Translating Evidence on AD Comorbidities Into Practice

Several studies showed associations between atopic dermatitis (AD) and a variety of comorbidities. The most well established of these are the atopic comorbidities such as asthma, hay fever, food allergies, and, recently, the recognition of eosinophilic esophagitis.¹ Atopic comorbidities appear to be directly related to the severity of AD, with more severe skin disease being associated with higher risk of patients developing these comorbidities later in life.²

In addition, recent studies demonstrated that the rates of major depressive disorder and generalized anxiety disorder are higher in patients with AD and that these also track with the severity of AD.^2,3 A higher occurrence of depression and anxiety and more severe symptoms of both disorders are often observed in patients with severe AD.^3-6 This is an area of further research to try and understand why this happens; however, these mental health conditions seem to be symptoms of AD per se in many patients.

A number of other comorbidities, particularly in the realm of cardiometabolic risk, cardiovascular risk factors, cardiovascular disease, obesity, hypertension, hyperlipidemia, diabetes, heart attack, stroke, congestive heart failure, etc, that have been shown in at least one study to be associated with AD.^2,7,8 This is still a new area of research with some studies showing that these effects may be more indirect and related to lifestyle risk factors, such as smoking. Whereas, other studies showed a direct relationship between AD and these cardiovascular risk factors and events. While we need more studies to investigate this further, current evidence suggests that patients with AD, particularly with moderate to severe disease, do in fact have a higher risk for cardiovascular risk and events.¹

Using These Findings in Clinical Practice

One of the first things dermatologists need to do when translating these findings into clinical practice is to recognize the presence of these comorbidities. Some of the comorbidities are still early in our understanding, and maybe those are not the highest yield for the dermatologist to worry about. However, there are now multiple meta-analyses showing and confirming associations with atopic and mental health comorbidities. Dermatologists should recognize that these are real and are part of the broader impact of AD in patients.

What can dermatologists actually do about these comorbidities? First, we need to recognize that for many of these comorbidities, if we do not treat them and address them properly, patients will ultimately suffer with respect to their sleep, quality of life, and everyday activities.⁹ In the same way that we in dermatology are trying to improve quality of life by addressing the skin issues, we need to at least be able to screen for some of these comorbidities and refer patients to the appropriate providers who can properly address and manage them.

Tools we can use to screen patients include open-ended questions, which are a good place to start during a visit, such as “Do you have asthma?” or “Have you been wheezing?” More structured tools, such as the Asthma Control Test and Asthma Control Questionnaire-6, among others, are also available. It is important to make sure that patients with asthma and/or wheeze are properly evaluated and managed by their primary care provider or asthma specialist.

There are a number of different tools for screening for mental health comorbidities. My colleagues and I recently published a study that validated the Hospital Anxiety and Depression Scale for assessing mental health symptoms in AD.¹⁰ Other tools include the Patient Health Questionnaire, Patient-Reported Outcomes Measurement Information System, etc. 

In addition, many mental health symptoms are a testament to the severity and the burden of the skin disease. The presence of depression and anxiety is a factor that should serve as a clue to the dermatologist that the patient’s skin disease is more severe than they may have realized. Dermatologists should incorporate symptoms of depression and anxiety as a cue to step up therapy. 

Lymphoma and to a lesser extent some solid organ malignancies may also be increased in some AD patients.^11,12 However, more research related to screening for comorbidities is needed to determine which patients should be screened. For example, consider the average young, healthy patient who is otherwise thriving and has their disease well controlled. Although, I would certainly want to ensure they are up-to-date with all of their age appropriate cancer screenings, I would not necessarily advocate for more aggressive screening for malignancies in this patient.

On the other hand, screening may be necessary for a patient with more severe AD who has either been treated with systemic immunosuppressants that might increase the risk for malignancy, or may have some potential underlying immunodeficiencies that may increase malignancy risk. Also, patients with later onset disease involving severe pruritus, refractory disease warrant consideration for potentially paraneoplastic process where the malignancy may be somehow related to the worsening of their itch or the worsening of their AD. In those cases, we consider lymphoma, but there could also be solid organ malignancies.

Future Research

For many of the comorbidities, we already have a solid body of literature to show a strong association with AD, particularly for the atopic comorbidities and the mental health comorbidities. The next generation of research needs to address the longitudinal piece—how these evolve over time, how these are impacted by different treatments, whether more aggressive control of the skin disease and the symptoms could potentially prevent or modify the risk of developing these comorbidities. Additionally, we need to determine how to best screen and manage these comorbidities in the AD patient population.

For more novel comorbidities, including cardiovascular risk, some of the neurologic or autoimmune comorbidities, and malignancies, we need more studies—both cross-sectional and longitudinal—to better understand:

• The causality of these associations.
• Whether AD truly leads to the development of these comorbidities, and if so, how to properly manage, screen, and prevent them.

Conclusion

Recent research has highlighted the systemic nature of AD, allowing us to recognize that although AD is a disease that manifests on the skin, it impacts much more than the skin. In addition to systemic inflammation, there is also a much broader impact on patients’ quality of life and other mechanistic underpinnings that lead to these different comorbidities, which shows that the broader impact of AD is not just skin-deep. 

Dr Silverberg is professor of dermatology at The George Washington University School of Medicine and Health Sciences in Washington, DC.

Disclosure: Dr Silverberg received honoraria for participation in advisory boards and/or as a consultant for Abbvie, Anaptysbio, Arena, Asana, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Glenmark, Kiniksa, Leo, Menlo, Novartis, Pfizer, Regeneron-Sanofi; speaker for Regeneron-Sanofi; received grants GlaxoSmithKline and Galderma.

References

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2. Silverberg JI, Gelfand JM, Margolis D, et al. Association of atopic dermatitis with allergic, autoimmune and cardiovascular comorbidities in US adults [published online August 6, 2018]. Ann Allergy Asthma Immunol. doi:10.1016/j.anai.2018.07.042

3. Silverberg JI, Gelfand JM, Margolis DJ, et al. Symptoms and diagnosis of anxiety and depression in atopic dermatitis in U.S. adults. Br J Dermatol. 2019;181(3):554-565. doi:10.1111/bjd.17683

4. Cheng BT, Silverberg JI. Depression and psychological distress in US adults with atopic dermatitis. Ann Allergy Asthma Immunol. 2019;123(2):179-185. doi:10.1016/j.anai.2019.06.002

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6. Yu SH, Silverberg JI. Association between atopic dermatitis and depression in US adults. J Invest Dermatol. 2015;135(12):3183-3186. doi:10.1038/jid.2015.337

7. Silverberg JI. Association between adult atopic dermatitis, cardiovascular disease, and increased heart attacks in three population-based studies. Allergy. 2015;70(10):1300-8. doi:10.1111/all.12685

8. Silverberg JI, Greenland P. Eczema and cardiovascular risk factors in 2 US adult population studies. J Allergy Clin Immunol. 2015;135(3):721-728.e6. doi:10.1016/j.jaci.2014.11.023

9. Silverberg JI, Gelfand JM, Margolis DJ, et al. Patient-burden and quality of life in atopic dermatitis in US adults: A population-based cross-sectional study [published online July 16, 2018]. Ann Allergy Asthma Immunol. doi:10.1016/j.anai.2018.07.006

10. Silverberg JI, Gelfand J, Margolis D, et al. Measurement properties of Hospital Anxiety and Depression Scale used in atopic dermatitis in adults. J Allergy Clin Immunol. 2019;143(2):AB130. doi:10.1016/j.jaci.2018.12.394

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Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: A systematic review and meta-analysis. J Am Acad Dermatol. 2015;72(6):992-1002. doi:10.1016/j.jaad.2015.02.1116

12. Halling-Overgaard AS, Ravnborg N, Silverberg JI, Egeberg A, Thyssen JP.

Atopic dermatitis and cancer in solid organs: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2019;33(2):e81-e82. doi:10.1111/jdv.15230