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Addressing Comorbidities in Patients With Atopic Dermatitis
In this exclusive interview as part of the National Eczema Association’s Atopic Dermatitis (AD) Expert Series, Zelma Chiesa Fuxench, MD, MSCE, joins us to discuss the association between AD and atopic and other comorbidities, including asthma, allergies, autoimmune conditions such as alopecia areata (AA), mental health disorders such as depression and anxiety, substance use, cardiovascular disease (CVD), and metabolic disorders such as diabetes.
The Dermatologist: Can you briefly define the term comorbidity?
Dr Chiesa Fuxench: There is limited consensus in the literature on the definition of comorbidity. It could be when you have 2 or more either acute or chronic diseases that are observed in a single patient.1 However, this may just be occurring by chance or selection, or because they sometimes share some sort of causal association. Moving forward, we should focus on a general definition of comorbidity as a disease state associated with worse health outcomes that often requires more complex clinical management and increased health care cost.
The Dermatologist: What is the role of comorbidities in the diagnosis of AD based on established criteria?
Dr Chiesa Fuxench: Multiple diagnostic criteria have been developed to help us better determine or establish a diagnosis of AD. These criteria were developed primarily for children, and they remain to be fully validated in adult cohorts. These include the Hanifin and Rajka criteria, the United Kingdom (UK) Working Party criteria, and, most recently, the American Academy of Dermatology (AAD) consensus criteria for the diagnosis of AD.2-4 Adults with AD may not necessarily fulfill some of these criteria. For example, we may have an adult patient who presents to the office with “new onset” AD, but maybe before age 2 they had something, which is one of the diagnostic criteria points in the UK Working Party criteria. Maybe they had a few scattered eczema patches here and there, but they do not remember, so there is a recall bias there.
The other thing in terms of the diagnostic criteria and limitations for adults is that sometimes adults may present with lesions that are not in the more classical locations for AD. They may have lesions that are not just on the skin faults, which would typically be associated with AD in the pediatric population, but they may have them in other areas, such as the extensor surfaces, or they may have them localized in certain areas of the skin, such as just the palms or the soles. And if we just base ourselves on those criteria, we may say, “Well, this patient does not fit the diagnosis of AD.” However, some of these diagnostic criteria do consider atopic comorbidities, such as asthma or a history of hay fever or seasonal allergies. And if we have a patient who fulfills those criteria, it can help us better establish a diagnosis. There is a role for comorbidities in helping us diagnose patients with AD, but we do have to be careful because not all patients will present with these comorbidities or diseases of interest.
The Dermatologist: Can you highlight the recently published AAD guidelines on comorbidities associated with AD in adults?
Dr Chiesa Fuxench: The purpose of the recent AAD guidelines was to provide an evidence-based summary of the literature to date to educate us as clinicians, our patients, and other important stakeholders on the association between AD and these comorbidities.5 Thirty two evidence-based statements were developed using a multidisciplinary approach. The goal was not to provide specific recommendations for screening or management, but to develop consensus criteria to help increase awareness of comorbidities in AD because this could have potential implications for treatment and management. The document explains specific associations for atopic comorbidities, such as asthma and allergies, and then nonatopic comorbidities, such as CVD, diabetes, other autoimmune conditions like AA, mental health disorders, and substance use.
The Dermatologist: Is there a relationship between childhood asthma and AD persistence?
Dr Chiesa Fuxench: It is estimated that close to 25% of adult patients with AD may have a history of asthma and they may have a 3-fold increased risk of developing asthma compared with individuals without AD, particularly among patients who have more severe disease.6 Although we must be careful how we interpret the data because a lot of studies are difficult to compare, overall, the association between AD and asthma is accepted in the literature.
The Dermatologist: What makes asthma so strongly associated with AD?
Dr Chiesa Fuxench: This is a question we continue to explore. There is discussion in the literature about the “atopic march,” which explains the association between having AD first and then developing another atopic disease such as asthma.1,6 This theory posits that it all starts with epidermal barrier dysfunction, allowing the introduction of allergens through the skin and resulting in inflammation, with a similar immune response occurring at other epithelial surfaces, such as in the lower respiratory tract in asthma or in the upper respiratory tract in allergic rhinitis. However, not all patients follow the atopic march; not everyone has AD first, and then gets asthma or seasonal allergies. Some patients just have asthma from the start, and they may not necessarily develop any other atopic comorbidities.
The other discussion in the literature is that AD and asthma may share genetic risk factors, as well as certain environmental exposures that may be triggers for both diseases.7 And that could also explain why we see such a strong association between them.
The Dermatologist: What is the prevalence of food allergy in patients with AD?
Dr Chiesa Fuxench: It is still difficult to determine, but we do know that the prevalence can vary anywhere from 6% to 16%.1 Like asthma, it is thought that food allergy is more associated with patients who have more severe AD. In my clinical practice where we primarily see adults with AD and we often have patients with “new onset” AD, they may ask, “Is there something I am eating that is now triggering this? Do I have a new food allergy?” And I try to explain to them that the prevalence of food allergy goes down as the population gets older. It is rare as an adult to develop a food allergy. And food allergy being a trigger for AD in adults if they do not have a previous history of it is rare as well. I also try to explain to my patients that the symptoms of a food allergy might be different than those they are experiencing with AD. They might be developing urticaria or hives. They might have difficulty breathing or abdominal discomfort, lip swelling, or throat swelling. Those are the symptoms we tend to associate more with a full allergy than just eczema or AD exacerbation.
The Dermatologist: What about allergic rhinitis?
Dr Chiesa Fuxench: We know that allergic rhinitis, or hay fever, is a recognized common comorbidity of AD in adults.1 It is one of the diagnostic criteria we can use to help diagnose AD. Interestingly, eosinophilic esophagitis is sometimes described in the atopic march, where you have AD, asthma, hay fever, seasonal allergies, and then eosinophilic esophagitis.8 But studies examining these associations are somewhat rare, and they cannot make a strong assessment regarding the strengths of the association between AD and eosinophilic esophagitis.
The Dermatologist: What is the prevalence of AA in AD?
Dr Chiesa Fuxench: The association between AD and immunemediated conditions is quite complex. There are people who support that AD is a disease that starts with a skin barrier defect, which leads to immune dysregulation, and then leads to more skin barrier defects. And there are others who think that AD starts with the process of immune dysregulation, which results in skin barrier disease, and then feeds into the immune dysregulation pathway again.
There are going to be some genetic risk factors shared between immune-mediated diseases that can perhaps explain these associations, which are still being studied. There are studies showing that patients with AD might be at a 2- or 3-times increased risk for having an autoimmune condition.9 We know that AA is associated with AD, and that having AD in a patient with AA can lead to worse outcomes. These are patients who, instead of just having localized patches, may have alopecia totalis or alopecia universalis, which means they lose the hair all over their body. And we know that patients with AD, if they have AA, could have more severe AA.
The Dermatologist: What is the association between mental health disorders and AD?
Dr Chiesa Fuxench: Focusing primarily on adults, patients with AD are more likely to have symptoms of depression and anxiety, and be diagnosed with depression or anxiety disorders, compared with their counterparts without AD. Patients with AD have about a 2-fold increase in self-reporting a diagnosis of clinical depression and about a 40% increase in anxiety.6 There are studies that have looked at potential risk factors for depression in AD, including the severity of AD. Patients who have more severe or uncontrolled disease can be at higher risk for depression and anxiety compared with patients who have mild disease.6
Suicidal ideation has been found to be higher in patients with AD, with about a 70% increased risk.6 But so far, the studies looking at data and examining death by suicide have shown mixed results. Some show a positive association, and some show no association at all. This is something that deserves more study.
We do not really have a full understanding of the association between AD and depression and anxiety. One common explanation is that there is a high psychosocial burden of AD. You have patients who are chronically itching, who are chronically sleep deprived, who have an overall decreased quality of life. They are not engaging in relationships, they are being passed over for promotions, their school productivity is impacted, and that can lead to symptoms of depression and anxiety.
Looking at questionnaires that assess depression and anxiety in clinical trials, there is a correlation between AD improving and depression and anxiety improving.10 It is so important that we control this disease as quickly as possible because it does have a direct impact on symptoms of depression and anxiety.
Another interesting explanation is the inflammatory basis of depression itself that still needs further characterization. There are studies discussing whether chronic inflammation, as you can see in AD, can be a critical disease modifier that could potentially promote susceptibility to depression.11 This is going to be hard to study in clinical trials, but it is something that we need to think about. How are depression and AD sharing some common pathway at the level of inflammation?
The Dermatologist: What are the limitations of the data on tobacco and alcohol use and why might these behaviors be increased in patients with AD?
Dr Chiesa Fuxench: I think the big limitation with studies that assess tobacco and alcohol use in patients with AD is that a lot of studies are cross-sectional. By cross-sectional, we mean that they are just providing a snapshot in time, you are not seeing the before and you do not have the ability to see the after. It is hard to make determinations if there is any cause or effect based on these data.
Second, it is hard to capture things like using nicotine products or alcohol in large population-based databases because you must understand where the data are coming from. If you come to a clinic, we put in a diagnostic code and then that goes into a database. But if we do not capture these data as part of the clinical encounter, then we do not have that information. My hunch is that it is probably underreported. So far there is limited evidence to support the association between AD and increased tobacco and alcohol use. Most of the studies that we have are coming from countries in Europe. For example, one study found increased alcohol use being more common in adults with AD, with a 30% increased risk.12
Although we do not have true estimates on the prevalence of these disorders, I think we can all agree that they are quite common and there are different theories to try to explain this association. Some would argue that like having depression and anxiety, the high burden of AD and having poorly controlled disease may increase the patient’s likelihood of engaging in these behaviors to cope with everything they have going on. It is hard to tell whether smoking is a risk factor for the development of AD. We do understand that exposure to secondhand smoke is a risk factor for patients with asthma, but that association is still somewhat unclear in AD.
I think regardless of the association at this point, and whether it is a true association or what we make of it, this is another important aspect that we need to recognize as clinicians caring for these patients who may not volunteer this information. Because it can also have implications for treatment selection, I tend to ask patients, “Do you smoke? How often? How long have you been smoking? Are you drinking alcohol? How much?”
The Dermatologist: Can you explain the link between systemic inflammation and CVD?
Dr Chiesa Fuxench: Systemic inflammation is a well-established risk factor for CVD. If you can target systemic inflammation, you can potentially decrease the risk of cardiovascular events. When we think about shared pathways in AD and CVD, we know that there are certain markers of atherosclerosis or vascular inflammation that correlate with markers of inflammation, particularly the inflammation in the skin and blood of patients with AD.
Among inflammatory skin diseases, perhaps the most well-known example is psoriasis. We know that psoriasis, particularly severe psoriasis, is recognized as an increased risk factor for CVD. We are still trying to understand how that association occurs, and I think the same thing can be said for AD. Is it a result of the inflammation in and of itself? Is it because of exposure to treatments that may increase cardiovascular risk? Or are there other factors? Are there lifestyle factors, such as smoking, sedentary lifestyle, and co-morbidities, that may be observed in a higher prevalence in these patient populations that can also increase the risk?
Although the risk of CVD in patients with AD is still somewhat small, it does show a positive association and the evidence continues to grow about increased risk of coronary artery disease, acute events such as myocardial infarction, and overall cardiovascular deaths.13
The Dermatologist: What is the relationship between diabetes and AD?
Dr Chiesa Fuxench: The AAD guidelines summarize the studies showing an overall inverse association with diabetes, meaning that patients with AD may be at a lower risk for diabetes overall, and a lower risk of type 2 diabetes compared with the general population.14 However, there is a US-based population study that did find an increased association, particularly among patients with more severe disease.14
Because diabetes is also such a common disease, it is something that I think does merit further study. There might be other risk factors that are more prevalent in patients with AD placing them at a higher risk for diabetes, and it is not necessarily the disease in and of itself. We could do lifestyle interventions, diet modification, exercise regimens, or pharmacotherapy if needed.
The Dermatologist: What would you say still needs to be done?
Dr Chiesa Fuxench: I think we still need to do a better job of defining what is a comorbidity in AD. What is a disease of interest and what is an actual comorbidity? And if it is an actual comorbidity, are there pathways being shared between both diseases that can explain the potential association and how does this impact morbidity?
The other question that I think about often is, if I address these comorbidities early on, or by using a more targeted treatment approach, can this result in better outcomes for our patients? Can we decrease cardiovascular risk? Can we decrease the risk of diabetes? And the other thing is, how do we assess comorbidities and what sort of treatment strategies can we recommend for our colleagues? Often, we may be the only provider who a patient with AD is seeing, they may not have a primary care physician. Do we need to do lipid screens? Do we just need to assess whether the patient is following up with a primary care physician and provide education on the importance of doing so? And how can different specialties work together to address the unmet needs of our patients with AD? How can we work with allergy and immunology? Do we need to work together with our cardiology colleagues? Maybe our gastrointestinal colleagues? How can we all come to a consensus on how to treat these different comorbidities in our patients with AD?
References
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2. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockholm). 1980;92(suppl):44-47.
3. Williams HC, Burney PG, Hay RJ, et al. The U.K. Working Party’s diagnostic criteria for atopic dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br J Dermatol. 1994;131(3):383-396. doi:10.1111/j.1365-2133.1994.tb08530.x
4. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis. Section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338-351. doi:10.1016/j.jaad.2013.10.010
5. Davis DMR, Drucker AM, Alikhan A, et al. American Academy of Dermatology Guidelines: awareness of comorbidities associated with atopic derma-titis in adults. J Am Acad Dermatol. 2022;86(6):1335-1336.e18. doi:10.1016/j. jaad.2022.01.009
6. Eczema stats. National Eczema Association. Accessed May 23, 2022. https:// nationaleczema.org/research/eczema-facts
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8. Hill DA, Grundmeier RW, Ramos M, Spergel JM. Eosinophilic esophagitis is a late manifestation of the atopic march. J Allergy Clin Immunol Pract. 2018;6(5):1528-1533. doi:10.1016/j.jaip.2018.05.010
9. Zhiyu L, Zeng N, Cheng Y, et al. Atopic dermatitis and risk of autoimmune diseases: a systemic review and meta-analysis. Allergy Asthma Clin Immunol. 2021;17(1):96. doi:10.1186/s13223-021-00597-4
10. Schonmann Y, Mansfield KE, Hayes JF, et al. Atopic eczema in adulthood and risk of depression and anxiety: a population-based cohort study. J Allergy Clin Immunol Pract. 2020; 8(1):248-257.e16. doi:10.1016/j.jaip.2019.08.030
11. Beurel E, Toups, M, Nemeroff CB. The bidirectional relationship of depression and inflammation: double trouble. Neuron. 2020;107(2):234-256. doi:10.1016/j. neuron.2020.06.002
12. Al-Jefri K, Newbury-Birch D, Muirhead CR, et al. High prevalence of alcohol use disorders in patients with inflammatory skin diseases. Br J Dermatol. 2017;177(3):837-844. doi:10.1111/bjd.15497
13. Are people with eczema at greater risk for heart disease? National Eczema Association. Accessed May 23, 2022. https://nationaleczema.org/heart-health-eczema
14. Anderson YMF, Egeberg A, Gislason GH, Skov L, Knop FK, Thyssen JP. Adult atopic dermatitis and the risk of type 2 diabetes. J Allergy Clin Immunol. 2017;139(3):1057-1059. doi:10.1016/j.jaci.2016.08.049
