IL-13: A Key Driver of Inflammation and Barrier Dysfunction in AD

Dr Andrew Alexis (Weill Cornell Medical College): IL-13, what is its role in atopic dermatitis? Well, it turns out it is a key driver of inflammation and barrier dysfunction in atopic dermatitis. It plays a central role in the pathogenesis of this disease.

[00:22:46]

Epidemiology, Pathogenesis, and Comorbidities

We all recognize atopic dermatitis as being an extremely common, very, very common, highly prevalent immune-mediated disease that we probably see on most days. It affects 3% to 20% of children globally. Symptom onset is most common pretty early in life, 3 to 6 months of age. In fact, among children who are diagnosed with atopic dermatitis, the overwhelming majority develop it by the age of 5.

However, about half of cases persist into adulthood. Then there is this cohort of patients who are diagnosed as adults, and it is estimated that 25% of cases may report symptom onset during adulthood. This has been an understudied patient population that we are beginning to appreciate more and more.

We recognize atopic dermatitis is characterized by cycles of flares of redness and scaling and itching. From real-world evidence, many of our patients with moderate to severe atopic dermatitis are not well controlled at all. They have an average of almost 2 flares per month, and 74%. So almost three quarters of patients reported not having any remission of their symptoms in the past year. So speaks to the lack of control among many of these patients who are not yet treated as well as they can be.

[00:24:27]

Overview of AD Immunopathogenesis

Thinking about the immunopathogenesis and the role of IL-13. IL-13 we know is a key Th2 cytokine. What is its role in atopic dermatitis? Well, its role involves the barrier disruption as well as the downstream immunologic cascade that is Th2 driven that we know characterizes atopic dermatitis. It contributes to epidermal barrier dysfunction by downregulating the expression of key structural proteins like filaggrin and loricrin and other structural proteins. There is even reduced expression of antimicrobial peptides in the epidermis, and this contributes to an increased development of staph aureus colonization.

There is increased chemokine expression and eosinophil recruitment, pruritus, which we will talk about some of the interesting crosstalk between the immune system and the sensory nervous system contributing to itch.

There is also a great deal of evidence that elevated IL-13 levels, correlate with disease severity, and targeting IL-13 with biologics has certainly been shown to have efficacy in improving atopic dermatitis signs and symptoms. We are going to be going through the data later on in the program.

[00:26:05]

Epidermal Barrier Dysfunction and Environmental Triggers

When we think about the epidermal dysfunction, and how much it plays a key role in the pathogenesis of disease and the signs and symptoms that we see in our patients. This compromised epidermal barrier will lead to increased permeability to pathogens, to irritants, to allergens, increased trans-epidermal water loss, contributing to greater cirrhosis, which is such a common feature of this disease.

Filaggrin mutations which are 1 of the more prevalent genetic factors associated with atopic dermatitis and reduced filaggrin expression disrupts cornea site integrity and impairs hydration. IL-13 actually reduces filaggrin expression as well. We have got genetic mutations in filaggrin that contribute to lack of expression. But we also have the effects of the Th2-driven immune cascade in reducing filaggrin expression.

We see reduced ceramide content in the stratum corneum as well, and IL-13 is associated with some of that reduction. There is suppression of the antimicrobial peptides, as I mentioned, leading to microbial dysbiosis with staph aureus colonization, and in some cases, secondary infection.

[00:27:45]

Epidermal Thickening and Abnormal Keratinocyte Proliferation

When we think of the clinical and histologic features of atopic dermatitis, we immediately recognize how heterogeneous the presentation is. While histologically spongiosis is such a key hallmark, clinically, depending on whether it is acute, subacute or chronic, the lesions that we are looking at, we might see oozing and crusting in the case of acute cases, subacute more scaling and redness and chronic, more lichenification and thicker papules and plaques.

Depending on the anatomic location, we see a great deal of variability in the morphology. So very heterogeneous disease and the spectrum of presentations all falling within atopic dermatitis. We might even see differences depending on the age of the patient. Different racial ethnic backgrounds and skin type can also play a role in altering what we see clinically.

[00:28:52]

Components of Pathophysiology of AD

Thinking about beyond IL-13, we have other factors that also play a role in the pathophysiology and also represent potential targets of our therapies. So therapeutic targets to help control this immune-mediated disease including oral hydrocarbon receptor and IL-4, and in addition to IL-13, TSLP, IL-31. The JAK-STAT pathway, of course, is a target because many of these cytokines that are key to the pathogenesis of atopic dermatitis depend on JAK-STAT intracellular signaling through the JAK-STAT pathway to modulate their effect.

Then we have OX40 and OX40 ligand interactions, which play a role in amplifying the Th2 response and sustaining it as well. We are seeing some medications in development there. So very, very, exciting time as we have a better understanding of the complex pathophysiology of disease and have all these additional targets for our therapies.

[00:30:12]

Neuroimmune Mechanisms of Itch

Now, when it comes to itch, which is, of course, the number 1 symptom of atopic dermatitis and contributes greatly to its adverse effects on quality of life, we really have a better understanding today of the non-histaminergic pathways and the crosstalk between the immune system and the sensory nervous system.

[00:30:38]

Neuroimmune Interactions in AD Chronic Itch

It turns out that on the sensory neurons we have receptors for IL-4, IL-13, IL-31, TSLP and others at creating this crosstalk between the immune system and the sensory nervous system, leading to the sensation of itch. When we inhibit to these key cytokines and the Th2 immune response, we get this improvement in itch through this pathway, among other mechanisms too.

[00:31:15]

Let us Revisit Our Patient Case

Let us revisit our patient case having that background of the pathogenesis and role of IL-13.

[00:31:22]

Patient Case: A 34-Yr-Old Female With Severe AD

We got the 34-year-old patient here with severe atopic dermatitis still waiting in the waiting room. She complains of persistent symptoms of redness, scaling and itching. She has tried topical corticosteroids, emollients. It has been worsening over the past year, difficulty sleeping, probably contributing to challenges at work, with lack of sleep.

[00:31:51]

Posttest 1

Post-test. Having heard about the mechanisms of disease and thinking about the various signs and symptoms in this patient, what is the role of IL-13 in atopic dermatitis? Which of the following best describes its pathophysiological contributions. Is it:

1. IL-13 enhances keratinocyte activity, but at least abnormal differentiation, weakening the skin barrier and increasing susceptibility to irritation;
2. IL-13 modulates immune signaling but skews the response towards an overactive Th2 profile, contributing to chronic inflammation; or
3. IL-13 influences fibroblast function, but instead of promoting effective wound healing, it disrupts normal tissue repair and regeneration; or
4. IL-13 disrupts the skin barrier, increases pruritus, and perpetuates inflammation by promoting Th2-mediated responses.

Looking forward to seeing your responses as they come in and see if there is a difference between the pre and the post.

[00:33:00]

Posttest 1: Rationale 

Excellent. We are seeing the shift in the proportion of folks with the correct answer, the best answer. Even though there might be elements of truth to some of the other answers, the best answer is indeed D, which is IL-13 disrupts the skin barrier, increases pruritus and perpetuates inflammation by promoting Th2-mediated responses. In this way, it plays a central role in the pathogenesis of atopic dermatitis and really contribute to that perpetual cycle of itching and scratching and inflammation, and would help to explain our patients persistent symptoms despite treatment with just corticosteroids and emollients.

[00:33:44]

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

With that, it turns out I did not even involve my colleagues in the case. I decided to go it alone. It is my pleasure to introduce, Dan Butler, from Tucson, Arizona, who is going to talk about Mastering the Evidence for IL-13 Inhibition in Moderate to Severe Atopic Dermatitis. Dan?

Dr Daniel Butler (University of Arizona College of Medicine): Thanks so much, Dr Alexis. First of all, you are never alone. Shawn and I were right behind you the whole time, ready to step in. But that was a great tour of the mechanisms underlying this really common disease. Obviously, this is something that we are challenged with every day whatever practice model you are in. But now we are really getting to understand those disease mechanisms, which I think then educates us on how to take those next steps forward with our patients to be able to say, all right, here is a treatment, here are the mechanisms by which it is working, what do you think? What would you like to do?

That is what we are going to do in this section, is mastering the evidence for IL-13 inhibition in moderate to severe atopic dermatitis. What we are going to do in this section is go over some of the treatment recommendations and hopefully help you all navigate, not necessarily giving you the answer or even feigning that there is a correct answer, but rather helping us all navigate what now is a busier, more option for discussion with our patients when we are treating them with atopic dermatitis and eczema.

[00:35:28]

Patient Case: A 42-Yr-Old Male With Refractory Moderate to Severe AD

As you know, we always start with a case. Let us talk about the case. Here is a 42-year-old male with refractory, moderate to severe atopic dermatitis. Current presentation. Of course this patient is struggling. There is intense itching, widespread lesions and poor quality of life. The medications, as most patients have, already been on. This patient has been on topical steroids. Then every once in a while they get systemic corticosteroids when they are flaring.

This dermatologist is talking with the patient about a biologic that specifically targets IL-13. When they do a laboratory evaluation, which step aside here, we do not typically do for atopic dermatitis, but can certainly be helpful in seeing the complexity and holistic nature of the disease. They do find out that there is an IgE elevation, as well as an eosinophil elevation, with CRP and ESR being elevated as well at 4.1 and 30, respectively.

[00:36:34]

Pretest 2

Pretest. Which of the following biologic therapies would be the most appropriate choice in targeting IL-13 specifically to improve the patient's barrier function and reduce inflammation? We already found out that IL-13 helps with barrier function and reduces inflammation. But which of these biologics specifically does it through the IL-13 mechanism? We will wait a second for everybody to get to work through this. Then once we have the answer there, we will move on to that navigation that I was talking about.

All right. Perfect. We have a pretty decent split between the biologics. Let us dive into that so that we can tackle the post-test when it comes up.

[00:37:27]

IL-13: A Key Driver of Inflammation and Barrier Dysfunction in AD

As we know, IL-13 is a key driver of inflammation and barrier dysfunction, and now we have ways to directly attack it.

[00:37:36]

Biologic Targets

Here is the broad schematic of every systemic AD medication that has come out in the last 10 years. Before this, we had the more historic immune suppressants, which were really developed for the more immune-focused conditions like transplant immune suppression. We were using things like methotrexate, cyclosporine, azathioprine. These were historic ones that we all got really comfortable using. But we had a revolution about 10 years ago when we first got to see dupilumab.

You will see dupilumab there, which is an IL-4, 13 inhibitor. It inhibits both IL-4 and 13. But it does this specifically by blocking the IL-4 receptor alpha subunit of that receptor.

Then as you look at those top options, you will also notice lebrikizumab and tralokinumab. These are the IL-13 specific inhibitors. These are the ones that specifically target IL-13. Dupilumab targets IL-4 receptor alpha, which allows it to secondarily block IL-4 and 13. But as far as direct IL-13 inhibition, lebrikizumab and tralokinumab are the ones you are looking at.

Then the newest kid on the block is the IL-31 agent, nemolizumab, which works similar to dupilumab in that its effect happens at the receptor level, not by blocking the cytokines specifically. Those 4 are our usual suspects when it comes to the biologics. When someone refers to the biologics for AD, those are the 4 that we have now. I think there is probably some more coming.

Now if we flip to the inside of the cell or the bottom part of this slide, you will see the JAK inhibitors that are available for treatment. These are oral agents. They are not biologics. We consider them systemic immune suppressing options. There we have baricitinib and abrocitinib and upadacitinib. These again are a little bit different in their classifications, not specific biologics, but we will talk a little bit about them anyway because they are wonderful options to use in certain circumstances.

Let us start to tease these all apart.

[00:40:10]

AAD 2024 Guidelines: Systemic Therapies for Moderate to Severe AD

The interesting thing of this slide is that the AAD is getting faster and faster at updating things. This is the AAD 2024 guidelines for systemic therapies for moderate and severe AD. Interestingly enough, last week, well after these slides were established, we actually got an update on these guidelines.

Here the guidelines show that for moderate to severe AD, dupilumab and tralokinumab were considered first-line therapy. Then we had added lebrikizumab and nemolizumab there with question marks because they came out in 2024, so we could not know if they were actually added. But recently they were both added to the 2025 guideline.

Long story short, those 4 biologics are considered first-line because of their safe and effective profiles. We are going to get a little bit more into those. After that, you see at the bottom of that slide, the JAK inhibitors that we talked about, upadacitinib, abrocitinib and baricitinib, those would be considered second-line for failures or those who did not tolerate.

One asterisks to baricitinib is it is actually not available for atopic dermatitis or not FDA approved for atopic dermatitis in the United States. It is for alopecia areata. You may see a couple of things. That is why it does not have that FDA stamp there.

Then over on the stage right here, you will also notice the methotrexate, azathioprine, ciclosporin, mycophenolate mofetil, systemic steroids. These are the old historic relics of the past, which we still dive into when we need to. But now we have much safer and more effective options. They have gone out of favor as certainly first-line agents.

[00:42:00]

FDA-Approved Biologic Agents

As we dive into the biologics, I think it is really important to start to see them in comparison. This is a busy slide. But each one of them offers a little bit of a unique nuance. Again, I am not going to try to go over this entire slide in detail, but a couple little things to point out.

Dupilumab, the first biologic that was commercially available about 9 years ago. It is the only 1 that is available for over 6 months of age. Tralokinumab and lebrikizumab, the IL-13 inhibitors, they are the ones that actually allow us to extend dosing profiles. When we are treating somebody and they get really good control, we can actually, by FDA approval, extend their dosing out from Q2 weeks to Q4 weeks, which is a huge boon for the patient to have less injections.

Then nemolizumab with its unique mechanism of action actually starts at that Q4 week dosing. Then, of course, I would be not doing my job to just highlight that the warnings for each are quite mild, things like conjunctivitis, which is reversible after treatment or discontinuation of the medications, and then hypothetical risks of parasitic infections for the IL-4 and 13 targeting agents, as well as avoidance of live vaccines for the IL-31.

Long story short, and we are going to dive into this a little bit more, these are very, very effective. The warnings are pretty mild at best.

[00:43:33]

Biologic Therapy Use in AD

It is a crowded market. How do we figure out which 1 to use in the right patient? We already talked about some of the differences in the biologics. Potential benefits of Q2 to Q4 week dosing. We want to look at failure rates of 1 vs another. We also love the group profile, which is that none of them require any lab monitoring. Then we should also know the common side effects for each group. Things like conjunctivitis we see in dupilumab, tralokinumab and lebrikizumab. We do not see it as much in nemolizumab.

Long story short is we are now trying. We are in this era where we are trying to differentiate between all the different available products. This is a little bit of why we are here today is to help us all work through that. As I go through some of the studies in the coming slides, I want to highlight something that I think is really important, which is that despite the fact that we are going to be scientists and clinicians and work through data that helps us figure out who is the right patient for each biologic, I do like to put an umbrella over all of it and say, you know what? These are really great medications. Certainly the 4 we have out, they have helped a ton of my patients, and we are still trying to figure out which 1 is perfect for the right patient, but boy oh boy is it nice to have something or some things to be able to give a patient when before it was always having to read them a long list of side effects to be able to go on mycophenolate or ciclosporin.

Long story short, I would like to put that umbrella out there. But with that being said, let us get into some of the comparative data.

[00:45:12]

Network Meta-analysis: Targeted Therapies Without Topical Corticosteroids for Moderate to Severe AD

The first piece of comparative data that I think is important looks at all of them. I was looking at all the ones that were available at the time. It was 13 trials, 32 total treatment arms, over 7,000 patients. This was a network meta-analysis where they basically take all of the clinical studies that were done on these medications, and they try to compare some of these similar endpoints.

Now, the asterisks to any network meta-analysis is that you really cannot compare the medications, even though they are looking at the same end points. There are unique differences in each study. We have to take this with some level of skepticism and caution and vigilance as to its results. But I think there is still some valuable takeaways as we are working through, which is the right biologic for which patient.

In this study, they actually included JAK inhibitors, which were upadacitinib, abrocitinib and baricitinib. But they had the 3 first FDA-approved biologics. They had dupilumab, lebrikizumab and tralokinumab as well.

The results, not surprisingly, showed that the highest efficacy was seen in the JAK inhibitor. Upadacitinib was number 1. That was at its highest dose of 30 mg. Number 2 was abrocitinib, which is the other JAK inhibitor at its highest dose of 200 mg and then upadacitinib at its second lowest, or at its lower dose. That is 15 mg.

Then overall, you started to see very similar efficacy when it looked at the biologics, including lebrikizumab, dupilumab and then of course adding abrocitinib and baricitinib at their lower dose as well. Baricitinib, that is its higher dose. But long story short I do not want you to get lost in it. It looked like the JAK inhibitors were more efficacious, but that the biologics, including dupilumab and lebrikizumab were absolutely effective, at the level seen by some of the lower JAK prescription rates.

What did we take from this? We take that, yes, JAK inhibitors outperform anything that is in the biologic realm. But everything is looking pretty good from an efficacy standpoint. We have to start to look at the data points to be able to really tell the difference there.

[00:47:44]

Heads Up: Upadacitinib vs Dupilumab for Moderate to Severe AD

How do we find good data points here? I am running forward too fast. We start to look at what available head to head data is there and the head to head data. This is not a network meta- analysis, so we can take some conclusions from this, looking at the king of the JAK inhibitors, upadacitinib, with the first biologic out on the market. As you would imagine, upadacitinib was better and faster at skin clearance in this 24-week study. But it did look like dupilumab, the biologic had a better safety profile.

There were less infections that were seen in the biologic category. Again, you are looking at risk benefits. A head-to-head study is probably the best way to be able to value that.

This head-to-head study really was transformative when we started to think of how we can guide people in biologics because they really had the crown when it looks at safety profiles. I often, at least in my practice, that is really the first place that I will go. Is this medication safe? This study told us, absolutely, dupilumab has the better safety profile than upadacitinib, the JAK inhibitor despite upadacitinib’s superior efficacy.

[00:48:59]

LIBERTY AD CHRONOS: Dupilumab Efficacy in Adults

Let us dive into some of the more minute data from the biologic trials. The LIBERTY AD CHRONOS trial was looking at dupilumab’s efficacy in adults. This is basically our ability to study the older or the adult population who are taking dupilumab.

What you will notice here, without having to dive into all the minute data, is that delta between the orange bar and the dark blue and lighter blue bars. Essentially, this is the pattern of efficacy rates as graded by IGA scores and EASI-75 scores, which are the clinical result scores that we look for in these clinical trials.

We are looking for that delta. In here you see a significant delta at week 16, at week 52 for both IGA scores and EASI scores. That delta is something you are going to see a lot of across these slides.

[00:50:03]

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

Dupilumab across its population looks pretty darn good. But how about when we take it a little further out? Does it maintain that efficacy? The answer is absolutely. Then of course the question we always have to ask is about safety. Does it maintain its great safety profile over time? This is a real gift. Because if we have a 24-week study, sure we can extrapolate something from that. But certainly the open-label extension of 4 years in this trial was something that we could really take a lot from.

Over those 4 years, we found that that safety profile sustained. That is really, really healthy when we are looking at broadly the biologic realm, despite the fact that it is new in this last decade, we now have the better part of a decade telling us that the safety profile is really good. So we did not see any major signals of infections. The only major thing that we like to see with these patients, or we do not like to see it, but we see it with these patients, is conjunctivitis. That was certainly something that we continued to see, but not in a dangerous realm.

[00:51:08]

Dupilumab Efficacy by Racial Subgroup: Wk 16

In addition to that safety profile and the efficacy profile, we started to look at, again, trying to find the right populations for each medication, we started to look at subgroups and demographically unique subgroups. This was a racial subgroup analysis from these LIBERTY trials the SOLO 1, SOLO 2, and the CHRONOS.

It was found that, not surprisingly, in all these racial subgroups White, Asian, Black, African American, you did see strong efficacy for dupilumab, just as you had seen in that initial trial data.

[00:51:47]

Dupilumab Safety by Racial Subgroup: Wk 16

We are going to actually look at that type of data across many of these biologics. Just prepare yourselves.

Then similarly, we did not see any absolute jumps off the page with any of these racial sub-analysis for dupilumab in these trials for the safety profile. We were seeing very similar safety profiles across these populations, which again emphasizes the safety of the biologic class in general.

[00:52:16]

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

Now we jump back into a network meta-analysis. We saw the CHRONOS trial. We saw the efficacy data for the general population and then the subgroups. Now let us see how the biologics compare with one another.

Again, network meta-analysis. We cannot take too much from this comparison because these are very different study designs. But long story short and the comparison of these 2, it was found that dupilumab plus topical corticosteroids demonstrated superior skin clearance, itch reduction and quality of life scoring as compared to tralokinumab plus topical corticosteroids.

This was a great addition to our discussion because it allowed us to finally compare something that targeted the IL-4 receptor alpha unit, which secondarily allows that 4, 13 inhibition vs tralokinumab, which was the first IL-13 specific inhibitor. This was another one that we were able to add to our work.

This was really important for us to be able to see the differences in these and ultimately make comparisons, but you can see we are seeing really similar trends as we dive into this data, which is we are seeing in network meta-analyses that the JAK inhibitors remain the king as far as efficacy, but safety continues to show strength for all the biologics.

[00:53:57]

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

Now, I want to dive into another specific look at an IL-13 inhibitor. This is tralokinumab. If you scroll back to that network meta-analysis that we just looked at, that was the 1 that was compared specifically with dupilumab and showed some lower efficacy rates.

Nevertheless, still a really great medication, as shown in the ECZEMA 1 and 2 trials, where you are looking, again, just focusing on the delta between that orange bar and the blue bar where you still see really great efficacy profiles. You still see a strong delta between those 2 bars. That is really what we are looking for across these different endpoints.

In this circumstance, they are looking at Investigator Global Assessment of 0 or 1 which essentially means the patient is completely clear. Again, you are seeing very strong comparative data for tralokinumab as compared to placebo in this 16-week trial.

[00:54:58]

ECZTRA 1 and 2: Additional Endpoints and AEs

As you would imagine, there are other things that were included in these trials, other endpoints with really great maintenance of response up to 52 weeks and beyond. Then, of course, they added the ECZEMA 3 trial to this. Again, you do not have to know all the names of these confusing trials but just know that the early trials were done without corticosteroid additions, topical corticosteroids. In ECZEMA 3, they did add the topical corticosteroids as an option in both the placebo and in the treatment groups with the IL-13 inhibitor. It showed the exact response, as you would imagine, which was more patients got clear, as shown by IGA scores of 0 or 1, and more patients were able to get to that EASI-75 score, when they added the topical corticosteroid.

Again, if we are thinking thematically, not getting lost in the data here, this is showing that tralokinumab still has an impressive efficacy profile despite the fact of its prior comparisons.

[00:56:04]

Tralokinumab Efficacy by Racial Subgroup: Wk 56 

As you know, we did want to make sure that the subgroup analysis is still shown, which shows unique signals in each population. Asian, Black and White populations still had great data for EASI-75, EASI-90, which again, are clinical endpoint scores, IGA 0 or 1, which is another clinical endpoint point score. Long story short, we are seeing themes across these. Well, it is not perfect for 1 single population. It is pretty good for all of them. That is what we take away from this longer term data.

[00:56:42]

Tralokinumab Safety by Racial Subgroup: Wk 56 

In addition to looking at the safety profile of these racial subgroup analyses, which basically shows exactly what you would expect, which again, this biologic, like the others, has a fantastic safety profile. Nothing that jumps out, nothing that would be different from the other biologics.

[00:57:02]

ADvocate 1 and 2, ADjoin: IL-13 Inhibitor Lebrikizumab

Last but not least, in the IL-13 inhibitor category, I want to take a closer look at lebrikizumab and its trials of ADvocate 1, 2 and ADjoin. This is the most recent of the IL-13 to be approved. What this did is it looked at short term 52-week data, which allowed us to evaluate clinical efficacy at that point. It showed really remarkable differences. So that IGA score, you are going to see the Delta here in a minute. But 43.1% of patients responded at a clear or almost clear level as compared to 12.7% at the placebo rate.

That is about 3.5 times improvement when compared. That is that delta that I am talking about. That is a really important piece here. Then ADjoin was the more longer-term data that we had for this. What I love to see about this, and there are a couple other slides about this, but of the patients who were good responders, you saw 80% of them on long-term data continue that response. That is another piece that we like to share with our patients, which is this is not just some short term solution, perhaps like the steroids that you have been on before.

This is a medication that for months and months and even years can provide clearance. That is what this study showed. Again, we are just adding to the menu that shows how clean these medications are with an impressive safety profile.

[00:58:43]

ADvocate1 and ADvocate2: Lebrikizumab Efficacy at 52 Wk

This is exactly what I was talking about. This is when we looked at the extension from week 16 to week 52. You will see there, those blue lines, they stay up pretty high 85% when you are looking at the different dosing protocols for lebrikizumab. But the 1 that really sticks out to me is for the patients who were responders to lebrikizumab at week 16, even when they came off the medication, look at that, almost three quarters of a year later, 60% of them were still under control, 66% of them. That durability of response is pretty impressive. This is measured by the itch NRS pruritus score. An improvement of greater than 4 is a pretty much a standard for the community, as showing really great itch control.

Long story short, there is a durable response here, whether you stay on the medication or after you can discontinue the medication.

[00:59:46]

Lebrikizumab Safety Considerations

As you would imagine, we have to look at some of the safety data. Again, as you would imagine, the safety comes back really impressive. With lebrikizumab as with the other biologics, conjunctivitis was the biggest signal that we saw. But again, nothing that required serious AEs or discontinuation at a level that was unprecedented. In fact, you can see there that the discontinuation rates, or the serious AE rates and the AE rates were actually higher in the placebo group than they were in the usage groups.

[01:00:24]

Lebrikizumab Efficacy by Racial Subgroup: Wk 16

The next thing that we are going to show you here, because we did it for dupilumab and for tralokinumab is the racial sub-analysis groupings. As you see there, strength maintains across racial subgroups. As you can see, the delta of the placebo there at the bottom, as compared to the lebrikizumab groups, there is really strength across all populations, which is so important as we maintain inclusivity in our clinical programs.

[01:00:56]

Lebrikizumab Safety by Racial Subgroup: Wk 16

Similarly, there is no signal from a side effect standpoint that affects 1 subgroup over another.

[01:01:03]

AAD 2024 Guidelines: Advanced Biologic Therapies for Moderate to Severe AD

That is a great add to our menu of options, our skill, our toolbox that we can provide the patient with. Again, this highlights those outdated AAD 2024 guidelines, which are now the 2025 guidelines and include not only dupilumab and tralokinumab but have lebrikizumab, the IL-13 inhibitor, and nemolizumab, the IL-31 inhibitor.

I will just point out there that there is a conditional recommendation that systemic steroids are not used. I think now we have these other options. We have other things that we can absolutely use that are more effective.

[01:01:42]

AAD 2024 Guidelines: Treatment Algorithm for AD

This algorithm again has been added to, but the themes are stable, which is if you have a moderate or severe patient, your first-line options should be the biologics. Dupilumab being a 4, 13 inhibitor, not just a 13 inhibitor. Tralokinumab and lebrikizumab, which are the 13 inhibitors specifically, and nemolizumab, the IL-31 inhibitor.

[01:02:09]

Comparing Newer Systemic Therapies: Network Meta-analysis

I want to show you this 1 last time to look at that network meta-analysis that we talked about a little bit earlier. If you look at the very top there. This is showing that the JAK inhibitors are the kings when it comes to efficacy. But if you look at the biologics which are your safest options, you will see great efficacy data for lebrikizumab, the IL-13 inhibitor. Then of course dupilumab and tralokinumab follow lebrikizumab, dupilumab being 4, 13 and tralokinumab being 13.

[01:02:50]

Faculty Insights and Key Takeaways

I believe we are going to go into the post-test really quickly. But the key take home is everybody needs their own tailored regimen. You want to make sure to use your new optionality, use the efficacy and safety data that is unique for each 1 to be able to come up with a personalized approach. Each 1 has a little bit of a nuance difference to it. But long story short, they are all safe. They are all effective.

[01:03:25]

Patient Case: A 42-Yr-Old Male With Refractory Moderate to Severe AD

Let us return back to the patient case. This is our patient. He is struggling. His dermatologist is considering an IL-13 inhibitor, of which there are 2 on the market.

[01:03:36]

Posttest 2

I ask you once again, which of these options would be most appropriate for targeting IL-13 when considering safety profiles as well as efficacy profiles? Again, I will just give you the spoiler alert here that IL-13 is the key.

We always have this split here. Hence why I keep pushing for IL-13. Dupilumab secondarily blocks IL-13. So lebrikizumab would be the correct answer there. But I totally understand the split answer. It is totally fair that there is confusion with those 2 because this is a hypothetical situation.

[01:04:30]

Posttest 2: Rationale 

IL-13 plays a central role as we heard from Dr Alexis earlier. Lebrikizumab of those options is the only 1 that specifically binds IL-13.

[01:04:41]

IL-13 Inhibitors in Practice: Patient Candidacy and Treatment Advancement Strategies

I do not think I have ever said IL-13 more times in my life. But I am going to say it 1 more time as I introduce our next expert here. This is Dr Shawn Kwatra, and he is going to talk about IL-13 inhibitors in practice. Dr Kwatra, please take it away.

Dr Shawn Kwatra (University of Maryland School of Medicine): Yeah. Thank you so much, Dr Butler, Dr Alexis, really for the great presentation. It is my honor to also discuss the next level. So patient candidacy and also treatment advancement strategies.

[01:05:18]

Patient Case: A 13-Yr-Old Female With Persistent Moderate to Severe AD

A really good way to start discussing this topic is with a patient case. This is a 13-year-old female that you all can think about presenting with persistent moderate-to-severe atopic dermatitis. 13-year-old female with widespread erythema, pruritus, lichenification, quality of life disruption and poor school performance. Also, history of asthma. Has had topical steroids and also oral steroids for severe flares and phototherapy. The IgE is 2,300; eosinophils, 9% as well.

[01:05:55]

Pretest 3

Let us move along. We will, of course, come back to this case, but we want to do our pre-test questions here. Considering the patient's clinical presentations, history and lab findings, which are the following factors most strongly supports initiating an IL-13-targeted biologic therapy for atopic dermatitis? Let us pick 1 of these. I will give you all a moment to do that.

[01:06:36]

Beyond the Surface: Evaluating Candidacy, Disease Severity, and Patient-Centered Outcomes in IL-13–Targeted Therapy for Atopic Dermatitis

Great. Let us keep going. Okay. Today, we are going to talk more in this section about evaluating the candidacy, disease severity and also patient-centered outcomes using IL-13-targeted therapy for atopic dermatitis.

[01:06:50]

Beyond Topicals

Let us first talk a little bit about when to advance therapy. I think this is an area where a lot of patients suffer because therapies are not offered in advance at appropriate times. The most important things to consider are persistent symptoms, despite optimized topical therapy, flare ups impacting quality of life and itch and sleep disturbances.

For example, in the pretest question, in the case as well, we had a patient who had severe symptoms despite topical therapy. That is it. That is enough. That is the most important thing needed to trigger the systemic IL-13 targeted therapies is persistence of symptoms, even though you are on topical therapies and they have been optimized. Very important we see many patients who have been passed around for years just on topical steroids, sometimes with [inaudible]. I would personally even argue that using a very targeted biologic type agent is safer, more efficacious and safer than using long-term topical steroids. So very important to consider that point.

Monitoring treatment response. There is some important scales, for clinical practice, the EASI score, Eczema Area and Severity Index, the Investigator Global Assessment or the SCORAD. There is also some itch severity scores which are from zero to 10, or sleep quality or dermatology life quality of index.

Advancing therapy. Someone has been on topical steroids. That is enough to advance therapy. We prefer our biologic or small molecule JAK inhibitor therapies. We have greater efficacy and safety than non-specific immune suppressive or modulating agents like methotrexate, cyclosporine, corticosteroids. Then patient-centered conversations we want to have are talking about expectations of biologic therapy, long-term benefits, but balancing that with any safety concerns or profiles and shared decision making as well.

[01:08:53]

Patient Voice Video

That is the forefront. Let us actually hear about everything from a patient's perspective. We will ask the team to play the video so that we are able to actually hear a patient's experience, and then we will go from there. All right, let us have the team play the video.

Chava Wald: My AD flare ups really vary, and that really depends on if the medication treatment plan that I am on is effectively managing my AD. When it is, it could be once a week, once every 2 weeks. However, when the treatment plan is not effective and not working very well, flare up could be as often as 3 times a week and sometimes go on for weeks or even months on end.

No doubt when my skin is not doing well and it is not flaring state, it really does impact everything from the choice of my clothes to the activities that I am able to do, to how productive I am throughout the day. All of these are impacted by my AD.

Having AD has a direct relation on my mood and my overall emotional well-being. That is because when my AD is not being managed and the itch is out of control, it impacts my sleep, which then impacts my ability to just function properly as a human being, as a mother, as a wife. Having a doctor who understands what it is like to live with AD, as well as a bit about my lifestyle, has really helped in terms of just the entire journey, keeping an open mind to try different treatments and perhaps stopping certain treatments, has really played a role in my journey, having family that is very supportive, very understanding who are there for me whenever I need, makes a huge impact, as well as finding community, finding others who are going through similar experience really just helps lighten the burden of this experience.

[01:11:14]

Clinical Assessment Tools

Dr Kwatra: All right. That is that is always helpful to hear the patient's perspective. Now what we will do is, is also look as we are transitioning. Look at some of the clinical assessment tools. So patient comes in. What are some of the tools that you are going to be thinking about. You can see the Eczema Area and Severity Index, where you actually grade different body areas by erythema, many of these other factors, pruritus.

The Investigator Global Assessment, in contrast, is based more on the appearance of lesions. So are these lesions how erythematous are they. How lichenified are they? Those are the very important features. You usually need an Investigator Global Assessment of a 3 or 4 to qualify for biologic or systemic therapy.

There is also the SCORAD and the POEM as well. There is quite a litany of different measures, but I would say the IGA and the EASI score are the 2 most important to document, especially in your note.

[01:12:15]

April, 15-Yr-Old Female

Where I practice, patients have to fail topical steroid therapy, medium and high potency and a topical calcineurin inhibitor, depending on the insurance usually. Usually, we do that first visit, have a quick follow up as well if we are thinking it is greater body surface area, greater itch disruption. I ask everybody on a zero to 10 scale how severe their itch is. That would trigger systemic therapy.

[01:12:46]

Identifying Patient Candidates for Biology Therapy

Let us also talk about a case. The case is of April, so I just skipped over that. I will bring it back up for you because I want to focus on many of these different metrics, bringing them to life with a patient.

Meet April, 15-year-old Black female, presents to dermatologist an increase in bothersome itching, especially in the last few weeks, affecting her sleep in school. Her atopic dermatitis was diagnosed in early childhood at age 5, full body itching, redness and scaling up from the age of 9 also with obesity, asthma as well. As a high school freshman, lives in New York City, eats fast food regularly, unable to exercise due to the increased flares from sweating.

Mom and her 2 sisters with AD or allergic disease. Here we see a patient who is having effects on her sleep and school as well. Also has a comorbidity of asthma. Also patients has family members that have a history of atopic disease.

[01:13:49]

April, 15-Yr-Old Female 

Let us do a review of systems, psychiatric that depressed mood anxious occasional wheezing itching and rash. You can see that the patient has around a 17% body surface area with eczema around joints in the face and a SCORAD around 48. Let us go through this treatment timeline. So the patients were diagnosed with AD age 5, had lukewarm baths, gentle cleansers and moisturizers. Age 8, you can see, use topical corticosteroids. Age 11, phototherapy. Age 15, crisaborole as well.

[01:14:28]

Discussion

But all of these therapies has not helped the patient. There is a few different aspects of this case. First, assessing April's current management of AD. Well, try topical steroids. Try even a non-steroidal for atopic dermatitis, tried phototherapy. Those are all a number of therapies and they have not controlled her sleep. She is having, like, a logical and psychosocial disturbance affecting her quality of life for her significantly.

Remember, the most important thing for escalating to biologics and IL-13-directed targeted therapies in particular are failure on traditional therapeutics, topicals which she has done. Which assessment tool for you guys? I think there is many. But what you need in your notes is probably the IGA score first, Investigator Global Assessment. That Investigator Global Assessment is able to look at, as I mentioned, the appearance of the lesion.

That is like a direct takeaway or clinic is being able to market from zero to 4. Four is very severe, redness or erythema. Dark or deep bright red marked in duration or elevation lichenification oozing and crusting. A 3 is noticeable erythema. Two is mild. That is like a little bit more mild but noticeable, whereas a 3 is distinctly noticeable redness. Then 1 is barely noticeable redness or in duration, lichenification. Zero is not affected at all. So zero is nothing. Four is the worst. That is a good way to guide it.

We talked about this before. But April would absolutely be a candidate for biologic therapy because she failed these traditional topical therapies. That is the key piece. Would your treatment decision be altered if April did not have asthma? For me, the answer is no. If your disease is not controlled, I would still escalate to biologic therapy, especially if sleep is affected, quality of life is affected.

Even a simple thing like asking patients about their itch score. What is the worst itch they have had in the last 24 hours? Zero to 10. If you have over a 5 or 7. We know that you actually have a lot of inflammation in your blood. We know that is deeply affecting your quality of life in many different domains.

In this situation, I think we would want to go to a biologic therapy either way. But sadly, we are still seeing every clinic. I am seeing patients with years of topical steroid use and inadequate disease control. I think forums like this are so fundamentally important to be able to change the narrative, about how we treat these patients. What I would like to see is earlier utilization of some of these new breakthrough therapeutics.

[01:17:16]

Clinical Presentation Variability

It is important to recognize is that there is some variability in the clinical presentation of atopic dermatitis. You can see here from these pictures that it can look a little different. You can have more affected areas on the cheeks and infants forehead and scalp, also the extensor extremities and flexural creases. You can see in adolescents face, the neck is a common area as palms and soles. And adults also flexural creases, dorsum of the hands and feet. Those are all important areas.

Some variability in especially darker skin, different skin types. You can see that you can have oftentimes in African-American patients, more popular follicular-based eruptions, especially many African-American children with follicular-based popular lesions distributed throughout the trunk as common misdiagnosis but a common presentation we see all the time.

I practice in inner city Baltimore, so I see a lot of these presentations. Also post inflammatory hyperpigmentation. It is a little bit darker hue to the skin. It is a less noticeable, the erythema. That is an important factor to keep into account.

Then also we see more pink and red erythema in light skin. We know that also many Asian individuals are more likely to get a psoriasiform appearance of scaling, which is important because if you do a biopsy, you could show psoriasis or psoriasiform dermatitis, but it could actually still be eczema. That is important to keep track of.

[01:18:54]

Presentation on Varying Skin Tones

Why do not we look at some photos now more, especially with this variability based on skin type. You can see the erythema also in this Caucasian individuals from the excoriation in the hand. Then you can also see the significant lichenification in some of these other pictures. You can also see different areas of erythema, scaling, as well in these different skin types.

[01:19:14]

Atopic Dermatitis Control Tool: ADCT

I would also like to address a very friendly, easy to use, straightforward tool called the Atopic Dermatitis Control Test or ADCT. This is validated, brief and easily scored self-assessment tool. Six questions to evaluate the different dimensions of AD control, identified as being relevant to both patients and clinicians:

• Overall severity of AD symptoms;
• Frequency of itch episodes, so intense episodes of itching;
• Extent of AD-related troubles;
• Frequency of sleep impact;
• Impact of AD on daily activities; and
• Impact of AD on mood or emotions can be self-administered by patients or using routine consultations, and is designed to help facilitate discussions.

I will actually show you guys a little bit more of all these different questions.

[01:20:01]

ADCT Measurements

If you give these patients this tool and the patients get over a 7 or greater, then they actually triggers utilization of the need for systemic therapy utilization. Over the last week, how would you rate your eczema-related symptoms. So non, mild, severe. Days of intense itching episodes because of your eczema over the last week have been bothered by it. How many nights do you have trouble sleeping? How do eczema affect your daily activities? How does your eczema affect your mind or emotions? These are really relevant questions that can help to measure things.

[01:20:48]

Let us Revisit Our Patient Case

Okay, let us revisit our case, shall we? We will go back to that.

[01:20:52]

Patient Case: A 13-Yr-Old Female With Persistent Moderate to Severe AD

Again, to remind you. This is our 13-year-old female with severe atopic dermatitis, redness and erythema throughout. Itching, lichenification or skin thickening, sleep disruption, has used topical steroids. Remember that is the most important thing to trigger being eligible for these biologic therapies have failure with topical steroids.

But they especially also got systemic steroids and flares and phototherapy. The IgE is 2,300%. Eosinophils, 9%. These blood biomarkers can be helpful because they're actually surrogate biomarkers of increased IL-13 or type 2 inflammation if you know that the IgE is not flare up. It can be helpful to see these different markers.

[01:21:37]

          Posttest 3

Let us do the question now. Okay. Considering the patient's clinical presentation history and lab findings, which of the following factors most strongly supports initiating IL-13 targeted biologic therapy for this patient's atopic dermatitis? Let us see what we get here.

Okay. Can we see the results? Yeah. Okay. Great. The audience did a great, great job here. Okay. 79% again highlighted that despite appropriate use and topical steroids, you are still having severe disease. That is the most important marker.

[01:22:24]

          Posttest 3: Rationale

That is excellent. You can see that the failure of standard treatments despite multiple interventions are what is needed for biologic-based therapy.

[01:22:36]

Key Takeaways

Some key takeaways. IL-13 drives atopic dermatitis pathology. We know that it impairs the skin barrier. We know that that is really important in AD that you have an impaired skin barrier. Filaggrin is like the brick and mortar of your skin barrier. What I would say is you can think about IL-13 is like a demolition crew that weakens that mortar. When IL-13 levels rise, Filaggrin in the brick and mortar of your skin, that production drops and the barrier falls apart, leading to increased water loss, allergens sneaking in and infections flaring up.

You really can think about this in many different ways, but if you have IL-13, it is causing more of those holes to appear.

When you have biologic therapies targeting IL-13, lebrikizumab, newer generation IL-13 greater efficacy also have the first-gen tralokinumab, and then dupilumab, which been FDA approved since 2017 as well. These agents are improving barrier function, reducing inflammation and pruritus. Having effects on all of those different tailored domains. Very important that we target all of those different aspects in the disease.

Let us keep going. Identifying biologic candidates. We know that these are all important features not of severe AD failed topicals, frequent flares for your itch. You want to be a little bit careful in patients are pregnant, immunosuppression, ocular side effects, monitoring therapy and also being able to advance therapy and EASI scoring and IGA also other scores of severity, SCORAD, DLQI, if you need.

Poor QoL, quality of life, sleep disruption are all features for advancing therapeutics. Patient-centered biologic discussions, conjunctivitis and injection reactions. Luckily, most of these biologics do not actually have much laboratory monitoring at all either, which is great. That is, I think, a great way, to tie it all together.

I think those are really our high level overview. I think what I would say is that the unifying, analogy is IL-13 is truly, like in many ways, a master conductor of a dysfunctional orchestra. It gives the wrong cues to every section. It tells the skin barrier to weaken. It tells the immune system and immune cells to overreacts. It fires up the nerves, lowers the barrier for the nerves to fire off itch signals, and the fire plots lay down scar tissue.

When you have IL-13 leading this dysfunctional orchestra, the result is a symphony of chronic inflammation, relentless itch, tissue inflammation and remodeling. It is very important to silence that conductor. IL-13 is 1 of the sparks that keeps relighting the fire. We know that from non-lethal skin, normal appearing skin in an eczema person. You saw actually in many cases have higher IL-13 even in the blood. It feeds the flames of the itch, weakens the skin's protective shell, and also helps develop some of that inflammation in the skin.

I think key features. We had a really great talks by Andrew and Dan. It is great to be able to bring it back together.

[01:26:12]

          Poll 3

Another poll for you all. Do you plan to make any changes in your clinical practice based on what you learned in today's program? Let us see the results.

[01:26:36]

          Poll 4

Then please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education. We will leave this question up. But we are more than welcome to move along to our question and answer session.

[01:26:57]

Q&A

Dr Kwatra: We will start. Dan, I will start with you. What is your spiel? Then we will see Andrew's take on it, too. We are all in the situation. We have patients, they see us. They have been stuck on topicals for a long time. We are talking about escalating therapy.

Sometimes people are resistant. They still have a lot of symptoms. Any pearls that come to mind and how you counsel, how you bridge that divide. We know that we only have a few minutes and many of these encounters, dermatologists, we have to see a lot of patients now. What is your mindset, Dan? Then we will see what Andrew thinks too. Any key pearls how you approach that?

Dr Butler: Yeah. I mean, well, first, I feel like I learned from you and Dr Alexis. But it is an individualized approach, knowing that moderate to severe patients often require, more systemic medications, obviously, with the recommendation being biologics and helping somebody understand that they do not have to live in this like topical cycle of I am doing okay, I flare, I am miserable, I apply topicals until the flare goes away. So I have a 2-week period where this is a real frustration. This is happening over and over and over again.

My suggestion is helping the patient understand that that cycle is something that the studies have shown that it breaks when you go to escalated therapies with biologics, but also being patient with the patient that if they are hesitant, you say, “Look, here are some things that I like to use as leverage or as scaffolding to make this decision. Are you sleeping? What is your activity level like during these flares?”

Those can be ways to sort of take a mirror back and say, “Hey, you know what? These are pretty significant and the topicals just are not doing it.” Those are usually the ones that I like to use the quality of life pieces. Dr Alexis, I would love to hear your pearls, too.

Dr Alexis: Yes. Thank you. I take a similar approach, Dan, and I will just highlight one other dimension to my interaction with patients with bridging from topical to systemic therapy. In very similar ways, I will identify how much of an impact the atopic dermatitis is having on that patient and then inform them that they do not have to continue doing the cycle of flares and putting out the fire of the flares, and not knowing when that next flare is going to be around the corner.

We can today with the agents that we have, we are able to bring the condition to more stability, have a smoother trajectory. No more roller coaster ride, but a smooth ride of being clear or almost clear for an extended period of time. We can do this by using safe and effective medications that are based on targeting mechanisms that we have now very much understand in atopic dermatitis. I kind of bring them up to speed on the latest options and get them excited about how we understand the condition.

It is not a mystery. We know where to target. We have agents that target these key pathways, and we can bring them to an existence where they can sleep the full night and not have to be disturbed by itching and that they can be free of visible, scaly lichenified plaques that sometimes they normalize. They have had it for so long, and they think that there is no life without them. But it is amazing once you put them on a biologic or other systemic agent, and they get to clear or almost clear after years of not experiencing that, it is really transformative.

Dr Kwatra: Incredible. Andrew, do you have any specific pearls? Because in my mind, you are the world leader in understanding and appreciating eczema in different skin types. I know I learn a lot from you. Do you have any pearls or, like I know you have seen so many patients in your career and so much great experience for people who may not have trained in very diverse environments about appreciating atopic dermatitis severity in skin of color patients, and when it may trigger a biologic or other type of therapy, and some clues or suggestions about what is different, maybe from your great expertise that we could help with the audience with.

Dr Alexis: Well, sure. Thank you, Shawn. I think that first and foremost, there is a tendency for atopic dermatitis to not just underrecognized, but even if you have the right diagnosis, atopic dermatitis, the assessment of the severity, can be underestimated, particularly in patients with darker skin types.

This is often with an overreliance on looking for erythema in its purest sense. I understand that the word erythema comes from the Greek word erythros, which means red. So classically we were looking for red. But we realized that in the context of more diverse skin types, this marker of clinical inflammation may not just be purely red. Instead, I like to say that we broaden our color palette and include shades of hues that are violacea-ish, reddish brown, gray.

When we broaden that definition, we can then really begin to appreciate more of the severity. Using the patient symptomatology, to really direct where to examine and also to assess the overall extent and severity is also helpful. Palpation, side lighting. So you can really appreciate, papulation and scale.

As far as appreciating color differences, I like to look at first any islands of non-lesional skin to get a sense of the patient's baseline skin complexion and appearance, and then move to the lesional skin and do a delta in your head. Then you really see when you look at the color change between the lesional and the non-lesional, then you start to really see the reds and the violet and the gray and all the color palette that go along with the inflammation that we call erythema. These are some of the things that I do.

Dr Kwatra: Great. I am going to briefly touch on a couple questions coming in. Have you seen dupilumab shift the immune balance sort of Th1 17 phenotype, which may exacerbate IBD? If yes, what is the risk? Any thoughts from you all on dupilumab shifting immune balance at all?

Dr Butler: Well, I was actually just, noticing all of Nicole's questions. Great questions.

Dr Kwatra: Great questions.

Dr Butler: Yeah. Nicole, you seem to have a GI flavor to your question, so I wonder what your practice is. I personally have not seen exacerbation of IBD, but it is theoretically, a very reasonable question. I do not know if Dr Kwatra, Dr Alexis have seen it. But we certainly see this, and the word shift is debated, whether it was just sort of like an unmasking of a sort of Th1, Th2 hybrid with some Th17 that you block Th2, and then the Th1 side becomes more prominent or if we are truly shifting the immune system over.

We have certainly seen that. Now dupilumab has warning in its FDA label about the risk of psoriasis and arthritis, which are as you probably know, are Th1, Th2 diseases. Then similarly for that along that same thread you asking about eosinophilic colitis. There is certainly themes in the blockade of the atopic conditions. Dupilumab has indications in GI, as you probably know, and probably the other learners here know as well, but it is indicated for eosinophilic esophagitis.

The question is does IL-13 blockade also protect against those? It is a nuanced answer, because some of the IL-13 agents have been tried certainly in the pulmonary world, and they have not worked as well, but there is probably still some efficacy. I send it over to Dr Kwatra and Dr Alexis, if you guys have any anecdotal evidence of either IBD exacerbation or the IL-13s cross talking with the GI system.

Dr Alexis: I have not had any cases of my own that where I have started a patient on dupilumab inhibiting IL-4 and IL-13 and then having them develop any gastrointestinal disease, including the ones mentioned. No, I have not had that experience. Dr Kwatra?

Dr Kwatra: Yeah. Very similar, I personally have not had any experience with the IL-13 inhibitors. But like Dan said, there is the small risk of this shift towards the Th1/17 axis. I would say that is not unique to any one inhibitor. I think it is now a recognized phenomena. I call an immune switching phenomena. It does not matter which biologic you give. If you cut off one dominant cytokine cascade, naturally, you will have a little bit of an imbalance. We have seen that throughout therapies.

I mean, if you even think about TNF inhibitors, you can get paradoxical reactions. A drug like say, dupilumab or any of these IL-13 inhibitors potentially. Yeah. Could cause Th1/17. We also see IL-31 inhibitors like nemolizumab shifting to Th2. We are actually going to learn more through the real-world data, how each specific cytokine blockade can then shunt you towards another axis.

I do not view that as an individual molecule, but as a common feature of biologics that is still exceptionally rare. Then for the IL-13, I think that is eosinophilic colitis or GI, I think it is important to know that IL-13 is a major player across mucosal surfaces, including the GI tract. We know it is implicated in the pathogenesis of eosinophilic esophagitis. There is also some data for eosinophilic colitis, where it promotes barrier dysfunction in the GI tract. Eosinophil infiltration, much like atopic dermatitis, you are just looking at a different interface and barrier.

I think that is why dupilumab’s approval for eosinophilic esophagitis. Also one reason, we saw the blood eosinophils levels or IgE. You see that some of these therapeutics are having positive data approvals or positive reports across many diseases. Atopic dermatitis or [inaudible] as well as pemphigoid itching of unknown origin. It moves on and on even across disease domains.

One of the common features is if you have systemic blood inflammation that is characterized by high eosinophils or IgE, that is correlating very tightly with IL-13 and IL-13 can disrupt many of these different systems. I think that is important to keep track of in my mind how I am actually viewing many of these diseases on a continuum and our labs actually trying to develop a blood biomarker test to help us better phenotype.

What I would like to see later, many years in the future, is using a biomarker to go through trials and approvals because there is so many different similarities even among these different multi-system, different system diseases in terms of pathogenesis. That is a very important question.

Dr Butler: I would just add one more thing, Nicole, to your final question there. I will piggyback off what Dr Kwatra was just saying, which is the hope there for your IBD patient who also has eczema, which is a very common duality, not as common as IBD and psoriasis, but certainly something we still see connected is ideally getting somebody on something that is going to beat 2 birds with 1 stone, 2 conditions with one stone.

Oftentimes we use the more broad immune suppression for those patients. But I think the Holy Grail, like Dr Kwatra was mentioning was being able to profile somebody's immune system and then subsequently attack it with the available medications, be it a biologic agent or something that may be a little bit more broad in its suppression. But you are totally right for those IBD patients, we are looking for something that is going to cross cover. Before it was basically only methotrexate for your psoriasis or for your atopic dermatitis patients. But now, we certainly have a couple others with the JAK inhibitors available.

Dr Kwatra: Absolutely. Let us see. We got a few more questions that came in. We have a question about consideration of biologics with any lichen conditions. I do not know if you guys have had any experience or thoughts on that, using any of these biologics for, say, lichen planus, lichen sclerosus?

Dr Alexis: It is a great question. I am not aware of any studies, looking at our current biologics for lichen planus or lichen sclerosus. I have not had any personal experience using that off label. How about you? Have you seen any developments there?

Dr Kwatra: Yeah. I actually have had one. I treat a lot of patients with immune checkpoint inhibitors as well. I had a patient with dupilumab treatment that actually got a little bit better with lichen planus that got better. There have been some reports of lichen planus. I also had some lichen sclerosus, actually, that seemed to improve actually with incredible itching.

I think a lot of these other diseases that we have not profiled or have not gone through trials and there is endo types, we are learning a lot just by the case reports and a few of these isolated reports coming out. I agree with you. It is totally unknown with like larger controlled studies. But it is incredibly fascinating how we are seeing in the real world now how response to therapeutics can actually, in a way, never before help us understand pathogenesis and pathology and disease biology. That is like the really fascinating, cool part, for us to all see in real time.

Dr Butler: Absolutely. I guess I would add mechanistically, I think we consider lichen planus, more of a Th1-driven disease. Yeah, do not automatically think of those biologics for AD as potentials. But you know what? Time will tell. It is understudied, lichen planus.

Dr Kwatra: Absolutely. Okay. We have another question. Dan, when do you think about discontinuing biologic therapy or weaning biologics? Then we will see what Andrew thinks also, or do you keep them on indefinitely? This is the question we all get.

Dr Butler: We get this for every one of these symposium. It is a great question. The answer is I do not think anybody has the perfect answer. My strategy for this is I tell the patient, we do not use the F word right away, which they always say, am I going to be on this forever? I say, we do not use the F word. We try to give people control for 3 to 6 months.

We say, “Look, you are going to be on this for 3 to 6 months. Let us see how things are going. Let us see how you are doing 3 to 6 months later. You have the control here. You can come off of it. You can extend the dose. You can stay on it. It is up to you.”

The answer to this is it is unique for everybody. We do see data. We saw that in some of the lebrikizumab studies that I showed of this primitive effect of the medications, but it is still TBD. I try to get people to stop thinking that they are going to be right when they start it on this indefinitely or forever, and make sure they know they have control along the whole process.

Dr Kwatra: Great. Any other thoughts on that, Andrew?

Dr Alexis: Yeah, that is well said. I find that patients are most concerned about that question. Am I going to be on this forever? They are most concerned about that right in that initial consultation like before like before they start the treatment. But once they are on the treatment and they have experienced life with their disease under great control, I am not getting too many patients, as many patients saying, can I get off of the drug? They actually are satisfied staying on it for the long term because of the benefits that deriving from it. I am comfortable keeping, them on it, unless there was an adverse. I think I would stop there.

Dr Kwatra: Great. Then I will just briefly answer the last question about a network meta-analysis. That is a statistical method, that allows us to compare multiple treatments. Even if they have not been tested head-to-head, it connects the dots and tries to use shared comparators, placebo. It is really complex. But I mean, my analogy, if you are like sports is it is like kind of like March Madness if you get a big bracket and if one team does not play the other team, we can kind of guess who wins based on how they both did against like a different team.

Like, say, they both played this other team, but then imagine all the statistics in it. Network meta-analysis comparing all the treatments, triangulating through common opponents.