Transcript
Naiem T. Issa, ...:Hello, my name is Dr. Naiem Issa. I'm a board certified dermatologist out of Northern Virginia. I'm also a professor of dermatology at the George Washington University School of Medicine in Washington, DC, as well as professor of dermatology at the University of Miami, Leonard Miller School of Medicine in Miami, Florida.
So the reason behind why barrier restoration is important for atopic dermatitis is many fold. First of all, when you have a poor barrier, it's akin to having a poor brick and mortar of your house. And so if the brick and mortar is not able to protect your house, you're going to have debris, or in this case infections and allergens come into your home, which is your skin, and that could be passed on into more inflammation. So you get the feedback loop or positive feedback loop, we should say. And in addition, that can also cause inflammatory spillage within the body as well, causing more positive feedback in terms of inflammation. So the barrier is very important, and that will also help to reduce the amount of fluid or water that is lost through the barrier as well. So atopic dermatitis, these patients are having barrier dysfunction, and so they're going to be losing hydration while also having portal ways for infection as well as allergens.
So the rationale behind using topical and/or oral steroids for that matter in atopic dermatitis has been quite interesting based on history. Before the current landscape of therapeutic options, we only had topical steroids, for example. So we were limited to using them as an anti-inflammatory to help with acute flares as well as for maintenance of flares and maintenance of that skin barrier. Now, of course, the most common problem is skin thinning or skin atrophy as well as telangiectasias and pigmentary change. And so we are limited to the amount that we could use, and that's why the current guidance for two weeks on usage or two weeks off comes from, specifically with that turnover of something called glycosaminoglycans, which takes about two weeks for that turnover to actually happen.
And so with that thought, as we have more options for non-steroidals, we have moved through this concept of steroid stewardship where for acute flares, it may be appropriate to use for that initial acute flare, a topical corticosteroid, but then to quickly move to a non-steroidal option for avoiding the adverse events that come with topical steroids. And I think that's where a lot of my clinician colleagues as well as the field at large are moving towards.
Aryl hydrocarbon receptor is a very unique molecular target when it comes to inflammatory dermatosis at large, and especially for atopic dermatitis. The thing to understand about aryl hydrocarbon receptor is that this is a very well-conserved protein throughout eukaryotic organisms and mammals such as you and me and other organisms in this space. The idea behind AHR or aryl hydrocarbon receptor is that it is a sensor molecule.
The idea here is that it is a large protein, kind of like what you see in the screen here with my hands, and it has a large binding pocket in the center. And what happens is that it will sense different molecules from the environment, such as pollutants or things that are exogenous that come into the body, as well as antibiotics or xenobiotics, as well as molecules that are produced from within such as tryptophan and molecular entities that are created by your microbiome. And the idea with AHR is that it will sense these different molecules and push you down different pathways depending on the cellular context or what cell you're in. So if you are going to give a danger signal, let's say to pollution, when pollution binds to AHR, it will go down a pro-inflammatory pathway and say red alert. This is pro-inflammatory. We need to have a response to maintain homeostasis to meet it in kind. And then let's say you're looking at tryptophan. This could lead to an anti-inflammatory response depending on the immune cell in which that is picking that up.
So AHR is ubiquitous. It is found in all the cell types, and it is acting as a massive sensor to really hone in on that homeostasis for inflammation. But in addition, AHR also helps to regulate your skin barrier, which is very important. So when AHR is activated in keratinocytes in that top layer of your epidermis, you can have that building of the brick and mortar again. But sometimes if it does that too well, when you have too much of that activation, that will lead to having a very strong brick and mortar. And sometimes you have more of that cement where you have those protein glues and you can get some bumps because of that.
In addition to inflammation, homeostasis, as well as the skin barrier, you have the antioxidant effect. And here you have with pollution and your genetics and so on, such as cellular activities, you have the development of pro-oxidation species, or reactive oxygen species, and what happens is that that can go and cause further inflammation. So AHR helps to regulate that balance of antioxidants and pro-oxidant species so that you can maintain that homeostasis as well. So in sum, aryl hydrocarbon receptor does a lot of jobs in many different cell types in our body. And most of all, it is helping to regulate that homeostasis.
In addition to the inflammatory sensing, if you will, when it comes to atopic dermatitis as well as psoriasis, the key cytokine players that come in with aryl hydrocarbon receptor, which is going to be downstream, include interleukin-17, which is in the psoriasis space, as well as interleukin-4, interleukin-13 and interleukin-31 when it comes to atopic dermatitis. So again, the concept here with AHR is that this molecule is regulating multiple type 1, type 2, and type 17 inflammatory patterns downstream from that biosensing portion.
