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In addition, food allergy was more common in patients who identified as nonwhite race. Gender distribution of comorbidities revealed that men with AD were significantly more likely to have high blood pressure and cardiovascular disease, while women were more likely to have neuropsychiatric issues such as anxiety and depression. A positive correlation between AD and autism spectrum disorder has been found in a systematic review, and this link been explained by psychological stress and sleep deprivation associated with AD.7
Other unproven but plausible factors explaining this association may be increased levels of pro-inflammatory cytokines in children with AD that have an impact on behavioral and emotional functions in the brain by directly passing the blood-brain barrier, and chronic inflammation that affects neurotransmitter metabolism or the hypothalamus-pituitary-adrenal axis.
Dermatology Advisor: How should the screening, diagnosis, and treatment of these comorbidities be addressed in clinical practice?
Dr Tamburro: Screening and diagnosis starts with history taking and a thorough review of systems, being careful to elicit symptoms suggestive of the following, especially in toddlers and school-age children.
· Respiratory system: wheezing, nocturnal chronic cough, decreased stamina compared with peers, asthma, rhinorrhea, ocular injection and drainage, and allergic rhinitis/allergic ocular findings
· Gastrointestinal: episodic or chronic vomiting or diarrhea, food allergies, eosinophilic esophagitis, and gastritis
· Diet that may contribute to obesity
During the physical examination, look for growth curves pointing to obesity and vital signs such as high blood pressure. Physical signs of allergic rhinitis/ocular findings include audible nasal congestion, scleral injection, erythematous and edematous eyelids, Dennie-Morgan folds, and infraorbital vascular congestion (allergic shiners).
Treatment for the extracutaneous comorbidities start with education of family on these concerns and, depending on severity, may require subspecialty consultation — most likely with a pediatric allergist.
Dr Fuxench: At this time, there are no specific guidelines for the diagnosis and treatment of comorbidities in patients with AD. Recommendations for screening should primarily focus on patients’ history and clinical examination. Perhaps the evaluation of comorbidities prior to the use of systemic medications in AD tends to be of more relevance for adult patients compared with pediatric patients, as these patients are older and tend to have other diseases of relevance.
For example, cyclosporine and methotrexate are systemic agents frequently used for the treatment of AD which are associated with potential increases in blood pressure as well as inflammation of the liver. In pediatric patients this may not be much of an issue. However, adult patients with AD may have a diagnosis of high blood pressure or have higher rates of alcohol consumption, all of which could potentially increase the risk for an adverse reaction when exposed to these systemic agents.
Dr Choudhary: First and foremost, making use of the knowledge of these associations and new findings is the key to addressing the issues as soon as they are identified. As suspicion for the presence of a comorbidity is raised, the appropriate referral and detailed investigation in that direction may be initiated. However, there is not yet enough evidence to be consolidated into clinical guidelines for consults. For example, while checking a celiac disease panel is not routine in every person with AD , if a patient has abdominal pain, diarrhea, and a certain skin rash, it may be crucial to send them for a gastroenterology referral as soon as possible. A thorough review of systems and family history can elicit such concerns from the patient to direct them to appropriate multidisciplinary care when needed.
Dermatology Advisor: What are additional considerations for clinicians who treat these patients?
Dr Tamburro: The general concept in treating children with AD is to see the diagnosis as a systemic problem, not purely cutaneous. This will aid the practitioner in being diligent to evaluate the entire body and to address health concerns that may be direct comorbidities or, as above, associated health concerns such as sleep abnormalities. Finally, because of the visual findings, pruritus, and now studies that point to pain with AD, we need to recognize and treat when possible the family dynamics that are affected by this diagnosis. More than enough studies have pointed to the decreased quality of life scores found in our patients with AD , highlighting the need to view this diagnosis as a systemic issue and to address each patient’s specific health concerns.
Dr Fuxench: Clinicians at the front line of care of these patients should understand that the paradigm of AD is changing. While this has been primarily considered a disease of children, there is increasing evidence to suggest that it is also a highly prevalent disease in the adult population. This could be due to an increase in the persistence of disease from childhood into adulthood, and/ or the diagnosis of new cases of adult-onset AD. As a result, when discussing disease prognosis and treatment care plans with patients and/or caregivers of patients with AD, this should be done with a long-term perspective and not just focused on treating the current disease “flare.”
For example, in patients whose disease cannot be controlled with a gentle skin care regimen and/or topical corticosteroids, oral corticosteroids may be prescribed to help control the symptoms of an acute flare rapidly. However, these should be prescribed for the least amount of time possible, and if needed, approaches for long-term control of the disease should be considered, such as incorporation of phototherapy or a systemic agent as needed.
Dr Choudhary: Treatment for AD is becoming more and more individualized with the availability of targeted and biologic therapies. This trend is likely to continue and will expand to the comorbidities as we learn more about these associations. There has also been a trend where these new targeted therapies have potential and actual success in treating these co morbidities, such as treatment of AD and asthma with dupilumab.8 On the other hand, new treatments introduce new side effect profiles that further require the involvement of necessary specialties in comanaging people with AD who are receiving these therapies.
Dermatology Advisor: What should be the focus of further research or patient education regarding this topic?
Dr Tamburro: Research in the area of AD is already taking the next steps, which are facilitating our ability to subclassify this diagnosis and delineate the reasons why one child with AD would have significant asthma findings and another would not. Our knowledge of the cutaneous and extracutaneous immune system continues to expand and, with that knowledge, we will have the ability to provide preventive measures.
Common to all of the skin disorders, there is a knowledge gap in health literacy as it pertains to AD. More often, patients and parents use the knowledge they have acquired from family and lay experts on the internet rather than seeking advice from medical professionals. We are not employing our medical knowledge of the cutaneous system to the same extent as other organ systems. As physicians we must understand the general population can see this “organ” (their skin), unlike other organs such as the lungs, for example. So, they may feel that they have enough knowledge, and they may not seek care or do not trust our medical treatment plans.
Dr Fuxench: There is great excitement among those of us who care for patients with AD that the coming years will signify the decade of eczema. Our increased understanding of the pathogenesis of this disease has led to the development of newer targeted approaches for the treatment of AD. Still, there is much work that needs to be done with respect to understanding whether or not adult onset AD has a similar prognosis as that of pediatric- onset AD.
In addition, AD is a disease that is known to have a significant impact on our patients’ quality of life, but further work also needs to be done to continue to examine the impact of AD on caregivers, as recent studies have shown it can have a detrimental impact on caregivers, including a substantial impact on maternal sleep loss.9 Lastly, future work should also continue to examine the issue of racial disparities in AD and its impact on patient care.
Dr Choudhary: The scope of discussion during physician-patient interactions will widen as more information is acquired and solidified with larger studies investigating the associations between AD and comorbidities. It will become more pertinent to treat and reduce the severity of AD in all populations, as we find that it affects more than just skin. Many studies are underway; aspects that need special attention in research include the pediatric population, where AD often begins and causes the most impact, as well as potential treatments for AD.
References
1. Silverberg JI, Gelfand JM, Margolis DJ, et al. Association of atopic dermatitis with allergic, autoimmune, and cardiovascular comorbidities in US adults. Ann Allergy Asthma Immunol. 2018;121(5):604-612.e3.
2. 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.
3. Dharmage SC, Lowe AJ, Matheson MC, Burgess JA, Allen KJ, Abramson MJ. Atopic dermatitis and the atopic march revisited. Allergy. 2014;69(1):17-27.
4. Strom MA, Fishbein AB, Paller AS, Silverberg JI. Association between atopic dermatitis and attention deficit hyperactivity disorder in U.S. children and adults. Br J Dermatol. 2016;175(5): 920-929.
5. Hagströmer L, Ye W, Nyrén O, Emtestam L. Incidence of cancer among patients with atopic dermatitis. Arch Dermatol. 2005;141(9):1123-1127.
6. Thomas EA, Kadyan RS. Alopecia areata and autoimmunity: a clinical study. Indian J Dermatol. 2008; 53(2):70-74.
7. Billeci L, Tonacci A, Tartarisco G, Ruta L, Pioggia G, Gangemi S. Association between atopic dermatitis and autism spectrum disorders: a systematic review. Am J Clin Dermatol. 2015;16(5):371-388.
8. Guttman-Yassky E, Bissonnette R, Ungar B, et al. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;143(1):155-172.
9. Ramirez FD, Chen S, Langan SM, et al. Assessment of sleep disturbances and exhaustion in mothers of children with atopic dermatitis. JAMA Dermatol. 2019;155(5):556-563.
