The Atopic March and Beyond – Other Health Issues Connected with Atopic Dermatitis

Articles

By Jodi L. Johnson, PhD

Published On: Jul 1, 2022

Last Updated On: Sep 28, 2022

Scientific studies and patient testimonials have firmly demonstrated that atopic dermatitis (AD) is much more than a skin disease, with impacts that can affect virtually every aspect of life. In addition to these AD-specific impacts, other diseases and symptoms have been associated with AD.1 We discussed several of the more widely known associations, such as food allergies, asthma and hay fever, in our article on the atopic march. However, researchers and clinicians are discovering that the list of conditions connected to AD is much larger than originally thought. This article explores the associations between AD and this broader range of other symptoms or diseases, called “comorbidities.”

Comorbidities of atopic dermatitis – what’s known and what isn’t?

A “comorbidity” is often defined as a set of symptoms or diseases that co-occur in the same individual and can worsen overall health, complicate disease management and increase health care expenses.2 When trying to understand comorbidities by talking to a physician or reading a study or news article, it is important to note that this term is not used with one single, commonly accepted definition. Sometimes it refers to two or more diseases that simply occur or exist in a patient but are not mechanistically linked to one another, meaning they may both be present at the same time, but one does not cause or directly impact the other. The term comorbidity can also mean that two co-occurring diseases have a shared biological cause (like a common genetic or immune cause), or the presence of one disease leads directly in some biological way to development of one or more other diseases. A third use of this term is to describe a statistical or mathematical relationship between two diseases that are “associated.” In this case, statistical analysis has usually been done on a large, defined patient population with a finding that two or more diseases frequently co-occur in this population. Throughout this article we follow the advice of Dr. Zelma Chiesa Fuxench, of the University of Pennsylvania, who said, “When two or more acute or chronic diseases are observed in a single patient, these may occur by chance or selection, or because they share a causal association.2 For our purposes, let’s focus on the general term of comorbidity as a disease state associated with worse health outcomes, more complex clinical management and overall increased health care costs.”

Some of the growing list of conditions and symptoms that have been associated with AD are shown in Figure 1. On the importance of researching, understanding and thinking about comorbidities to guide patient care in AD, Dr. Jonathan Silverberg, PhD, of George Washington University, said, “Many things are intertwined with AD with symptoms impacting each other. For example, depression, anxiety and stress can be major triggers for AD and AD is associated with increased symptoms of depression and anxiety … we cannot understand one without the other. Additionally, patients who experience skin bacterial or viral infections often experience AD flare-ups and AD leads to increased risk for skin infections. The presence of symptoms like depression, anxiety and infection may signal more severe and uncontrolled AD and may warrant prompt, more aggressive or additional skin treatment. Some clinical trials have shown that achieving control of AD using various topical, oral systemic and biologic therapies results in lower rates of skin infections and decreased symptoms of depression and anxiety. Addressing comorbidities can improve quality of life and potentially even longevity of patients.” Further, researchers have speculated about the impact of early, and more effective control of AD on the overall risk for some of these comorbid conditions.3,4               

Figure 1:    

Figure 1: Comorbidities and the impact of atopic dermatitis (modified from7). AD is not simply a disease of the skin.  The comorbid conditions and symptoms associated with AD continues to grow and includes sleep disturbance, depression, anxiety, allergy-associated diseases, allergic skin rash, skin infection, alopecia areata and bone density loss and possible cardiovascular and neurological associations, among others. Many researchers and healthcare providers are now reframing discussion of AD as not skin-based alone, but as a chronic, systemic disease.

What is currently known about comorbidities with AD?

Associations (some with clear biological links and some that are statistically linked) exist between AD and other atopic and allergy-based diseases such as contact dermatitis, asthma, food allergies and rhinitis (sometimes called hay fever).5-9 Another allergy-based disease that impacts the esophagus, called eosinophilic esophagitis has also been discussed as part of this list, but not yet firmly established.10 Neurological disorders such as attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorders have been statistically associated with AD in several studies in children and a small number of studies in adults.10,11 Immune system-mediated diseases such as allergic skin hives (urticaria) and alopecia areata (hair loss) among others frequently co-occur with AD.12 Bone mineral density loss and bone fractures have also been associated with AD in both youth and adults.13 Finally, several studies have reported associations between AD and cardiovascular-related risks. There is a known link between AD and systemic inflammation and another known link between systemic inflammation and heart or cardiovascular diseases, so it may make sense that these diseases are associated. However, these associations are currently mathematical (or statistical), and the strength of the association (called magnitude) is often low.10

The Journal of the American Academy of Dermatology (JAAD) recently published an important paper that summarized the state of the field regarding AD comorbidities in adult AD patients.10 This paper was meant to clarify language and provide guiding definitions on strength of associations such as high, moderate, low or very low. The authors issued a series of statements about these associations based on a review of evidence from the medical literature. Associations with moderate or high quality of evidence are shown in Table 1. Other associations that have been discussed in the literature, but with low quality evidence thus far, are not included in the table. More research is needed to determine whether there are mechanistic links or causal pathways between these diseases or symptoms. This important paper provides an up-to-date snapshot of comorbidities with AD that can potentially influence care conversations but does not provide guidelines for screening for these other diseases in AD patients.

Where is the research taking us? Can we move beyond associations?

While the first step has been to uncover co-associated symptoms and diseases, ongoing research is now beginning to elucidate how various patient demographics combined with AD symptom duration and severity impact the occurrence and severity of comorbidities with AD. Dr. Chiesa Fuxench outlined some of the important research questions the field is now asking such as, “Can we better understand differences among AD phenotypes including those with early versus late onset and differences in the prevalence of these comorbidities across AD disease severity? How do race, ethnicity, genetics, environmental factors and other factors influence co-development of diseases? Can aggressively treating AD early on decrease the risk of developing comorbid conditions later?”

We are learning that the age of onset, duration and severity of AD symptoms can impact the occurrence and severity of other diseases co-occurring with AD. For example, research has shown that early-onset, persistent AD comes with a high risk for multi-morbidity, particularly associations between AD and other atopic diseases.14 Early AD onset and longer AD duration has been associated with low bone mineral density in young adults (ages 19-50).15 And in adults, increased duration of AD (how long the patient continued to have AD symptoms) and AD severity were associated with increased occurrence and severity of other atopic diseases and possibly with hypertension.16

Race and ethnicity can influence AD comorbidities, but so far very few studies have been done to more deeply investigate these considerations outside of the co-associated diseases of the atopic march. In a study of 8,014 participants enrolled in the Pediatric Eczema Elective Registry, of whom 37.7% were white and 52% Black, children with longer AD duration had increased risk of additional allergic diseases. Black children overall had lower risks of developing asthma, allergic rhinitis, food allergies and animal allergies than their white counterparts in this study but further study is needed to confirm this finding.17 White race associated with psychologic comorbidities of AD, but many other factors besides race may influence this finding.18

Studies are also aimed at understanding how the immune system, genetics, the environment and the microbiome may contribute to the presence of more than one AD-associated disease.14 For example, AD, asthma, rhinitis and food allergies are all part of the same immune system response called Type II Immunity, which was discussed in our article on the atopic march. Briefly, inflammation is the body’s defense against infection or injury and is tightly regulated. Types I, II and III immunity protect the body against microbes inside cells, parasites and bacteria and fungi outside of cells, respectively, using different types of immune reactions involving different cells and different signals between cells.19 However, all three of these beneficial immune reaction types can also cause diseases if they inappropriately respond to the wrong things and become dysregulated. Common genes underlying diseases associated with AD have been uncovered with the most widely studied being filaggrin. Asthma, AD, rhinitis and other atopic diseases share up to 227 different types of filaggrin variants or mutations according to a recent study.20 Early establishment of the microbiome and environmental factors like diet, antibiotics and exposure to environmental allergens can impact whether other diseases form, at least the other allergic diseases.21,22 Dr. Chiesa Fuxench pointed out that studies trying to understand how genetics, race and ethnicity may work together to impact these possibly interrelated diseases are still in their infancy or have not been adequately explored. She said, “Most genetic studies in AD, including studies on the filaggrin gene which is the strongest known genetic risk factor to date, have primarily been developed in populations of European or Asian descent with less studies including Black or African American populations and limited studies in the Latinx population. Before we can dig deeper into the study of gene-environment interactions in AD, we need to characterize more fully the genetic variants in AD that increase disease risk across diverse populations.”

AD symptoms and their influences on quality of life and lifestyle can greatly influence AD comorbidities. For the mental health diseases co-associated with AD such as anxiety and depression, intense itching, high rates of sleep disturbance, stigma, social isolation, poor quality of life and neuro-inflammation are thought to play roles.7 AD patients have potential risk factors for cardiometabolic disease, including chronic sleep disturbance, sedentary lifestyle, obesity, increased cigarette smoking and alcohol consumption and adverse effects from systemic AD treatments.7,12 Hypertension has been associated with obesity and history of prednisone or cyclosporine use.23,24 All of the cardiovascular comorbidities have been associated with chronic inflammation as well. Adequately controlling AD symptoms may lead to decreased associations with issues such as sleep disturbance, social isolation and sedentary lifestyle, improving quality of life and reducing risks of these other comorbidities. However, even treatment options to control AD symptoms can influence comorbidities. Published articles like the one from JAAD described above and others have recommended that physicians and patients should dialogue continuously about the benefits of AD therapies as well as how risks of adverse events from medications used to treat AD may impact the risks of other symptoms and disease development later in life.7,10

More work is needed to understand the complexities of how comorbidities of AD influence each other. Dr. Silverberg said, “At this point we really know very little about the mechanistic underpinnings for some of these comorbidities or why some patients get them and others do not. We do see more comorbidities in the moderate-to-severe AD population. There are definitely differences in comorbidities by demographics. For example, children and adolescents tend to have more symptoms of depression, whereas adults tend to have more anxiety. Little is known about differences by race, though previous studies found disparities with respect to higher prevalence, more persistent and more severe AD in Black and Hispanic children in the United States. Disparities leading to more severe AD likely also lead to increased comorbidities.” More large-scale, population-based studies are needed to further understand how demographics, lifestyle, the immune system, genetics, the environment and the microbiome impact comorbidities with AD. While these questions are being addressed in allergic-based diseases associated with AD and included in the atopic march, there is almost nothing in the literature to date about underpinnings of other AD-associated diseases.

How should understanding comorbidities impact the dialogue between patients and healthcare providers about co-managing symptoms and holistic care?

Dr. Chiesa Fuxench said, “Recognizing a higher prevalence of specific diseases of interest in AD impacts how I counsel patients. I try to emphasize to my patients that AD is not just a skin disease. It is often a chronic disease that like other non-skin related diseases such as diabetes or hypertension will require long-term management. Some comorbidities may require early intervention to potentially limit disease burden. For example, I tell my patients that while my goal is to control the inflammation that is leading to AD, it is also important to address additional impacts of AD like effects on their mental health. Co-occurring symptoms can also impact treatment selection (i.e. can the use of a targeted treatment approach help manage multiple diseases in a single patient?). Finally, recognizing associations provides an opportunity for us to put a care team together to provide counseling, coordinate treatment approaches to target multiple symptoms and refer patients to appropriate specialists.”

Much effort is being made to create models of multidisciplinary care teams and determine whether this approach will change the long-term trajectory of co-associated symptoms for AD patients. One model is to bring together allergists, lung specialists, dermatologists, ear, nose and throat specialists and pediatricians to co-manage the care of a patient with multiple symptoms caused by underlying inflammation.25 Adults with persistent symptoms would potentially need a different type of multi-disciplinary care team, but studies are needed to determine evidence for the best care models in these cases.25,26 For older adults (≥65 years), managing comorbidities and making treatment decisions to best ensure that treatment for one disease does not worsen symptoms of another should be the priority and yet there is limited evidence yet in the literature to guide treatment decisions in this population.

Research continues to validate that AD is a multidimensional complex disease. Its relationship with a growing list of comorbid conditions adds to this complexity. Much more work is needed to help affected individuals and their healthcare providers understand how to best approach the lifelong management of AD and its co-related diseases.

Take home points:

  1. AD is not just skin deep but can be associated with diseases of many other organ systems in the body.
  2. Active areas of current research are sorting out which diseases and symptoms are truly co-associated with AD and understanding how the contributing biological mechanisms and factors like environment, genetics and patient demographics impact development of comorbidities.
  3. Diseases that co-occur in a single patient, whether or not they are mechanistically related to each other, can impact decisions about treatment approaches, medications and care.
  4. Patients and healthcare providers should continue to work together to understand the full range of impact of AD for an individual to make holistic treatment decisions together and use comprehensive healthcare teams as needed.

References:

1.  McCleary KK. More Than Skin Deep: Understanding the Lived Experience of Eczema. Paper presented at: Eczema Patient-Focused Drug Development Meeting; March, 2020, 2019.

2.  Valderas JM, Starfield B, Sibbald B, Salisbury C, Roland M. Defining comorbidity: implications for understanding health and health services. Ann Fam Med. 2009;7(4):357-363.

3.  Paller A, Jaworski JC, Simpson EL, et al. Major Comorbidities of Atopic Dermatitis: Beyond Allergic Disorders. Am J Clin Dermatol. 2018;19(6):821-838.

4.  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 e603.

5.  Paller AS, Mina-Osorio P, Vekeman F, et al. Prevalence of type 2 inflammatory diseases in pediatric patients with atopic dermatitis: Real-world evidence. J Am Acad Dermatol. 2022;86(4):758-765.

6.  Sanclemente G, Hernandez N, Chaparro D, Tamayo L, Lopez A, Colombian Atopic Dermatitis Research G. Epidemiologic features and burden of atopic dermatitis in adolescent and adult patients: A cross-sectional multicenter study. World Allergy Organ J. 2021;14(12):100611.

7.  Silverberg JI. Comorbidities and the impact of atopic dermatitis. Ann Allergy Asthma Immunol. 2019;123(2):144-151.

8.  Spergel JM. Epidemiology of atopic dermatitis and atopic march in children. Immunol Allergy Clin North Am. 2010;30(3):269-280.

9.  Tsakok T, Marrs T, Mohsin M, et al. Does atopic dermatitis cause food allergy? A systematic review. J Allergy Clin Immunol. 2016;137(4):1071-1078.

10.  Davis DMR, Drucker AM, Alikhan A, et al. AAD Guidelines: awareness of comorbidities associated with atopic dermatitis in adults. J Am Acad Dermatol. 2022.

11.  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.

12.  Andersen YMF, Egeberg A, Skov L, Thyssen JP. Comorbidities of Atopic Dermatitis: Beyond Rhinitis and Asthma. Curr Dermatol Rep. 2017;6(1):35-41.

13.  Wu D, Wu XD, Zhou X, Huang W, Luo C, Liu Y. Bone mineral density, osteopenia, osteoporosis, and fracture risk in patients with atopic dermatitis: a systematic review and meta-analysis. Ann Transl Med. 2021;9(1):40.

14.   Paller AS, Spergel JM, Mina-Osorio P, Irvine AD. The atopic march and atopic multimorbidity: Many trajectories, many pathways. J Allergy Clin Immunol. 2019;143(1):46-55.

15. Kim S, Choi J, Cho MK, Kim NH, Kim SG, Kim KJ. Bone mineral density and osteoporosis risk in young adults with atopic dermatitis. Sci Rep. 2021;11(1):24228.

16.  Campanati A, Bianchelli T, Gesuita R, et al. Comorbidities and treatment patterns in adult patients with atopic dermatitis: results from a nationwide multicenter study. Arch Dermatol Res. 2021.

17.  Del Pozo DV, Zhu Y, Mitra N, Hoffstad OJ, Margolis DJ. The risk of atopic comorbidities and atopic march progression among Black and White children with mild-to-moderate atopic dermatitis: A cross-sectional study. J Am Acad Dermatol. 2022.

18.  Hou A, Silverberg JI. Predictors and age-dependent pattern of psychologic problems in childhood atopic dermatitis. Pediatr Dermatol. 2021.

19.   McCormick JP, Lee JT. Insights into the Implications of Coexisting Type 2 Inflammatory Diseases. J Inflamm Res. 2021;14:4259-4266.

20. Salama RH, Rasheed Z, Ahmed AA, et al. Missense, silent, non-sense and frame-shift mutations in exon 3 of the filaggrin gene in patients with bronchial asthma, atopic dermatitis, allergic rhinitis and mixed atopy. Nucleosides Nucleotides Nucleic Acids. 2021;40(3):357-367.

21. Amat F, Soria A, Tallon P, et al. New insights into the phenotypes of atopic dermatitis linked with allergies and asthma in children: An overview. Clin Exp Allergy. 2018;48(8):919-934.

22. Gabryszewski SJ, Dudley J, Grundmeier RW, Hill DA. Early-life environmental exposures associate with individual and cumulative allergic morbidity. Pediatr Allergy Immunol. 2021;32(5):1089-1093.

23. Silverberg JI, Becker L, Kwasny M, Menter A, Cordoro KM, Paller AS. Central obesity and high blood pressure in pediatric patients with atopic dermatitis. JAMA Dermatol. 2015;151(2):144-152.

24. Yousaf M, Ayasse M, Ahmed A, et al. Association between atopic dermatitis and hypertension: a systematic review and meta-analysis. Br J Dermatol. 2022;186(2):227-235.

25. Senna G, Micheletto C, Piacentini G, et al. Multidisciplinary management of type 2 inflammatory diseases. Multidiscip Respir Med. 2022;17(1):813.

26. Hassoun D, Malard O, Barbarot S, Magnan A, Colas L. Type 2 immunity-driven diseases: Towards a multidisciplinary approach. Clin Exp Allergy. 2021;51(12):1538-1552.

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