<p>The disruption of the epidermal barrier is central to atopic dermatitis (AD) pathogenesis, allowing water loss and the entry of irritants, allergens, and microbes and their proteases. Experts explore how genetic factors, inflammation, microbiome imbalance, and skin pH changes interact, and how repairing the epidermal barrier is key for the effective management of AD.</p>

The skin barrier is a fundamental part of AD pathogenesis. When the epidermal barrier is impaired, especially at the stratum corneum, water can escape, and irritants, allergens, and microbes and their proteases can get in, which can lead to a higher skin pH. This higher pH can create an atmosphere for bacteria to grow, and proteases then activate and start cutting holes in the outer skin layer.

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There are definitely a lot of different important players, like how there are many bricks in a wall. For example, the structural protein FLG is really important for specific molecules, lipids, and other proteins that are like the glue between the bricks. When you are missing FLG, it is more likely that your skin will dry up and water will leak out, which allows for the irritants to come in. I think that a lack of some of these fundamental skin barrier proteins may trigger this process.

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And then you have the triggering of alarmins in the inflammatory ecosystem, which, in turn, stimulates downstream immune cells, T cells, and specific cytokines such as IL-4, IL-13, and IL-31. IL-13, in particular, is a biomarker for itch, skin barrier integrity, and disease severity. We want to strengthen the skin barrier, and blocking key cytokines can allow for it to reheal. Many of the novel therapeutics that we have target these key cytokines.

I like the idea of there being connections between all the different parts. The microbiome is intimately related to skin barrier stability. We have seen this with chemicals such as diisocyanates, which are present in wildfire smoke and in industrial processes. They can poison the microbiome and damage the skin barrier, which will then start to fall apart. We also know that the acid mantle is so important. When the skin pH starts to rise and become neutral or even alkaline, we can see an exponential increase in Staphylococcus growth, and then things can start to fall apart. There are acidic and alkaline substances, as well as pathogens, touching our skin, and there are pollutants in the air, and you realize just how resilient the skin is.

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How do we strengthen, support, and maintain the skin barrier? Once it is broken, how do we fix it? We often have to address multiple pieces to put the skin barrier back together. If you just try to fix one thing and the other parts are not falling into place, then you have a domino effect where the skin barrier just keeps failing over and over again.

Like everything in AD, the skin barrier is complex, and I do not think that we have a profound appreciation of everything that goes on and of how easily we can knock something out to create this cascade effect. I am interested in studying the pathogenic variants in the FLG gene. We know that certain individuals have pathogenic variants in the FLG gene that may put them at risk for more severe, persistent disease, but that does not explain the entirety of the story for all patients with AD. Also, we have not extensively studied the FLG gene across populations with different ancestries. For example, in the Latino community, different ancestries are contributing to the genetic pool. We need to study that a little bit more.

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We do not typically test for genetic mutations in the clinic, as there is no common test that is easily available, and a lot of our patients with AD may not actually have pathogenic variants in the FLG gene. There might be other genes that are important, such as FLG2, which also codes for important structural proteins. The story is complicated, but emerging data are showing that maybe we should be paying more attention to these genetic risk factors. However, at this time, this cannot be easily translated into clinical practice.

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Bringing this topic back to the clinic, I tell patients that we want to treat their AD from the inside—and also from the outside. So, we will give systemic medication, but we should also talk about what we will do with respect to emollients, moisturizers, and lotions. I think that it is important to think about tackling it from both sides, whether you are in the camp that thinks this disease starts exclusively because of a skin barrier defect or the camp that sees it as more inflammatory in nature, involving dysregulation of the immune system. You have to focus on both aspects of the disease to treat it effectively.