPEAKER_00: So we are talking about CSU.
• 0:55
  SPEAKER_00: We're going to talk about the pathophysiology of CSU, the kind of pathway that leads to histamine release, and maybe even some other mediators that can be related to the itch associated with CSU.
• 1:06
  SPEAKER_00: And who who better to talk with than the director of the Center for Itch and Neurosensory Disorders?
• 1:12
  SPEAKER_00: So I'm, you know, so excited to have a true expert here.
• 1:16
  SPEAKER_00: You know, the drug that we're referring to is Remy brutinib, which trade named is is Rhapsodone now on the market.
• 1:23
  SPEAKER_00: And Remy Serena is a BTK inhibitor.
• 1:26
  SPEAKER_00: And maybe if you don't mind, you could just start talking about Bruten's tyrosine kinase and what it does, where it is, and why it's such an important therapeutic target.
• 1:36
  SPEAKER_02: Absolutely.
• 1:37
  SPEAKER_02: So Bruten's tyrosine kinase or BTK is a it's a cytoplasmic enzyme and kinase that is expressed in a couple of immune cells that's really important in mast cells and in mast cell degranulation, hence why it is the target and focus of reminibrutinib.
• 1:57
  SPEAKER_02: And essentially what BTK does is it's important for kind of activating immune cells.
• 2:05
  SPEAKER_02: So it in a mast cell, it leads to activation of kind of calcium flux in the cell.
• 2:12
  SPEAKER_02: And when BTK is activated downstream of kind of IgE engagement of the high affinity IgE receptor in the mast cell, that leads to an intracellular cascade that activates BTK.
• 2:25
  SPEAKER_02: BTK ends up activating other enzymes that lead to shifts in calcium that cause the granules that contain histamine and proteases and various other active mediators, including cytokines, chemokines, to fuse with the intracellular membrane and then cause release that then activates all those downstream targets, right?
• 2:49
  SPEAKER_02: The vessels and the nerves, which are clearly important in the development of verticaria, right, which is defined by wheels and itch.
• 2:58
  SPEAKER_00: Yeah.
• 2:58
  SPEAKER_00: So let's okay, so thank you so much.
• 3:01
  SPEAKER_00: We understand the BTK's role now in terms of the histamine release and other mediators, as you said.
• 3:07
  SPEAKER_00: But if we go a little bit upstream now in terms of the true pathophysiology of CSU, we've got kind of two pathways, right?
• 3:15
  SPEAKER_00: The type, what is it, the type 1 and the type 2b pathways uh in terms of autoimmune versus auto allergic.
• 3:22
  SPEAKER_00: Maybe we could just focus on autoimmune first.
• 3:25
  SPEAKER_00: Would you mind just walking us through that?
• 3:27
  SPEAKER_02: Yeah, I mean, it's such an important part that quite frankly, for so much of my own career, and even when I was first learning this, used to kind of um, I'd say, kind of muck me up a little bit when I was trying to figure out, oh, does somebody have autoallergic or type one CSU?
• 3:44
  SPEAKER_02: So that's when you actually are developing an autoreactive IgE.
• 3:50
  SPEAKER_02: So an IgE that is binding to an autoantigen, say like um TPO or IL-24 or you know, double-stranded DNA.
• 4:00
  SPEAKER_02: So something innate to us, an autoantigen, you have an IgE that is now autoreactive to that, and that's binding to these high-affinity IgE receptors, cross-linking those receptors and leading to activation of those intracellular cascades in the mast cell that are then triggering mast cell degranulation, including that part of that pathway is BTK.
• 4:24
  SPEAKER_02: Now, when, yeah, go ahead.
• 4:26
  SPEAKER_00: Well, no, I'm just thinking, um, thank you.
• 4:28
  SPEAKER_00: I was just thinking, okay, is there a because you mentioned this and it made me think, is there a way to determine a type 1 versus a type 2 B patient?
• 4:36
  SPEAKER_02: So there certainly is a way where we can start to look for auto antibodies.
• 4:42
  SPEAKER_02: Um, it's a little bit easier in a way to kind of clarify those, those, um, you can you can screen for some of them, right?
• 4:50
  SPEAKER_02: Like looking for anti-TPO antibodies.
• 4:53
  SPEAKER_02: You can screen for um for for those for sure, but you can also just do certain other autologous tests that will then look for other um IgEs that will then bind, right, to IgE or the high affinity IgE receptor that will then also trigger that cascade.
• 5:14
  SPEAKER_02: And so right now we usually tell people, right, if you're going to be screening for these IgEs or these IgGs, you have to have a uh a lab that will allow you to do that.
• 5:24
  SPEAKER_02: And when you kind of look across different places in the US and even really across the um, you know, kind of the global uh, you know, experience, not everybody has access to those tests.
• 5:35
  SPEAKER_02: But it is important to remember that in chronic spontaneous articaria, about 50%, almost 50% of patients will have some degree of autoimmunity, whether it's that type 1 auto allergic IgE or the type two, which again, that's more of it's an IgE.
• 5:51
  SPEAKER_02: Yeah.
• 5:52
  SPEAKER_00: Yeah.
• 5:52
  SPEAKER_00: Okay, so so go do dive a little bit deeper into the type two for me.
• 5:56
  SPEAKER_02: Right.
• 5:57
  SPEAKER_02: So the the type two autoimmune is mediated by an IgG or actually even an IgM autoantibody to the high affinity IgE receptor or to IgE itself.
• 6:10
  SPEAKER_02: Okay, so that's the testing where you can actually look for that autoantibody on those autologous serum skin tests.
• 6:17
  SPEAKER_02: Um, you may see it as ASST, some people can do that, or the basophil activation tests, or those immunoassays where they do an ELYSA to look and see if basophils from the patient are actually reacting to certain things.
• 6:29
  SPEAKER_02: And that's um that is an important part of distinguishing this.
• 6:33
  SPEAKER_02: And most people, I would say, have access to that.
• 6:36
  SPEAKER_02: When you're looking for the type 1 autoallergic, again, you would be looking for anti-TPO antibodies, anti-double-stranded DNA antibodies, um, anti-IL-24.
• 6:46
  SPEAKER_02: You know, these are some of the auto antigens that are associated with CSU.
• 6:52
  SPEAKER_02: And those are, depending on where you practice, less readily available.
• 6:57
  SPEAKER_00: Yeah.
• 6:58
  SPEAKER_00: And then you you mentioned the autologous serum skin test where you draw blood, you spin it down, you take a little bit of the serum, and you just do a little intradermal wheel, and and that leads to a much bigger wheel and flare, doesn't it?
• 7:11
  SPEAKER_02: Yeah, and fewer of us, I think, actually do that.
• 7:14
  SPEAKER_02: More of us are likely to send off the test, right, for these, these other amino assays, the ELISAs, um, the basophil activation test or the the chronic urticaria index test.
• 7:26
  SPEAKER_02: That's what I think so many of us do.
• 7:28
  SPEAKER_02: But around the world, you know, people do actually perform that ASST.
• 7:33
  SPEAKER_00: Okay.
• 7:33
  SPEAKER_00: The the chronic urticaria index test, I've never heard of that.
• 7:36
  SPEAKER_00: Can you explain that?
• 7:37
  SPEAKER_02: Well, that's the basophil activation test.
• 7:39
  SPEAKER_02: It's just another, it's just another name for it.
• 7:42
  SPEAKER_01: Yeah.
• 7:42
  SPEAKER_01: This episode is sponsored by Navartis with content independently created by the Science of Skin podcast.
• 7:48
  SPEAKER_00: So we go through BTK.
• 7:50
  SPEAKER_00: It seems like all paths seem to lead to BTK, right?
• 7:52
  SPEAKER_00: Am I missing any kind of CSU pathway that doesn't involve BTK?
• 7:57
  SPEAKER_02: Well, I will say this mast cells are incredibly complex, and there are many ways that a mast cell can be activated.
• 8:06
  SPEAKER_02: So, in addition to some of the immune factors that we discussed, um, which all do rely heavily on BTK to the extent that we know, uh, there are other pathways that are considered non-immunologic.
• 8:22
  SPEAKER_02: So even if they involve parts of the innate immune system, like if, you know, for example, um other things that can bind directly to receptors on the mast cell that don't require an IgE or an IgG, they can activate mast cells too.
• 8:39
  SPEAKER_02: So that includes complement, right?
• 8:40
  SPEAKER_02: That includes some of the neuropeptides, some of the cytokines that have receptors directly on the mast cell.
• 8:46
  SPEAKER_02: Um it can even be pathogens themselves, right?
• 8:49
  SPEAKER_02: Drugs, you know, we've all heard of Redman syndrome.
• 8:52
  SPEAKER_02: So that's mediated by, you know, vancomycin or other antibiotics that can bind directly to something called mass-related G protein coupled receptor X2, MRG X2.
• 9:02
  SPEAKER_02: And that, those other, those other pathways may be independent of BTK, but BTK is central to what I think is relevant to so many CSU patients.
• 9:16
  SPEAKER_00: Well, if I could, and and I know we're really talking about CSU, but I've always wondered this, about what about inducible urticaria, Serena?
• 9:24
  SPEAKER_00: And and if we did like a delayed pressure urticaria, and how how is that causing mast cell release?
• 9:30
  SPEAKER_00: Do we know?
• 9:31
  SPEAKER_02: Yeah, I mean, so we're still learning so much about the inducible or physical urticarias, and those also seem to act through various receptors, sometimes including Ig, you know, the IgE, um, high affinity receptor, and even through other Ig receptors that can de that can degranulate or cause degranulation of a mast cell.
• 9:54
  SPEAKER_02: But there are these intrinsic factors that then will induce the um the fusion of the mast cell granules with the membrane that are sometimes independent of that in inducible urticarias.
• 10:10
  SPEAKER_02: Now, that being said, that still may involve BTK.
• 10:14
  SPEAKER_02: And we know, even I think, you know, you can tell me your experience in managing these patients.
• 10:19
  SPEAKER_02: A lot of these patients, you know, 10 to 20% of these patients, sometimes even more, will have a, will have CSU, right?
• 10:27
  SPEAKER_02: Chronic spontaneous urticaria that has no identifiable trigger or reproducible trigger, but they will also have inducible urticarias, particularly symptomatic dermatographism or cold or heat, you know, um other mechanical triggers.
• 10:42
  SPEAKER_02: And so in those cases, when you manage these patients with drugs like Remibrutinib that are functioning through BTK, we know that a lot of their inducible urticaria also get better.
• 10:55
  SPEAKER_02: So BTK is central to that.
• 10:58
  SPEAKER_00: Okay, okay.
• 10:59
  SPEAKER_00: And of course BTK, Remybrutinib is is only FDA approved for CSU as of today, which is August 27, 2026.
• 11:11
  SPEAKER_00: Um, so let's, if you don't mind, if we could just focus on Remy brut nibs binding to BTK.
• 11:18
  SPEAKER_00: Because it's kind of unique, isn't it, in the way it binds and and into in the formation of BTK that it binds to, from my understanding.
• 11:26
  SPEAKER_02: Yeah, I mean, so this is a really important point.
• 11:29
  SPEAKER_02: Remy brut nib binds kind of covalently but irreversibly to BTK, and it prevents its further activation of all that calcium signaling, right?
• 11:39
  SPEAKER_02: PLC activation and all the calcium signaling and influx that that is required for those granules to fuse with the membrane.
• 11:47
  SPEAKER_02: And it is it is a BTK, sorry, wemibrutinim actually targets a BTK that is expressed kind of preferentially in basophils and in mast cells.
• 12:01
  SPEAKER_02: And even though we haven't spent a lot of time talking about basofils, they also can BTK activation in basophils can also be uh lead to activation and kind of degranulation of the basal cell, leading to release of histamine and other pro-inflammatory mediator.
• 12:17
  SPEAKER_02: So that's important.
• 12:18
  SPEAKER_02: And remabrutinib kind of specifically targets uh that as opposed to BTKs that may be expressed to any high affinity that may be expressed in B cells, right?
• 12:30
  SPEAKER_02: Um, you know, kind of hearkening on the earlier days with drugs like a bruten nib and other ones that um other BTK inhibitors that may have bound a little bit more to what we see in B cells or in in platelets, where we would see a lot of off-target effects.
• 12:45
  SPEAKER_02: We don't have to worry about that as much with REM abrutenib, and that's great.
• 12:50
  SPEAKER_00: Yeah, so from my understanding, and please correct me if I'm wrong, Serena, because you're the true expert, it it uh REM-ibrutinib binds to the inactive form of BTK covalently but irreversibly, as you said.
• 13:03
  SPEAKER_00: And from my understanding, by binding to the inactive form of the enzyme, it it further differentiates itself from the BTK inhibitor group of medications, as well as um is much more powerful because by binding to the inactive form, we never get the activated BTK, which which leads to all the downstream effects that you that you mentioned.
• 13:26
  SPEAKER_00: But is that a correct kind of discussion?
• 13:29
  SPEAKER_02: Yeah, and that is an important distinction why patients who are treated with rhymoburtinib, again, don't get those same kind of off-target effects, because this is so much more highly selective.
• 13:40
  SPEAKER_02: Uh, and in it again, can prevent that degranulation, but still specifically within the mast cell and the basophil.
• 13:50
  SPEAKER_00: You know, I think it's interesting.
• 13:51
  SPEAKER_00: We we've now thank you.
• 13:53
  SPEAKER_00: We've un now we understand how remi-rootinib works, we understand the different mechanisms of CSU pathogenesis.
• 14:01
  SPEAKER_00: But you you mentioned different granules and different inflammatory mediators that are released from mast cells, because all we really I feel like we just focus on histamine, and yet we know at least 50% of patients that with CSU don't respond to antihistamines.
• 14:16
  SPEAKER_00: So there's probably other things going on.
• 14:18
  SPEAKER_00: Uh and and maybe we spend a few minutes if we can just talking about the other inflammatory mediators that are released from histamine, uh, from mast cells, excuse me.
• 14:27
  SPEAKER_02: Yeah, absolutely.
• 14:28
  SPEAKER_02: I mean, that's such an important thing because these patients often will have many other aspects to you know their symptomatology that will sometimes even include fatigue or um you know some degree of you know GI disturbance and and other aspects.
• 14:47
  SPEAKER_02: We also know these patients are at higher risk of had having angioedema, which is kind of the deeper um the deeper inflammation and edema that will be associated in patients who have who have activation of histamine, but also proteases, leucotrienes, prostaglandins, and cytokines.
• 15:06
  SPEAKER_02: And these are important mediators not only for activating kind of the the targets of the blood vessel as well as the nerve, um, but they are important for also talking to T cells and for eosinophils, which are part of that kind of mix in milieu that will then go on beyond the mast cell to propagate kind of articole disease, right?
• 15:31
  SPEAKER_02: So these little vasoactive mediators, the ones I mentioned, right, the proteases, histamine, leucotriums, they themselves act on these multiple cell types.
• 15:40
  SPEAKER_02: And it just fuels this kind of ongoing pro-inflammatory state for these patients.
• 15:47
  SPEAKER_00: Why is it, do you think, that angioedema lasts longer than an urticarial wheel, right?
• 15:53
  SPEAKER_00: We we commonly think of CSU wheels as as lasting, what, less than 24 hours, but angioedema tends to last for days, not hours.
• 16:01
  SPEAKER_00: And why why is that?
• 16:02
  SPEAKER_00: Do we have any idea?
• 16:04
  SPEAKER_02: Yeah, I mean, typically we think of angioedema, you know, so there there can be different forms.
• 16:08
  SPEAKER_02: In that case, you know, there can be um, you know, some people suspect that it's just the dilation of the larger vessels, and it takes a longer period of time to kind of revert that, but there's also higher activation of braidikinin.
• 16:23
  SPEAKER_02: Um, you know, we we know in hereditary forms, now this is different than CSU, but hereditary forms of of angioedema, there can be elevated levels of of braidinin, and that has kind of a more potent effect and leads to the different presentation that we see.
• 16:42
  SPEAKER_00: Gotcha.
• 16:43
  SPEAKER_00: So interesting.
• 16:44
  SPEAKER_00: Wow, we know so much, and and yet only recently do we have you know medications that are really targeting CSU.
• 16:50
  SPEAKER_00: I mean, thank goodness we have them, uh, but um, you know, because these poor patients, but it's uh it's frustrating that it's taken us this long to get to this point, isn't it?
• 17:00
  SPEAKER_02: Well, yeah.
• 17:01
  SPEAKER_02: I mean, I think for a long time we all assumed that the the whole role of of the whole role and mechanism by which mast cells were active was all through histamine release, which obviously plays a huge role in CSU.
• 17:17
  SPEAKER_02: So we focused on antihistamines.
• 17:19
  SPEAKER_02: And as you said, a large majority of patients actually don't respond completely to antihistamines or actually can't tolerate them due to their side effects.
• 17:28
  SPEAKER_02: And since 2014 or so, we've had omolysimab, right, which is an anti-IgE antibody that you know essentially prevents IgE from binding to the IgE receptor, high affinity IgE receptor on mast cells.
• 17:43
  SPEAKER_02: Now, that's important because it really controls a major contributor to mast cell degranulation.
• 17:50
  SPEAKER_02: And when you look across patients who actually are on a melysumab, they do they do quite well.
• 17:55
  SPEAKER_02: However, when with these newer agents, we are finding that we're able to control to control the mast cell degranulation from the inside out, okay, as opposed to trying to control the IgE binding, we're actually controlling the intracellular signaling cascade that leads to the mast cell degranulating in so many instances.
• 18:17
  SPEAKER_02: Again, downstream, regardless of whether somebody has, you know, an I an auto-IgE or an auto um IgG.
• 18:26
  SPEAKER_02: Uh, and that is really, really important.
• 18:28
  SPEAKER_02: And again, having promised to stabilize a lot of those patients with CSU as well as their comorbidities.
• 18:37
  SPEAKER_00: There you go.
• 18:37
  SPEAKER_00: I think it's uh that's a great way to end.
• 18:40
  SPEAKER_00: Um, well, thank you, uh, Serena.
• 18:42
  SPEAKER_00: This is Dr.
• 18:42
  SPEAKER_00: Serena El Maria.
• 18:44
  SPEAKER_00: El Maria, gosh darn it, I almost had it right.
• 18:46
  SPEAKER_00: We're so close.
• 18:47
  SPEAKER_00: Closer than so close.
• 18:49
  SPEAKER_00: Dr.
• 18:49
  SPEAKER_00: Serena Almeria.
• 18:52
  SPEAKER_00: El Maria.
• 18:53
  SPEAKER_00: El Maria, thank you.
• 18:55
  SPEAKER_00: She gave me a little way to remember it.
• 18:57
  SPEAKER_00: Serena Elmeria, uh, MD PhD out of UCSF.
• 19:01
  SPEAKER_00: She's a professor of dermatology and she directs the Center for Itch and Neurosensory Disorders and just a wealth of knowledge.
• 19:08
  SPEAKER_00: Thank you so much for sharing that with us today.
• 19:10
  SPEAKER_00: Uh, if you enjoyed this episode, please give us a five-star rating.
• 19:14
  SPEAKER_00: Please subscribe.
• 19:15
  SPEAKER_00: And we found that the growth of this podcast really occurs by word of mouth.
• 19:19
  SPEAKER_00: So please tell your colleagues what we're trying to do with the Sciences Kin podcast, which is keep you at the very cutting edge of dermatology.
• 19:26
  SPEAKER_00: Uh, for Dr.
• 19:27
  SPEAKER_00: Serena Elmeria, I am Dr.
• 19:29
  SPEAKER_00: Ted Lane.
• 19:30
  SPEAKER_00: Thank you so much for listening.
• 19:39
  SPEAKER_01: This episode is sponsored by Navartis, with content independently created by the Science of Skin podcast.