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Clinical Heterogeneity of AD
​​​​​​In this podcast, Dr Zelma Chiesa Fuxench met with The Dermatologist to discuss the heterogeneity of AD including specific patient demographics, molecular heterogeneity, and more.
Zelma Chiesa Fuxench, MD, MSCE, is a clinical instructor at the University of Pennsylvania Perelman School of Medicine in Philadelphia, PA. She specializes in inflammatory diseases particularly psoriasis and atopic dermatitis.
Transcript:
Jessica Garlewicz: Hello. This is Jessica Garlewicz, associate digital editor for The Dermatologist. With me today is Dr. Chiesa. We're here to discuss atopic dermatitis as part of our National Eczema Association, or NEA, Approved Feature of Atopic Dermatitis Expert Series.
Dr. Chiesa is a clinical instructor at the University of Pennsylvania Perelman School of Medicine. She is really known for her work focused on inflammatory skin diseases, primarily psoriasis and atopic dermatitis. She's actively involved in the conduction of clinical trials on psoriasis and AD as part of Dr. Gelfand's clinical research lab.
Dr. Chiesa, would you like to give us an insight into your clinical practice?
Zelma Chiesa Fuxench: Hi, Jessica, and hello to everyone who's listening to us today. Thank you for the very kind introduction. Yes, my name is Dr. Zelma Chiesa Fuxench, and I'm an assistant professor of dermatology at the University of Pennsylvania. My clinical practice is primarily focused on taking care of adult patients with chronic inflammatory skin disease, for example, atopic dermatitis, psoriasis, hidradenitis and, also, patients with skin cancer and other conditions.
I'm very excited to be here today discussing one of my favorite diseases, which is atopic dermatitis.
Jessica Garlewicz: Of course, thank you for joining us. Now, our first topic of discussion is the clinical heterogeneity of atopic dermatitis. Currently, we're discussing the clinical and patient-specific domains contributing to the heterogeneity of AD. Would you like to go into detail on that?
Zelma Chiesa Fuxench: I think this is an excellent topic to start a discussion talking a little bit about is all AD the same? I think we are becoming increasingly aware that that's not the case, that there are many factors that come into play, that patients with atopic dermatitis are very different. We have different age of onset. We have patients that present with AD very early in life, and these are sometimes referred to as childhood onset atopic dermatitis, infantile onset atopic dermatitis, and then we have patients who present a little bit later, maybe between the ages of eight and 17, and those are considered late childhood atopic dermatitis, and then we have our patients who might be presenting with new onset atopic dermatitis as an adult, meaning, older than 18. I think that's one of the discrepancies we can see across age ranges.
Also, depending on race ethnicity, we know that the clinical presentation can be quite different. We tend to see that patients who have darker skin types may present with more lichenified or more follicular prominent lesions. Sometimes, it's very difficult to assess the erythema in patients who have darker skin types, so that's another contributing factor to the heterogeneity of the disease.
When we talk about the disease severity, the extent of the disease, the location of the lesions, the clinical presentation overall can also be quite different. We have patients that present anywhere from mild to moderate, severe, and how you'd even define that, that is also... There's a lot of heterogeneity there because you can use outcome measures that are from physician perspective. We just look at the extent of disease, the intensity of the lesions, how red, how thick they are or how excoriated they are, how lichenified they are, and then you have assessment of disease severity from the patient's perspective, the impact on itch, on sleep, on quality of life. Again, we see variations across the spectrum, so I think it's very important to think about all those things when you're assessing a patient in clinic.
I treat a particular patient population, and those are patients that are a little bit older, so the comorbidities that we are seeing in my particular group of patients may not be the same comorbidities that we see in the pediatric population. We might see, in the pediatric cohort, maybe a higher prevalence of other atopic diseases, for example, asthma, hay fever or seasonal allergies, food allergies and, sometimes, in my adult population, particularly those who have more adult onset disease, you might not necessarily see those comorbidities. They might not have a higher prevalence of asthma or food allergies which has been demonstrated in clinical trials. I think those are important distinctions that we need to recognize, that not everyone is going to fit into that same picture, that so-called classical definition of AD, which is usually this young child who developed atopic dermatitis, has these other atopic diseases that then will develop later in life.
There's increasing data to suggest that patients with atopic dermatitis may be at higher risk for other diseases like, for example, maybe cardiovascular disease, maybe certain malignancies, maybe other inflammatory systemic disease like inflammatory bowel disease. That research is still in infancy, but those are things that we need to start thinking about when we try to get global picture of who our AD patients are.
Of course, the impact on quality of life and mental health I think is very critical in this day and age, the impact not only on the patient, but also on caregivers. As a child, what is the impact of quality of life on that child, but also on the person that's caring for that child, that shared mental health burden, and then, in the adult population, how that impacts their occupation I think is very important to recognize as well, and also treatment. When you're thinking about what treatment option you're going to choose for your patients with atopic dermatitis, I think it's very important to recognize that there might be differences in what's driving the inflammation, what's that cytokine signaling, that there may be responses depending on the patient, that not all currently available systemic agents are approved for all the different age ranges. You have to take those things into consideration when you're thinking about how to appropriately design a treatment plan for your patients with AD.
Going back to the main point about the heterogeneity of atopic dermatitis, it's a highly autogenous disease. We can see variations in age of onset, in the distribution and morphology of the lesions, but one point that I do want to get across is that even though, your patients, they may all look different and their treatment plan may all look different, I think it's important to recognize that it doesn't really matter if it's an adult or a child. The impact of the disease in terms of the severity of it, it can happen across the spectrum. You can have children with very severe disease and adults with very severe disease as well.
I think it's important to recognize that because there's a lot of misconception out there that this is a disease that most people will outgrow, and that's not necessarily the case for a lot of our patients. There's still discrepancy in the data about what is the percentage of patients who outgrow the disease and what is the percentage of patients who will continue to have persistent disease. If we just say, "Oh, atopic dermatitis is a disease of children. You will outgrow it," I think that's doing a disservice to the care of adult patients with AD.
Jessica Garlewicz: Now, regarding discussing the concept with the patients, how do you respond to, let's say, like, "This doesn't look like eczema," or, "I've been told that I have psoriasis," and anything similar to that?
Zelma Chiesa Fuxench: I think this is another excellent question, and this is the question that I will also frequently get in clinic. It goes back to the nature of my patient population. These are patients who are in their late adolescent period or they're adult patients, and oftentimes they'll come in to my clinic with what looks like a new onset of skin rash, and then you do your assessments and you feel like, "Well, based on your symptoms, the distribution, the clinical presentation, this fits into what would be atopic dermatitis," and a patient will say, "Well, I've never had this before. This has to be some sort of food allergy," or, "I've been told that this can't be eczema because adults don't get eczema." There's a lot of misconceptions there, and oftentimes I have to take a step back and provide education and take those misconceptions away and say, "Listen, adults can develop eczema. There is such a thing as adult-onset atopic dermatitis.
There's still we don't know about this disease because we don't know if this is true adult-onset atopic dermatitis or if a particular patient may have had some milder form of atopic dermatitis as a child maybe just manifesting as dry skin, and it is now only through time that that disease has now gotten worse and worse, so there's a lot of recall bias. Sometimes, the patient may not remember that they had something similar to AD in their childhood.
Oftentimes, when I'm in clinic and I'm meeting a patient for the first time and they're talking about the flare that they're having, how uncomfortable they are, how this is new, I take a step back and I tell them, "Try to think back into your childhood. Do you remember someone saying you have dry skin? Maybe your mother or dad or another caregiver was always trying to moisturize your skin, making sure you didn't dry out. Do you remember any of that?" or I'll go back and ask them questions about maybe other atopic diseases. Is there a family history of other atopic diseases that could help us pinpoint the diagnosis?
This can also be quite challenging in the adult patient because, in adult-onset atopic dermatitis, a lot of our patients don't have other atopic illnesses. That confuses the picture a little bit, but I do tell them, if it looks like eczema and you aren't itchy and the distribution fits, it most likely is that, and so we have to provide this kind of reassurance to the patient that this could be atopic dermatitis that's just presenting new for you, and so it's important to have that discussion with the patients as well, like what is what isn't and that, yes, you can present as an adult with new onset atopic dermatitis even though that's not the vast majority of the cases that we see in clinic.
Jessica Garlewicz: Definitely, and when we're focusing on patient demographics and how they figure into your care, you've at least covered so much about pediatric AD versus what adults would, but what about geriatric type of AD or even, particularly, patients who are of a different ethnicity than, let's say, white patients, so skin of color patients? How exactly does that figure into your care?
Zelma Chiesa Fuxench: Right, and so let's talk first about the geriatric atopic dermatitis because I don't think we have a formal validated definition in the literature of what that is. I think some people will say anyone above age 65, but, recognizing that I'm getting closer to 65, I don't want to call that geriatric age, and so we don't really have good diagnostic criteria for saying someone has this so-called geriatric atopic dermatitis or this atopic dermatitis of the elderly. We don't really know what the clinical presentation of those patients are. We don't really know the prognosis, what's driving the inflammation. We don't even understand, I think, very well if these are the same diseases or separate diseases, so, definitely, there needs to be more research in that area.
I have certainly had the experience of... Because I care for, again, in the more adult population, I do get a fair number of patients that come to my clinic who are above age 65 with what looks to be new onset atopic dermatitis, and I think it's very important as physicians that we need to almost treat this as a diagnosis of exclusion. Why is that important? Because a lot of these patients, when they come in, they may not have a history of other atopic illnesses or family history of atopic dermatitis to help substantiate or support that diagnosis of AD in them. They might have been healthy overall and maybe all they say is, "I just had a little bit of dry skin, but nothing more." When you think about the differential diagnosis in these patients, probably they'll be quite different than your pediatric population.
I think for pediatric atopic dermatitis, you look at it and you're like, "Oh, yep, this is atopic dermatitis. It is what it is." We diagnose this for adults. Especially the older ones, I tend to be a little bit more cautious. I think about things like contact dermatitis because there's a high prevalence of atopic dermatitis coexisting with contact dermatitis in the adult population. I think about cutaneous T-cell lymphoma. I think about drug hypersensitivity reaction because a lot of these patients are taking multiple medications that could exacerbate or produce something like an eruption that seems very similar to atopic dermatitis.
Whenever I see one of these patients in clinic, new onset atopic dermatitis in adults, I'd tread very carefully. I try to make sure that we exclude other potential diagnoses, particularly contact dermatitis, cutaneous T-cell lymphoma, hypersensitivity reactions maybe to medications, and, sometimes, even psoriasis. When you would think, oh, psoriasis is pretty cut and paste. It's very straightforward, and my experience has been that that is not the case. There have been a number of instances where I see a patient and I think this is psoriasis. It's the distribution. It's the clinical appearance of the lesions and their biopsy, and then, the biopsies, there's not a drop of psoriasis in there. Everything is more spongiotic dermatitis, and so you start to question that diagnosis.
That has implications for treatment because, when you're thinking about designing a treatment plan for these patients, it's very important to recognize that a lot of patients who have atopic dermatitis as an adult will not outgrow their disease. This is going to continue throughout their lifetime. I tell them... to try to make myself... So that patients can understand me a little bit better, I say, "Think about diabetes and hypertension." Pretty much every adult can relate to that. Even if you don't have it, you know about it. These are chronic diseases. You're going to have them for a long period of time, but you can manage them. We manage them either with lifestyle modifications or with a treatment, a systemic treatment, oral treatment, topical treatment.
The same thing is true I think for adults with atopic of dermatitis. I think most of them will have long-term disease, so, when treating them, we're thinking about treating chronically, and if we're going to be doing that, if we're going to be using a systemic agent, for example, we want to make sure that we have their correct diagnosis because it would be so sad to put someone on these medications and it turns out that maybe they just had a contact dermatitis to something that they were coming into contact with. That's a very important point in terms of addressing how to manage these patients in clinic, and so what are some of the differences?
I think it's very important to recognize that the clinical presentation of atopic dermatitis can vary depending on the concept of race in patients. For example, I've had numerous situations when I'm in the clinic with another colleague or a resident and then we're looking at a patient who has a darker skin tone, and it's sometimes difficult to assess the erythema, and it can be frequently confused with just post-inflammatory hyperpigmentation. If you don't have much experience in these types of patients, you might just go into the room and say, "Oh, that's just PIH or post-inflammatory hyperpigmentation. The disease is very quiet. It's not active," and then we could actually be doing a disservice to the patients. We might not be as aggressive in terms of treatment.
Whenever I have patients who have darker skin tones, I really, really look very, very carefully at the skin. I use different lighting. I will move my phone around or my magnifying glass, my dermatoscope and try to get a better sense of the level of erythema, which can be very difficult to appreciate in some cases. I think it's important to recognize that.
I think, when you think about severity across race and ethnicity, if you look at the studies, it's difficult to interpret the data. I think we do still need to do more work on this area. It's not necessarily that patients of a certain race or ethnicity have higher prevalence of atopic dermatitis, but what some of the studies have shown is that, in these particular cases, patients may present with more severe disease, and we don't know if that's a result of biology or is it because of social determinants of health? Are these the patients that just don't have access to healthcare? Maybe they're at a lower socioeconomic level and have other social determinants of health that are impacting their level of disease control, so I think we have to be very cognizant of that.
Jessica Garlewicz: Absolutely, and how exactly would sex and gender may be playing into this and choosing a great treatment option?
Zelma Chiesa Fuxench: In terms of sex and gender, again, the data does vary and with some studies showing that it might be more prevalent maybe in a child and in boys versus girls, but, again, I think it's very tricky. In the adult population, we haven't really seen much difference in terms of sex distribution. There may be some studies that look specifically at adults with atopic dermatitis that show maybe a higher prevalence in women, but, again, you have to be careful. There's a lot of bias in some of those studies, like who is the patient that's seeking more care, that's participating? Women tend to seek more care than men, so I think you have to be careful about that.
Again, I think the point to get across is, no matter the age, the sex or the race or ethnicity, patients with atopic dermatitis can present with, again, severe disease regardless of any of those factors. It's important to recognize and properly diagnose so that we can effectively treat.
Jessica Garlewicz: Absolutely, and I know we were touching upon the access to care. Now, how would things like income, insurance or even their geographical location, how does that play into this as well?
Zelma Chiesa Fuxench: If you look at some of the studies that have been published in the utilization of healthcare resources, there's very interesting articles in the literature showing that patients of a certain race or ethnicity might have more frequent visits to the ER, or of a certain social economic status or income, may have actually more visits to the ER than the regular physicians. I think it's important to understand that, if you have patients that are going to the ER constantly to seek care, these are your revolving patients. They just come into the ER and then they go home. They get a flare. They come back, and they're not being properly managed, and so it's important to recognize that these patients may not be having adequate access to care and that we need to be better at that.
Also, I think patient education is critical. Maybe the message is not getting to them, that what they have is atopic dermatitis, that this is a disease that we can effectively treat in the vast majority of cases. It's important to recognize that there might be more populations that are vulnerable to having uncontrolled or poorly managed disease just because they don't have access, and these are particularly patients who are either blacks or African-Americans or patients who are, again, on the lower socioeconomic scale or who have maybe other types of government-sponsored insurance that may not have adequate access.
Jessica Garlewicz: Now, looking at the molecular heterogeneity of AD, can you briefly discuss with us maybe the microbiome, immune skewing, genetic differences?
Zelma Chiesa Fuxench: Again, this is a topic that I think we can be on it for hours. It's going to be, I think, different according... Or there's data showing that there can be variations depending on the age of onset, depending on the particular population on their study, even race. If you think about risk factors for atopic dermatitis, they just talk a little bit about genetic risk factors, and so, for most people out there, I think that the one we know is the FLG gene, which is code for filaggrin. We all know that that is a structural... an important structural component of the skin, and it's important for the skin barrier to function properly.
It's the genetic risk factor that's more strongly associated with the risk for development of atopic dermatitis. However, you have to look at it with caution at that data, where that data is coming from, because most of the studies that were done in genetics of atopic dermatitis looking at the FLG gene have been done in a particular subset of patients. They're either patients who are more of European descent or Asian, and they do have variations in terms of what is the particular filaggrin variant that's associated with the disease in these patients, but then we really have no data about these genetic risk factors in other populations, for example, the Latino community or in the Latinx community. We have no idea about how prevalent these genes are in this population or if it makes even a difference for them.
I think the other thing to recognize is that, the phenotype, the skin presentation will vary across different age subsets, but, when you also look at the immune phenotype, what are the cytokines that seem to be driving inflammation, they can also vary. Again, we don't have many studies, but I think we're getting better at that. More recently, there were a couple of studies that were being published out of a collaboration, I believe, with Emma Yassky Guttman and also Amy Paller, who done work in this area looking at different cytokine expressions across groups. What their studies have shown is that, for maybe early onset atopic dermatitis, they do have the Th2 expression which we know is the main driver of inflammation in atopic dermatitis at this point, which promotes the secretion of IL-4 and IL-13, but there might be other signals there like, for example, Th17. It may be that that is also a very similar profile to maybe a particular group of adult patients with atopic dermatitis, so, again, there's discrepancies in terms of what the inflammatory signals are.
In my personal experience, I've seen patients that don't respond to certain FDA-approved agents for atopic dermatitis, and I'm always thinking back to those patients and say there has to be something else that's driving this that's not just Th2. It might be Th22. It might be Th17. Those differences are there.
In terms of skin microbiome, I think this is also a work that's in infancy. When you think about microbiome, you're not just only thinking about the microorganisms that are living on the skin, but that interaction between genetics. The totality of those things is what would actually constitutes the skin microbiome and how the presence of certain bacteria influences genetic expression and vice versa and maybe inflammation in atopic dermatitis.
In terms of atopic dermatitis and skin microbiome, I think one of the examples is staph aureus or staphylococcus. We do know that patients with atopic dermatitis tend to have higher expression of these bacteria compared to maybe non-lesional skin or maybe patients who don't have atopic dermatitis. It's important to recognize that. I think we still need to do more work in terms of whether or not that expression is different between adults with atopic dermatitis and children with atopic dermatitis because that could certainly lead to different therapeutic approaches.
Going back to genetics, I mean, we only talked about the filaggrin gene, but there are other Candida genes that are increasingly being studied. There's TSLP and other genes that form part of the skin barrier complex that we have only barely scratched the surface, which maybe even more important than the FL gene going down the line.
Jessica Garlewicz: Segueing here, now, looking towards how far we've come with characterizing and treating atopic dermatitis, what can you tell us are the biggest things we've learned about the characterization of AD in the past decade?
Zelma Chiesa Fuxench: I think this is a very exciting time for atopic dermatitis. I think there's interest in the scientific community. I think, for patients, that will result in better and more targeted therapeutic approaches. I think the pharmaceutical industry is also interested in supporting this research as well. I think that interest is also driving the science as well.
I think one of the major things is understanding, first of all, the pathogenesis of atopic dermatitis is very complex. If you go into the literature, you could maybe see two different camps. There's like this skin barrier camp or people who say, "It all starts with a defect in the skin barrier. That's what leads to immune activation, and then that's what just drives the continuum," and then there's people that say, "You know what? No. This all starts with immune dysregulation, and that's what is causing an alteration in the skin barrier and then the system. The wheel just keeps turning."
I think that, regardless of whatever camp you are in, immune dysregulation seems to also continue to drive this process, and so I think, the more we understand about that underlying pathogenesis, that's led to the development of newer therapeutic approaches. Let's talk about our understanding of atopic dermatitis being primarily driven a Th2 disease for the vast majority of patients. We know that for Th2, IL-4 and IL-13 seem to be key cytokines that are driving this process, and so that has led to the development of targeted approaches for atopic dermatitis. Actually, it led to the development of the first systemic FDA-approved agent for patients with AD, and that was a very exciting time because, as a clinician, you're thinking, "Yes, I know what we're going to target now, and I know what I'm reaching for when I'm treating patients."
Before, we would rely on systemic agents that were not really FDA-approved, and we don't really understand how they work in atopic of dermatitis. We used them because, historically, they were the only things that we had and they did work, but we just didn't know anything more about it.
I think, in addition to understanding the different cytokines that drive atopic dermatitis that are leading to the development of other biologics, I think it's also a very interesting time as we're learning more about JAK inhibitors. Janus kinase inhibitors are these groups of enzymes that help to drive certain inflammatory processes after activation, and that's just in a nutshell, and so, the more we understand about the role that they play in inflammatory skin diseases, particularly atopic dermatitis, that has led to the development of newer therapeutic approaches that target that specific pathway, so we have topical JAK inhibitors that are currently available for use. We have systemic JAK inhibitors that have been recently approved for use in patients with atopic dermatitis.
The more we understand about that immune dysregulation, I think we're getting there. It's not to say that the skin barrier is not important. There's great work that's being done in how can we restore that skin microbiome with application of topicals that actually contain certain number of bacteria that we know can be helpful for restoring that skin microbiome, so, again, it's targeting the disease from different approaches.
I think, for atopic dermatitis, to me, that's exciting. It's not just we're putting all our ducks in a row and we're just going down this pathway. No, we're trying to hit this very burdensome disease from so many different angles that, at the end of the day, I think it's just going to relay into being great for our patients because, if we can get their disease under control as quickly as possible, then that will translate to better quality of life for them.
Again, I think understanding the immune dysregulation, particularly the role of inflammatory cytokines that are driving this process and also understanding the role of JAK inhibitors is going to be very critical for patients with AD.
Jessica Garlewicz: Thank you for that. Now, are there any other insights you'd like to offer to your colleagues regarding AD?
Zelma Chiesa Fuxench: I think it's a very exciting time for our patients with atopic dermatitis. I think a couple of those bullet points that you'll always want your audience to come across and the audience to take with them is that, one, atopic dermatitis can be a chronic disease for a lot of our patients and it can be highly burdensome; two, that we need to understand that when we're designing a treatment plan for these patients, if you understand that it's a chronic disease, the way I think about it is we're going to be treating the acute flares, but what are we going to be doing for these patients long term, particularly those who are going to have the disease for many years? What is going to be my long-term treatment plan? I'm thinking about those two things when I'm seeing patients.
The other thing is assessing the patient experience. When you're in clinic, and we're all very busy, we're seeing patients in and out, in and out, but I think it's very important at least during that first visit to take the time to know your patients if you can. It will save you time in your followup visits. I promise you that. There are different outcome measures that you can use. You can assess disease severity just looking at the extent of body surface involvement. You could do something like an investigator global assessment, and you can Google these things and you can put them in your note. I actually have them built into my note to make it easier when I'm in the clinic.
Another outcome measure that I use is the Patient-Oriented Eczema Measure. Again, this is free to use. There's actually an app for that. You can download this app. Your patient can do it, and they can fill it out on their phone, and they can share it with you if you want to. I just ask the questions when they come in to see me. It's a way for me to get a sense of what my patient has been going through, and it's just not me and what my eyes are seeing, but what my patient is experiencing.
There other outcome measures that you can use. For example, there are numerical rating scales that you can use to assess itch or the impact on sleep and even asking them... If you don't have the time to do this, even just asking open-ended questions like, "From zero to 10, how itchy have you been in the past 24 hours?" or, "Tell me how many nights have you been waking up because you've been itching during the past week?" I think those types of questions will give you a sense into how your patient is doing.
I will also ask about, "Are you in any pain?" Pain is, I think, an under-reported symptom in atopic dermatitis. Patients don't seem to be wanting to volunteer that information. They seem to be very... These are patients that have been dealing with the disease for a long time, so you sometimes have to pry that information because they've gotten used to living with it.
Also, the impact on their mental health, I will ask them about, "How are we doing today? Do you have any depression or anxiety? Do you think this is related to your atopic dermatitis?" because, if the answer is yes, I may follow those patients more closely. I may see them on more frequent visit, and I may be more aggressive with treatment because they are really suffering.
It's important to always assess the patient experience especially during that first visit. I think your patients will appreciate that. They'll probably trust you more, and they'll probably be more adherent to treatment and come back when you need them to come back. Those would be my final points.
Jessica Garlewicz: Thank you so much again for meeting with us and providing us that insight.
Zelma Chiesa Fuxench: Great. No. This was great, Jessica. Thank you for taking the time to meet.
Jessica Garlewicz: Absolutely. Now, for those listening, again, this podcast is part of the ongoing collaboration with the National Eczema Association, that's NEA, for our atopic dermatitis experts series. You can find more from the insights tab located on the homepage of The Dermatologist.
Thank you for joining us today.
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