Dr Heather Woolery-Lloyd (University of Miami Miller School of Medicine): I am going to talk about the fundamentals of chronic itch in patients with atopic dermatitis and prurigo nodularis. And it is something that we all see in clinic.

You know it is a very common condition, atopic dermatitis. It affects up to 20% of children and onset is usually in infancy. So between the ages of 3 and 6 months of age and of those people diagnosed with atopic dermatitis, 60% develop the condition by the age of 1 year old and 85% develop it by the age of 5.

So it is definitely something that we see in kids very frequently. And for many of these children, it persists into adulthood. So, around 50% of people, pediatric atopic dermatitis persists into adulthood.

It can have a variable course. So some people say, oh, I had eczema when I was a kid, but it resolved, and I really do not have it now. However, I would say there is a little bit of a caveat there because when it comes to eczema, that type of patient who is had quote unquote childhood eczema, they tend to have sensitive skin into adulthood, although they do not have a quote unquote diagnosis of atopic dermatitis.

And then some patients develop atopic dermatitis out of the blue as an adult. So, 25-50% of adults with atopic dermatitis did not have symptoms as a child. And when you have adult atopic dermatitis, it tends to be more localized and more lichenified.

Let us talk about prurigo nodularis. So it is seen in around 72 per 100,000 people. And the median age of onset is 62 years old. So this is in contrast to eczema or atopic derm, which we see in younger patient populations in general. Prurigo nodularis we see typically in adults. It is 3 to 4 times more common in Black patients than it is in White patients.

And in general, disorders that involve itch, sos atopic dermatitis, prurigo nodularis, and just itch in general is more common in black patients and also in Asian patients. It affects up to 5% of people with HIV, and 46% of patients with prurigo nodularis have either a predisposition to atopic dermatitis or a personal history of atopic dermatitis.

So what are the common pathways between atopic dermatitis and prurigo nodularis? First of all, both diseases have an increase in the number of nerve fibers in the papillary dermis. Both diseases have a cutaneous neuropathy. So they have small fiber neuropathy that increases that perception of itch. They have increased TRP, expression of TRP, which are channels within the neurons that again drive this sensitivity to itch. There is neural dysregulation and this Th2 cytokine profile.

So these patients are at increased risk for itch. And when you think about atopic dermatitis, there are 2 ways to think about it. There is the inside-out and the outside-in concept.

So the inside-out is this concept that at baseline, patients with atopic dermatitis have this pro-inflammatory environment in their skin. So they have more IgE production. They have this Th2 differentiation.

This causes inflammation in the skin, and therefore they get barrier disruption. And that is the theory behind that inside-out, that you have this baseline predisposition, this pro-inflammatory Th2 profile that disrupts your barrier. And what we see clinically is itching and scratching.

Then there is the outside-in thought process. And that kind of concept is that there is an impaired barrier at baseline. So, you know, that abnormal filaggrin and other things in our skin barrier that are abnormal in our patients with atopic dermatitis, that this outside-in makes the skin more vulnerable to these exogenous insults.

So we know our atopic patients react to detergents. They react to wool clothing. They react to changes in climate and so forth when the humidity drops. And then that induces the inflammation. And you see the IL-4 and 13 and these pro-inflammatory cytokines.

So there are 2 ways to think about atopic dermatitis, and it is probably a combination of both, but it is a nice way to kind of categorize why this condition exists.

So there are some key cytokines in atopic dermatitis and key players in the immune system. And we are going to be talking about these throughout this whole session. So I want to kind of form this baseline so you can understand when we are thinking about the pathogenesis of atopic dermatitis, how this works.

So there are 4 key cytokines that are really important in the pathogenesis of atopic dermatitis, and they are IL-4, IL-13, IL-31, and TSLP. So these cytokines bind the receptors on the outside of the cell and activate this inflammatory process in the skin. When you hear all of these new biologics that are used to treat atopic dermatitis, know that they are binding the cytokine or the receptor on the outside of the cell.

In contrast to that, we have the JAK-STAT pathway that is also involved in the inflammatory process of atopic dermatitis on the inside of the cell. So you can see on this slide underneath, you see the JAK-1 and JAK-2, which are the ones that most of our therapeutics are affecting, work on the inside. So basically, how this works is that the cytokine binds this receptor on the outside, and it activates that JAK-STAT pathway.

The JAKs, the Janus kinases, they dimerize, and they activate these signal transducers that go to the nucleus and tell the nucleus to turn on and create more of these inflammatory cytokines. So biologics work on the outside of the cell, and they bind either the interleukin itself or they bind the receptor, where JAK inhibitors are small molecules, and they work on the inside of the cell to stop signal transduction.

So now we are going to hear a little bit about a patient's perspective and the impact of itch and the impact of, you know, having atopic dermatitis on his quality of life.

I would like for you to listen to this video.

Speaker: So when I had noticed that I had atopic dermatitis, it was a direct impact on my personal, social, and business life. I was not able to sleep. As a result, flare-ups were weeping and bleeding.

The only resort I had at that particular time was to use Benadryl, which unfortunately made me like a zombie the next day. So as a result, I had stopped going to the gym because I was covered with flares for most of my body. It impacted my work life, my personal life because it was bleeding through my dress shirts and in some cases through my suit pants.

Ultimately, I had to stop working. I stopped going to the gym and all the other activities that I normally pursued, I stopped as well. It was a very miserable time for me.

Dr Woolery-Lloyd: Okay. So it was really interesting to hear that patient's perspective. And you know that atopic dermatitis has this tremendous impact on quality of life.

And when we look at symptoms like pain, and pain when it comes to atopic dermatitis is generally burning and stinging. You can see here that at all age groups, so when you look at children, 6 months to 6 years of age, 6 to 12 years of age, or 12-18 years of age, that symptom of pain increases with severity of atopic dermatitis.

So you can see that blue bar is mild. The green bar is moderate atopic dermatitis and severe atopic dermatitis is the gray bar. And across all ages, that symptom of pain or burning and stinging increases with disease severity.

Now, another thing that people really complain about, and it is very burdensome is the impact of atopic dermatitis on sleep. And this is something that you will hear from parents of children with atopic dermatitis. So I know this is a very, very busy table, but to simplify it, when you see the orange color, that means that the atopic dermatitis had no impact on sleep. So they slept every night. These children slept every night. And when you see the yellow, that means it had a tremendous impact on sleep, and it impacted sleep every single night of the week.

So when you look at children, 6 months to 6 years old, which is where sleep is often reported the most from parents and really sleep affects people of all ages with atopic dermatitis. And I really want to emphasize that because we all know when you do not get a good night's sleep, you definitely do not have a good day. So I think all patients report this impact on sleep, but we hear it particularly from parents in these young children.

So when you look at that section of 6 months to 6 years old, you can see for mild, even for mild atopic dermatitis, over 50% of the parents reported that the children's sleep was impacted. And when you look at severe atopic dermatitis in that 6 months to 6 year age group, 42% of children were not sleeping at all, meaning their atopic dermatitis impacted their sleep every single night. And you can imagine the impact that has on the child.

And then, of course, the impact that has on the parent, because you know if your child is not sleeping, then you are not sleeping either. So this is something that is so important. It tremendously impacts quality of life. And it is something that treatment really impacts, helps because once you are not itching, you get to sleep, and it really improves quality of life.

Now, what about overall burden on quality of life? This is a similar graph to what we saw for the pain, which was burning and stinging. And this is just looking at the DLQI or quality of life. And again, you can see the more severe the atopic dermatitis is, the more severe the impact on quality of life. Then beyond this, there are other associated health effects of atopic dermatitis and prurigo nodularis.

So atopic dermatitis is associated with depression, anxiety, shame, and disgust. My patients will say, when I go to the grocery store, nobody wants to take their change from me because they think what I have is contagious. Sleep disturbances, we just spoke about.

Social anxiety is a big one. If you have dermatitis on your hands, you do not want to shake hands. You do not want to go to social events or dinner parties where you will be shaking hands because you are nervous that people will not want to touch you because you have scale and maybe even oozing or cracks on your hands.

There is a stigma associated with all skin diseases. Immediately when someone sees someone with skin disease, they make snap decisions about that person. And patients with atopic dermatitis are very aware of this.

Obsessive compulsive disorder is something that we see particularly in our patients with prurigo nodularis. And suicidal ideation is a big one. When people say, oh, this is just a skin disease, you know, at least it is not affecting, you know, your heart or other parts of the body.

People do not realize the impact on quality of life and how people with skin diseases have higher rates of suicidal ideation. So in patients with atopic dermatitis, they are 44% more likely to have suicidal ideation and 36% more likely to attempt suicide.

And I do a lot of clinical trials. So in the clinical trials for atopic dermatitis at every visit, we actually ask about suicidal ideation because it is so common. 20% of patients with atopic dermatitis have depression, which is 2 times higher than the general population. And when it comes to prurigo nodularis, it is associated with depression, anxiety, hypertension, kidney disease, fibromyalgia, and IBS.

And of course, our patients with atopic are more likely to have the allergic mark like march, such as allergies and asthma. And then there is another concept, and I do not speak French, but the moi-peau concept is that the skin really holds significant psychological meaning. So it is really our barrier between our inside world and the outside world. And we know that chronic skin conditions can disrupt both the physical and the psychological well-being of our patients.

Martha Sikes: You are absolutely right, Dr Woolery-Lloyd. I am a mom of an atopic patient and them not having adequate sleep, it really shows the next day. And you can understand those associated medical conditions that they have too, because if you are feeling like you are scratching, you know, you are so itchy from the inside-out, and it is unrelenting on many of the days of the year, you can see why they would feel the way that they do.

It is not a stretch, right?

Dr Woolery-Lloyd: Absolutely. Yes. I am also the mother of a child with atopic dermatitis, and there is nothing worse than the sound of a scratching baby in the middle of the night. It is just breaks your heart. It is a very, very difficult condition to deal with.

Martha Sikes: Exactly. I could not agree more. All right. Well, let us take a look at our first case. We have Emily, who is a 28-year-old woman who tells you, I cannot stop scratching. It is driving me crazy.

So she presents to our dermatology clinic for follow-up of her moderate atopic dermatitis, which has flared over the past month. She reports intense, persistent itching that is worst at night, which leads to poor sleep and increased stress.

The itching is most severe on her arms, neck, and the back of her knees. She has been using a topical corticosteroid and a basic moisturizer, but reports that it does not help enough. She sometimes scratches until the skin breaks, which she finds both painful and embarrassing.

So what factors are involved in the burden of itch for Emily?

Dr Woolery-Lloyd: So this is a typical patient. That concept of the itch that you cannot stop scratching and there is no relief is something that we hear all the time in clinic and patients with atopic dermatitis. It is very, very challenging clinically for our patients to deal with itch. It is the most burdensome symptom of atopic dermatitis.

Victoria Garcia-Albea (Lahey Hospital and Medical Center): I agree. We frequently hear that it worsens at night when you are not distracted, you are trying to relax, you are trying to, you know, read a book or watch TV or go to sleep. So this is something that is common for patients with any kind of disease that causes itch.

Martha Sikes: Yes, absolutely. And then you lead into the poor sleep does not allow you to deal with your day the next day as well. And so that causes more stress, right?

Dr Woolery-Lloyd: Yes, absolutely. I think that sleep is underrated. Everyone focuses on so many things, but that impact of poor sleep tremendously affects quality of life. And we all know, all of us know when you really do not get a good night's sleep, when you really sleep poorly, it impacts your whole day, and you cannot really make it up.

Actually, studies show that like, when you lose sleep, it is not like you can sleep more the next day and make it up. It really has some long-term impacts. And so for busy working people with atopic dermatitis, beyond the discomfort of the constant scratching, and itching and feeling uncomfortable, on top of that, you are not sleeping. And so it really does impact those patients.

Victoria Garcia-Albea: I agree. I think we cannot overstate the importance of sleep there. The only thing you cannot do to get into the Guinness Book of World Records is try to break the record for longest time staying awake. Think of all the crazy things you can do, you can eat unhealthy things, you can do all these unhealthy things to your body, but you cannot try to break that streak of not sleeping because it is so unhealthy. So it is just so important.

Martha Sikes: Yes, I could not agree more. All right, well, let us, let us look at another patient here. We have Marcus, who is a 62-year-old man who complains that the itchy bumps will not go away. And he cannot stop scratching.

And he was diagnosed with prurigo nodularis about a year ago, but he has progressively worsened. And he often scratches to the point of bleeding, especially at night. So we see that trend, right? He has been using over-the-counter creams and antihistamines, but with no lasting relief. Is this typical of what you all see in your clinic as well?

Dr Woolery-Lloyd: Yes, I think it is. It is interesting that you can see here that he is 62. Typically, older patients develop prurigo nodularis, as I mentioned in my talk. And again, these patients are so uncomfortable.

This is also just like atopic dermatitis. Physically, you know, when people see these excoriated nodules all over people's arms, it is very, very difficult to go about your everyday life. No one wants to kind of see someone scratching next to them in line. So this is another condition that tremendously impacts quality of life. I always tell patients, because sometimes people say they will feel almost embarrassed, like to complain about it. And they will say, it is just my skin.

And I say, no, itch is worse than pain. You know, you can take something to make pain go away. However, that chronic severe itch untreated is just so challenging for our patients.

Victoria Garcia-Albea: I agree. And I would be interested in finding out how many body areas are involved for this patient. If anything happened when it started, you know, any stressful event that happened that occurred before his scratching started because it started about a year ago. And then talk about what kind of creams he has been using, because obviously, there are many that are actually not really that great for your skin. You know, ones with fragrance, etc. So there are lots of avenues to explore to figure out what this patient has really been doing, and how we can get him some relief.

Dr Woolery-Lloyd: And you bring up a really good point about what types of creams, because I saw over-the-counter creams. And you made me think about things like all of the home remedies that people will do, they will put apple cider vinegar. You know, the number of strange things that people will try out of desperation to address itch is something that we would probably do not talk about, and the amount of expense. So this gets expensive, because when you are desperate, and you are itchy, and uncomfortable, you will try anything.

And 1 thing is $10, the other thing is $20, something is $30, next thing is $20. And you know, several months later, these patients have spent hundreds and hundreds of dollars on topical treatments that are not working for them over-the-counter.

Victoria Garcia-Albea: And I think it can be frustrating when they come in to us, and we say, we are going to give you a cream. And they are like, but I have tried all the creams, they say that to us. However, we feel like they have not tried any of the creams that we would recommend. So it is a little bit of a battle.

Martha Sikes: It is. Right. And a lot of it to your point, Tori, a lot of those over-the-counter creams can actually make the condition worse, right? They can accentuate the barrier dysfunction.

Victoria Garcia-Albea: Right.

Martha Sikes: All right. Well, let us look at another patient here.

We have Sarah, who is a 34-year-old woman who complains that her eczema is flaring again and nothing seems to help. Sarah has a longstanding history of atopic dermatitis with recent flares over the past 3 months that affect her neck, hands and eyelids. She has been using topical corticosteroids and moisturizers as prescribed, but she states this has really given her minimal relief.

She works as a graphic designer and says the condition is affecting her ability to focus at work due to constant itching and visible redness on her face and hands. She feels self-conscious in client meetings and has started avoiding social events.

Victoria Garcia-Albea: Well, I was going to focus on we call high-impact areas that are at play here in this patient.

You know, traditionally we think about disease in terms of how much body surface area it covers, but this patient may have a very low BSA, but has such a high impact based on the importance, based on the location. So the eyelids, the face, the hands, these are what we call high-impact areas. So it increases the severity because it is more impactful psychosocially.

So when you look at a patient like this, and obviously, she is complaining significantly. So you already know her severity is high, but you can think of her as more severe than somebody maybe who has very involved fungal eczema that is not as visible, so it may have a lower impact compared to this patient.

What were you going to say, Dr Woolery-Lloyd?

Dr Woolery-Lloyd: I agree that when we fill out forms, when we are prescribing some of our medications, they ask for total body surface area. So 1% body surface area is a hand, right? And a lot of times for some medications, insurance companies might require 10% total body surface area.

However, let us say you are both of your hands are severely affected with atopic dermatitis. And you know, that is only 2% body surface area, but it is cracked, oozing, itching, and you work as a graphic designer, where you need to be typing at your computer and meeting clients and shaking hands, then you cannot function. If your hands are affected severely by atopic dermatitis, you really cannot do many of your activities of daily living.

It hurts to wash your face, to cook if you are a busy person who is making food or doing just regular things around the house that tremendously impacts quality of life. So those sensitive areas are something that are important for us to understand because even if the body surface area is not very high, it can impact quality of life. And they would be great candidates for some of the medications that we are going to talk about today.

Martha Sikes: Yes, absolutely. And you bring up great points, both of you, especially with those high-impact areas, you know, think of all the people like you were saying, who have these jobs where they have to use their hands every day, and they are cracked and bleeding, and they, they almost cannot work. So it is very difficult.

Dr Woolery-Lloyd: I would argue that in most jobs, you really are using your hands.

Victoria Garcia-Albea: I am trying to think of one where you do not. Maybe like a singer.

Martha Sikes: They are still holding a microphone, right?

Dr Woolery-Lloyd: And they still have to meet their fans and shake hands and so forth.

Dr Woolery-Lloyd: It is really helpful to give our patients the grace to kind of be angry, be mad that they have their skin disease, because I spend a lot of time reassuring, it is okay to be frustrated, angry, upset at how this is affecting your quality of life. Because I sometimes find not all patients, but some patients almost feel guilty about complaining about this. And I want them to feel very comfortable saying, it is okay, you have every right to be frustrated, angry that you are uncomfortable in your skin.

Victoria Garcia-Albea: I think that is true. A lot of them will say, I know, it could be worse, right? We hear that all the time. It is not cancer, it could be worse. However, it is a chronic, relapsing and remitting condition you have no control over. That is stressful, you do not know when it is going to flare up.

So I agree, it is best to sit down, validate their concerns, just listen, and you know, then come up with a plan.

Dr Woolery-Lloyd: And the 1 thing you said you mentioned is not cancer, that is such a good point, because they actually did a study. And they looked at severe skin disease and the impact of quality of life, let us say severe eczema or severe psoriasis. And interestingly, they found that severe skin disease had a greater impact on quality of life than things like insulin-dependent diabetes, certain cancer diagnoses.

Victoria Garcia-Albea: Heart disease, heart failure, yes.

Dr Woolery-Lloyd: Yes, exactly. And the reason why that is, is because severe skin disease, everyone knows, every time you go to the store, you have a birthday party that you have to go to for your kids, all of these events that you have to go to, you go to work, everyone can see your skin disease, you can never hide, you are never invisible.

And so I tell my patients actually that statistic, because I want them to understand that it does impact quality of life. And it is okay to be angry and frustrated, and they can talk about it with me.

Victoria Garcia-Albea: Agree. Yes.

Martha Sikes: So that brings me to a great point here with what are some additional questions that you would ask this patient. Because one of the ones that kind of comes to my mind with patients is, is it the itch that bothers you more? Or is it the appearance that bothers you more? And it is different for each patient type, and where they are at in their life.

Victoria Garcia-Albea: I agree. And, you know, you are starting to think about what treatments, you know, which way you are going to go. So I think it is a great time to talk about, I just usually start by saying, you know, giving them the toolbox, and then asking them what, what sounds good to you? What are some concerns you might have about topicals, about phototherapy, about injections, about pills? You know, what would work best for you?

Dr Woolery-Lloyd: Yes, I agree. I usually present almost all the options and or what is appropriate, the options that are appropriate for that patient, and discuss the risks and benefits and which ones and together, we kind of come up with a plan. And some other questions, if you have a patient who you really think you are looking at them, and it looks like something that would really impact their quality of life, you can even ask to just get a little bit more details, specific questions, like they might not volunteer it, but you might ask, does this disrupt your sleep? Does your atopic dermatitis make you not want to go out to social events, and so forth. And it is very helpful to document those questions in the medical records, especially when we are trying to get some of these more difficult to get medications that can be a little bit more challenging, like biologics and JAK inhibitors. Because when we have documentation of the impact on quality of life, it can help for approval for many of these medications.

Victoria Garcia-Albea: And 1 other thing, because if this patient were coming in, and you see the areas, the face, the hands, that is what they are complaining about. However, do not forget that some patients have it in the groin area, and they do not want to say it. And so you can prompt and just say, you know, it is actually really common for eczema to affect any part of your body, including the private areas. Is that something that has ever happened for you? Does your disease interfere with your sexual life? You know, questions like that, to make the patient feel more comfortable disclosing other sites that you might not know, are involved as well.

Dr Woolery-Lloyd: That is a good point because skin disease tremendously impacts young people who are dating. It is very hard to date if you have skin diseases because people are concerned that, again, the person they are dating might think it is infectious, or that they are contagious. So those types of questions are very helpful that patients might not volunteer.

Martha Sikes: Yes, and Tori, I think you make a good point. And I am sure Dr Woolery-Lloyd, you have seen this as well. If you do not ask them about those more sensitive places, they are not going to volunteer it, right?

Dr Woolery-Lloyd: Right.

Victoria Garcia-Albea: I think we think of psoriasis as being fairly often in the groin, but eczema can be there too. Their skin is sensitive, they might even just be getting like a contact derm from some product they are using. Our patients who have impaired barrier function, that is more common. So it is just good to keep in mind.

And the more you ask about it, the more comfortable you feel talking about it with other patients, and it just rolls off your tongue. So, you know, practice doing it.

Martha Sikes: And there is 1 question that has come in, and I think this is a good time to ask it, is with the psychosocial impact related to atopic dermatitis and prurigo nodularis, do you feel that the majority of patients should be referred out for mental health counseling?

Victoria Garcia-Albea: I think it is not a bad idea. Yes.

Dr Woolery-Lloyd: I think that once you develop a relationship with the patient, I think on the very first visit, unless it is very clear, like a patient has suicidal ideation, I think on the very first visit, it is helpful to kind of set the groundwork on the rapport. And then in a follow-up visit, I think that that is very reasonable, especially for patients with moderate-to-severe disease. Because as I mentioned, in my section, they do have higher risk of suicidal ideation.

And in a study setting, we ask at every visit about suicidal ideation. And I know that most of us probably do not do that in our regular clinic, but it is just interesting that we do it in all of our studies. So maybe the baseline visit, because you do not want the patient to think that you are thinking it is all in their head kind of thing. However, at follow-up, once you have established a relationship with the patient, I think it is absolutely appropriate.

Atopic Dermatitis and Prurigo Nodularis: The Impact of Chronic Itch

Dr Heather Woolery-Lloyd (University of Miami Miller School of Medicine): I am going to talk about the fundamentals of chronic itch in patients with atopic dermatitis and prurigo nodularis. And it is something that we all see in clinic.

You know it is a very common condition, atopic dermatitis. It affects up to 20% of children and onset is usually in infancy. So between the ages of 3 and 6 months of age and of those people diagnosed with atopic dermatitis, 60% develop the condition by the age of 1 year old and 85% develop it by the age of 5.

So it is definitely something that we see in kids very frequently. And for many of these children, it persists into adulthood. So, around 50% of people, pediatric atopic dermatitis persists into adulthood.

It can have a variable course. So some people say, oh, I had eczema when I was a kid, but it resolved, and I really do not have it now. However, I would say there is a little bit of a caveat there because when it comes to eczema, that type of patient who is had quote unquote childhood eczema, they tend to have sensitive skin into adulthood, although they do not have a quote unquote diagnosis of atopic dermatitis.

And then some patients develop atopic dermatitis out of the blue as an adult. So, 25-50% of adults with atopic dermatitis did not have symptoms as a child. And when you have adult atopic dermatitis, it tends to be more localized and more lichenified.

Let us talk about prurigo nodularis. So it is seen in around 72 per 100,000 people. And the median age of onset is 62 years old. So this is in contrast to eczema or atopic derm, which we see in younger patient populations in general. Prurigo nodularis we see typically in adults. It is 3 to 4 times more common in Black patients than it is in White patients.

And in general, disorders that involve itch, sos atopic dermatitis, prurigo nodularis, and just itch in general is more common in black patients and also in Asian patients. It affects up to 5% of people with HIV, and 46% of patients with prurigo nodularis have either a predisposition to atopic dermatitis or a personal history of atopic dermatitis.

So what are the common pathways between atopic dermatitis and prurigo nodularis? First of all, both diseases have an increase in the number of nerve fibers in the papillary dermis. Both diseases have a cutaneous neuropathy. So they have small fiber neuropathy that increases that perception of itch. They have increased TRP, expression of TRP, which are channels within the neurons that again drive this sensitivity to itch. There is neural dysregulation and this Th2 cytokine profile.

So these patients are at increased risk for itch. And when you think about atopic dermatitis, there are 2 ways to think about it. There is the inside-out and the outside-in concept.

So the inside-out is this concept that at baseline, patients with atopic dermatitis have this pro-inflammatory environment in their skin. So they have more IgE production. They have this Th2 differentiation.

This causes inflammation in the skin, and therefore they get barrier disruption. And that is the theory behind that inside-out, that you have this baseline predisposition, this pro-inflammatory Th2 profile that disrupts your barrier. And what we see clinically is itching and scratching.

Then there is the outside-in thought process. And that kind of concept is that there is an impaired barrier at baseline. So, you know, that abnormal filaggrin and other things in our skin barrier that are abnormal in our patients with atopic dermatitis, that this outside-in makes the skin more vulnerable to these exogenous insults.

So we know our atopic patients react to detergents. They react to wool clothing. They react to changes in climate and so forth when the humidity drops. And then that induces the inflammation. And you see the IL-4 and 13 and these pro-inflammatory cytokines.

So there are 2 ways to think about atopic dermatitis, and it is probably a combination of both, but it is a nice way to kind of categorize why this condition exists.

So there are some key cytokines in atopic dermatitis and key players in the immune system. And we are going to be talking about these throughout this whole session. So I want to kind of form this baseline so you can understand when we are thinking about the pathogenesis of atopic dermatitis, how this works.

So there are 4 key cytokines that are really important in the pathogenesis of atopic dermatitis, and they are IL-4, IL-13, IL-31, and TSLP. So these cytokines bind the receptors on the outside of the cell and activate this inflammatory process in the skin. When you hear all of these new biologics that are used to treat atopic dermatitis, know that they are binding the cytokine or the receptor on the outside of the cell.

In contrast to that, we have the JAK-STAT pathway that is also involved in the inflammatory process of atopic dermatitis on the inside of the cell. So you can see on this slide underneath, you see the JAK-1 and JAK-2, which are the ones that most of our therapeutics are affecting, work on the inside. So basically, how this works is that the cytokine binds this receptor on the outside, and it activates that JAK-STAT pathway.

The JAKs, the Janus kinases, they dimerize, and they activate these signal transducers that go to the nucleus and tell the nucleus to turn on and create more of these inflammatory cytokines. So biologics work on the outside of the cell, and they bind either the interleukin itself or they bind the receptor, where JAK inhibitors are small molecules, and they work on the inside of the cell to stop signal transduction.

So now we are going to hear a little bit about a patient's perspective and the impact of itch and the impact of, you know, having atopic dermatitis on his quality of life.

I would like for you to listen to this video.

Speaker: So when I had noticed that I had atopic dermatitis, it was a direct impact on my personal, social, and business life. I was not able to sleep. As a result, flare-ups were weeping and bleeding.

The only resort I had at that particular time was to use Benadryl, which unfortunately made me like a zombie the next day. So as a result, I had stopped going to the gym because I was covered with flares for most of my body. It impacted my work life, my personal life because it was bleeding through my dress shirts and in some cases through my suit pants.

Ultimately, I had to stop working. I stopped going to the gym and all the other activities that I normally pursued, I stopped as well. It was a very miserable time for me.

Dr Woolery-Lloyd: Okay. So it was really interesting to hear that patient's perspective. And you know that atopic dermatitis has this tremendous impact on quality of life.

And when we look at symptoms like pain, and pain when it comes to atopic dermatitis is generally burning and stinging. You can see here that at all age groups, so when you look at children, 6 months to 6 years of age, 6 to 12 years of age, or 12-18 years of age, that symptom of pain increases with severity of atopic dermatitis.

So you can see that blue bar is mild. The green bar is moderate atopic dermatitis and severe atopic dermatitis is the gray bar. And across all ages, that symptom of pain or burning and stinging increases with disease severity.

Now, another thing that people really complain about, and it is very burdensome is the impact of atopic dermatitis on sleep. And this is something that you will hear from parents of children with atopic dermatitis. So I know this is a very, very busy table, but to simplify it, when you see the orange color, that means that the atopic dermatitis had no impact on sleep. So they slept every night. These children slept every night. And when you see the yellow, that means it had a tremendous impact on sleep, and it impacted sleep every single night of the week.

So when you look at children, 6 months to 6 years old, which is where sleep is often reported the most from parents and really sleep affects people of all ages with atopic dermatitis. And I really want to emphasize that because we all know when you do not get a good night's sleep, you definitely do not have a good day. So I think all patients report this impact on sleep, but we hear it particularly from parents in these young children.

So when you look at that section of 6 months to 6 years old, you can see for mild, even for mild atopic dermatitis, over 50% of the parents reported that the children's sleep was impacted. And when you look at severe atopic dermatitis in that 6 months to 6 year age group, 42% of children were not sleeping at all, meaning their atopic dermatitis impacted their sleep every single night. And you can imagine the impact that has on the child.

And then, of course, the impact that has on the parent, because you know if your child is not sleeping, then you are not sleeping either. So this is something that is so important. It tremendously impacts quality of life. And it is something that treatment really impacts, helps because once you are not itching, you get to sleep, and it really improves quality of life.

Now, what about overall burden on quality of life? This is a similar graph to what we saw for the pain, which was burning and stinging. And this is just looking at the DLQI or quality of life. And again, you can see the more severe the atopic dermatitis is, the more severe the impact on quality of life. Then beyond this, there are other associated health effects of atopic dermatitis and prurigo nodularis.

So atopic dermatitis is associated with depression, anxiety, shame, and disgust. My patients will say, when I go to the grocery store, nobody wants to take their change from me because they think what I have is contagious. Sleep disturbances, we just spoke about.

Social anxiety is a big one. If you have dermatitis on your hands, you do not want to shake hands. You do not want to go to social events or dinner parties where you will be shaking hands because you are nervous that people will not want to touch you because you have scale and maybe even oozing or cracks on your hands.

There is a stigma associated with all skin diseases. Immediately when someone sees someone with skin disease, they make snap decisions about that person. And patients with atopic dermatitis are very aware of this.

Obsessive compulsive disorder is something that we see particularly in our patients with prurigo nodularis. And suicidal ideation is a big one. When people say, oh, this is just a skin disease, you know, at least it is not affecting, you know, your heart or other parts of the body.

People do not realize the impact on quality of life and how people with skin diseases have higher rates of suicidal ideation. So in patients with atopic dermatitis, they are 44% more likely to have suicidal ideation and 36% more likely to attempt suicide.

And I do a lot of clinical trials. So in the clinical trials for atopic dermatitis at every visit, we actually ask about suicidal ideation because it is so common. 20% of patients with atopic dermatitis have depression, which is 2 times higher than the general population. And when it comes to prurigo nodularis, it is associated with depression, anxiety, hypertension, kidney disease, fibromyalgia, and IBS.

And of course, our patients with atopic are more likely to have the allergic mark like march, such as allergies and asthma. And then there is another concept, and I do not speak French, but the moi-peau concept is that the skin really holds significant psychological meaning. So it is really our barrier between our inside world and the outside world. And we know that chronic skin conditions can disrupt both the physical and the psychological well-being of our patients.

Martha Sikes: You are absolutely right, Dr Woolery-Lloyd. I am a mom of an atopic patient and them not having adequate sleep, it really shows the next day. And you can understand those associated medical conditions that they have too, because if you are feeling like you are scratching, you know, you are so itchy from the inside-out, and it is unrelenting on many of the days of the year, you can see why they would feel the way that they do.

It is not a stretch, right?

Dr Woolery-Lloyd: Absolutely. Yes. I am also the mother of a child with atopic dermatitis, and there is nothing worse than the sound of a scratching baby in the middle of the night. It is just breaks your heart. It is a very, very difficult condition to deal with.

Martha Sikes: Exactly. I could not agree more. All right. Well, let us take a look at our first case. We have Emily, who is a 28-year-old woman who tells you, I cannot stop scratching. It is driving me crazy.

So she presents to our dermatology clinic for follow-up of her moderate atopic dermatitis, which has flared over the past month. She reports intense, persistent itching that is worst at night, which leads to poor sleep and increased stress.

The itching is most severe on her arms, neck, and the back of her knees. She has been using a topical corticosteroid and a basic moisturizer, but reports that it does not help enough. She sometimes scratches until the skin breaks, which she finds both painful and embarrassing.

So what factors are involved in the burden of itch for Emily?

Dr Woolery-Lloyd: So this is a typical patient. That concept of the itch that you cannot stop scratching and there is no relief is something that we hear all the time in clinic and patients with atopic dermatitis. It is very, very challenging clinically for our patients to deal with itch. It is the most burdensome symptom of atopic dermatitis.

Victoria Garcia-Albea (Lahey Hospital and Medical Center): I agree. We frequently hear that it worsens at night when you are not distracted, you are trying to relax, you are trying to, you know, read a book or watch TV or go to sleep. So this is something that is common for patients with any kind of disease that causes itch.

Martha Sikes: Yes, absolutely. And then you lead into the poor sleep does not allow you to deal with your day the next day as well. And so that causes more stress, right?

Dr Woolery-Lloyd: Yes, absolutely. I think that sleep is underrated. Everyone focuses on so many things, but that impact of poor sleep tremendously affects quality of life. And we all know, all of us know when you really do not get a good night's sleep, when you really sleep poorly, it impacts your whole day, and you cannot really make it up.

Actually, studies show that like, when you lose sleep, it is not like you can sleep more the next day and make it up. It really has some long-term impacts. And so for busy working people with atopic dermatitis, beyond the discomfort of the constant scratching, and itching and feeling uncomfortable, on top of that, you are not sleeping. And so it really does impact those patients.

Victoria Garcia-Albea: I agree. I think we cannot overstate the importance of sleep there. The only thing you cannot do to get into the Guinness Book of World Records is try to break the record for longest time staying awake. Think of all the crazy things you can do, you can eat unhealthy things, you can do all these unhealthy things to your body, but you cannot try to break that streak of not sleeping because it is so unhealthy. So it is just so important.

Martha Sikes: Yes, I could not agree more. All right, well, let us, let us look at another patient here. We have Marcus, who is a 62-year-old man who complains that the itchy bumps will not go away. And he cannot stop scratching.

And he was diagnosed with prurigo nodularis about a year ago, but he has progressively worsened. And he often scratches to the point of bleeding, especially at night. So we see that trend, right? He has been using over-the-counter creams and antihistamines, but with no lasting relief. Is this typical of what you all see in your clinic as well?

Dr Woolery-Lloyd: Yes, I think it is. It is interesting that you can see here that he is 62. Typically, older patients develop prurigo nodularis, as I mentioned in my talk. And again, these patients are so uncomfortable.

This is also just like atopic dermatitis. Physically, you know, when people see these excoriated nodules all over people's arms, it is very, very difficult to go about your everyday life. No one wants to kind of see someone scratching next to them in line. So this is another condition that tremendously impacts quality of life. I always tell patients, because sometimes people say they will feel almost embarrassed, like to complain about it. And they will say, it is just my skin.

And I say, no, itch is worse than pain. You know, you can take something to make pain go away. However, that chronic severe itch untreated is just so challenging for our patients.

Victoria Garcia-Albea: I agree. And I would be interested in finding out how many body areas are involved for this patient. If anything happened when it started, you know, any stressful event that happened that occurred before his scratching started because it started about a year ago. And then talk about what kind of creams he has been using, because obviously, there are many that are actually not really that great for your skin. You know, ones with fragrance, etc. So there are lots of avenues to explore to figure out what this patient has really been doing, and how we can get him some relief.

Dr Woolery-Lloyd: And you bring up a really good point about what types of creams, because I saw over-the-counter creams. And you made me think about things like all of the home remedies that people will do, they will put apple cider vinegar. You know, the number of strange things that people will try out of desperation to address itch is something that we would probably do not talk about, and the amount of expense. So this gets expensive, because when you are desperate, and you are itchy, and uncomfortable, you will try anything.

And 1 thing is $10, the other thing is $20, something is $30, next thing is $20. And you know, several months later, these patients have spent hundreds and hundreds of dollars on topical treatments that are not working for them over-the-counter.

Victoria Garcia-Albea: And I think it can be frustrating when they come in to us, and we say, we are going to give you a cream. And they are like, but I have tried all the creams, they say that to us. However, we feel like they have not tried any of the creams that we would recommend. So it is a little bit of a battle.

Martha Sikes: It is. Right. And a lot of it to your point, Tori, a lot of those over-the-counter creams can actually make the condition worse, right? They can accentuate the barrier dysfunction.

Victoria Garcia-Albea: Right.

Martha Sikes: All right. Well, let us look at another patient here.

We have Sarah, who is a 34-year-old woman who complains that her eczema is flaring again and nothing seems to help. Sarah has a longstanding history of atopic dermatitis with recent flares over the past 3 months that affect her neck, hands and eyelids. She has been using topical corticosteroids and moisturizers as prescribed, but she states this has really given her minimal relief.

She works as a graphic designer and says the condition is affecting her ability to focus at work due to constant itching and visible redness on her face and hands. She feels self-conscious in client meetings and has started avoiding social events.

Victoria Garcia-Albea: Well, I was going to focus on we call high-impact areas that are at play here in this patient.

You know, traditionally we think about disease in terms of how much body surface area it covers, but this patient may have a very low BSA, but has such a high impact based on the importance, based on the location. So the eyelids, the face, the hands, these are what we call high-impact areas. So it increases the severity because it is more impactful psychosocially.

So when you look at a patient like this, and obviously, she is complaining significantly. So you already know her severity is high, but you can think of her as more severe than somebody maybe who has very involved fungal eczema that is not as visible, so it may have a lower impact compared to this patient.

What were you going to say, Dr Woolery-Lloyd?

Dr Woolery-Lloyd: I agree that when we fill out forms, when we are prescribing some of our medications, they ask for total body surface area. So 1% body surface area is a hand, right? And a lot of times for some medications, insurance companies might require 10% total body surface area.

However, let us say you are both of your hands are severely affected with atopic dermatitis. And you know, that is only 2% body surface area, but it is cracked, oozing, itching, and you work as a graphic designer, where you need to be typing at your computer and meeting clients and shaking hands, then you cannot function. If your hands are affected severely by atopic dermatitis, you really cannot do many of your activities of daily living.

It hurts to wash your face, to cook if you are a busy person who is making food or doing just regular things around the house that tremendously impacts quality of life. So those sensitive areas are something that are important for us to understand because even if the body surface area is not very high, it can impact quality of life. And they would be great candidates for some of the medications that we are going to talk about today.

Martha Sikes: Yes, absolutely. And you bring up great points, both of you, especially with those high-impact areas, you know, think of all the people like you were saying, who have these jobs where they have to use their hands every day, and they are cracked and bleeding, and they, they almost cannot work. So it is very difficult.

Dr Woolery-Lloyd: I would argue that in most jobs, you really are using your hands.

Victoria Garcia-Albea: I am trying to think of one where you do not. Maybe like a singer.

Martha Sikes: They are still holding a microphone, right?

Dr Woolery-Lloyd: And they still have to meet their fans and shake hands and so forth.

Dr Woolery-Lloyd: It is really helpful to give our patients the grace to kind of be angry, be mad that they have their skin disease, because I spend a lot of time reassuring, it is okay to be frustrated, angry, upset at how this is affecting your quality of life. Because I sometimes find not all patients, but some patients almost feel guilty about complaining about this. And I want them to feel very comfortable saying, it is okay, you have every right to be frustrated, angry that you are uncomfortable in your skin.

Victoria Garcia-Albea: I think that is true. A lot of them will say, I know, it could be worse, right? We hear that all the time. It is not cancer, it could be worse. However, it is a chronic, relapsing and remitting condition you have no control over. That is stressful, you do not know when it is going to flare up.

So I agree, it is best to sit down, validate their concerns, just listen, and you know, then come up with a plan.

Dr Woolery-Lloyd: And the 1 thing you said you mentioned is not cancer, that is such a good point, because they actually did a study. And they looked at severe skin disease and the impact of quality of life, let us say severe eczema or severe psoriasis. And interestingly, they found that severe skin disease had a greater impact on quality of life than things like insulin-dependent diabetes, certain cancer diagnoses.

Victoria Garcia-Albea: Heart disease, heart failure, yes.

Dr Woolery-Lloyd: Yes, exactly. And the reason why that is, is because severe skin disease, everyone knows, every time you go to the store, you have a birthday party that you have to go to for your kids, all of these events that you have to go to, you go to work, everyone can see your skin disease, you can never hide, you are never invisible.

And so I tell my patients actually that statistic, because I want them to understand that it does impact quality of life. And it is okay to be angry and frustrated, and they can talk about it with me.

Victoria Garcia-Albea: Agree. Yes.

Martha Sikes: So that brings me to a great point here with what are some additional questions that you would ask this patient. Because one of the ones that kind of comes to my mind with patients is, is it the itch that bothers you more? Or is it the appearance that bothers you more? And it is different for each patient type, and where they are at in their life.

Victoria Garcia-Albea: I agree. And, you know, you are starting to think about what treatments, you know, which way you are going to go. So I think it is a great time to talk about, I just usually start by saying, you know, giving them the toolbox, and then asking them what, what sounds good to you? What are some concerns you might have about topicals, about phototherapy, about injections, about pills? You know, what would work best for you?

Dr Woolery-Lloyd: Yes, I agree. I usually present almost all the options and or what is appropriate, the options that are appropriate for that patient, and discuss the risks and benefits and which ones and together, we kind of come up with a plan. And some other questions, if you have a patient who you really think you are looking at them, and it looks like something that would really impact their quality of life, you can even ask to just get a little bit more details, specific questions, like they might not volunteer it, but you might ask, does this disrupt your sleep? Does your atopic dermatitis make you not want to go out to social events, and so forth. And it is very helpful to document those questions in the medical records, especially when we are trying to get some of these more difficult to get medications that can be a little bit more challenging, like biologics and JAK inhibitors. Because when we have documentation of the impact on quality of life, it can help for approval for many of these medications.

Victoria Garcia-Albea: And 1 other thing, because if this patient were coming in, and you see the areas, the face, the hands, that is what they are complaining about. However, do not forget that some patients have it in the groin area, and they do not want to say it. And so you can prompt and just say, you know, it is actually really common for eczema to affect any part of your body, including the private areas. Is that something that has ever happened for you? Does your disease interfere with your sexual life? You know, questions like that, to make the patient feel more comfortable disclosing other sites that you might not know, are involved as well.

Dr Woolery-Lloyd: That is a good point because skin disease tremendously impacts young people who are dating. It is very hard to date if you have skin diseases because people are concerned that, again, the person they are dating might think it is infectious, or that they are contagious. So those types of questions are very helpful that patients might not volunteer.

Martha Sikes: Yes, and Tori, I think you make a good point. And I am sure Dr Woolery-Lloyd, you have seen this as well. If you do not ask them about those more sensitive places, they are not going to volunteer it, right?

Dr Woolery-Lloyd: Right.

Victoria Garcia-Albea: I think we think of psoriasis as being fairly often in the groin, but eczema can be there too. Their skin is sensitive, they might even just be getting like a contact derm from some product they are using. Our patients who have impaired barrier function, that is more common. So it is just good to keep in mind.

And the more you ask about it, the more comfortable you feel talking about it with other patients, and it just rolls off your tongue. So, you know, practice doing it.

Martha Sikes: And there is 1 question that has come in, and I think this is a good time to ask it, is with the psychosocial impact related to atopic dermatitis and prurigo nodularis, do you feel that the majority of patients should be referred out for mental health counseling?

Victoria Garcia-Albea: I think it is not a bad idea. Yes.

Dr Woolery-Lloyd: I think that once you develop a relationship with the patient, I think on the very first visit, unless it is very clear, like a patient has suicidal ideation, I think on the very first visit, it is helpful to kind of set the groundwork on the rapport. And then in a follow-up visit, I think that that is very reasonable, especially for patients with moderate-to-severe disease. Because as I mentioned, in my section, they do have higher risk of suicidal ideation.

And in a study setting, we ask at every visit about suicidal ideation. And I know that most of us probably do not do that in our regular clinic, but it is just interesting that we do it in all of our studies. So maybe the baseline visit, because you do not want the patient to think that you are thinking it is all in their head kind of thing. However, at follow-up, once you have established a relationship with the patient, I think it is absolutely appropriate.