Patient Perspective: The Burden of AD

Dr Benjamin Ungar (Icahn School of Medicine): All right. We are going to start off the meat of the talk hearing from a patient discussing his perspective on the burden of AD. So I will start this video.

Jarrad (Patient): Going to share a little bit about my experience with atopic dermatitis, and I think about it through 3 stages, one of which was when it first occurred and before I was diagnosed, and then later in the early stages of treatment after diagnosis, then the more ongoing maintenance treatment over time.

When I first started to develop atopic dermatitis, I did not know what it was. In fact, the first time that I spoke with a dermatologist, which was not through the hospital system that I am part of now, we did not have a unifying diagnosis even after a skin biopsy. In fact, there was a period of time when we thought it might have been psoriasis. That was a challenging time because, without proper diagnosis, you cannot really treat things effectively. It actually spread and got worse for a period of time in the run-up to my diagnosis. Once it was properly diagnosed, I actually had switched doctors and gone into a hospital system at that point. That is when I was able to start treating it more effectively, and so started with topicals, steroids at first, and then there were some non-steroidal topical options as well. Of course, steroids are not something you can use on an ongoing basis. Ideally, there is something that is used sparingly for flares and not to treat chronic eczema. People have different degrees of severity with their eczema. Some people do need to do it more ongoing than others. Mine was something where I could get away with not using steroids ongoing.

Once I started to incorporate an injectable, which was something that I discussed with my doctor, we decided that the risk profile was fairly low and that the potential upside for reducing the severity of my eczema far outweighed that. We got on it, and I have now been on the injectable for 4 years or so. It has been really great in the sense that, when I first had eczema before I was properly treated, it was dictating things like what I wore, the activities that I did, how I worked out, it was pervasive in that sense. Now it is a little bit more of a background consideration. I do have to consider it sometimes, and every once in a while I do have a flare, in which case I have to take more proactive steps and it might dictate certain activities that I do, but it is not the majority of the time.

I would also just note that my personal treatment plan, which changes for people, I probably fall somewhere in the moderate atopic dermatitis rather than severe, but it is chronic, so it never completely goes into remission. With me, I am on an ad hoc usage of non-steroidal topicals, which I use relatively regular for maintenance and just to keep things from becoming bad. If I have a flare, I do actually incorporate steroids for short-term use. Then otherwise, the injectable is something that I do not stop or go. It is always there, and it helps to contain things.

Dr Ungar: [Inaudible]. I think here that this really highlights one of the themes that I think we need to discuss here, which is putting the patient perspective in mind, because we are going to be discussing different aspects about the disease, ways to measure severity, even patient-reported outcomes. But at the end of the day, as this patient said, there are aspects about people’s lives that are dictated by this condition. Our goal really should be so that this is truly a background concern.

[00:25:36]

Patient Burden for AD: Pain

Now, one of the symptoms that I think is underappreciated in AD, and I do want to call attention to, is skin pain. We think about itch as a core component, and certainly that is going to be the most common symptom. Pain plays a role as well and we can see here in the pediatric population that pain is non-zero in even mild AD, and then as moderate and severe AD we can see increasing levels of pain. When we think about assessing patients’ symptom burden, itch, but also pain, should be something that we think about.

[00:26:13]

Patient Burden: Sleep

Now sleep is arguably one of the most important consequences, or sleep disturbance, the most important consequences of AD. The itch, pain, whatever the symptoms are, affects sleep, and sleep, when it is not good-quality sleep on a regular basis, has tremendous negative downstream effects. Impaired social functioning, interpersonal relationships, absenteeism from work and school and so on. I think these data here really highlight just how much of an impact AD actually has on sleep. If we look at the most severe patients, and it is true in all ages of the pediatric, whether smaller children or older children, adolescents, we see here that something like 2-thirds of the severe patients have 5- or 6- or every-day sleep disturbances. Most of their days of sleep is affected.

Even looking at moderate AD, half the patients have 3 or 4 days or more. In fact, actually a minority of patients, even from mild AD, have no days of sleep disturbance. It really cannot be underestimated just how important it is to actually treat AD and really get things under control, not just for the immediate symptom burden, but also the downstream effects of saying, “We need to get the sleep doing well.” That way people can flourish, hopefully, as much as possible.

[00:27:36]

Patient Burden for AD: Quality of Life

Now we talk about sleep, skin pain, itch, and so on, but AD just generally has a very poor quality of life impact on patients. We can see here, looking at again children from the younger to adolescent children that the more severe the disease, the more significant the quality of impact, which, typically, is the pattern we would expect with a disease that has that quality of impact. In fact, these are the CDLQI scores 21, 17.3, 19.1, different age. That is quite a very significant impact. We know that these children are really negatively affected in terms of their quality of life.

[00:28:22]

Associated Health Effects of AD

There are other things to consider with AD as well. We treat people as a whole, not just their skin. AD is associated with depression, anxiety, shame, disgust, sleep disorder, social anxiety, a whole host of mental health and mental health-related considerations. Patients with AD are 44% more likely to have suicidal ideation and over a third more likely to attempt suicide. 20% of patients with AD have depression, significantly higher than the general population. And so again, when we think about treating patients, it is not just so that their skin looks clear; it is that we are treating everyone as a whole.

[00:29:00]

Mental Health Effects

The mental health effects of AD are quite significant, and there is this concept of moi-peau where the skin holds significant psychological meaning. Now, not everyone necessarily is thinking about this in explicit terms, but I do think this encapsulates the idea that the skin plays a crucial role. It is the container for positive stimuli during infancy. It is the interface that guards against external threats. We know that is a barrier between the patient, the individual, and the outside. It is a unique place that facilitates communication is a surface for interpersonal connections.

For numerous, numerous reasons, chronic conditions can disrupt both physical and psychological wellness, and that is true on a direct basis – a number of things we discussed already – but just, even indirectly, the idea that the skin, which is that protective container, is disrupted itself has negative psychological consequences for many people.

[00:30:02]

Clinical Assessment Tools

Now, we talk about different severities of AD, and it is important to identify what the severities are because that, to a large extent, will dictate treatments. Certainly, the initial treatment approaches and so on, and there are different ways to do it. The different tools capture different aspects about the disease. There is some that maybe are a little easier to use, maybe a little more convenient. But I think it is good to keep in mind different aspects.

Here we have a number of different tools that incorporate the patient perspective – patient-reported aspect. So peak pruritus numeric rating scale – we know that itch is so crucial, and actually assessing the itch and how well they are doing I think is an important part of understanding how well-controlled or poorly controlled the disease is. The numeric rating scale for pain, as we talked about as well.

There is the atopic dermatitis control tool, which is a 6-question tool that can really help capture different domains about AD disease-specific aspects and again assess how controlled it is. There is a DLQI (dermatology-like quality index) which is a little more broad for skin but is used routinely in clinical trials and has cross-disease applicability. Then, probably the tool that is used most commonly is the POEM; the patient-oriented eczema measure, which again is an AD-specific way of eliciting from the patients how well they are doing.

[00:31:27]

Posttest 1  

Let us return to the now the posttest question 1. You are seeing a 3-year-old boy with moderately severe AD. Which of the following approaches best incorporates patient-reported outcomes into the diagnosis, severity assessment, and treatment decisions for this patient?

A. Base treatment decisions on objective measures such as BSA and EASI scores;

B. Use a validated PRO tool such as the POEM to assess symptom burden and treatment response over time;

C. Focus on caregiver-reported symptoms rather than the child’s reported symptoms when adjusting treatment; or

D. Initiate systemic therapy based on severity scores, even if the child and family perceive the symptoms as mild.

Again, we will give everyone a moment to answer. We have the majority of people answering B: use a validated PRO tool such as POEM to assess symptom burden and treatment response over time. Indeed, that is the answer. Again, there are different ways to assess disease severity and to help guide treatment decisions. When we are thinking about incorporating patient-reported outcomes, it is very helpful to use a tool like the POEM, which is a validated patient-reported outcome tool.

[00:32:55]

Monitoring Treatment Response

When we think about treatments for AD, it is not just about where they are when they come in. It is not just about the initial treatment, and it is not even just about evaluating in broad terms how they are doing. It is helpful to track with some of these outcomes as well how patients are doing on treatment. When we are, for example, using the POEM, it is not the only option. If you get that at baseline when we are coming in, then we can see does that improve with treatment? Does that achieve actually that minimal disease threshold that we are looking for? Does it get us to clear almost clear skin with minimal itch? In a condition like AD that is waxing and waning and can flare and patients often just feel a lot better even if they are not at that threshold, these kinds of patient-reported outcomes can be helpful to actually assess are we actually getting to that level of control that we are looking for.

[00:33:53]

Patient Case 1: Sarah  

Let us take a patient case here or discuss a patient case that illustrates an aspect. Sarah has a long-standing history of moderate to severe AD since childhood, primarily affecting her hands, arms, face, and neck. She has managed her AD with topical corticosteroids and topical calcineurin inhibitors for several years, along with regular emollient use. Despite good treatment adherence, Sarah’s symptoms remain poorly controlled, as persistent pruritus and frequent flare-ups affect her sleep and daily life.

Three months ago, Sarah started a biologic agent due to inadequate response to topical therapy. She tolerated the treatment well and has no significant adverse effects. At follow-up, she reports significant improvement. On examination, Sarah’s only skin involvement is erythema on her face and lichenification on her arms. However, she continues to experience pruritus rated 6 out of 10, particularly at night, and it disrupts her sleep.

Just briefly, even before going to the next slide, we will say, she is doing great and that she looks like she is doing great. She is still having quite a bit of itch, and so that is important to elicit that because we are not going to see that. It is still having an effect on her.

[00:35:02]

Strategies to Incorporate Systemic Therapies Into Treatment Plans

Let us move on to strategies to incorporate systemic therapies into treatment plans.

[00:35:08]

Poll 5  

We have poll 4 here. What factors do you consider when determining if a patient is appropriate for systemic therapies in the management of moderate to severe AD?

A. Clinical severity score;

B. Patient-reported disease burden of disease;

C. Patient’s age or other characteristics;

D. The cost of therapy; or

E. Other.

Maybe more than 1 applies. A mix where it looks like most people are incorporating multiple considerations there.

[00:35:53]

Differentiating AD Severity

One of the most important first steps in assessing some of the AD, of course, is to determine how severe they are, because we know that different treatments – and we are going to discuss some of this – may have implications, or different disease severity may have implications for different treatment approaches. Mild AD will have a few patches of dry skin, some itching; minimal impact on quality of life or sleep. We know that it is not zero impact so that they can have some, but it is usually not a major component. Perhaps they will be a little easier to treat them.

In the moderate ranges that dry skin, frequent itching, we often will see excoriation, certainly we’ll see skin redness, and we know from all the data and experience that has a significant impact on quality of life and sleep. Then we have severe patients. Large areas of their body are affected by that dry skin redness. They have constant itching, excoriation, and impedes their daily routine and sleep. In that spectrum, getting comfortable and assessing that severity is important. Particularly the difference between mild and moderate to severe has significant implications for treatment decision-making.

[00:37:05]

Total POEM Score: Severity Scoring

Now, we talked about POEM as a tool and for assessing how the patient is doing. Again, it is always useful to look at the outcomes, and so we actually know what the numbers look like. This is, I think it is a good guide to say, our goal should be where someone fills out a POEM and have that zero to 2 range. Three to 7, we are doing better. Then, beyond that, we are really in that moderate to severe, even very severe range.

[00:37:35]

AAD 2024 Guidelines: Baseline Therapy for AD

Now, when we think about treating patients and assessing patients, there are the 2024 AAD guidelines that help provide us a lot of guidance as the goal is, of course, on how to approach and think about the steps involved in treatments and the level of recommendation that the expert consensus came to on different treatment approaches. There is, of course, the severity assessment, and we have already discussed a lot of that. Understanding how bad the disease is, symptom severity, comorbidities, the extent of quality of impact in life. If there are exacerbating factors like allergens, irritants, and so on, that certainly is important to discuss that. In practice, that is sometimes something you can identify. Often, it is not so clear cut, because we know there is a lot of internal inside-out flaring that we may not be able to pinpoint to an external allergen or inciting factor. Now, baseline therapy, particularly if it is quite mild, can use moisturizers and emollients. It has a strong level of recommendation, bathing practices, a conditional recommendation. In general, those are going to work primarily for very mild patients.

[00:38:48]

AAD 2024 Guidelines: Topical and Maintenance Treatment for Mild to Severe AD

Now, when we move away from those very mild patients and to the more mild to moderate range, although it is potentially an option even for the severe, but typically these are going to be more in the mild to moderate, there are FDA approval and strong recommendations for topical corticosteroids, topical calcineurin inhibitors, crisaborole, which is a PDE4 (phosphodiesterase 4) inhibitor. Ruxolitinib cream. The wet dressings have a conditional recommendation, I think typically do not play a major role in treatment at this time. Then there are also FDA approvals for roflumilast cream and tapinarof cream. Neither of those were included in the AD guidelines because they were not approved yet, so the guidelines preceded them. It is my opinion that these are likely to be listed alongside with that strong recommendation, although we will have to wait for the next guideline updates for that.

There are different approaches to how to address the treatment. There is an “as needed for flares” approach. There is a proactive approach, where if you know that there are hotspots, you continue using some degree of these topical anti-inflammatories preemptively. Certainly, not a good idea to do that with topical corticosteroids on a regular basis, frequently because then there are side effects, but those are options as well. A lot of that has to do with the conversation with the patient and what fits best for them. There is no one-size-fits-all, and we are going to be discussing shared decision-making a little more. I think it really is crucial to be on the same page with the patients about what is the best way for them.

Now, if those are not working, there are a couple of options and a couple paths forward. There is the possibility that in fact, the patient does not have atopic dermatitis. Now, hopefully, our diagnosis from the initial visit is the correct one. That is not always going to be the case. I think it is important to keep in mind, at the very least at the back of your mind, sometimes a little more upfront, is there something else, like contact dermatitis or, in relatively uncommon cases but can happen, cutaneous lymphoma? If there is still that level of confidence, in fact is atopic dermatitis, it is not a different diagnosis, then adding either phototherapy or systemic therapy at this point is warranted because if they are not controlled, we should not be just putting our hands up and saying, “You are doing better or you are doing okay.” Our goal really should be for the patients to be doing great.

[00:41:17]

AAD 2024 Guidelines: Systemic Therapies for Moderate to Severe AD

When we look at the systemic therapies – and we will put phototherapy in there as well. Phototherapy is a conditional recommendation, often use can be monotherapy or in combination with topicals or other systemic therapies as well. There are 4 approved biologics: dupilumab, tralokinumab, lebrikizumab, nemolizumab. The first 2, dupilumab and tralokinumab, made it into the AD guidelines as strong recommendations. The next 2 listed there again were approved after the guidelines, and again, in my opinion, likely are to be listed alongside with strong recommendations based on all the clinical trials and real-world evidence that exists so far.

There are also 2 FDA-approved oral JAK inhibitors, upadacitinib and abrocitinib, and it is important to note baricitinib is included as well. It is not FDA-approved in the United States for atopic dermatitis. It is in Europe, and it is, I think, important to keep in mind, certainly that baricitinib is approved to treat severe alopecia areata in adults. Very often, there is comorbid atopic dermatitis and alopecia areata. In some cases, if someone’s being treated for alopecia areata, it may be good to assess how their AD is doing.

Then there are conditional recommendations for the traditional systemic immunosuppressants: methotrexate, azathioprine, cyclosporine, and mycophenolate. Then, really a strong recommendation against the use of systemic corticosteroids. I think there are many practitioners still that use systemic corticosteroids in many cases. In previous eras where we did not have this plethora of treatments, they played a crucial role, in many cases helpful. At this point, we have better options, whether it is for the acute cases, chronic and so on. Really should be avoiding systemic corticosteroids.

[00:43:09]

Poll 6  

All right. Now let us move on to the next poll question. What percent of caregivers of children with moderate to severe AD are satisfied with available treatments?

A. 30% to 39%;

B. 40% to 49%;

C. 50% to 59%; or

D. 60% to 69%; or

E. Greater than or equal to 70%.

We will give everyone a moment to answer. The most common answer was the first: 30% to 39%. Maybe a little better level of satisfaction, but again, 40% to 49%, that means a majority of caregivers of patients with moderate to severe are satisfied with available treatments. That may be at least in part because we collectively are not utilizing the available treatments to their maximum potential.

[00:44:00]

Available Topical Therapies

What are the available topical therapies for AD? Of course, corticosteroids play an important role. They’re often used as a first-line treatment. That really makes sense, but typically in the shorter term, non-continuously you have to think about different areas that are sensitive in particular with steroid potency. Many patients have steroid hesitation, so those are all considerations. There are topical calcineurin inhibitors: tacrolimus ointment and pimecrolimus cream. Those can be used as well in many cases.

Different depending on the concentration and formulation, approved for patients 2 years and over. Sometimes there can be transient burning or stinging sensation, a little more appropriate for not just short-term use, not necessarily something we use long-term, but can be used a little more consistently than topical steroids. There are 2 approved PDE4 inhibitors: crisaborole, which was approved several years ago, and roflumilast cream, which is a little more recent. These are a different targeting approach than either corticosteroids or calcineurin inhibitors. Safe and effective. Then again, depending which one have different ages approval, it can be very beneficial as well.

There is a topical JAK inhibitor, ruxolitinib cream, which is approved for non-continuous use and can be an option as well as a non-steroid in adolescents on the label. The idea is not to apply it all over the body or there is 20% BSA or greater, because there is concern at that point that there is enough systemic absorption that we start thinking about some of the considerations for oral JAK inhibitors.

Then lastly, most recently was this tapinarof cream, which is an AhR hydrocarbon receptor modulating agent approved for patients 2 years and up. There are a couple of adverse events, at least, to think about, and none of them are particularly common and can be used in different areas of the body, and is an excellent option as well.

[00:46:29]

Assess AD Severity

We discussed this, but just taking a step back to frame this. We look at mild to moderate AD where we think about non-pharmacological measures and then optimize topical therapy. In the moderate to severe range, we are doing all of the above. If that is not working, we are adding systemic therapies. Moving from left to right on these arrows, I think it is important that we are not dragging this out and delaying. It is almost not well-controlled, and that is not to say the next day, a few weeks or a couple of months, it is really time to think about optimizing and adding systemic therapies.

[00:47:05]

Candidates for Systemic Therapy for AD

Who is a candidate for systemic therapy? 25% of patients with moderate to severe AD are not controlled with topical therapies. The question really, or the answer to this question, is bolded in the bottom. Consider systemic therapy for children with inadequate response to or intolerance of topical therapies. Now it is a conversation with the caregivers, potentially patients, about whether systemic therapy is appropriate and so on. The idea of initiating that conversation is important when they are not doing well. If they are not at that point, we are thinking that clear, almost clear, that should ring a bell to say, “Hey, maybe it is now time to have the conversation,” even if we are not starting the treatment today. Thinking about moving that direction.

Why do topical treatments fail? Well, for one thing, they just may not be sufficiently effective. Even if someone bathes in it every day, just may not work. It is also difficult in many cases. I have had patients recently come in and say, “Hey, can I actually have a cream instead of an ointment, because it is getting all over my clothes?” They have a cream and say, “I just cannot apply it all over the place.” Actually adhering to treatment is important. Even if we have a perfect treatment, if patients cannot do it, then that is going to be an issue. It is also the case that their disease flares. If there are triggers that are contributing to worsening disease, it just may not be sufficient to use the topicals. Then again, if the disease severity exceeds what topicals can do, time to move on.

The other thing to think about here is that this is a chronic condition. Does the patient have this disease for years? This was 1 study that said the disease duration was for 15 years, and mean EASI score was 11.2. That is not super well controlled. A third of patients were untreated with anything, which, again, in moderate to severe patients, really should not be happening. 44% used routine topical corticosteroids and calcineurin inhibitors, only 7% with systemic therapies. Now, not everyone who has moderate AD is going to require systemic treatments, but it is certainly more than 7%. That is a gap right there where people are not ultimately being well controlled.

2.8% were completely satisfied with the treatment. That is understandable because they are not either getting enough or they are not getting enough disease control, or it is too burdensome to actually adhere to the treatment regimen when we are talking about topicals.

Adults, similar perspective. If they are not responding, they cannot handle their intolerance to topical therapies, time to think about systemic therapy. Steroid resistance can develop. There is economic considerations. Financial burden of topical therapies. Maybe they are not applying it correctly, and that can sometimes be they are not applying it frequently enough. In some cases you have patients, you give them a jar of triamcinolone, they come in having been instructed to only use it for 2 weeks daily, and they come back 3 months later having use it every day. There are side effects, and they may have concerns, and we certainly have concerns as well.

[00:50:14]

Systemic Therapy Considerations

Now, when we think about systemic therapies, we have talked about disease control. In general, moving beyond the idea of, is someone a candidate for therapy?, which is an absolutely crucial step to say, “Hey, am I really sufficiently treating them? Then there are questions of which therapies and so on. The answer to that is complicated. Some of the considerations that go into selecting whether someone should be on a systemic therapy and then which one if they are includes the phenotype clinically, comorbidities, different treatments have different risk-benefit profiles which may differ from patient to patient. Their preferences, oral injectable therapy. Their level of risk tolerance. Drug interactions and clinical monitoring. Do you need to check blood? Are they on other medications that might interact? Then, ultimately, access to treatment, of course, is crucial. If they cannot get or afford the treatment, does not matter how great it is, it is not going to improve their AD.

[00:51:11]

Traditional Systemic Therapy

Historically, traditional systemic therapies have been used. In many cases, they may still be used. The recommendations, certainly from the guidelines, are weaker. In general, I would encourage people who still use these for these treatments to think about moving to some of the newer treatments that generally have a better efficacy profile and safety profile in most cases. Also, these can take some time in addition to the side effects. Cyclosporine tend to work a little quickly, and there may be a role in some cases for flare to calm things down quickly, but azathioprine and methotrexate, and mycophenolic – they all take a number of weeks to kick in.

[00:51:51]

Traditional Systemic Therapy: Safety Considerations

The toxicities and safety considerations for these traditional immunosuppressants, and on top of that corticosteroids in addition to that, as you can see, are a very long list. Unlike many of the lists of side effects and so on, where if you listen to one of the ads that are on TV, there is a long list, and those are quite rare, these actually are not rare and are very real considerations that may impact patients. In a world where these are the options, we do the best that we can to mitigate these side effects. In a world where we have other options that have efficacy that exceeds these and safety that is tremendously higher or some combination of the 2, these really should be reserved for last-ditch efforts.

[00:52:38]

Biologic Targets

We talked about the 4 FDA-approved and additionally the additional approved in Europe treatments for AD that are systemic, that are the newer treatments. The first one approved now 8 years ago is dupilumab. I am going to discuss briefly the mechanisms. Dupilumab blocks the IL-4 receptor alpha subunit, so the receptor which signals for both IL-4 and IL-13. So it blocks IL-4 and IL-13 by blocking the receptor.

Then the next approved was tralokinumab, followed subsequently by lebrikizumab and nemolizumab in terms of biologics, and the lebrikizumab and tralokinumab both block as this shows as in the diagram IL-13 directly the cytokine. Nemolizumab again a recently approved antibody in biologic as well blocks IL-31 receptor, blocking IL-31 signal.

Now, if we go to the bottom of the diagram, we see that abrocitinib, upadacitinib, which are the FDA-approved treatments, both block JAK1. Baricitinib also blocks JAK1, JAK2. If you look at all the cytokines that are being blocked by antibodies, in part, they are signaling through JAK1. We know that those are treating and blocking and hitting a number of the key cytokines that are being targeted through other mechanisms by the biologics.

[00:54:01]

Newer FDA-Approved Systemic Agents for AD

Here we have a list again of the newer FDA-approved systemic treatments for AD. We talked about the mechanisms of the different treatments. Dupilumab is approved for infants 6 months and older. The rest of the treatments are currently for adolescents 12 years and older. The first for subcutaneous injections depending on the treatment every 2 weeks, which is the approved treatment for dupilumab. Two to 4 weeks for tralokinumab. Four weeks for lebrikizumab – 2 to 4 weeks, depending. Four to 8 weeks for nemolizumab and then abrocitinib, upadacitinib are oral medications taken once daily. I am not going to go through the dosing here. That is something you can review at length, but there are different doses for pediatric populations in some cases. The injectable medications generally concerned with things like conjunctivitis, parasitic infections, vaccinations, abrocitinib, and upadacitinib have boxed warnings with high potential risks that need to be addressed. Serious infections, mortality, malignancy, MACE and thrombosis as well.

[00:55:08]

Biologic Therapy for AD

When we think about biologics, what are the benefits and flipside considerations? They are self-administered subcutaneous injections. Two to 4 weeks depending on the time and the loading and the specific medication. They work very well in many cases there is demonstrated efficacy, and that includes after failing other treatments, including many cases, other systemic treatments. They have durable efficacy so, if someone responds, they are likely to continue responding. None of the biologics require any routine lab monitoring, which is a great feature as well.

Conjunctivitis in at least some of the treatments. Not really nemolizumab, but the other ones to some extent, need to be considered can be treated with artificial tears or in some cases ophthalmologic input as well. They can be associated with injection site reactions, headache, upper respiratory tract infections, onset of new autoimmune disease. Those are a little less common and maybe not as much. Major considerations, all important to keep in mind. Vaccinations also, there is a little bit of a gray area in terms of what is recommended by the FDA and the label and updated guidelines and so on. That can vary from patient to patient depending on the specific circumstances.

[00:56:24]

LIBERTY AD PED-OLE: Dupilumab for Pediatrics With AD

Let us look at some of the data here, and this is the LIBERTY AD PED-open label extension, so dupilumab for pediatric patients with AD. As I mentioned approved for infants 6 months and older. This open-label study was for patients 6 months up to 18 years looking at the safety and then also the efficacy as well. In the different age groups, whether 6 months to 5 years, 6 to 11 years, 12 to 18 years, we see relatively consistent safety profiles, which are overall pretty well tolerated. Yes. There is some nasopharyngitis, particularly in the younger infants, which we are likely to see in any population of infants and younger kids. Upper respiratory tract infections, cough, and so on. When we look at the efficacy, it is quite encouraging. Roughly speaking, 80% of patients are getting a 75% improvement or more of their EASI. 50% to 56%, 58% are getting EASI 90 scores, and that is 90% of improvement. Roughly speaking, 40%, give or take, are getting clearer, almost clear skin. We know that it works well and also does so safely.

[00:57:37]

ECZTRA 6: Tralokinumab for Adolescents With AD

Tralokinumab, again that IL-13 inhibitor approved for adolescents with moderate to severe AD. When we look at ECZTRA 6, which was tralokinumab for 16 weeks in patients age 12 to 17, then they were randomized either 2 weeks or 4 weeks until 52 weeks, again plus or minus topicals. Looking at efficacy and safety again, we see that it does work and these exceeded placebo rates. 20 or so percent give or take achieving IGA of 0/1. 30% getting that 75% improvement and EASI very well tolerated from the safety perspective. Again, very low rates of adverse events. Another excellent option.

[00:58:23]

ADore: Lebrikizumab for Adolescents With AD

More recently approved is lebrikizumab, which is the second IL-13 inhibitor directly for patients 12 years or older. Then the ADore study is that open label extension. We see a theme here. All the drugs go through these trials. Open label extension for 52 weeks, and again, that we are going to see very similar processes, low rates of nasopharyngitis. Upper respiratory tract infection, headache, some maybe flares or so on – it is sometimes hard with the clinical trials to know exactly – rashes of AD. Then looking at those EASI 75 responses, so definitely improving over time. Relatively low rates of week 4, but then a big jump by 16 weeks 28% to 73% EASI 75. 44% EASI 90. 46% IGA at week 16 and we see actually quite a bit of improvement even subsequent to that. It is not the maximum effect to see efficacy is at 16 weeks.

[00:59:34]

ARCADIA 1 and 2: Nemolizumab for Adolescents With AD

Then ARCADIA 1 and 2, which is nemolizumab for adolescents with AD, so IL-31 inhibitor as we discussed. These are patients getting nemolizumab vs placebo for 48 weeks. There is a loading dose, and then responders are randomized either to every 4 weeks or every 8 week dosing for this long-term extension. We see here again really nice response rates. Week 16, EASI 75 response. 40%, 42% improving over the course of a year, and those exceed placebos. IGA of zero or 1, which is a stricter threshold. Again, at week 48 a year in almost 2-thirds achieving IGA of 0/1. Very, very low rates of side effects. Really roughly in range of placebo.

[01:00:24]

JAK Inhibitor Efficacy and Safety for AD

Now, JAK inhibitors are an option as well. I think, there are sometimes some hesitation but I think it is worth thinking about first looking at the efficacy as well as the safety of the JAK inhibitor. JADE regimen was a randomized trial of abrocitinib either 100mg or 200mg vs placebo for 40 weeks in that adolescent population. Who responded to abrocitinib 200 milligram induction? We can see here again, looking at that 200mg EASI 75 responses exceeding 70. IGA of zero, 1 that clear, almost clear. Quite high level, 60, 60-plus percent. In fact, actually low rates of severe adverse events. Low rates of serious infections. Important to keep in mind that there is a warning and that should be respected and discussed and considered, and factored into the treatment. We also use the data to guide us and low rates of those things happening.

Now, the second, the other oral JAK inhibitor that is improved, which is upadacitinib in AD Up, which is a randomized trial of 15 or 30mg plus topical corticosteroids vs placebo in patients 12 and up, with the placebo group randomized to upadacitinib at week 16. Let us see if we control to week 16. Then everyone then got 15 or 30. Again, we see that, a year in, people have excellent IGA 0/1 scores. 33%, 45% EASI 75 depending on the dose, 50%, 70%. And again, low rates of serious adverse events. Eight per 100 patient years.

[01:02:14]

JAK Inhibitors

Let us discuss JAK inhibitors a little more. Their systemic therapy is approved for use in patients with inadequate control or having other contraindications to topical therapies and biologic agents. Potential benefits. There is a lack of immunogenicity concerns that accompany monoclonal antibodies, which is to say the body’s immune system reacting to this foreign protein or antibody. Many patients prefer oral therapies over parenteral options. I think in many cases that is particularly true of the pediatric population.

As a general rule, I would say children and adolescents are less likely to tolerate injections. They have a short half-life. That is why they are taken daily. That can have the benefit of being able to “turn it on and off” a little more easily. If it is controlling things well, there is the potential for maintaining disease control long term. To some extent, you can decrease that to the lowest efficacious dose. It is not necessarily on the label described, but in practice, you can taper slowly to say, “Where can we keep things controlled at a lower dose?”

Monitoring is required, so typically speaking, blood counts, LFTs, lipids those are something you are going to monitor on an ongoing basis, looking for infections, cancers, thrombosis. Should not be taken during pregnancy. There is also the warning that we discuss with the 5 significant risks that are listed, although those have not manifested in any AD trials thus far with either abrocitinib or upadacitinib.

[01:03:52]

Posttest 2  

Let us revisit the following question. Which of the following patients with moderate to severe AD would be the best candidate for biologic therapy?

A. 22-year-old woman with AD involving 5% of her BSA controlled with topical steroids and emollients;

B. A 45-year-old man with an AD involving 15% BSA who has achieved partial improvement with topical steroids and antihistamines;

C. A 30-year-old man with AD involving 30% BSA with persistent pruritus despite consistent use of high potency topical corticosteroids and phototherapy; or

D. A 60-year-old man with AD and a history of well-controlled hypertension who has not yet tried topical calcineurin inhibitors.

We will give everyone a moment to answer. The vast majority of people answered C. This patient has 30% of his body involved. He is itchy. He is using topical steroids, phototherapy. At this point, it is clear that these are not working and advancing to a biologic therapy really makes a lot of sense for him.

[01:05:09]

Emerging Therapeutic Agents

Briefly touch on some emerging therapeutic agents because we are fortunate that there are a number of approved therapies, but there are other therapeutic agents emerging as well. Amlitelimab is an OX40 ligand inhibitor. Jumping to the bottom we have baricitinib, which is an OX40 inhibitor. Two treatments blocking the 2 sides of the OX40 ligand interaction. That interaction is involved in activating T cells and getting them revved up. By blocking that, maybe we are calming down that immune system. Baricitinib we discussed is oral JAK1, 2 inhibitor approved in Europe. It remains to be seen if there is an attempt to get it approved in the US, but given approval for alopecia areata, it is important to understand that it does work in AD as well based on the clinical trials data. Certainly, we see in Europe. Etrasimod is an S1P receptor modulator and to some extent, plays a role potentially in keeping the T cells that may be pathogenic from getting to the skin as well. It will be interesting to see how these develop in the clinical trials data that comes out for each of these.

[01:06:21]

When Should You Refer to a Subspecialist?

One question definitely is, when should you refer to a subspecialist? There may be some very difficult-to-treat cases, and important to think about, “When should I be sending a patient as someone who really sees a lot of AD?” If someone is not responding to first- or second-line treatments, there is a question of what the next step should be and a subspecialist may be a good option. Diagnostic uncertainty or lack of confidence in correct diagnosis. We heard from the patient earlier he had been misdiagnosed, or at least there was some diagnostic uncertainty even after biopsy. That has implications of treatment, and maybe a subspecialist would be warranted. If there is uncertainty that a patient is a candidate for systemic therapy, getting the patient connected with someone who can better get to that decision may be warranted as well.

[01:07:11]

Patient Case 2: Emily, 6-Yr-Old Girl

Patient case 2 here is Emily, a 6-year-old girl with a 2-year history of moderate to severe AD that primarily affects her face, neck, and flexural areas of her elbows and knees, experiencing persistent pruritus that disrupts sleep, leads to frequent scratching, excoriation, secondary infections. Her parents rather have managed her condition with emollients, mid-potency topical corticosteroids, topical calcineurin inhibitors, and despite good adherence, so she is applying them. She continues to experience frequent flares and discomfort that significantly affect her sleep and performance. Her POEM is 18, which we know from earlier is very severe. What can we offer Emily for treatment?

To me, at this point, I think it is quite clear that she probably is a good candidate at least for a discussion on systemic therapy and likely actually beginning systemic therapy. She is 6 years old, and we have an approved safe, effective option for a 6-year-old with moderate to severe AD with dupilumab. In many respects, I think that is a good next step to discuss with her parents to see if that is something that she might benefit for.

[01:07:29]

Patient Case 3: Mark, 34-Yr-Old Man

The next case is Mark, who is a 34-year-old man. 10-year history of moderate to severe AD, primarily affecting his face, neck, and flexural areas. He has been treated with mid- and high-potency topical corticosteroids, topical calcineurin inhibitors. He is using emollients regularly. Continues to experience persistent in pruritus, erythema, lichenification, flare-ups interfering with work and sleep, and severe POEM score of 19. At follow-up, he reports an itch that is still a 7 out of 10. Poor sleep due to nocturnal scratching, erythema, excoriation, thickened skin, and affected areas. He is expressing frustration over the lack of improvement and impact on daily life and mental health. What can we offer Mark for treatment?

The first step, as always, is to decide is he well controlled. Hopefully, it is quite clear that he is not. He has severe AD despite all these topicals. Then we think about what systemic therapy may be best for him? We discussed there are a number of options, and certainly superficially, he may be a candidate for really any of them. Part of answering that question is going to be a conversation with Mark.

[01:09:29]

Taking a Patient-Centered Approach to Managing Moderate to Severe AD

That brings me to the next point, which is that patient-centered approach to managing moderate to severe AD.

[01:09:34]

Poll 7  

Next poll question. When determining a treatment plan for patients with moderate to severe AD, how frequently do you consider a patient’s lived experience and personal preferences?

A. Less than 25%;

B. 25% to 50%;

C. 51% to 75%, or

D. 76% to 100%.

Alright. The majority of people are at least 50-plus percent of the time.

[01:10:15]

Shared Decision-making Principles

Now, Mark, that last patient, I think raised a really good scenario, which is we agree that he is a candidate for systemic therapy. Which one? To get to that decision, there is no one size fits all, and there is so many different factors that come into play. I think at the core is engaging the patient to help make a decision that is right for the patient in front of us because there are so many factors that come into play, whether it is preferences, goal, cultural considerations, access to resources, appointment needs. If someone can only come in once in a while, that may direct us away from a treatment that requires more frequent monitoring. Someone wants immediate relief, that is going to be different than a patient or a treatment that takes longer. The only way we are going to get that correct is if we engage the patient in sharing those ideas.

[01:11:03]

Employing Motivational Interviewing

At the end of the day, if the patient has buy-in to the treatment decision, they are more likely to get that great response long term. They have the buy-in. They are going to give it the time that is necessary. They are going to be consistent in here with treatment, much more so than if they are not participating with that treatment decision. Part of that has to do with all the things that we have learned in training. Asking permission, building an alliance, asking questions. “What aspects are most important to you? Here are the options that some of the pros and cons of each one. Which one of those resonates? Do you have additional questions? What are you thinking about? How would you like to proceed?” Because again, if that patient is participating in the decision, they are going to be happy with going down that path, and frankly, more likely to say, “You know what? We are going to try this. Maybe that did not work. Let us go on to the next treatment and get that long-term result.”

[01:11:58]

Avoid Common Triggers

We talked about avoiding some common triggers. This often can be helpful. Dust mites, pollen, humidity, weather extremes, and it is something important to keep in mind. In many cases, it is not going to play a major role, but should be thought about as well. We are talking about pharmacologic treatments. They are behavioral considerations and environmental considerations as well.

[01:12:19]

Pediatric AD Action Plan

Many people find it helpful to use a pediatric AD action plan so that there is something on paper with steps that can be implemented at home to think about how to approach treatment, whether that is in that maintenance phase if things are going well. If there is mild, moderate flares, begin stepping up that treatment. If there is severe or significant quality of life impairment, maybe we have to shift as well. This is a tool that can be helpful in many cases, and often, particularly this one is geared towards pediatric patients.

[01:12:52]

Adult AD Action Plan

There is also an adult AD action plan that is available as well, and often it can be helpful again for patients to have on paper, “How do I approach things? Here is some information.” This is not necessarily a tool that everyone is going to use, but should be aware and think about, “Hey, maybe this is something that is going to work for me. I am going to send them home with this action plan. When they follow up, we are going to be better positioned to have that conversation about where things go next.”

[01:13:17]

Patient/Provider Video  

Here is a follow-up video we are going to get to listen, get to hear me chat a little bit with Jarrad, this patient over here. An example of some discussion on considerations with therapeutic options.

It is good to see you again and continue the conversation that we have had over the last several months and years in terms of treating your atopic dermatitis. I know that you currently are on an injection medication that is been doing a pretty good job of keeping things well-controlled. I do want to continue the conversation about whether that makes sense to continue that treatment, thinking about alternative treatments, or even have them in mind for the future. Based on that and some of the discussion we have had in the past, what questions do you have about the different treatment options?

Jarrad: Yeah, for sure. When we first came onto the injectable, when starting a new drug, my considerations were just what are potential side effects and how to weigh those against the benefit of the treatment. I understood those to be potential development of face eczema, like dry eyes, and then I remember asking you about if it was inhibiting my immune system more broadly or if it was targeted. Essentially, started the medication and any potential risk, which felt nominal, was outweighed by the fact that it does greatly reduce the severity of my eczema and has allowed it to be more of a background consideration vs something that is dictating a lot of decisions of my life every single day.

Of course, I am always interested in understanding new drugs that are going to be coming on the market or alternatives that I could take. I do understand, for example, that there are some pill options that I do not know too much about, and I would be interested in learning about those.

Dr Ungar: Yeah, absolutely. I think your point is such an important one where we have to think about the benefits and risks weigh the potential upside of the treatments. Think about what the side effects or risks may be. You are on a very safe injectable medication that fortunately is not causing any side effects for you, and there are some other potential injectable medications to think about also that work a little differently.

One of the options that may be beneficial for many people are these oral medications. They are pills typically taken once a day that can be quite effective in treating atopic dermatitis. As well as with any treatment we have to think about some of the aspects may be different. In the case of the oral medications, there is some degree of lowering of the immune system. As you mentioned, that was a major consideration for you and thinking about what the effects of the treatment would be.

Now, in reality, and according to all the studies that we have so far, the likelihood of infection is pretty low with these oral medications, these JAK inhibitors, but they are something to keep in mind. It is in general, a personal decision weighing how much the impact of the condition the atopic dermatitis is vs what the benefit of treatment is. In your case, there is another consideration you are thinking about what the impact of injections are. How easy it is to do that consistently vs potentially taking the daily oral medication. For some people, that might be an easier thing to do. Avoid needles. Some people may find it easier to say, “I only think about this every 2 to 4 weeks when I do the injection and do not have to think about the oral medication.”

One last point I will just add, and it is always important to discuss this when discussing the possibility of JAK inhibitors, is the FDA has put a warning on these medications, all of them, about some potential risks that we have to think about and contextualize. So far, in the studies in treating atopic dermatitis, these medications appear to be very low risk. There is some uncertainty both from the infections and some other side effects that we have to think about as well.

Alright. It is a conversation, at least in part, alluding to many of the things we have discussed today, that is representative of conversations that I have with patients all the time. Although I will say it is always interesting to see yourself speaking about it.

[01:17:55]

Posttest 3  

We will go up to posttest question 3. You are considering initiating systemic biologic therapy for a young boy with AD. To incorporate shared decision-making into the treatment plan, which of the following would be the most effective approach?

A. Discuss the child’s and parents’ treatment goals and concerns and decide together on the next steps in treatment;

B. Recommend the biologic therapy based on clinical guidelines and instruct the parents on how to administer the treatment;

C. Provide detailed information about the benefits and potential side effects of biologic therapy, and ask the parents to decide what they would like to do; or

D. Present the treatment options, recommend that parents conduct their own research, and schedule a follow-up discussion.

We will give everyone a moment to answer that. Alright, so the most common answer was A, which is the answer. When we are thinking about shared decision-making, the core of that is understanding the goals and concerns that the child or, in this case, patient’s parents have and then coming together to make a decision.

[01:19:10]

Posttest 4  

Next question. After participating in this activity, how confident are you in your ability to treat all of your patients with moderate to severe AD?

A. Not confident;

B. Somewhat not confident;

C. Somewhat confident;

D. Confident; or

E. Very confident.

Alright. Most people are now somewhat confident or confident. Excellent.

[01:19:44]

Key Takeaways

Some key takeaways. Again, AD significantly impairs quality of life for patients and caregivers, and really I think we owe patients good treatments because we have them. Topical therapies remain first-line treatment, but there are also newer systemic options for patients with severe or moderate, or refractory AD. Engaging patients and caregivers in shared decision-making is, again, really imperative, crucial to getting that long-term control in terms of disease severity and quality of life. It is important to develop patient-specific action plans to address barriers to care and optimize outcomes, as they really reflect in the individual patient itself.

[01:20:34]

Poll 9

Next poll is please take a moment to enter one key change that you plan to make in your clinical practice based on this education, or any specific barriers that will prevent you from changing your practice. Short answer of less than 500 characters.

[01:21:17]

Poll 8

Then we are going to move to the next one. Do you plan to make any changes in your clinical practice based on what you learned in today’s program?

A. Yes;

B. No; or

C. Uncertain.

We will give another 1 or 2 here.

[01:21:44]

Question and Answer Session

Now it is time for some Q&A. Again, if you do have questions you have not entered, please feel free to do so in the Q&A tool. We will start with the first question where someone asks, does laser therapy have a role in treatment for AD? The laser that is likely being referred to or the one that I would actually use here or think about is excimer laser, which is a very close in wavelength to narrowband UVB, the phototherapy that we discussed, and it is similar to phototherapy, and that it can be helpful. Now, typically speaking, it is not practical to administer it to large areas of the body. I would say more often than not it is going to have a role in relatively limited body surface area, often with more severe focal areas, often hand eczema or maybe thick plaques that are not widespread but that are very severe where they are. The answer is that there can be a role as well, particularly, perhaps, if topical therapies are insufficient.

The next question we have here is, I struggle with how long I should recommend patients use topical corticosteroids or topical or calcineurin inhibitors. Do you have recommendations or have a resource for the length of use for these, or education for patients on how to use these topicals? That is a difficult question, and it is going to depend on the individual. For me, often there is a question of how severe the patient is. If I am sitting there and they are in that moderate to severe range, I know that the likelihood that they are going to have tremendous improvement with topicals is going pretty low, whereas if it is more mild, it is more likely. In most cases, that is a conversation to have with the patient to get their preferences in mind and then also see where we go from here.

For those patients at initial visits, I will often have them come back relatively quickly for me to assess in conversation with them how they are doing. Something like a 4 week follow up. Typically, we should be seeing some meaningful improvement if they are going to respond to topical corticosteroids or calcium interneuron inhibitors. If someone does not have meaningful improvement, it is unlikely, in my opinion, that giving another 2 or 3 months is going to make the difference. Now, I am not saying that they should be clear, and I am not saying that they should have a tremendous response, but we should be seeing some improvement. I would say as a general rule, the trajectory of approximately 4 weeks in is going to guide me towards saying, “Hey, we are on the right track. topical therapies have a potential to work,” or in many cases, what ends up happening is especially in that moderate to severe range, they come back in 4 weeks. They are not really doing meaningfully better. We say, “Now it is time to shift.”

Now, many of the systemic therapies are not going to have tremendous improvement in 4 weeks either. Again, we know that we are on that trajectory, and for those, assessing where things are often is going to be more meaningful in that 12, 16, 20, even 24-week range. We do not want patients who are not responding in a few weeks to topical steroids or calcium inhibitors to continue use them for 6 months. There is, in my opinion, somewhat of a plateau, just how effective they are.

Now, educating patients on how to use these topicals, there are often resources available – the National Eczema Association and so on. It is difficult because even with topical steroids and calcineurin matters, there is not a one size fits all to how it should be used depending on where it is on the body, the age, the potency. For that reason, that is one of the reasons why when appropriate, I really shift away from using topical steroids, because we are so fortunate to have other options that can be effective, whether they are non-steroidal topicals or systemic therapies.