When Topicals Aren’t Enough: Role of Advanced Biologic Therapies Targeting IL4/IL-13 and IL-13 for Moderate to Severe Atopic Dermatitis

Dr Benjamin Ungar (Icahn School of Medicine): Let us get started. When Topicals Are Not Enough: Role of Advanced Biologic Therapies Targeting IL-4/IL-13 and IL-13 for Moderate to Severe Atopic Dermatitis.

It seems from the polling questions that there is a mix of people who certainly do have a lot of experience treating AD as well as some level of confidence. Hopefully there will be some bits of this program that will be helpful in moving forward in terms of treating patients.

[00:05:08]

Epidemiology, Pathogenesis, and Comorbidities

Just to get started, a reminder of the background. Atopic dermatitis, AD is very common, affects upwards of 20% of children, often starting quite early in infancy. Most people diagnose known childhood, develop it by an early age, age 1, even age 5, and many cases persist into adulthood.

There is also very commonly adults who develop symptoms for the first time in adulthood. So it is important to keep in mind that it is not just children that develop that and persist into adulthood.

It is characterized by cycles of flares and worsening symptoms. Some real-world evidence suggests that these flares are quite common. In moderate to severe AD average of over 7 flares per year, and I would say a shockingly high percent of people experiencing no remission or less than 3 months of remission in the past 12 months, really suggesting that many, many people are being undertreated.

Our goal should be to aspire to really minimize or even eliminate the flares and put people in a state of what amounts to clinical remission.

[00:06:19]

Patient Burden: Pain

Now, 1 of the symptoms I think that is underappreciated in AD is the burden of pain. We think about itch as being a common core component of AD, and it certainly is, but pain plays a role as well. This was a study looking at the pediatric population, where pain NRS was identified across a range of severity. The more severe the AD, the higher the level of pain, which really again, demonstrates that kind of process that is a disease specific process. That is true across different ages. So infants, younger children and adolescents as well.

[00:06:55]

Patient Burden: Sleep

Sleep disturbance, again, is 1 of those things that I think most people appreciate as being very central to this, but really should not be understated, both because of the direct effects of lack of sleep or insufficient sleep. Perhaps just as importantly, all the extreme negative consequences that are downstream of insufficient sleep: impaired functioning at school, interpersonal relationships and so on.

As we can see here that in the severe AD patients across the different age groups, we have over two thirds of children having sleep disturbance 5, 6 days a week or every day. Even in the moderate, we see upwards of 50% of the children with 3, 4 days or more. Even in mild AD, not too many people, minority people have no days of sleep disturbance.

The AD burden is significant one, and even 1 to 2 days of impaired sleep is really negative in many children and adults lives.

[00:08:05]

Patient Burden: Quality-of-Life Impact

The quality impact again is often tremendous in this disease, associated again with lower quality of life, increased school absences. In some respects, that just scratches the surface.

Here is the DLQI scores for the children. We see that the worst the disease, the worst impact on quality of life. These numbers, it is not just that it is worsening are quite significant. This is a very high negative impact on quality of life.

[00:08:37]

Available Topical Therapies

When we think about treating AD and we are going to go through to some more of these details, but there are topical therapies that can often be effective and appropriate, particularly in the mild to moderate range. Corticosteroids certainly play a role for a long time and still often play a role in treatment to topical calcineurin inhibitors, topical phosphodiesterase-4 inhibitors, as well as topical JAK inhibitor and aryl hydrocarbon receptor modulating treatments.

I am not going to go right now through all the details of these recommendations and approvals and so on. But it is important to keep in mind that we do have some good therapies that are topical, including non-steroidals. But often those are insufficient, and that is when we really think about moving to systemic treatment.

[00:09:28]

Safety Concerns With Prolonged Use of Topical Corticosteroids

I am sure that we have all had the experience of patients coming in, having been treated by other physicians or practitioners, and have been using topical steroids for long periods of time.

Now for the most part, adverse events are not that common, but they certainly can occur and there is a risk, particularly with inappropriate use, whether that be steroids that are too high, potency in sensitive areas, or use on a consistent basis for too long with significant side effects.

I certainly have had the experience that I am sure everyone else has, where a patient comes in having been given instructions to use it for 2 weeks or 3 weeks, and then only periodically after that, they come back 2, 3 months later having consistently used it every day. That is something that we want to avoid. Often it can be difficult for patients to adhere to that schedule.

There is also the potential for systemic absorption that can affect so many aspects about health, ocular side effects as well. Then potential risk for rebound eruptions. Although there is certainly a role for topical corticosteroids hopefully an increasingly small role.

[00:10:40]

Burden of Topical Corticosteroids: Patient Survey Responses

When patients are asked about the burden of topical steroids, there are a number of aspects that are less than ideal, lack of efficacy, and certainly in many cases in the moderate to severe range, topical steroids are just going to be insufficient.

Just lower satisfaction overall with topical therapies compared to systemic, because it can be burdensome to apply topicals, especially to large surface areas all over, as we can see in the bottom right here. Just in general, people with moderate to severe AD reported that the treatments did not fully meet their expectations. I think that given the patient perspective and also the goals and targets that we have, I think that we can aspire to a higher level of success, both in terms of patient preferences and patient perspectives as well as more objective measures.

[00:11:31]

Financial Burden of Topical Therapy

It is also important to remember that the financial burden of topical therapy is not zero. Patients reported significant out-of-pocket spending on topical medications, emollients, over the counter products, cleaning supplies. 42% of patients over $1000 a year. This can add up and become burdensome as well.

[00:11:56]

Assess AD Severity

Now, when we are thinking about treating AD, there is an initial assessment of the severity, which to large extent I think directs where we start with treatment. When it is in the mild to moderate range, I think often we try non-pharmacologic measures, gentle skincare practices, emollient use, and then when that is insufficient, which, often it is, if it is not very, very mild, we try to optimize topical therapy.

In the moderate to severe range, the combination of non-pharmacologic, but really topical therapies are often used and optimized and in a large majority of cases, that is insufficient to achieve the clinical responses we are looking for. So systemic therapy really is needed at that point, and that is when we think about it.

[00:12:39]

Candidates for Systemic Therapy

Broadly speaking, who are candidates for systemic therapy? That is, I think in many cases the decision point or the branch point about how to approach treatment. People who are inadequately controlled with topical therapies, and I think there is a little bit of a gray area of what that means, but a large proportion of pediatric patients are inadequately controlled with topical therapies.

When that does happen, when the patient and family comes in and says, “Hey, this is not really achieving the goal that we are looking for”, that is when the discussion and consideration for systemic therapy comes up. That is a conversation between the practicing provider as well as patients, caregivers and so on. The reality is that when we look at algorithms for treatment, that has to factor in the real world use of, hey, maybe it is difficult to adhere to treatment applying greasy emollients may just not be feasible in many cases. There can be triggers that are unavoidable. So topical therapies can often fail.

In many cases, it may feel like it is a path of least resistance to try tweaking things, but often it really is necessary to step to the systemic treatment.

[00:14:00]

Systemic Therapy Considerations

When thinking about systemic therapies, we are fortunate now to be in an area where there are a number of different options, and we can start thinking about factors that may play a role in the decision, both whether or not they should be treated systemically more broadly, but then also which specific therapy may be appropriate. I think that as much as possible, 1 of the themes I would like to encourage is that shared decision making to get the patient to buy-in and have their preferences expressed in a way that leads to better adherence and ultimately better outcomes.

Some of that has to do with the AD phenotype, comorbidities or potentially whether a treatment can treat more than 1 aspect of their health, or maybe there is a comorbidity that precludes certain treatments, the overall risk-benefit profile, patient preferences on a number of different axes, including administration. We have oral medications, injectable medications, drug interactions, monitoring, access to treatment. These are all factors ultimately that are going to play a role, hopefully in the decision about what treatment to pursue.

[00:15:03]

Traditional Systemic Therapy

Traditional systemic therapies, in some respects are still options for treatment. I certainly hope that these are ones that are used extremely infrequently, if at all, but they can be effective to a certain extent. I think key here with the so-called traditional systemic therapies is to avoid systemic corticosteroids really all possible. That is going to be something I return to as well.

[00:15:29]

Traditional Systemic Therapy: Safety Considerations

The treatments can take several weeks with maybe the exception of cyclosporine, which tends to work a little more quickly. These are, in many cases, can be effective. But the list of potential side effects, toxicities, risks are quite extensive with all of these treatments. I am not going to read all the side effects and risks that are listed here because it will take too long. But I think we know that the levels of efficacy in particular relative to the side effect profile and risks are not the most favorable for these therapies, and really should be reserved for extenuating circumstances.

[00:16:09]

Leveraging Advanced Biologic Therapies in Moderate to Severe Atopic Dermatitis

Okay. With that in mind, let us talk about leveraging advanced biologic therapies in moderate to severe atopic dermatitis.

[00:16:18]

Case Study: Jacob, 19 Yr Old

To do that, we will start off with a case that hopefully will illustrate some aspects about treating this. Jacob is a 19-year-old patient with AD diagnosed in early childhood that worsened a few years ago. No significant health history otherwise. Has been missing days of school, difficulty concentrating, tough time completing projects, exercises impaired due to fatigue, sweating when he does increase his flares. Let us say this is clearly not controlled and it is having a big impact on his life.

On physical exam, we see cirrhosis, eczema, red-crusted hyperpigmented patches. A SCORAD of 48 indicating severe disease, ADCT of 18 indicating severe disease. The treatments currently are topicals. He's had multiple courses of oral steroids. That is not usually a best sign that things are well controlled and did try phototherapy in the past without much improvement.

[00:17:16]

Pretest 1

With that in mind, let us do a pretest question for the audience. Based on Jacob's clinical presentation, what would be the most appropriate next step in management of the AD?

1. Switch to a different high potency topical corticosteroid;
2. Add a systemic corticosteroid to current therapy;
3. Initiate use of a systemic immunosuppressant like cyclosporine; or
4. Discuss starting a biologic therapy.

We will give a few moments for people to answer.

Speaker: Poll is open. Five more seconds for incoming answers. Okay, couple more answers coming in. Thank you. We will close the poll and share the results.

Dr Ungar: Two thirds said, discussed starting a biologic therapy and then a little mix of switching to different high-potency topical corticosteroid and initiating use of a systemic immunosuppressant.

[00:18:32]

Biologic Targets

Let us keep that in mind as we proceed and we will start talking about the biologics and the systemic treatments.

I personally have found this diagram to be helpful in just visualizing what is happening. We will start with dupilumab, which I think we all know is the first approved treatment 8 years ago. Dupilumab blocks the IL-4 receptor and one of the irrelevant pieces there, it is a little different than some of the other biologics because by blocking that receptor, as we see here, it blocks both IL-4 and IL-13.

The next 2 biologics, lebrikizumab and tralokinumab, which were approved, in the case of tralokinumab a couple years ago, and lebrikizumab last year. Those block only IL-13. A little different mechanism, although somewhat similar in that the core of the way it works is by blocking that IL-13 signaling, but it blocks IL-13 directly, whereas dupilumab blocks both IL-4 and IL-13.

Also recently was the approval of nemolizumab, which blocks IL-31, often called the “itch cytokine”. It actually blocks the receptor, but thereby blocking IL-31 signaling. Then at the bottom we see the 2 approved oral JAK inhibitors, abrocitinib and upadacitinib, which block JAK1.

If you will note at the receptors for each of the cytokines listed that JAK1 is playing a role in those signaling. It is blocking a bunch of the cytokines and thereby has broader blockade of the different inflammatory signals.

[00:20:12]

LIBERTY AD CHRONOS: Dupilumab Efficacy in Adults

Keeping in mind that the mechanisms are a little different, we will talk about some of the clinical trials data that may be relevant in thinking about treatment selection. The first one, dupilumab approved now several years ago.

We will look here at the LIBERTY AD CHRONOS, which looked at 52 weeks of treatment. We can see on the left IGA score of zero or 1, which is kind of a stricter threshold than EASI-75, which is the same 75% improvement in EASI. We can see here in these graphs that there is a clear difference between treatment and placebo responses, both at week 16 and week 52.

The responses at week 52 were similar to week 16, meaning that the responses typically were maintained. In this trial, you can see that the differences between weekly and every other week dosing were really minimal, if anything, which I think is largely explains why the approved dosing is every 2 weeks rather than every week. Although I will say anecdotally, there are some people who benefit from weekly dosing off-label in some instances as well.

[00:21:22]

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

Overall, the safety profile for dupilumab is definitely very favorable. This was an open-label extension patients up to 4 years. On the right, we see that 1-year placebo controlled randomized period. Then the left is an open-label extension. 2600 people at that point. The overall picture that we see here is that compared to placebo in that shorter timeframe, the rates of serious infections, non-herpetic skin infections, all of these were, if anything lower in the dupilumab group than the placebo, either lower or similar. Very low rates across the board in that open-label extension. That is really a reason why this is not considered to be immunosuppressive.

[00:22:06]

Dupilumab Efficacy by Racial Subgroup: Wk 16

Now, it is definitely crucial to make sure that different populations with AD are benefiting from treatment. One of the factors that can play a role, at least in differential clinical presentations, potentially different molecular phenotypes is racial background. In this subgroup analysis, looking at White individuals, Asian individuals, and Black individuals, all with moderate to severe AD, we do see that there is a clear benefit to dupilumab treatment over placebo in each of the groups in this study. Again, supporting the idea that it works in diverse backgrounds.

[00:22:42]

Dupilumab Safety by Racial Subgroup: Wk 16

Similarly, with the safety across different racial subgroups, this was through 16 weeks. You can see the placebo vs dupilumab treated groups across the board were typically either similar or even better in the case of dupilumab vs the placebo, with the exception that conjunctivitis typically was elevated in the dupilumab treated group across the different racial groups.

[00:23:10]

Heads Up: Upadacitinib vs Dupilumab for Moderate to Severe AD

Now when we think about relative efficacy of 1 treatment for another, this is something I am going to discuss maybe once or twice, I think it is really is important to keep in mind that different clinical trials are designed differently and really cannot be compared head-to-head. We can get broad strokes about rough ranges of efficacy and so on, but it is really hard to compare directly.

Now, the way to address that is when a head-to-head trial is done. That was done in the case of the Heads Up trial comparing upadacitinib vs dupilumab. In this case, it was the 30 mg higher dose of upadacitinib, and it was a 24-week trial, where people were randomized. What was identified is that at Week 16, which was the primary endpoint, there was a significantly greater proportion of patients who achieved EASI-75 with upadacitinib treatment than dupilumab.

They also identified faster itch relief and overall skin clearance at week 16 with upadacitinib vs dupilumab. Certainly in that timeframe, it appears to be more effective.

Now, there was increased infections with upadacitinib, particularly zoster and eczema herpeticum compared to dupilumab. Conversely, dupilumab was associated with increased conjunctivitis and perhaps not surprisingly injection site reactions.

The conclusion when we look at upadacitinib vs dupilumab is that upadacitinib offers superior and faster skin clearance, but there is a higher infection risk. And so, as with many of these treatment considerations, there is a balancing act to figure out which can differ from patient to patient, efficacy vs safety. Those are core factors. There are other things to consider, like administration route and so on.

[00:25:03]

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

Now, 1 of the other analytical approaches to comparing clinical trials, because as I said, and we will be happy to repeat over and over again, you really cannot compare them directly when they are different trials, is to do network meta-analyses, which are an attempt to compare efficacy across different trials. I think that this approach can be useful, and from my perspective, should be taken with a grain of salt. Because at the end of the day, there are different trials, but this at least makes it more comparable than just looking at raw numbers.

In this network meta-analysis, comparing dupilumab and tralokinumab, which was the second approved treatment in this case with topical corticosteroids for severe AD, it was determined that dupilumab showed greater efficacy than tralokinumab at week 16 as well. Efficacy both in terms of EASI scores, itch scores, DLQI, as well as superior skin clearance.

Based on this analysis, the suggestion is that dupilumab may be a bit more effective than tralokinumab.

[00:26:08]

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

Looking at the clinical trials data for tralokinumab, this was ECZTRA 1 and 2, we do nevertheless see that tralokinumab can be very effective. It is more effective than placebo. It is a good example of the trial showing different results probably because different investigators and just different factors that play a role, even though there were similarly designed studied.

[00:26:36]

ECZTRA 1 and 2: Additional Endpoints and AEs

In terms of the efficacy and safety of tralokinumab, significantly more patients in tralokinumab achieved improvement in worse daily itch scores. The majority of people maintain the response. If they respond to treatment, there is a very good chance that they will continue to respond to treatment.

Overall safety comparable to placebo. Again, a very safe medication. Again, there are multiple measures to think about when we are assessing efficacy. Those include strict IGA 0/1, EASI-75 thresholds. Cumulative corticosteroid use was decreased with tralokinumab. So overall an appropriate option as well.

[00:27:19]

Tralokinumab Efficacy by Racial Subgroup: Wk 56 

Similarly, when we look at different racial subgroups, because it is important, again, to make sure that we are not just making assumptions about that.

In this ECZTEND study looking through week 56, we do see high rates of maintenance of response. Again, that is very important as well. Then overall efficacy across different populations. I think depending on the measure that we look at, perhaps was a little less effective in Asian individuals than Black and White individuals. But it is in the same ballpark. This medication is effective across different populations.

[00:27:54]

Tralokinumab Safety by Racial Subgroup: Wk 56 

Safety against similarly in different populations. They were safe. When we look at either percent or number of events per patient years, in fact the adverse events were most common in white individuals. And very low rates across the board of severe adverse events. Very few people dropped out of the trial due to adverse events, again, suggesting not only that we know that it is efficacious but also well tolerated.

[00:28:22]

ADvocate1 and ADvocate2: Lebrikizumab Efficacy at 52 Wk

Switching gears now to lebrikizumab, the next up in terms of approved treatments. These studies, ADvocate 1 and 2, these are extension from the original 16-week endpoint. What we see on the left is the IGA 0 and 1 score at week 52, EASI-75 responses at week 52, again, so very high rates of maintaining the response on every 2 or every-4-week doses.

We can see, in fact, debatably every 4 weeks was slightly better numerically at the very least, again, which is why that maintenance is every-4-week dosing in terms of the approval. We see also, again, that high maintenance of pruritus improvement as well.

Interestingly, the placebo responses, which was withdrawal of lebrikizumab, people who did respond at week 16, actually two thirds maintained an improvement, suggesting that at least in some people, there may be this durable effect after stopping therapy. Not necessarily that that is recommended, but it is good to keep in mind for people who might need to stop therapy for whatever reason.

[00:29:29]

Lebrikizumab Safety Considerations

Safety considerations, again quite favorable rates overall at the range or potentially lower than placebo. Most common conjunctivitis in the treatment groups which is what we have seen with dupilumab mirroring that as well.

[00:29:51]

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

In skin of color, again, lebrikizumab showed excellent efficacy as well at week 16 here. EASI-75 and EASI-90 responses. 70% of people achieving EASI-75 in people with skin of color. Then even the stricter threshold of EASI-90 or IGA 0/1, which usually correspond approximately in these trials, we see upwards of 45%. Again, efficacious in different backgrounds.

[00:30:22]

ADmirable: Key Secondary Endpoints at Wk 16

Again, the different endpoints are going to show a similar pattern, greater than 4-point improvement in PP-NRS, almost 60%. DLQI over 70%, a little less improvement in PP-NRS, two thirds. So 50% improvement in DLQI. Again, very efficacious in the skin of color population.

[00:30:49]

ADmirable: Hypo/Hyperpigmentation at Wk 16

Now, 1 of the aspects about AD that in many cases I think is underappreciated, but has a dramatic impact on the disease burden and quality of life, in particular for darker skin individuals, is pigment alteration secondary to an inflammatory process. That can be hyperpigmentation, I think in a majority of cases, but often hypopigmentation as well.

Even after the symptomatology is reduced and the actively inflammatory burden is reduced, pigment changes can continue to impact patients pretty significantly.

Here, looking at pigment at week 16, hypo or hyperpigmentation, a third saw improvement in hypopigmented lesions, and of that, a non-trivial number or percent at normalization of skin tone and two thirds give or take saw improvement in hyperpigmented lesions with 20% of those improvement to normal skin tone. 16 weeks for pigment changes is quite rapid. That is actually quite an impressive improvement overall.

[00:31:52]

Differentiating IL-13 Inhibitors

Okay. We talked about the 3 treatments that block IL-13 inhibition. I do want to take a step back again and just have an overview a little bit of some of the differences. The major difference mechanistically among these 3 is that dupilumab blocks both IL-4 and IL-13 by blocking the IL-4 receptor.

Tralokinumab and lebrikizumab each, both directly block IL-13 alone by blocking the IL-13 cytokine itself. Now they bind to different parts of IL-13, so they block different IL-13 receptor or IL-4 receptor binding and interactions. But that is the major difference.

They all have high affinity binding. Lebrikizumab is a slow dissociation rate as well. The time to response is 4 weeks, 2 weeks in some cases. There is some variability person to person. Some people can start seeing improvement in itch even as early as a few days in. Some people take a little longer to have that improvement. Works across different areas of the body. All have good safety and efficacy profiles. We have discussed some of the most common AEs, primarily conjunctivitis injection site reactions and so on.

[00:33:21]

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

Now going back to the networking meta-analysis, comparing different treatments. Again, just we will repeat 1 more time. There is a grain of salt that should be maintained with this. But nevertheless, this compared 13 trials, 32 total treatment arms comparing 6 agents, upadacitinib, abrocitinib, which we talked about as the JAK1 inhibitors; dupilumab, lebrikizumab, and tralokinumab, the 3 treatments that block IL-13 signaling with dupilumab also blocking IL-4. And baricitinib. The relevance of baricitinib here is that it is approved to treat atopic dermatitis in Europe.

Although it is not approved to treat AD in the US, it is approved to treat severe alopecia areata in adults in the US. AD is often a comorbidity of alopecia areata and vice versa. There might be some instances where someone is on or there is a consideration of treatment with the baricitinib for the alopecia areata, and there may be off-label improvement in the atopic dermatitis as well.

Based on this network meta-analysis, upadacitinib 30 mg, which is the higher dose was identified as the most effective across all the endpoints with abrocitinib, that is the higher dose and upadacitinib about 200 mg and upadacitinib 15 mg, the lower dose were second.

Similar efficacy between lebrikizumab, dupilumab, abrocitinib 100 mg lower dose, and baricitinib 4 mg the higher dose, with the lowest efficacy reported as lower dose baricitinib 2 mg and tralokinumab. The JAK inhibitors outperformed IL-13 inhibitors in short-term efficacy. Over time, some of that gap is reduced as well.

The clinical implications here extend to what we have been discussing all along the way is that there are a number of nuanced differences between these treatments that may factor in, and it is hard to make blanket statements about which ones should be factored, because often those are going to be personalized decisions based on the patient specific characteristics and also preferences.

[00:35:27]

Let’s Revisit Our Patient Case

Let us go back to our patient case with all that in mind.

[00:35:29]

Case Study: Jacob, 19 Yr Old

As a reminder, Jacob with longstanding severe AD that is having a big negative impact on his life being treated with topical corticosteroids, courses of oral steroids, phototherapy. These topicals are not really helping him.

[00:35:49]

Posttest 1

Based on his clinical presentation, what would be the most appropriate next step in management of Jacob's AD?

1. Switch to a different high-potency topical corticosteroid;
2. Add a systemic corticosteroid to current therapy;
3. Initiate use of a systemic immunosuppressant like cyclosporine; or
4. Discuss starting a biologic therapy.

Speaker: Poll is open. Please vote. Five more seconds for incoming answers. Thank you. We will close the poll and share the results.

[00:36:32]

Posttest 1: Rationale

Dr Ungar: The majority of people answered discuss starting a biologic therapy. I would agree with that answer. At some point if someone is having very severe AD despite different topical therapies, the likelihood of switching to another 1 that is going to be the 1 that works, I think is relatively low, especially in his case with long-standing disease, not responsive to phototherapy.

Given how much it is affecting him, I think starting with biologic therapy would be the appropriate next step.

[00:37:08]

Practical Strategies for Disease Assessment and Treatment Advancement in Moderate to Severe Atopic Dermatitis

The next section is to discuss Practical Strategies for Disease Assessment and Treatment Advancement in Moderate to Severe Atopic Dermatitis.

[00:37:15]

Case Study: Sara, 13 Yr Old

We will start off with a different case to get us started. We have Sara, a 13-year-old who is struggling with intense itching, widespread lesions, poor quality of life, disturbed sleep. She also has a history of asthma. It is affecting her ability to socialize, to concentrate at school. She has elevated IgE levels, pretty significantly of 2300, increased eosinophilia, 9% eosinophils, CBC and LFTs are normal. No TB or hep virus screening concerns. Very dry, itchy skin. Everything stings to her.

Her SCORAD is 43 and ADCT are 17, both indicating severe disease. Current medications include topical corticosteroids and systemic corticosteroids for severe flares and phototherapy, and she has been adherent. The fact that she is severe here, despite that probably means that things are not adequately treated and the dermatologists are considering a biologic therapy that targets IL-13.

[00:38:17]

Pretest 2

We will start off with that pretest question two. Considering Sara's clinical presentation and history, which of the following factors most strongly supports initiating an IL-13 targeting biologic therapy for her atopic dermatitis?

1. Despite appropriate use of topical corticosteroids, phototherapy, and systemic corticosteroids, her symptoms remain poorly controlled, justifying the need for biologic therapy;
2. Her immune profile is consistent with a Th2-driven inflammatory response suggesting potential responsiveness to IL-13 inhibition; or
3. IL-13 inhibitors are approved by the FDA for pediatric patients and her asthma is not a contraindication.

Speaker: The poll is open. Five more seconds for incoming answers. Thank you. We will close the poll and share the results.

Dr Ungar: We have a little bit of a mix. Most common answer is A, with a mix of B and C and we will revisit that as a post-test question.

[00:39:33]

Pretest 3

Pretest question 3. When assessing a patient's candidacy for advanced biologic therapy, targeting IL-13 in AD, which factor or factors is most indicative of the need for treatment escalation? You can select all that applies.

1. EASI score of 8 indicating mild disease;
2. Long-standing AD with occasional flares controlled by topical therapies;
3. Mild disease flare in the past year; or
4. Inadequate response to topical therapies and significant impact of AD on mental health and quality of life.

Speaker: Poll is open. Please vote. Five more seconds. Thank you. We will close the poll and share the results.

Dr Ungar: We see here most commonly two thirds answer D with a mix of A and C.

[00:40:41]

Beyond Topicals

Okay. Some considerations of moving beyond topical. The first question I think is when to advance therapy. The short answer to that is if people are continuing to have symptoms, to continuing to have flares, burden of itch, sleep disturbance despite treatments with topicals, then advancing therapy should be a consideration.

It is true there is potentially an opportunity for optimizing topicals, but in many cases, unless you are getting very close to having things under control, moving from a Class II to a Class I potency corticosteroid is not going to be sufficient to really bridge that gap of the response.

Monitoring treatment response is important as well. We should be, I think to large extent, factoring in some measures of disease severity and tracking the improvement that can be itch severity, sleep quality, quality of life instruments like DLQIs. Part of that is going to be our own assessment of how the patient is doing, like EASI scores or SCORAD.

I think in practice when we are busy seeing many patients a day calculating out EASI scores and SCORADs may not be doable. Things like body surface area assessment involvement can be a little quicker and easier. IGA or Investigator Global Assessment, these are ways to have kind of an objective score that is maybe more doable.

Then we think about what treatments to advance. One is when do we advance? How do we monitor the advance? Then what are the options? There are traditional systemic immunosuppressants. There is the biologics or JAK inhibitors. These targeted therapies that may address certain components of the disease in different ways.

Part of the success for treatment is going to be that the patient is on board with treatment, and many people have fears expectations that may or may not be aligned with our understanding of the treatments. If someone is expecting 100% improvement after 1 day of treatment, they are going to be disappointed.

But if they understand that there can be improvement over the course of several weeks, they are more likely to stick with treatment. If they are concerned about side effects, immunosuppressant depression, all of that, those are concerns that are potentially can be allayed and again, will lead to better outcomes.

Then the long-term benefits and safety profiles of many of these treatments really can be a major reason for people to consider doing it, but ultimately that shared decision-making which again is going to play a role hopefully increasingly in how people approach the conversations because of the different options will lead to better outcomes because there is that patient buy-in, patient adherence and there are patient specific factors that make a difference in terms of how well they do.

[00:43:40]

PATHFINDER-AD: Patient-Eligibility and Readiness for Advanced Therapies Targeting IL-13 in Moderating to Severe Atopic Dermatitis

Now, with that said, I do want to call attention to this PATHFINDER-AD tool that is available, I think currently on the CEA website. You can see the information there, which gives a guide about thinking about how to assess the patient, thinking about whether they are a candidate for systemic treatment, and then mapping out what the dosing schedule is, follow up care plan and so on. This may be a tool that people find to be helpful in treating AD patients.

[00:44:11]

Updates on Topical and Maintenance Treatment for Mild to Severe AD

Now let us talk about the updated guidelines by the AAD in treating AD. We are going to start off with topicals, which are true mild to severe, but going to be more appropriate in that mild to moderate. Then we will move on to the systemic treatment.

There are strong recommendations by the AD for the use of topical corticosteroids, topical calcineurin inhibitors, crisaborole, ruxolitinib cream and some recommendation but not a strong recommendation for wet dressings.

I will also note that roflumilast 0.15% cream and tapinarof cream were both approved after or too late for inclusion in the guidelines. They are not officially in the guidelines. My personal feeling is that they probably would be in the same position but that should be noted.

There are recommendations in terms of how to approach treating AD. There is 1 approach of being reactive. When there is a flare, you apply it vs proactive. In some cases, particularly with some of the non-steroidals that were less concerned for more consistent use, maybe you preempt flares by applying it onto relatively normal appearing skin, where you know there is likely to be a flare.

There is no necessarily right answer to that. Part of that is, again, the shared decision-making to think about patient satisfaction, their ability to adhere to it and thinking about what kind of approach aligns with their priorities as well.

Now, if topical therapy is optimized and it is not working as we have discussed, then we are likely going to be discussing additional treatment with phototherapy and/or systemic agents.

Now, I will say it is important to keep in mind that not all clinical presentations that are consistent with atopic dermatitis ultimately are exclusively AD. When there is not the treatment response that we would necessarily associate with it, we should think about alternative diagnosis like contact dermatitis, either exclusively or in part, cutaneous lymphoma, thinking about possible alternatives as well, if there is inadequate response.

[00:46:25]

Updates on Systemic Therapies for Moderate to Severe AD

Now, the updates on systemic therapies for moderate to severe AD include this partial conditional recommendation for phototherapy, either alone or with other treatments as well. Then there is a strong recommendation for dupilumab, tralokinumab, upadacitinib, abrocitinib, and baricitinib. We talked about the fact that baricitinib is not actually approved in the US.

Similar to what we saw with some of the newer topicals, lebrikizumab and nemolizumab were approved too late to be included in the guidelines. Again, my opinion is that these would be alongside dupilumab and tralokinumab in terms of strong recommendations.

There is also conditional recommendations for methotrexate, azathioprine, cyclosporine, and mycophenolate. We talked about all the drawbacks and the guidelines are conditional, so probably should not be first or even second, or many cases, third line treatments.

Then I do want to just emphasize, and this is something that I will emphasize till the cows come home. There is a strong recommendation against the use of systemic corticosteroids. In place of systemic corticosteroid use, there are other options now that do not have the risk of the significant side effect burden and also the risk of rebound flares that are accompanied with systemic corticosteroids.

[00:47:50]

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

In terms of the biologic therapies, again, and these advanced therapies more broadly, dupilumab is often favored as a first-line systemic treatment. Tralokinumab is efficacious, but arguably a little less so than dupilumab. As mentioned, lebrikizumab and nemolizumab were not included in these guidelines yet. Probably would play a role similar to that.

Upadacitinib and abrocitinib have high efficacy but are reserved in most cases for patients who have failed prior systemic therapies, and that is consistent with the FDA approval with the label. Then there are conditional recommendations for the systemic immunosuppressants. Again, just to reemphasize, systemic corticosteroids are not recommended.

[00:48:40]

Network Meta-analysis: Systemic Therapies for AD

This was additional network meta-analysis approach comparing lebrikizumab and dupilumab in terms of EASI scores, so objective measures, and POEM, which is patient-reported outcome for adults in the 8- to 60-week period. And basically no real difference compared to dupilumab, again suggesting that it is in a similar range of efficacy.

[00:49:05]

FDA-Approved Biologic Agents

Again, just comparing the FDA-approved biologic therapies, we saw a table that is somewhat similar to this, but has different aspects about it. Just in brief, some of the differences are the targets. Dupilumab IL-4 receptor blocking IL-4 and IL-13. Tralokinumab and lebrikizumab both block IL-13 only.

Nemolizumab blocks IL-31 signaling. Dupilumab is approved for infants 6 months and older. The other 3 are approved for adolescents, 12 years and older. All are Sub-Q injections. Different dosing depending on age potentially. There is, in some cases, different loading and maintenance doses. I do not think this is a place to go into those details, but it is something to think about as well.

Then there is warnings either for conjunctivitis, parasitic infections, live vaccines those are relatively rare circumstances.

[00:50:02]

Biologic Therapy Use in AD

Benefits of biologic therapy. Number 1, it is self-administered, so relatively easy to do once patients are appropriately trained, which is not too difficult. Efficacy even after failure of other therapies. The fact that something has not worked does not mean that these are not going to, durable efficacy, well tolerated, no lab monitoring required. These are all big pluses of this group of medications.

There is some safety considerations that like conjunctivitis that are a little different between them, but often respond very well to artificial tears and, if not, can be managed with the help of ophthalmology colleagues. It is not necessarily something that requires cessation of treatment.

Injection-site reactions. The other 1 is headaches, upper respiratory tract infections are pretty uncommon. Then vaccination is a question that can be answered in conjunction with guidelines. Other providers that are involved in the care. Then ultimately also the patient specific circumstances. And vaccination with live vaccines is different than with killed or protein based vaccines.

[00:51:14]

Clinical Assessment Tools

When we are thinking about clinical assessment, we have touched on some of this before, but I do want to dig into it a little more. In clinical trials, usually the primary endpoints are EASI, Eczema Area and Severity Index and Investigator Global Assessment.

EASI is cumbersome to calculate, so probably not going to be used routinely in a busy clinical practice. IGA here is more straightforward and often is a good measure to use for insurance approval. I would strongly encourage, always at least including IGA, often a BSA, body surface area involvement as well to indicate that severe or moderate disease.

SCORAD, again, a little less commonly used these days as a clinical trials outcome measure, but sometimes still used, and also a little cumbersome to use.

POEM, the Patient-Oriented Eczema Measure is a good patient-reported outcome to assess disease severity as well.

[00:52:09]

Atopic Dermatitis Control Tool: ADCT

I do want to call attention to this atopic dermatitis control tool or ADCT, which is a brief 6-question questionnaire, evaluating different dimensions of an AD that can be administered in a consultation or patients can fill it out before the visit, and is a tool that can help assess the disease severity, the impact on the patient and whether or not their disease is in fact controlled as the name of this tool suggests.

[00:52:37]

ADCT Measurements

Just brief glance. This is what it looks like. There are different points assigned for the answers that the patient may give. If the score is greater than equal to 7, or there is at least 1 answer in the shaded area or the overall score has increased by 5 points since the last visit, those are all suggestive of inadequately controlled AD.

[00:52:58]

Clinical Presentation Variability

Would like to just give a brief reminder of some of the heterogeneity and variability that clinical presentations of AD can kind of span. Traditionally, we think about AD and infants on the cheeks, extensor extremities, flexural creases; in adults, more so the hands and flexural creases; adolescents, neck, face, palms. The reality is it can affect all parts the body and in the age group. Just keep in mind that just because an adult has eczema on their face, their cheeks does not mean that it is not eczema, atopic dermatitis.

Then the variability based on skin color. Dark skin often have more papular or follicular eruptions. In some cases, you may not see like erythematous[?] plaques across the board, but these kind of follicular-based inflammatory process. We talked about the hyperpigmentation, the post-inflammatory. Erythema may not be quite as obvious or easy to appreciate, so requires careful physical examination. Conversely in lighter skin, it may be more pink or red as well.

[00:54:05]

Presentation on Varying Skin Tones

In Asian patients, often the eczema can be a little more psoriasis form in appearance as well. In darker skin individuals, in Black patients, it is more likely to be lichenified and hyperpigmented. Again, very important to keep in mind that there is this heterogeneity differences in presentations and just do not jump to say this is not eczema because of that, or underestimate the severity, really have to look carefully to make sure that you are actually encompassing all of that.

[00:54:33]

Shared Decision-making in AD

We have talked about shared decision-making a few times, and I just really want to take another moment to discuss. I think the importance of this, because we have different treatment options that are all in their own ways really excellent. It is an opportunity to think about not picking the 1 that is going to be given to everyone, but think about the 1 that is right for the patient in front of us.

That has to do on various practical considerations, patient preferences, cultural considerations, access. If they need closer follow ups that may preclude some patients from going down that path. There are may be economic considerations, copays, things like that that may differ from treatments as well. These all should be factored in, and it is not a proscriptive kind of process, but it involves engaging the patient as well.

I think these are kinds of elements that we have learned in our training as early back as school. But does not hurt to be reminded what some of the strategies to get that. Ask questions, elicit open-ended questions, elicit from the patient, what part of this is bothering you most, which aspects about the kinds of treatments we are talking about seem to you to be the most important for you.

Some people may be very needle-phobic, other people that may have no concerns about that, and that is going to impact the treatments that we go through. And also how likely they are to actually follow up and get that improvement.

[00:56:02]

Key Takeaways

Some key takeaways. AD has a significant negative impact on quality of life for patients and caregivers. Topical therapies remain first-line, particularly in mild to moderate cases, but there are a number of burdens associated with them, and there may be inadequate response to treatment.

There are new options available that have a number of benefits, including improved efficacy, symptom control, varying dosing schedules and route of administration, unique intolerable safety profiles and different mechanistic targets.

Again, engaging with the patients and caregivers to get that shared decision-making is going to really lead to best outcomes.

[00:56:41]

Let’s Revisit Our Patient Case

Let us revisit our patient case.

[00:56:45]

Case Study: Sara, 13 Yr Old

This is Sara, and summing this up. Very significant disease burden, both in terms of symptoms, quality of life, objective measures. Her laboratory results show elevated IgE and eosinophils. She is on topical corticosteroids and systemic steroids for flares, adherent to therapy and phototherapy. The dermatologist is considering a biologic that targets IL-13.

[00:57:08]

Posttest 2

Considering Sara's clinical presentation and history, which of the following factors most strongly supports initiating an IL-13 targeting biologic therapy for her atopic dermatitis?

1. Despite appropriate use of topical corticosteroids, phototherapy and systemic corticosteroids, her symptoms remain poorly controlled, justifying the need for biologic therapy;
2. Her immune profile is consistent with a Th2-driven inflammatory response suggesting potential responsiveness to IL-13 inhibition; or
3. IL-13 inhibitors are approved by the FDA for pediatric patients and her asthma is not a contraindication.

Which is the one that most strongly supports initiating?

Speaker: The poll was open. Five more seconds for incoming answers. Thank you. We will close the poll and share the results.

Dr Ungar: Okay, so the majority of people answered despite appropriate use of topical corticosteroids, phototherapy, her symptoms were made really controlled.

[00:58:15]

Posttest 2: Rationale

This is the answer that I would select. There is some justification for B. It does have a Th2 response. IL-13 inhibitors are approved for pediatric or adolescent patients. Asthma is not a contraindication, but I think the strongest supporting factor is that she has been treated with a number of different therapies and it is inadequately controlling her symptoms. So that justifies biologic therapy.

[00:58:42]

Posttest 3

Posttest question 3. When assessing a patient's candidacy for advanced biologic therapy targeting IL-13 in AD, which factor or factors is the most indicative of the need for treatment escalation? We have:

1. EASI score of 8 indicating mild disease;
2. Long-standing AD with occasional flares controlled by topical therapies;
3. A mild disease flare in the past year; or
4. Inadequate response to topical therapies and significant impact of AD on mental health and quality of life.

Speaker: Poll is open. Five more seconds. Thank you. We will close the poll and share the results.

[00:59:33]

Posttest 3: Rationale

Dr Ungar: Alright, 100% of people answering D. Excellent. We are aligned here. This is inadequately controlled and so that really is indicative of the need for treatment escalation.

I know that we are running up on time, but hopefully some people are able to stick around for a couple more minutes just to go through a few questions that were coming in.

[00:59:55]

Q&A

Dr Ungar: The first question that I am having here is how do you decide which patients with moderate to severe atopic dermatitis should receive biologic therapy?

I think to some extent, we have gone through a lot of the considerations here. I would say the short answer to that is if someone is not well controlled and really that means a minimal burden on their life, then that is a consideration.

Now in some cases that may be someone who is really almost too severe to - that we also almost know in advance that topical therapies are not going to be adequate and you can “waste time” for a couple months trying topical therapies. But if someone is very severe, it is unlikely to make an impact.

In some cases, someone is maybe on the more mild end of moderate, but they are just not getting that disease control with topicals. To me, there should be a low threshold to advance to biologic therapy because that can be really life changing in terms of how much it can improve their situation.

The next question is, what factors help you choose between an IL-4/IL-13 inhibitor and a JAK inhibitor?

There is a long answer to that question that we can spend quite a while discussing. Part of the consideration really in this case is a conversation with the patient. I know there is an element of repeating myself, shared decision making, but I think that it is difficult to say for me, meeting someone for the first time, or maybe we even had a few follow up visits in relatively short visits to say what is right for them.

I actually discuss with the patients what the different considerations are, both in favor and potential drawbacks of the different treatments. We come to decision together which 1 might be the most appropriate. I tell them, we could try an injection medication with all the safety benefits that we have. There are oral treatments that have, and then we discussed the boxed warning, monitoring requirements. But there is also considerations like speed of onset, which may favor JAK inhibitor. Which ones may be easier to continue long term.

I do not think there is a right answer. I do my best to lay out the considerations and help decide with the patients. The caveat to that is if someone is not a candidate for a JAK inhibitor, for example, had a MI 2 years ago or a DVT, we are not going to go that down that route. Then the “many of options” that we talk about is going to be more limited.

I think those are the factors. There may be some instances where someone is very severe, very strongly flaring, and the need for very quick treatment response may take a higher priority. That may be someone that I nudge towards a JAK inhibitor, but at the end of the day, if that is not something that they feel comfortable with, then we will start a biologic therapy and have a conversation that may take a little longer to work.

Then I think we have another question here that asks, at what point would you consider switching from 1 biologic to another due to AEs? That is a great question. We are fortunate now because we have different biologics, we do not have to “suffer” with AEs just for the sake of the efficacy. To some extent, it depends on how significant they are.

If you take maybe a prototypical case of someone who is on dupilumab and has conjunctivitis, there is still a question of how much it is bothering them. To me, that is worth asking. Because if it is a little bit, they use eyedrops and their skin is doing great, it may not be worth “risking” a different treatment that may or may not be as efficacious.

Conversely, if someone is doing pretty well but then develops facial flares, facial rash, then I would generally have a low threshold for switching when we are talking about AEs. Because the different treatments are mechanistically varied, I think it allows for us to say whether due to efficacy or due to side effects we have other options. We should be aspiring as much as possible the best clinical control with the lowest burden of adverse effects and adverse events and side effects.

It depends on how much the AE is bothering the patient, but I have a relatively low threshold to switch from 1 to another, just because I have a lot of confidence that for many or most people, the efficacy will be in there with the alternative and may not have the side effects that is bothering them.