Transcript
Dr. Christopher Bunick:
What we've seen in atopic dermatitis with regard to topical treatment is a real evolution towards non-steroidal advanced therapies. We know that overuse of topical corticosteroids occurs and has real impact on atopic dermatitis patients. Ultimately, the need in the atopic dermatitis space was to have some consensus guidelines on how to use an aryl hydrocarbon receptor agonist like tapinarof, because this represents a new class of therapy in atopic dermatitis. Therefore, we need guidelines on how to use this particular family of agents in our atopic dermatitis patients, and we need to know how to use, really, how to use them outside of the corticosteroid realm. How do we really push that boundary of efficacy, safety, and tolerability with our atopic dermatitis patients and not over rely on the topical corticosteroids? In the big scheme of treating atopic dermatitis topically, the issue is that chronic topical corticosteroid use has potential for side effect.
It has potential to thin the skin, cause other atrophy changes. It also can damage the skin barrier with long-term use. In the case of tapinarof, which is the only topical aryl hydrocarbon receptor agonist currently approved in atopic dermatitis, the benefits are the ability to have a non-steroidal mode of action, but not just any mode of action, an advanced mode of action targeting this particular receptor, the aryl hydrocarbon receptor. And what's beautiful about the aryl hydrocarbon receptor is that it's not just something that's going to decrease immune pathways and inflammation. It's also going to promote barrier function and even has some antioxidant activity. And I think it's important that we break that down. When we think about the inflammation driving atopic dermatitis, we often think Th2 driven inflammation. Cytokines like IL-13, IL-4, IL-31 driving the atopic dermatitis. Aryl hydrocarbon receptor is involved in being able to modulate Th1, Th2, Th17, and Th22 pathways.
That means a more comprehensive control and regulation of the cytokines involved in the pathogenesis of atopic dermatitis when you have this agonism of the receptor. Outside of this immunology and controlling the inflammation across all of these types of inflammatory pathways, there is the ability to restore barrier function. In atopic dermatitis, barrier function is critical. And we see in our patients, this loss of barrier function is problematic. In particularly, we measure it with the loss of proteins like filaggrin, keratins 1 and 10, involucrin. What we've seen with aryl hydrocarbon receptor agonism is a restoration or increase in some of these barrier proteins, reduce transepidermal water loss. This barrier restoration feeds back into helping decrease the inflammation and then that feeds back into, again, promoting barrier restoration. Probably one of the benefits of targeting the aryl hydrocarbon receptor that hasn't really been talked a lot about in dermatology are some of the antioxidant effects that the aryl hydrocarbon receptor may play.
And it's thought to be involved in the NRF2 pathway, which drives some of these antioxidant activities. There's probably a lot more to the biochemistry there, but ultimately that's the trifecta of targeting and agonizing the aryl hydrocarbon receptor. And that MOA, in our consensus statements, we highlight that this is a unique MOA amongst atopic dermatitis topical therapies. And this is the reason why the science supports it. When clinicians are choosing an advanced nonsteroidal topical therapy, it's important to understand the biology that we just talked about, the immune modulation, the barrier restoration and the antioxidant activities, because I think that when you tell patients, "Here's why I'm giving you this advanced nonsteroidal topical. Here's what your copay or here's what your insurance, here's what you're paying for. You're paying for this advancement, the ability to achieve all these things without the baggage, without the risks of topical corticosteroids."
And the clinical trial data goes a step further and really shows that for some patients, they can have meaningful, durable responses that last months after treatment. And I think that that's an important message to communicate to patients. When we think about topical steroid stewardship, this is taking hold in atopic dermatitis and psoriasis where tapinarof and other advanced nonsteroidals are approved. Topical steroid stewardship is very important because what we have learned, whether it's topical or oral, corticosteroid use over time has consequences on the body. The whole reason advanced nonsteroidal therapies, again, especially in the topical realm, have been developed is to give us the clinicians and the patients more efficacious, safer, and more tolerable therapies. Topical steroid stewardship has already come into the guidelines in the psoriasis realm. And particularly what we saw from the International Psoriasis Council in the past year is a real definition of what topical failure means in psoriasis.
When you've treated a patient with a topical for two four-week consecutive blocks and they do not achieve clear or almost clear skin, then that is considered a topical failure or a recalcitrant patient that's eligible for systemic therapy. In my clinical practice, I like that framework for thinking about how I approach either the psoriasis or the atopic dermatitis patient that's using an aryl hydrocarbon receptor agonist or any other advanced topical nonsteroidal therapy. And that is, if you have a patient, psoriasis or atopic dermatitis that has had two four-week consecutive blocks of a topical corticosteroid, and they are not achieving clear, almost clear skin, you should choose something different. And what we have different in the topical space and what this consensus paper and what we as the authors of this paper tried to achieve was to explain how using these guidelines, how using this framework of thinking can inform our clinical decision to move on to a potentially more efficacious, safer, more tolerable therapy that's better for the patients.
And what's really neat about the aryl hydrocarbon receptor agonist class is that we have an atopic dermatitis approval down to two years of age. This is safe in the pediatric population. And in the psoriasis patients, it's approved for adults 18 and over. But what's really, really important about the safety and tolerability of aryl hydrocarbon receptor agonists like tapinarof is this: they can be used on any body site. That's really important when you have disease activity on the face or in the intertriginous regions like the groin or the armpits. They can be used on any body surface area. You're not limited to 10 or 20%. You can use it anywhere for as much as you need. And I think that is really important. And then the last point is you can use it as long as you need because you're not going to have some of those steroid atrophy effects that really limit and push us towards having the concept of topical steroid stewardship.
One area of education that we felt very important to add into this consensus paper was around the use of aryl hydrocarbon receptor agonists in phototherapy. In the case of phototherapy, tapinarof itself has been shown to potentially be a little bit unstable with UV exposure. And therefore what we have recommended is that you do not use tapinarof ahead of phototherapy, but you would use it after phototherapy because the use with phototherapy has not been explicitly studied, but some of the chemistry, preclinical chemistry suggests that it's probably not a good idea to use it during phototherapy. Ultimately, maybe more studies will come, but the point is that when you have the body site need, the body surface area need, or the longevity need, the point is that this pathway, the aryl hydrocarbon receptor pathway, is a great option and part of the bigger picture of topical steroid stewardship in dermatology.
