Hitting the Target in Atopic Dermatitis: Interdisciplinary Team Training for Leveraging IL-13 Inhibitors to Address the Burden of Disease

Dr Anne Marie Singh (University of Wisconsin School of Medicine): So why are we talking about this? Why is this subject important? What do patients feel and want when they are thinking about their moderate to severe atopic dermatitis?

[00:07:43]

Which of the following have impacted your ability to receive care for your atopic dermatitis? (n = 42)

The first set of slides, we are going to talk about some of the answers to some of these questions.

When we ask patients, "What has impacted your ability to receive the care that you want for your AD?" The main barriers were related to access, and that could be access to healthcare professionals who they felt understood their disease, which was the number 1 answer. Access to culturally understanding professionals, but then access in general, such as, are they able to get the care that they need, or are they inhibited by some barriers, including missing work, insurance coverage, transportation, and then, of course, cost? If it is not something that you can afford, then it is hard to access the medication. In general, patients have a lot of concerns. You can see across the board, affecting about a quarter to a third of patients receiving the care that they wish they were getting for their AD.

[00:08:40]

How important are each of the following factors when making decisions about your skin treatment? (n = 89)

When we ask patients, how important are each of the following treatment factors when making your decisions? You can see most patients are looking for something that is effective. 72% of the time they are willing to try something and to buy in if it is going to be effective. Then, of course, they want to hear about risk-benefit ratio, so they want it to be effective, but they also want to minimize side effects and control their disease. Reduce relapse.

[00:09:11]

How well do you understand the possible side effects of advanced treatments (like injectable medications) for atopic dermatitis? (n = 14)

Now when we start thinking about more advanced therapies beyond our topicals, how well do patients understand the side effects of advanced treatments like injectable medications? Most patients actually do not have a really good understanding. They report limited understanding of the side effects, with over half saying not at all or not very well. It means patients do not really know what their options are and what the side effects may be to make an informed decision.

[00:09:43]

How thoroughly has your HCP educated you about recognizing side effects from your AD treatments? (n = 15)

One of the questions is, why is that? Why do not patients feel like they know everything? I think part of it is they feel that perhaps their healthcare professional did not educate them as well as they would have liked. Most patients, 33% felt that they did not receive a very thorough education about recognizing treatment-related side effects. 26% of patients reported they received any information. That means only 26% reported they received any education, which means that 74% of the time patients are reporting they did not receive any education. It is hard to think about taking that next step to a biologic. The patients want something that is effective. They want something that is going to work for them, but it is hard for them to do that when they do not feel their provider understands it very well or explained it to them. Actually, it is probably a better interpretation.

[00:10:37]

Smart Patients Survey Summary

If we look at how the patients replied in these open-ended questions. If we start in the upper left, something that was uniform is that patients with moderate to severe AD have complex treatment journeys, ups and downs. We all know this. Roller coasters, valleys, and they have cycled through a lot of treatments, including topical steroids, sometimes systemic immunosuppressants and biologics. Here you can see some quotes there. That someone was put on methotrexate, and they were very happy, but they were so afraid of it because they did not understand it or what it was.

Then, with someone else on Dupi, thought within a few days their eczema started to recede significantly and were very happy.

Addressing access, insurance and cost barriers. Insurance restrictions and cost barriers were very common. Patients reporting that it took forever to get something approved, or they got an approval, but it was short, and then they lost it. Then, also having trouble finding the information that they needed to advocate for what they wanted and turning to the Internet or other sources. Then we all know about the hoops that, as providers, we have to jump through of step therapy, where you have to try something and it may get denied, or you have to fail something before you could try maybe a better or more appropriate medication.

Obviously, safety concerns were reported, and patients reported both expected and unexpected adverse events. Here you can see some of those quotes listed on this slide. Someone saying that they got the drug, but then they did not know how to use it, or they did not know how to inject themselves, or they did not understand some side effects such as stinging or burning with some of the topicals.

Then finally, when we talk about patient-healthcare provider communication, patients with moderate to severe AD, their experiences really varied depending on the relationship they had with their provider, and some felt things were amazing, that honesty and openness increased my confidence in my healthcare provider. Where others felt like maybe my provider did not listen or did not understand what I was saying. I got blank stares, or I felt dismissed, or the doc had not really talked to me about my treatments and why they work. If patients do not feel that confidence or they do not understand why they are doing something, it can be hard for them to get buy-in and to try something new or to make that step to a biologic.

[00:13:14]

Foundational Concepts: The Pleiotropic Role of IL-13 in Atopic Dermatitis  

To address some of these concerns that patients may have, let us talk about the pleiotropic role of IL-13 in atopic dermatitis, or understand what the IL-13 is doing so that when we target IL-13, we know why it might be working.

[00:13:31]

Overview of AD Immunopathogenesis

When we think about what causes atopic dermatitis, or I should say, what is happening pathophysiologically, we all know, especially in a dermatology clinic like this, that AD is a chronic inflammatory skin disorder, and it is driven by immune dysregulation as well as barrier dysfunction. Often those 2 things go together. That barrier dysfunction can drive immune dysregulation and vice versa. Immune dysregulation can then drive barrier defects. We know IL-13 is a key Th2 cytokine that is central in the role of AD pathogenesis, particularly in acute AD. We know IL-13 contributes to that epidermal barrier dysfunction.

How it does that is it downregulates our filaggrin and other structural proteins so that we lose that tight, great epithelial barrier at the skin. That epidermal barrier dysfunction, I always tell my patients that it is almost like having an umbrella with holes in it. When you have a barrier that is supposed to protect you, but it is not working properly, then that allows our irritants and allergens and things to cross through that barrier, get into the lower layers of the skin to promote inflammation.

Once that inflammation is started, then we get the expression of our Th2 cytokines and chemokines that then lead to inflammatory cell recruitment. Then, obviously, also IL-13 can act directly onto the sensory neurons to promote itch. That is some of our neurogenic itch. That is what is happening in the skin on an immunologic level, as illustrated in this figure, but we know that in patients who have more severe disease, they will have elevated levels of IL-13 in their blood. Then targeting IL-13 with biologics has been shown to be efficacious in improving their symptoms of AD.

[00:15:34]

Epidermal Barrier Dysfunction and Environmental Triggers

If we dive in a little bit more into this epidermal barrier dysfunction and environmental triggers, it is just as I mentioned, is once you have that defective barrier that allows irritants and allergens to cross through that barrier more easily, making the skin more sensitive, more itchy, and more likely to have disease. Again, this could be things like increased temperature, humidity, irritants, scents. We all know these: detergents, soaps, incorrect soaps, and things like that, stress and allergens. When we think about what are the key factors that contribute to this dysfunction that allows these things to trigger, it would be filaggrin mutations. We know when we have reduced filaggrin expression that disrupts our integrity and impairs hydration of the skin.

Lipid abnormalities, including decreased ceramide, will also weaken the skin barrier. Then, once we have upregulation of our Th2 cytokines, including IL-4 and IL-13, that suppresses repair of the skin barrier as well as barrier protein synthesis. It promotes more inflammation again, cycling through making everything worse. Then, as we all know, microbial dysbiosis, or alterations to the microbiome of the skin, including Staph. aureus colonization and an increase in Staph. aureus and lesions to worsen inflammation and barrier dysfunction.

[00:17:00]

Epidermal Thickening and Abnormal Keratinocyte Proliferation

When we think about what is happening at the skin, and again, this is probably review for everybody in this audience. When we look at normal skin, we have a really beautiful, epidermal-dermal junction here. Nice and clean with a homogeneous thickness of the stratum corneum. You can see nice and pink in the lower layers, no inflammatory infiltrate. However, when we get to an acute lesion in atopic dermatitis, we see the spongiosis and then all this purple infiltrating in where we get infiltration of T-cells and macrophages, as well as spongiosis.

Then if we think about dyshidrotic eczema or dyshidrosis, when we think about it on our hands and maybe our feet, we get the thickened stratum corneum here at the top with spongiosis, and then the vesicles in our blue circles. Then again, more acute AD and the upper right here, showing the spongiosis here in these circles, as well as the infiltration of inflammatory cells, getting recruited to the inflammation, and then finally progressing to chronic lesions with hyperkeratosis, thickening of the stratum corneum and then again, still that inflammatory infiltrate and fibrosis.

[00:18:24]

Components of Pathophysiology of AD

When we think about the components of the pathophysiology here, we can see a lot of molecules have been implicated. When we think about the pathophysiology, including our aryl hydrocarbon receptor, which has been shown to strengthen skin barrier genes. We have talked about IL-13 as well as IL-4, which are key Th2 pro-inflammatory cytokines that are promoting that inflammation and recruitment of those inflammatory cells. Then, once the epithelial barrier gets activated at the epithelium, we get the release of epithelial cytokines IL-25, IL-33, and TSLP, which are sometimes called alarmins, that are activated when we get destruction at the epithelial barrier.

IL-31 is involved in itch, as we all know, in suppression of filaggrin expression. A lot of these cytokines will then signal through the JAK-STAT pathway. That is where we have our JAK inhibitors to inhibit the signaling through the JAK-STAT pathway and then newer molecules in clinical trials that target OX40-OX40 ligand, which triggers that T lymphocyte response and our memory response of allergens and antigens. Then finally S1P, which is a signaling molecule that inhibits proliferation and induces differentiation. These are all different components. When we think about the pathophysiology of AD, all that have some molecules in development or FDA-approved to target for AD.

[00:19:58]

Neuroimmune Mechanisms of Itch

Now as we know, we now talk a lot about the neuroinflammation in AD or the neurogenic itch. What we know when we think about neurogenic itch is that there are several cytokines, including IL-31, IL-13, and IL-4, that will bind directly to the sensory neurons and then signal through the JAK pathway, including JAK1 to cause some itch. We know IL-31 is important in acute itch. IL-13 in chronic itch. Then histamine also is more common in acute itch, and then IL-31 also in chronic. Just showing that not only is this inflammatory infiltrate causing inflammation and inhibition of filaggrin expression in the skin barrier, but we can also get itch directly through the direct signaling through the neurogenic pathways.

[00:21:00]

Adaptive Immunity

When we think about the role of adaptive immunity, again, here is our epithelial barrier, or our cartoon of the skin. We get either scratching micro fissures or other things, and we get our allergens and irritants that can cross through here and then activate our immune response here in this drawing here. Then once we get activation of our immune response, including activation of our Th2 arm, of our immune system, which then leads to our increase, IL-4, -5, and -13, and acute lesions.

Then in some patients, particularly non-White patients, maybe some of our Asian or Hispanic participants, we may see some increase in IL-17, and IL-22, and IL-23, and then chronic lesions, we see some Th1. Then that leads to our inflammation. In addition, some of these cytokines can then react directly with the sensory neurons to promote itch. Here you can see that inflammatory cascade, and here are all the molecules that are either FDA-approved or under development to try to target all along these signaling pathways.

Including ours that target IL-13 alone, which would be Tralo and Lebri. Then those that target the IL-4 receptor, which will inhibit IL-4, and IL-13, which would be Dupi. Then some of the others, as you can see, targeting IL-17, IL-23, and OX40-OX40 ligand, molecules that inhibit that. Here we are with a nice overview slide of where we are in 2025 when we think about targeting the adaptive immune response.

[00:22:50]

Th2-Mediated Inflammation

When we think about this Th2-mediated inflammation, the thing about once this inflammatory cascade starts, once you start this inflammatory cascade, it is not as if the IL-4 or the IL-13 or IL-5 just stays in the skin and we only get skin. Once we get activation of these Th2 responses either through, barrier dysfunction, or more likely, allergens that are able to now cross through this defective barrier and cause differentiation of our dendritic cells to an inflammatory phenotype to then promote our naive T-cells to differentiate to Th2 T-cells.

Once we have the -4 or -5 and -13 that are released, then they can go and do their effector functions. This could be again increasing our IgE, increasing our total IgE, our specific IgE to increase our eosinophils. Then also these Th2 cytokines have been shown to inhibit. We all know this already. Our antimicrobial peptides. That increases the risk of skin infection in these patients. Then once you have these cytokines, now they are in the bloodstream, and they can leave the skin and then migrate to other mucosal surfaces. This leads to when we start thinking about the atopic march, or the development of food allergy asthma and allergic rhinitis in these patients.

[00:24:22]

Promoting Itch-Scratch Cycle

In addition, once you have this inflammation that is going on, that will go ahead and promote that itch-scratch cycle. Once you start to get some inflammation, the skin becomes more sensitive to these irritants and allergens. Then that makes the patient more itchy, so then they start scratching, and then that causes more inflammation. We get this continuation of the itch scratch cycle. Then these cytokines will react, as I mentioned, directly on the sensory neurons at the C fibers to start signaling through the neuron, through the dorsal root ganglion, and trigger that itch sensation, that neurogenic itch.

[00:25:05]

Neuroimmune Interactions in AD Chronic Itch

This happens acute as well as chronic, and so I just talked about this already where we get skewing of the immune response, especially in our acute lesions to the Th2 phenotype with release of IL-4 and -13, which can then react directly on the neuron to cause itch. In addition, that epithelial dysfunction will cause the keratinocytes to release TSLP, which can then also activate other receptors, including our TSLP receptor, to promote itch as well as TRP channels and direct calcium influx.

[00:25:45]

Case 1: Dan, AI Simulation Patient Video

Now that we have gone over what is happening with the immune system, when we start thinking about this itch, we are going to go through these simulations. I know there are some questions that were put in the chat. I am not ignoring those. We are going to cover those at the end of the talk.

Dan: Hi, I am Dan. I have had eczema since I was a kid. Back then it would come and go. Some lotion, a mild steroid cream, and I would move on. As I got older, it stopped fading between flares. Now it is everyday thick moisturizer, morning and night, and strong steroid creams just to get through the week. The past 2 years have been the worst. Constant itch, scaling, and recurrent flares that do not fully calm down. Nights are the hardest. I am awake scratching when I should be sleeping. It is hitting my work. I am tired, distracted, slower than I used to be. Simple things take more energy when your skin will not give you a break and it messes with social life.

I think about what people can see if I start itching in public. Sometimes I just say no to plans. Me and my primary care clinician were hesitant to use high-potency topical therapies, and I was referred to a dermatologist. I even tried phototherapy weeks of appointments, and nothing really changed. I am doing everything: daily emollients, high-potency topicals, and I am still stuck in this cycle. I want itch relief that lasts, real sleep, and skin that does not control my day. My doctors never explained to me why and what triggers my itch. I am ready to talk about what is next. Something that actually quiets this for the long run.

[00:27:35]

Discussion

Dr Singh: Let us see. I know this is an AI-generated patient, so a little bit artificial, but I think we have all seen patients that are like this, especially in a subspecialty practice. The points of discussion here are, are there any thoughts about this patient? Do we think Dan's experience is common? How should we counsel and educate patients regarding the underlying drivers of their itch? What are some targeted therapies that can directly address these factors? If anyone wants to put any comments in the chat, go ahead and do so. Otherwise, I will just say that this is certainly common. These patients get on the tilt-a-whirl or the roller coaster of using medications, getting things under control, and then they seem okay for a while, and then it comes right back, and this up-and-down cycle.

Then the frustration, once they have this bad disease, it starts to affect so many different aspects of their life, including activities, I think was mentioned in that patient. Sleep was mentioned in that patient. Again, all very common. I see 1 comment in the chat about that. This is common.

With that, I think we can move on. I will mention I am on the guidelines committee, The Atopic Dermatitis Guidelines Committee for the AAD. We recently published a manuscript about these nonallergic and allergic comorbidities with AD, and that is sleep, anxiety, depression. All of that is on there and more common in patients with AD.

[00:29:24]

Practical Evidence in IL-13 Inhibition for Moderate to Severe Atopic Dermatitis

What is the evidence that IL-13 inhibition for moderate to severe atopic dermatitis, actually works?

[00:29:31]

Poll 3: What do you perceive as the primary challenge in managing moderate to severe AD?

This leads to our next polling question, which is: What do you perceive as a primary challenge in managing moderate to severe AD?

A. Diagnosing the disease and how severe it is;

B. Getting patients to adhere to the treatment that you have recommended;

C. Access to advanced therapies; or

D. Understanding the current treatment guidelines.

Speaker: Polling is open. Please vote. We will allow a few more seconds for incoming replies. We will go ahead and close that poll.

Dr Singh: I am pretty evenly distributed across the line, just illustrating that there are a lot of challenges and barriers. To really get at this, we really need to address all of these things. Thank you for sharing your experience.

[00:30:30]

Biologic Targets

What are our choices, or what do we have that is approved? Here, we have our FDA-approved therapies for atopic dermatitis, including our biologics at the top, which are our injectables, and then our small molecules at the bottom, which are our JAK inhibitors here. As we mentioned, dupilumab will target the IL-4 receptor, so this is the IL-4 receptor, this purple part of the antibody or the signaling here. When you inhibit the IL-4 receptor, we inhibit signaling for IL-4 and IL-13. We also have our IL-13 selective antagonists, including lebrikizumab and tralokinumab. Both IL-13, there are some differences in the molecules for these drugs. The lebrikizumab is, I think, a little bit better of a molecule.

In terms of the pharmacokinetics and dynamics with regard to how well it binds and how strongly it binds, and then Nemo, which is our IL-31 receptor. Then again, our JAK inhibitors are selective JAK1 inhibitors, including abrocitinib and upadacitinib. These would be our oral JAK inhibitors. Again, the JAK inhibitors are much less selective. With that, you may see inhibition across multiple cytokines, but then that also leads to more immune suppression that are targeted biologics.

[00:32:04]

FDA-Approved Biologic Agents

Let us see. Here are FDA-approved biologic therapies all together in 1 table. Again, Dupi, Tralo, Lebri, and Nemo across the top. Then we just went through their mechanisms on the last slide. As far as the 3 on the right, are 12 and above, where Dupi has been approved down to age 6 months. Here you can see the timing of injection. Again, ranging from every 2 weeks to every 4 or 8 weeks, depending on the drug as well as the dosing in our pediatric and adult patients. Each 1 of these has their own warnings or side effects. Of course, if we are going to inhibit Th2 cytokines, we need to think about parasitic infections. The conjunctivitis side effect, which we are going to talk about in a little bit more. Then some of these, not just Nemo, has an indication to avoid live viral vaccines.

[00:33:13]

LIBERTY AD CHRONOS: Dupilumab Efficacy in Adults

What is the data for the efficacy and then the safety of these drugs?

Dr Singh: If we start first by reviewing the LIBERTY AD CHRONOS trial, which looked at the efficacy of Dupi in adults. These were adult participants with moderate to severe AD, and all of these patients could also use topical corticosteroids and or calcineurin inhibitors with the Dupi. They were randomized to 300 mg SC either every week or every other week vs placebo for a year. Here you can see that the Dupi it worked. It worked nicely. If we look at the percent of patients who got an IGA of zero or 1, which would be a skin that is clear or almost clear, you can see both every 2 weeks and every week for the Dupi at week 16 and sustained efficacy down out to week 52, with about 40% of patients achieving this IGA score. If we look at a 75% improvement in the EASI or the EASI-75, again, we see efficacy at 16 weeks in the 60%, maybe up to 70% range and sustained efficacy out to week 52. Again, here is our data for efficacy of Dupi in adults. Again, remember these numbers. 40% with our IGA of clear or almost clear in between 60% to 70% achieving the EASI-75.

[00:34:46]

LIBERTY AD OLE: Safety of Dupilumab in Adults for Up to 4 Yr

That was the efficacy. What about the safety? This is now the LIBERTY AD open label extension. SOLE stands for open label extension, which looks at the safety of Dupi up to 4 years. Again, overall, these molecules are quite safe. Low rates of serious or severe infection, and in fact, infection decreases, while they are on the GP. I think this is just because they have better skin control, as well as lower rates of non-herpetic skin infections. Then here are some of the skin infections of interest, including eczema herpeticum, herpes, and zoster. Again, similar across the groups comparing placebo and Dupi and then across the open label extension.

[00:35:42]

Dupilumab Efficacy by Racial Subgroup: Wk 16

If we next look at the efficacy of Dupi across different race and ethnicities. Here is some data that separates out our White patients from Asian and Black patients. Here you can see, first of all, there is some efficacy across all race and ethnic groups across LIBERTY AD, SOLO 1, SOLO 2, and CHRONOS. Maybe these are overlapping confidence intervals, maybe a little less efficacious in our Black participants, but again, overlapping confidence intervals. Again, you can see there is some variability in response and the tightest is favoring Dupi as among our White participants. There can certainly be some variability of responses in our patients of color..

[00:36:36]

Dupilumab Safety by Racial Subgroup: Wk 16

If we look at adverse events now across our different subgroups, again, it is pretty similar across. The top is our treatment-emergent adverse events. Then the second row is our severe treatment-emergent adverse events, and then the third row is adverse events making somebody stop the drug. Again, most participants continued with the drug throughout the study. Again, these are not clinically significant across the groups. You can see conjunctivitis is common. Maybe a little bit more common in our Asian and White participants compared to our Black participants, but again, pretty similar across the groups.

[00:37:19]

Heads Up: Upadacitinib vs Dupilumab for Moderate to Severe AD

Moving on from Dupi, what about our JAK inhibitors? This is comparing upadacitinib vs dupilumab for moderate to severe AD head to head. This is a heads-up trial, which is 24-week head-to-head comparator that enrolled 673 patients. Again, the primary endpoints being EASI-75 and itch relief in IGA. Basically, you can see patients on upadacitinib had a statistically significantly better response when looking at EASI-75, as well as faster itch relief at 1 week with the Upa, the upadacitinib vs Dupi, as well as clear skin at week 16 and the upadacitinib vs Dupi safety.

However, as we talked about, the JAK inhibitors are a little bit less selective, and maybe you can have a little bit more immune suppression. There were some increased infections with the upadacitinib group compared to Dupi, including herpes zoster and eczema herpeticum. Then on the Dupi side, there was increased conjunctivitis, as we all know is a side effect of Dupi. Then obviously injection site reactions would only happen with Dupi. Upa is oral. In conclusion, upadacitinib offers superior and faster skin clearance but a higher infection risk.

When we start thinking about which 1 of these medications we should choose, this becomes shared decision-making where we need to talk about patients' preferences as well as risk factors with regards to some of the side effects and the balance of efficacy vs safety. I also want to mention what is not on the slide, is we all know about the MACE, the major adverse cardiac events, has a warning on our JAK inhibitors. Again, this is borrowed from the experience in the rheumatoid arthritis literature. It is certainly there, and needs to be discussed, and especially, our adult patients, when considering these drugs.

[00:39:28]

Network Meta-analysis: Dupilumab vs Tralokinumab Topical Corticosteroids for Severe AD

Now what about head to head Dupi vs Tralo with topical steroids for severe AD. Again, this is 575 adults with severe AD and inadequate response to topical corticosteroids. Here, Dupi plus topical corticosteroids showed greater efficacy vs Tralo with the topical steroids at 16 weeks, and that includes improvement in the EASI 75 itch scores. That is the NRS, the PPE. This patient-perceived numerical rating scale for itch. That is the blue. Then our dermatology quality-of-life, in the green. Basically, Dupi plus topical steroids demonstrated greater odds of achieving these key endpoints compared to Tralo. Better skin clearance, more itch reduction, and quality of life.

[00:40:28]

ECZTRA 1 and 2: IGA 0 or 1 Response Rates at Wk 16

What is the evidence for Tralo? This is the ECZTRA 1 and 2 trials. Again, showing the percent of participants who achieve that skin that is clear or almost clear or the IGA of zero or 1 at week 16. Here you can see there is a significant improvement in those who received Tralo, but again lower than our Dupi participants. Here you can see between 15% and 24%. There is certainly an improvement compared to placebo, and the patients who were able to achieve clear or almost clear skin, but this is lower than for Dupi. If you remember, that was around 40. Here we are closer to 20-25 patients use of the rescue topical steroids though with the Tralo. There was some improvement, less need for rescue, but a lower percent of patients were able to achieve that clear or almost clear skin.

[00:41:26]

ECZTRA 1 and 2: Additional Endpoints and AEs

Patients with Tralo also had improvement in their itch, with a 4-point improvement in their itch numerical rating scale. And the patients who did respond to Tralo, though, had a sustained response. They continued to work to eat to 52 weeks, and adverse events were comparable. Again, showing that there is efficacy with Tralo.

[00:41:54]

Tralokinumab Efficacy by Racial Subgroup: Wk 56

What if we look at efficacy now across racial subgroups? Again, you can see it is pretty equal throughout. Around 70-80% are able to achieve skin that is clear or almost clear. I am sorry, 70%, 80% were able to achieve a 75% of improvement in their EASI-75. Fewer were able to get EASI-90 lowest in our Asian participants, and then again, our skin that is almost clear, is here in the middle of the slide, between 37-69%, maybe more efficacious for our Black participants compared to Asian.

[00:42:40]

Tralokinumab Safety by Racial Subgroup: Wk 56

Here are adverse events across our different patient populations. Again, pretty similar across the groups and very few patients, needed to stop the drug due to withdrawal.

[00:42:58]

ADvocate1 and ADvocate2: Lebrikizumab Efficacy at 52 Wk

Now let us move on to Lebrikizumab. These are the ADvocate1 and ADvocate2 trials looking at lebrikizumab efficacy at 52 weeks, and here we see fantastic or very good efficacy. Not the 40% that we saw with Dupi and certainly not the 15% to 20% we saw with Tralo. Instead, we are seeing 70-80%, so when we look at our IGA skin, that is clear or almost clear, we are up into the 70s now, 71.2% or 76.9% depending here, at the top, whether it was ADvocate1 or ADvocate2.

Then at the lower half of the slide, we are seeing close to 80 or into the 80s for our EASI-75 response. Again, also, we are seeing an improvement in itch here with that 4-point improvement. Again, showing efficacy with Lebri. Although both Tralo and Lebri are both IL-13 inhibitors, I think this is evidence that the molecule matters. Which one that you are using does matter. I think that has to do with how well it binds and the affinity for the molecule for the receptor.

[00:44:16]

Lebrikizumab Safety Considerations

What about safety considerations with lebrikizumab? Here you can see rates pretty similar to the previous studies we looked at, but also, if we look at our serious adverse events, they are low maybe in the first trial. It looks like it is only 6 participants, but maybe a little higher in Lebri, but then you can see the percentages are flip flopped when you get to ADvocate2. Again, pretty similar across the groups. AD exacerbation is listed as an adverse event. Conjunctivitis, again a common one. Nasopharyngitis and headaches. If we look at infection and herpes infection, you can see the rates at the bottom of the slide as well. Pretty similar comparing placebo vs Lebri.

[00:45:11]

ADmirable: Lebrikizumab Efficacy at Wk 16 for Moderate to Severe AD in People with Skin of Color

What about in patients with skin of color? This is an ADmirable study that looked at the efficacy of Lebri at 16 weeks in people with skin of color. Again, demonstrating efficacy in the percent of patients that achieve an EASI-75 or an improvement in their EASI-90. Here you can see 69% will achieve an EASI-75 or 45% achieve EASI-90, and 45% of our patients with skin of color get to our skin that is clear or almost clear.

[00:45:49]

ADmirable: Key Secondary Endpoints at Wk 16

As far as our other endpoints, these are listed here, including improvement in itch. 70% will get an improvement in their quality of life. Again, a 3-point improvement in itch then goes from 60s to mid-60s, and then certainly an improvement in their quality of life score.

[00:46:07]

ADmirable: Hypo/Hyperpigmentation at Wk 16

When we think about our patients of color, I think changes in pigment becomes very particularly important in patients with more pigmented skin tones. If you look at this specifically, 33% saw improvement in lesions that were hyperpigmented, in which 17% of these lesions improved to normal skin tone and 63% saw improvement with hyperpigmentation, Up to 20% achieving back to normal skin tone. I think this is, very important, or can be very important, particularly in our patients of color. And so here you can see a picture of a patient, that you can see this improvement to a normal skin tone.

[00:46:52]

ADmirable: Safety

I changed the slide, but I also want to mention, and I think this may come up later, but just as a reminder that hopefully everybody in this room knows this. Atopic dermatitis can look different in patients with skin of color. We know there are health disparities, where the severity is often underappreciated or the skin is more severe before they get offered treatments or more advanced therapies. This can be because the erythema or the redness that we see in all of our textbooks and all of our slides, is much harder to appreciate in patients with skin of color. It may have more of that gray violaceous appearance or that papular follicular pattern, which may differ from our White patients.

[00:47:36]

Clinical Profile of IL-13 Inhibitors

Sorry. If we go back here and look at safety again in our patients of color in our ADmirable study. You can see again, very safe. Most of the side effects are mild, maybe moderate, few severe, and just a low rate. Just about 4% had treatment-emergent adverse events.

[00:48:01]

Clinical Profile of IL-13 Inhibitors

Here is our clinical profile of our IL-13 inhibitors again comparing across. Again, Dupi blocks are IL-4 receptor, and then IL-13 molecules, which are Tralo and Lebri. I think the difference here is that lebrikizumab will also block across the IL-4 receptor complex. It has a higher affinity and a slow disassociation rate. I alluded to that before that it binds tightly and then stays bound longer. All of these have been shown to improve AD severity and quality of life. I think what Lebri has going forward is it can have a sustained AD symptom and severity reduction.

Because of the high affinity, some of these you can inject less frequently. I think there is some data to think about lengthening the intervals for some of these drugs, particularly with the lebrikizumab. There is efficacy across all body sites and regions, including, face, hands, in the body, and then the adverse events are pretty similar across the board.

[00:49:13]

Case 2: Amy, AI Simulation Patient Video

Just, we have our next patient, Amy.

Amy: I am Amy, a 36-year-old female. I have lived with eczema most of my life, but this past year it has been different. Worse. I also suffer from asthma, which is well controlled with ICS/LABA. My skin is raw and itchy, and I have done a lot already with steroid and calcineurin creams.

My atopic dermatitis covers a big area and keeps flaring. I use strong prescription creams, steroids, and calcineurin inhibitors, plus daily emollients. Still the redness, itching, and scaling keep coming back. The itch is non-stop. Nights are the hardest. I do not sleep. Then the next day everything feels heavier.

It is very difficult to apply cream everywhere on my body. It is hurting my work and my social life. I plan my clothes, my schedule, even my mood around my skin. It feels like an itch-scratch loop I cannot break. I have 2 kids and am not planning pregnancy in the near future. I would like to know my options and understand what we can do next.

[00:50:19]

Discussion

Dr Singh: This video, I think, there are certainly some similarities with our last patient. What are some next steps for this patient? When we think about when is it that we would escalate to a biologic therapy. Any of the ones that we talked about or small molecule therapy, certainly if somebody is failing our topical therapies, but also along with that would be if they cannot keep up with the therapies. There certainly have been studies to show that if patients do exactly what we tell them, they bathe in lukewarm water for up to 15 minutes and then pat dry and use emollients and use their topicals, that whole routine takes an hour.

Then if you are asking them to do that twice a day, we are looking at 2 hours a day. It is a part-time job, 14 hours a week trying to take care of their skin. If either the treatments are not working, they cannot keep up with the therapies, or obviously, if it starts affecting other parts of their life. It is affecting daily activities, activities they want to do: sleep learning, concentration, anxiety, depression, all of those things. All these participants would be reasons to think about escalating therapy.

[00:51:40]

Evaluating Patient Candidacy for IL-13 Inhibitors

That leads us into when should we evaluate a patient as a candidate for an IL-13 inhibitor?

[00:51:48]

Beyond Topicals

This is when we start thinking about going beyond topicals. I just talked about this in the context of the last patient. We talked about persistent symptoms despite best topical therapy or frequent flares or exacerbations, despite their therapy or flares that are impacting their quality of life. They are not going to things or canceling things. I see mostly kids. I have had teenagers who quit the soccer team or have quit the tennis team because when they get sweaty, it flares their eczema. I have had other patients who withdraw from their social circles and their friends, because they are embarrassed about how their skin looks and things like that.

We have all had these experiences. Significant itch and sleep, that is also a thing. If someone cannot sleep, that starts affecting all parts of their life, including how they present when they are awake, how they are doing, how alert they are, and then when you cannot sleep, that can also lead to mood issues and things like that. How do we monitor if somebody is responding or if they have some of these issues? This is where we have some really nice questionnaires, which I will go over in the next slide if you want to look for these things, including itch, sleep, quality of life. Then, how severe their eczema is, you can look by doing an EASI or a SCORAD.  

Then when we talk about our therapies, if you look at the guidelines, like we mentioned, there are these beautiful tables that show which ones have strong recommendations using grade methodology, which medications have a strong recommendation for or a conditional recommendation for, or perhaps a conditional or strong recommendation against. Our strongest recommendations or that strong recommendation for, are with our biologic and our JAK inhibitors. Then there is a recommendation against oral corticosteroids because of rebound and things like that.

Then obviously, if we think back to the beginning of our talk when we talked about, what are patients concerned about? What are they looking for their health care provider? Let us just make sure we are addressing their fears, set the expectations from what they can expect on biological therapy, including the long term benefits and safety profiles. Then, of course, shared decision-making.

[00:54:13]

Clinical Assessment Tools

Here are clinical assessment tools if I can get back there. Here is our numerical rating scale that you can use for itch. Just a simple 10-point scale. How itchy do you feel? Then also pain. I have not talked about this much, but if we remember, the itch and pain are along the same neurons. When those get activated, these patients can have pain. If you want to assess their AD control, there is an AD control tool, or you can look at a POEM, and then our dermatology quality of life. Again, these are short, sometimes very short, questionnaires that we can use to assess how the patient is doing and then how they respond to therapies..

[00:54:54]

Clinical Presentation Variability of Atopic Dermatitis

I talked about this already. We know there is variability in clinical presentation depending on age and skin of color. I do not think we need to harp on this too much, but we know that the location of lesions may change depending on the age across the top of the slide. Then we did talk about the variability in presentation, where our textbook pictures are often shown in lighter skin tones where we are looking at those pink and red erythematous lesions. Where in our darker skin tones, we may see the papular or follicular distribution and then as well as changes in pigmentation, and then that gray, ashen, or violaceous appearance that may be harder to appreciate on a darker skin tone.

[00:55:37]

Presentation on Varying Skin Tones

Here are some photos. Again, this is certainly more moderate to severe disease. Again, showing a white patient on the left and then a patient with a darker skin tone, a Black patient, on the right. Here you can see that thickened gray distribution with some scaling. Then again, here we can even see a little bit of papular distribution, a little bit more widely here, and that hyperpigmented ashen appearance. Then in an Asian participant again, maybe less likely to see erythema, and it may look more darker for chronic. This is really important. I do not want to go too fast through it. Here we can see that violaceous or gray appearance, maybe a little bit more well-demarcated. Again, lacking some of that erythema that we may see that we are used to seeing in a White participant.

[00:56:41]

Patient Burden for AD: Pain

I did talk about pain. Pain is actually common in patients with AD and often not talked about. Some of this associated pain with AD in these patients feeling a little shackled by the pain or losing hope with being able to get treatment for the pain can really lead to some anxiety, depression, and even suicidal ideation among patients with AD, which are all higher. This has been shown in children. Here is our pediatric burden for pain, and similar has been shown for adults.

[00:57:20]

Patient Burden for AD: Sleep

We talked about the impact of sleep. Sorry, I am just noticing I need to move a little faster here. Our impact of sleep, and here you can see sleep disturbance is common even among mild AD. Over half of patients, almost two thirds will have an impact on sleep 1-2 days a week. That is a lot. That is a lot of sleep disturbance, and it is across ages and across severities, especially when we are talking about a pediatric population, if the child is not sleeping, the adults in the household are not sleeping, too. That is just another thing to kind of consider the impact on the whole family.

[00:58:01]

Patient Burden for AD: Quality of Life

Here is patient burden of quality of life. Here you can see just a big impact on quality of life that is proportional to severity of disease across age groups.

[00:58:12]

Associated Health Effects of AD

We have talked about this already. AD is associated with increased depression, anxiety, shame, disgust, sleep disturbances, stigmatization. As I mentioned, the suicidal ideation. Patients with AD are 44% more likely to have suicidal ideation and 36% more likely to attempt suicide compared to patients who do not have AD. 20% of patients with AD will have depression, which is twice as high as the general population.

[00:58:43]

Mental Health Effects

We all know what these mental health effects come from. There is the toll that the itch and the sleep take. Also, when you have something in your face affecting the skin and how you appear to the world and how you present to the world, that can really affect our wellness..

[00:59:04]

Patient Satisfaction With Previous Therapies

In general, you can see lots of patients are happy with their therapies, but not all. Up to a quarter and a half are not happy with their current therapies. as you can see. They may want to make a change. Even patients who are put on a systemic you can see most patients are happy. They can have improvement, but just not always. Sometimes we need to switch the systemic therapy somebody is on.

[00:59:40]

Shared Decision-making in AD

When we do this and we are thinking about making these changes, this is where shared decision-making is really important. We should talk to our patients, listen and engage, understanding what are their goals and preferences, how does their cultural skincare practices affect their skin, and how we can support patients making this decision.

[01:00:02]

Case 3: Jeremy, AI Simulation Patient Video

We have 1 more patient. It is basically similar to the other ones.

Jeremy: Hi, name is Jeremy. An 18-year-old male. I have been struggling with AD since I was a kid. It used to flare and fade. Now it is everywhere, and it does not let up.

I use prescription creams every day, and when it gets bad, I have taken short courses of oral meds. The itch quiets, then comes roaring back. I have been using ointment since childhood. I am exhausted. My parents nag me to use them regularly, but they are greasy and difficult to use on large areas, especially when I play sports.

The itch is intense, especially at night. I am waking up scratching without even knowing it. Sleep is a mess. Showers sting. Clothes rub. At school, I am distracted and tired. It is hard to keep up when your skin will not give you a break. I am worried about my grades. I cancel plans more than I want to. I am always thinking about what people see, and when the next flare will hit. This makes me anxious and depressed about how I look and feel.

Creams and the occasional steroid are not enough. I need a plan that relieves my symptoms and the itch so I can sleep, work, and show up for my life.

[01:01:14]

Discussion

Dr Singh: This case is just highlighting the teenage aspect of this, difficulty concentrating in school, sleep, and then affecting activities, sports, and how they show up with their friends.

[01:01:27]

Key Takeaways

Here are our key takeaways. We know IL-13 can drive our AD pathogenesis by impairing the skin barrier with decreased expression of filaggrin and loricrin, increased inflammation and itch. Our biological therapies targeting IL-13 include Dupi, Tralo, and Lebri which help improve barrier function and reduce inflammation.

Identifying candidates we talked about, including those with moderate to severe AD. Those that have failed topicals or cannot keep up with the regimen or it is affecting their quality of life. Then, obviously, we need to monitor these patients and make sure they are getting better, and if not, advance their therapy. We talked about our tools that we can use to assess and then share decision-making.

[01:02:14]

Posttest 1: A 36-yr-old patient with long-standing, moderate to severe AD has widespread erythematous, scaly plaques, intense pruritus, and frequent secondary infection. Topical steroids and calcineurin inhibitors provide only transient relief. She asks why an advanced therapy that targets IL-13 might help more than nonspecific immunosuppression. Which statement best explains the pathophysiologic rationale for IL-13–targeted therapy in AD?

With that, we will go to the posttest. First question. A 36 year old patient with long standing moderate to severe AD has widespread erythematous, scaly plaques, itching, and they have tried topicals, and they want to know what is the best mechanism or drugs that target IL-13 work.

A. Strengthen the skin barrier by upregulating our barrier proteins;

B. Strengthen the skin barrier by downregulating our barrier proteins;

C. IL-13 increase Th2 by blocking A13? Would that increase our Th2 activity; or

D. Does it affect the neutrophils.

Speaker: Polling is open. Please vote. You have a few more seconds for incoming replies, and we will go ahead and close that poll and share.

Dr Singh: The correct answer is A, that IL-13 helps strengthen our skin barrier by upregulating our barrier proteins, including filaggrin and tight junction proteins. The reason why C is wrong is because IL-13 is a Th2 cytokine. If we block IL-13, that will decrease our Th2 activity. I am sure they just read this question quickly. It decreases our Th2 activity.

[01:03:42]

Posttest 2: Mark has been diagnosed with moderate AD and is struggling with intense itching, widespread lesions, and poor quality of life. He tried topical corticosteroids and systemic corticosteroids for severe flares previously. He would like to consider a biologic therapy that targets IL-13. Which of the following biologic therapies would be the most appropriate choice for targeting IL-13 to improve this patient’s skin barrier function and reduce inflammation?

Our next question. Mark has been diagnosed with moderate AD, and struggling with itching lesions, poor quality of life. He has tried topicals and wants to consider something else. What would be the most appropriate choice for targeting IL-13 alone to improve his skin barrier function?

A. Dupi;

B. Nemo;

C. Lebri;

D. Upadacitinib.

Speaker: Please vote. Give a few more seconds for incoming responses. Go ahead and close that poll and share.

Dr Singh: These are both our IL-13 inhibitors. This is absolutely right. Lebrikizumab would be our only targeted IL-13 alone, where Dupi would target our IL-4 receptor, which is for M13. The best answer to this response is C, but Dupi also targets IL-13 just with IL-4 as well.

[01:04:52]

Posttest 3: Mei is a 36-yr-old woman with severe AD with eyelid involvement and prior dry eye/blepharitis. She is motivated to start a biologic therapy to get symptoms under control. What is the next best step for Mei?

I think we have 1 more after this. Mei is our 36-year-old with severe AD and eyelid involvement, and she wants to start a therapy. How do we handle it when someone has an ocular history?

A. Avoid an IL-13 inhibitor forever because of the ocular history;

B. Do we go ahead and initiate it, but then refer to our ophthalmology colleagues for support if symptoms occur;

C. Instead, do we not use it and instead do oral corticosteroids; or

D. Do we delay systemic therapy until the eyelid symptoms completely resolve.

Speaker: Sorry about that little technical issue. Give everyone just about 20 seconds to read through and answer real fast. We will give a few more seconds here, and we will go ahead and close and share. Thanks for your patience.

Dr Singh: Everyone got that right. The answer is B, go ahead and start it. If the symptoms recur, we will refer to ophthalmology. Almost always patients can treat through ophthalmology symptoms with either lubrication or sometimes other drops.

[01:06:23]

Posttest 4: How confident are you in identifying patients who are candidates for biologic therapy targeting IL-13?

Our final 2 posttest questions. How confident are you in identifying patients who may be a candidate for step-up to a biologic therapy targeting IL-13?

A. Not confident;

B. Somewhat not confident;

C. Somewhat confident;

D. Confident; or

E. Very confident.

Speaker: Polling is open. Please vote. A few more seconds for incoming replies, and we will close that poll and share.

Dr Singh: All right. Excellent. More participants we did skew our curve to the right, which was the goal of this presentation. Going from not confident now to either somewhat confident or very confident. Excellent.

[01:07:20]

Poll 5: Do you plan to make any changes in your clinical practice based on what you learned in today’s program?

Then our last question. Do you plan to make any changes to your clinical practice based on what you learned today?

1. Yes;

2. No; or

3. Uncertain.

Speaker: The poll is open. Please vote. A few more seconds for incoming replies. We will go ahead and close and share.

Dr Singh: I am so happy to hear that the presentation was useful today and that you learned something that may affect your clinical practice. Thank you for being here.

[01:08:05]

Poll 6: Please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education.

If you have a moment, you can scan this QR code to text 1 change that you plan to make, or you could put it right here in the chat. I will leave that open.

[01:08:18]

Question and Answer Session

Then I know we are a little bit past the hour, and I want to be respectful of everybody's time, but do we have time for a question or 2 while people are filling out the poll?

Speaker: Yes, if you have time, Dr Singh, that would be fine. Are you able to see those that are in the Q&A? I will let you address the ones you think you can get to. Thank you.

Dr Singh: We can go through these. The first 1. Can IL-13 inhibition alter long term disease course or remission likelihood? This is data that was not shown in this presentation, but I have seen data that long-term disease course or remission is hinted at in some of the lebrikizumab data where patients were able to lengthen the interval and has sustained response with the linked-in interval or even after the lebrikizumab was discontinued.

I think the answer to this first question is more to come, and especially as a pediatric specialist in allergy immunology, rheumatology, I am really excited about, is there potential for this playing a role in the atopic march or the expression of other atopic diseases? I think more to come, and a really intriguing and exciting,  thing that could be coming down the line.

The next question. For a patient who had a partial response to Tralo, but still had persistent itching at 6 months, what would I suggest? I think a change, and so I think that was shown in 1 of the slides with the bar graph of how happy are you with your current therapy. A lot of patients, even when they get some response, if they are still having incomplete response, it may certainly be worth a change. You could certainly try another IL-13 inhibitor.

I think the lebrikizumab does have a better efficacy over Tralo, as shown by the percent of patients that get clear or almost clear, or the percent that get improvement in their itch. We also know the molecule is different and so, a little higher affinity and stays bound longer. You could try a different, just switching classes as well. That would be a choice.

The next question would be any strategies to address patients with depression stemming from their AD. I see my role in this is screening, but I am not qualified to treat depression. My qualification is to take the best care of their skin as I can, and that may help some of the depression symptoms. If somebody reports to me that they are depressed or if I do 1 of these scales and it comes up, then I refer them. I can tell you, I refer them to a mental health specialist. I ask because I think that is a part of being an atopic dermatitis specialist, but I do not treat.

In my template, again, my patient population skews younger. In my template that on my visit note in Epic, I have questions like do they suffer from attention difficulties, ADHD, difficulty in school, depression, anxiety? It is quick. It just takes me ten seconds in my visit. If anyone responds yes, then I just address it, and I refer them to a mental health professional.

Then the last question is someone is already on Dupi and doing well, but they wanted to know how long they will respond. I think this is hard to answer. I always tell my patients that I do not have a crystal ball, but as long as they are responding, you can stay on it. We know from the open-label extension of LIBERTY OLE that if you have a response at 1 year and you continue to take the drug at 4 years of open-label extension, patients were still responding. Again, I think it is just important to continue to have that conversation with your provider. If at any point it is not working, do not give up because we have other choices, and we should try a different medication.

I think what I want to leave this session with, and I think that is all the questions, is just for so long we did not have all these choices. All we could do is give somebody steroids and more steroids and then maybe oral steroids or maybe some broad immunosuppressants, methotrexate, or something like that. Monitoring for side effects, but this is a really exciting time to be taking care of patients with moderate to severe AD. We have so many more choices for targeted therapies that are safe. We just need to make sure our patients have access to them. Really, we have an opportunity to make just such a difference in our patients lives.