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Evidence-Based Care in Atopic Dermatitis: Mapping IL-13 to the Clinical Manifestations of Moderate to Severe Disease
Released: June 23, 2025
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Well, I am going to begin with a broad description of the role of IL-13 and how it links to the clinical manifestations of atopic dermatitis that we see. Then I will be turning it over to my colleagues for the remaining sections. We are going to have a lot of discussion in between too.
When we think about the pathogenesis of atopic dermatitis, we have learned so much over the past 10, 15 years and really understand the role of barrier dysfunction and Th2 immune axis and the various players that drive the clinical features that we see at the level of the barrier and further downstream.
It turns out that IL-13 is being a key Th2 cytokine plays a central role in the pathogenesis of AD. In fact, it contributes to epidermal barrier dysfunction by downregulating important barrier proteins like filaggrin and loricrin. It is a key driver of the Th2 response. It actually contributes to pruritus, itch, by stimulating sensory neurons. There are actual receptors on sensory neurons for IL-13 receptors. So key driver of itch as well.
It also can reduce the expression of antimicrobial proteins, which in turn leads to microbial dysbiosis with the increased colonization with staph aureus. These are just some of the key ways that IL-13 is really central to the pathogenesis and clinical manifestations that we see in atopic dermatitis.
What are the consequences of these various factors? Well, we know that with the compromise and epidermal barrier function this leads to increased permeability of allergens, irritants, pathogens. These are the serious consequences of the compromised barrier, which then in turn would induce downstream immune responses that would manifest clinically as erythema and scaling and lichenification and oozing and crusting and etc..
Of course, on top of this, there is the effect of environmental triggers, which can exacerbate various aspects of atopic dermatitis from climatic factors, exposures to irritants, stress, exposures to allergens, etc..
We briefly mentioned about the importance of microbial dysbiosis with increased staph aureus. There is also risk of other infections beyond staph aureus colonization and secondary infection, viral infections including molluscum, particularly in children. We can see widespread molluscum contagiosum or eczema herpeticum when we see herpes simplex virus infections in the context of poorly controlled eczema and the compromised barrier.
So just some of the dysfunctions that are very clinically relevant to our patients who suffer from AD.
With that, this set the stage for targeted therapies that can specifically target IL-13 and other key cytokines in the immunopathogenesis of this disease. Today, we are really focusing on IL-13. Two of the available agents that specifically target IL-13 are tralokinumab and lebrikizumab, and we will be hearing more about those from my colleagues.
We also have dupilumab, which inhibits IL-4 and IL-13 signaling by binding to the IL-4 receptor alpha subunit and thereby blocking both IL-4 and IL-13 signaling.
As I mentioned, when it comes to the sensory neuron, they are actually receptors for IL-13. This contributes to the pruritus that we see.
With that background, let us take it to a typical case. The first case is a patient named Jane, who is a 34-year-old woman, who is complaining of worsening symptoms of her atopic dermatitis over the past year.
She reports persistent itching, redness, scaling despite adherence to her topical corticosteroids and emollients, which she has been using for a while. She has severe pruritus that disrupts her sleep, and she is growing increasingly frustrated that her current therapy worked initially in the short term, but she reports it only providing temporary relief at this time.
Past medical history, other than having moderate atopic dermatitis since childhood and now progressing to more severe disease. There are no other significant medical history there.
Physical exam. She has got widespread erythematous plaques, excoriations, lichenification as well as post-inflammatory hyperpigmentation.
She has richly pigmented skin, skin type probably a phototype six with the erythema is not just red. There is sort of a deep red brownish hue. In some areas even a violaceous to grey hue within this lesion. We see excoriations, we see lichenification, we see scale. It is involving the antecubital fossa, it is involving the forearm and the wrist and other areas. Some of the areas are particularly lichenified and raised, so clearly not well controlled at all. Then you couple that with the pigmentary changes, you can see why she is quite distressed.
Let us have a little discussion about how does IL-13 contribute to a patient like Jane? How does it contribute to the barrier dysfunction? What about her description of her symptoms worsening despite having an initial response to therapy or topical corticosteroids and emollients that she was using? What is the potential mechanism here?
I would like to invite my colleagues, doctors Butler and Kwatra, to chime in as well.
Let me start with Dr. Butler with that first question. What do you think here is the contribution of IL-13 to barrier dysfunction in atopic dermatitis in general.
Dr. Daniel Butler (University of Arizona College of Medicine): Thanks, Dr. Alexis, and tour de force so far on IL-13. I think we are all putting together some of the pathophysiology of AD that we know simplistically with the barrier disruption. There is immune overactivation. There is a propensity for over-colonization of certain microbial species.
But when it comes to the barrier dysfunction, we definitely know that there is an impact on the keratinocytes from IL-13. That disruption is ultimately a huge part of the breakdown in this patient's presentation. I like to simplistically think of it as just there is a direct barrier disruption there.
IL-13, how it contributes to that is that it really impacts the specific keratinocyte. I think that is the thing that I want to get across to all the learners here today.
Dr. Alexis: Yeah. Thank you for that. That is a really good point to emphasize. How about when you think about this patient's description of, well, I was doing well initially with the topical corticosteroids, but they do not seem to work anymore, or certainly not as well as they used to. It feels like I am only treating the symptoms partially, but I am not getting the type of control that I am looking for. What do you think is going on here?
Dr. Butler: Yeah. First of all, I just commiserate with everyone in the audience here and certainly the patient, which is like, we have heard this story before, right? Everything is getting worse. I was better for a period of time, but overall, I just keep having these blips of really bad symptoms.
I think that thinking of atopic dermatitis, not just as a sort of one trick pony, meaning like there is just one error that needs to be fixed. That is why I like the discussion here of talking about both the barrier disruption and some of the immune dysregulation, because I think when you are just using topicals, you are probably only solving one of those parts of the equation. You are probably only hydrating the skin, or only getting rid of a modicum of the inflammation that is going on.
But I think we really need to think about AD almost as a Venn diagram that there is disruption of the barrier that ultimately leads to some microbial species growth, which ultimately leads to some immune overactivation. I should not be leading in saying that one goes to the other because we are not really sure what comes first, the chicken or the egg.
In this situation, I do think that it is a product of just having one more mild treatment, like a topical steroid. You are only going to cover one or partially a couple of the Venn diagram parts. You really need more targeted control to be able to get more significant disease control overall.
Dr. Alexis: Yeah. Well said. So when you are with a patient like Jane, how do you consider? Is this a scenario where you might consider moving away from just topical therapy alone to systemic therapy?
Dr. Butler: Yeah, 100%. I think that with the availability of all these new medications out there, this discussion has perhaps gotten a little bit more complex. But I personally enjoy it a lot more because I know that I have more in my hand. I think this is a product of shared decision making, not forcing somebody to go to a biologic or a more advanced medication. But as you are explaining the disease, it used to really be topical immune suppression and then more significant oral immune suppression.
Now with these newer agents, we are able to really attack that Venn diagram of contributors of disease with these biologics. And so it is a pleasure to be able to prescribe some of these medications that we know are going to hit on several of those contributing etiologies, barrier inflammation, staph overgrowth, and to do it in a safe way. In this patient's case, I think that is a no-brainer.