Transcript
Dr. Neal Bhatia:
Which actually brings up another topic, which is pigment. And we don't think about pigment with some of these treatments, and yet pigment is everyone's hot topic now, especially as we advance towards vitiligo treatments that are coming to fruition and things like that.
But when you think about post-inflammatory pigment, or you think about a straight-up pigmentary disorder, is this a mechanism that could be at play even though it's not, again, what the labels were, the product to the world? Are we actually seeing normalization of pigment as an upside, or are we seeing post-inflammatory change resolve? I mean, I always use the concept of you throw a rock in the water and the pigment is the ripples, right? It's gradually either going to fade or it's just going to smolder, but would we see maybe a normalization effect from that as well?
Dr. Joshua Grosshandler (31:45):
I think it's really, really complicated, Neal, and I don't know that there's a pure yes or no in this, so let me try to set it up the best way that I think I can. So getting back to thinking about what are ligands, what are things turning this aryl hydrocarbon receptor on in some sense? And interestingly enough, ultraviolet light, one of the things that this aryl hydrocarbon receptor is doing is it's actually looking at your skin's interaction with ultraviolet light.
So it breaks things down and then we get this tryptophan byproduct, and that is some of the signal. And when it does that, interestingly enough, just straight AhR activation that way actually upregulates melanogenesis-related genes. So it's turning on tyrosinase, it's turning on TRP-1 and 2, it's turning on the microphthalmia-associated transcription factor, the MITF that some of us may be used to calling it that way. And so, in some senses, it's your tan response. It's what's actually turning that on when you're out there in the sun. OK?
So I want to set the scene that way. So for me, I think if you're dealing with less pigment, sure, maybe you're able to... Post-inflammatory hypopigmentation, maybe you're able to help things in that sense. Interestingly enough, there's some case reports in vitiligo where, hey, they used tapinarof and saw some improvement. Now, again, case report's view. I think it's a hot area. People are going to explore it, because it would be amazing to have another one of these topicals that we could use, or a pathway or something else.
On the other side though, we also know that one of the ways that the aryl hydrocarbon receptor, or again, tapinarof is really the medication that we're using nowadays to work on this receptor is, again, back to that oxidative antioxidant pathway, it works two ways. So, the aryl hydrocarbon receptor, or the tapinarof combo, actually goes and scavenges reactive oxygen species.
And so we know that, again, some of that damage is probably leading to this post-inflammatory hyperpigmentation, or again, maybe even the post-inflammatory hypopigmentation, but there's this other pathway and it's called the Nrf2 pathway, and it too is another way to help be more antioxidant. So in my mind, thinking about maybe more this PIH, or the post-inflammatory hyperpigmentation, I have to think maybe it's a little bit more of this antioxidant side of things.
In addition to that, I think that, again, maybe not only the antioxidant, but back to inflammation, right? We've always seen and known that inflammation does it. If we look at some of our other mechanisms or medicines that we've used, and where we see that post-inflammatory hyperpigmentation goes down. But if you look at a lot of the pictures from the studies or you look at patients, I mean, I've seen it, you see it where sometimes, hey, they've gotten better and quickly. And whether it's the PIH or the hyper or hypo, there's this difference. So I think it's an interesting play because aryl hydrocarbon plays on both sides.
One other little tidbit that I think is wild and interesting, putting some things together in some other conditions that we're used to seeing. So Tinea versicolor, I think a lot of us agree that Malassezia is the reason, if you will, that it happens. And there's this thing called malassezin, and it comes from these Malassezia. It also binds to the aryl hydrocarbon receptor. It's one of those ligands, and some people believe that's why you get some of that hypopigmentation. So back to it.
So, there's a lot of these little things that I don't think we've ever really realized or connected, but this receptor really is important in so many of those avenues. So I think there is a role, but again, I think we need some more time, and really honing in on what's actually helping us, or maybe even causing some of the problem.
Dr. Neal Bhatia (35:46):
No, but that description of what's under the hood, I mean that stuff we never would've thought about decades ago, and now, here it is. And like I said, in front of you. See, that's good stuff. That's how it should be.
Dr. Joshua Grosshandler (35:56):
Right. It's farmed.
PART SEVEN
Dr. Neal Bhatia (35:57):
Well, this was a pretty good review of not only the role of aryl hydrocarbon receptor biology as well as where it fits clinically. Talked a little bit about tapinarof, talked about some of the ways to, again, incorporate a lot of these treatments into play. Anything you want to leave our audience with or any other pearls that you have?
Dr. Joshua Grosshandler (36:17):
Yeah. I mean, I think there's some other fun little factoids. I don't know. I don't know why I always remember these things. I think one thing to remember is we first learned, you first learned about aryl hydrocarbon from something called dioxin. Do you remember dioxin?
Dr. Neal Bhatia (36:33):
Those were-
Dr. Joshua Grosshandler (36:36):
Chloracne, right? Chloracne, I never saw it, but you're in the VA clinic and the Agent Orange guys were always talking to, "Hey, does this cause this and this cause that?" And you're like, "Well, the only thing was chloracne, which you don't have." But that's one of the things that actually how we used to think about it, so toxicologic.
I think one of the things to just bring it home in that and second is the chimney sweep disease. Again, chimney sweeps back in the day, naked, these little kids are going in the chimneys, and they were getting the phenyl chlorinated biphenyls, or the PAH, the polyaryl hydrocarbons, and we were seeing cancers.
So one of the things about, I think when you're talking about aryl hydrocarbon, there can be too much. And a lot of these, what this mechanism we saw in chloracne is that that ligand isn't shut down. It's just continuously there and creating this.
And so I think there is this too much, and getting back into some of the use case, we know that, again, we saw in using tapinarof, folliculitis. And if you think about folliculitis, it isn't the true folliculitis. If you've seen it, Neal, it's some of this keratosis pilaris-looking.
And I think that may be because again the barrier is being hyperstimulated, I guess if you want to call it that. And so there's that too much and too little. And so I think things that I would just tell people is, especially on the psoriasis side, I think we learned you need to keep it on the spot. I think you need to not use too much.
And that may be that too much use, if you will, back to that, "Hey, how should we coach patients?" And maybe it really is, "Hey, you should stop." In the atopic dermatitis side, not something that was seen as much. Still saw some folliculitis, but definitely less. And I think that gets back to maybe that barrier repair. Again, you have a little less in psoriasis than in atopic derm, but again, nice to have the ability to play on both sides.
Dr. Neal Bhatia (38:36):
No, completely. And I totally agree with that. I was watching it, I never thought it was folliculitis either, and it was always at the periphery, if you did see it. So it goes back to, are you using too much and too much margin perhaps?
But I always thought it looked more like miliaria, or something of that kind of maybe different, more spongiotic process if you look under the microscope. I don't know. I wanted to do biopsies of it, and we can have that conversation for another hour. So that's easy. Well, Josh, this was great. I mean, it was very comprehensive, and thanks for bringing your wisdom and your A game to this discussion. I really appreciated it.
Dr. Joshua Grosshandler (39:08):
No, I appreciate you, and thanks for having me. And yeah, we'll have to do it again.
Dr. Neal Bhatia (39:12):
For sure. For sure. And this was another installment of Dermatology Dialogues, and we'll see you next time.
