Abstract
Atopic dermatitis is a worldwide prevalent chronic inflammatory skin disease. Although primarily recognized as a disease of children, there is increasing evidence suggesting that it is more common in adults than previously thought. Both immune dysregulation and cutaneous barrier dysfunction are involved in the pathogenesis of the disease, although the exact mechanisms are still unclear. The concept of atopic dermatitis as a biphasic Th1-Th2 disease is changing, as recent evidence supports systemic activation of other multiple Th-cell subsets. Atopic dermatitis has been associated with an increasing number of comorbidities, possibly sharing some common pathological mechanisms. The atopic march is well known and represents the natural progression of atopic diseases in a considerable number of patients, usually starting with the development of atopic dermatitis followed by other atopic conditions, such as asthma and allergic rhinitis. Association of atopic dermatitis with cardiovascular disease, autoimmune diseases, as well as cutaneous and extracutaneous infections have been increasingly reported, although the link is not yet clear. Furthermore, the association between atopic dermatitis and neuropsychiatric conditions has also been widely studied, with an increased risk of mental health disorders strongly influenced by sleep disorders. Altogether, these associations contribute to the burden of atopic dermatitis, which increases the need for a more focused therapeutic approach that includes prevention or early diagnosis and treatment of comorbidities that may arise. This review explores the recent associations with atopic dermatitis and the possible underlying mechanisms involved, which supports the concept of atopic dermatitis as a systemic disease.
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References
Weidinger S, Novak N. Atopic dermatitis. Lancet 2016; 387: 1109–22.
Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study. J Allergy Clin Immunol 2013; 132: 1132–8.
Chiesa Fuxench ZC, Block J, Boguniewicz M, et al. Atopic Dermatitis in America Study: a cross-sectional study examining the prevalence and disease burden of atopic dermatitis in the US adult population. J Invest Dermatol 2019; 139: 583–90.
Sandstrom Falk MH, Faergemann J. Atopic dermatitis in adults: does it disappear with age? Acta Derm Venereol 2006; 86: 135–9.
Hanifin JM, Reed ML, & Eczema Prevalence and Impact Working Group. A population-based survey of eczema prevalence in the United States. Dermatitis 2007; 18: 82–91.
Sidbury R, Khorsand K. Evolving concepts in atopic dermatitis. Curr Allergy Asthma Rep 2017; 17: 42.
Gittler JK, Shemer A, Suárez-Fariñas M, et al. Progressive activation of TH2/TH22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol 2012; 130: 1344–54.
Irvine AD, McLean WH, Leung D. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 2011; 365: 1315–27.
Mõcsai G, Gáspár K, Nagy G, et al. Severe skin inflammation and filaggrin mutation similarly alter the skin barrier in patients with atopic dermatitis. Br J Dermatol 2014; 170: 617–24.
Margolis DJ, Apter AJ, Gupta J, et al. The persistence of atopic dermatitis and filaggrin (FLG) mutations in a US longitudinal cohort. J Allergy Clin Immunol 2012; 130: 912–7.
Mortz CG, Andersen KE, Dellgren C, Barington T, Bindslev-Jensen C. Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities. Allergy 2015; 70: 836–45.
Paller A, Jaworski JC, Simpson EL, et al. Major comorbidities of atopic dermatitis: beyond allergic disorders. Am J Clin Dermatol 2018; 19: 821–38.
Saunders SP, Moran T, Floudas A, et al. Spontaneous atopic dermatitis is mediated by innate immunity, with the secondary lung inflammation of the atopic march requiring adaptive immunity. J Allergy Clin Immunol 2016; 137: 482–91.
Schneider L, Hanifin J, Boguniewicz M, et al. Study of the atopic march: development of atopic comorbidities. Pediatr Dermatol 2016; 33: 388–98.
Suárez-Fariñas M, Dhingra N, Gittler J, et al. Intrinsic AD shows similar Th2 and higher Th17 immune activation compared to extrinsic AD. J Allergy Clin Immunol 2013; 132: 361–70.
Pinart M, Benet M, Annesi-Maesano I, et al. Comorbidity of eczema, rhinitis, and asthma in IgE-sensitised and non-IgE-sensitised children in MeDALL: a population-based cohort study. Lancet Respir Med 2014; 2: 131–40.
Wan J, Mitra N, Hoffstad OJ, Gelfand JM, Yan AC, Margolis DJ. Variations in risk of asthma and seasonal allergies between earlyand late-onset pediatric atopic dermatitis: a cohort study. J Am Acad Dermatol 2017; 77: 634–40.
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: 604–12.e3.
Czarnowicki T, Malajian D, Shemer A, et al. Skin-homing and systemic T-cell subsets show higher activation in atopic dermatitis versus psoriasis. J Allergy Clin Immunol 2015; 136: 208–11.
Czarnowicki T, Gonzalez J, Shemer A, et al. Severe atopic dermatitis is characterized by selective expansion of circulating TH2/TC2 and TH22/TC22, but not TH17/TC17, cells within the skin-homing T-cell population. J Allergy Clin Immunol 2015; 136: 104–15.e7.
Ungar B, Garcet S, Gonzalez J, et al. An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease. J Invest Dermatol 2017; 137: 603–13.
Brunner PM, Suárez-Fariñas M, He H, et al. The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins. Sci Rep 2017; 7: 8707.
Vekaria AS, Brunner PM, Aleisa AI, et al. Moderate-to-severe atopic dermatitis patients show increases in serum C-reactive protein levels, correlating with skin disease activity. F1000Res 2017; 6: 1712.
Andersen YMF, Egeberg A, Gislason GH, Skov L, Thyssen JP. Autoimmune diseases in adults with atopic dermatitis. J Am Acad Dermatol 2017; 76: 274–80.e1.
Narla S, Silverberg JI. Association between atopic dermatitis and autoimmune disorders in US adults and children: a cross-sectional study. J Am Acad Dermatol 2019; 80: 382–9.
Silverberg JI, Silverberg NB. Association between vitiligo and atopic disorders: a pilot study. JAMA Dermatol 2013; 149: 983–6.
Augustin M, Radtke MA, Glaeske G, et al. Epidemiology and comorbidity in children with psoriasis and atopic eczema. Dermatology 2015; 231: 35–40.
Barahmani N, Schabath MB, Duvic M. History of atopy or autoimmunity increases risk of alopecia areata. J Am Acad Dermatol 2009; 61: 581–91.
Betz RC, Pforr J, Flaquer A, et al. Loss-of-function mutations in the filaggrin gene and alopecia areata: strong risk factor for a severe course of disease in patients comorbid for atopic disease. J Invest Dermatol 2007; 127: 2539–43.
Wu L-C, Hwang C-Y, Chung P-I, et al. Autoimmune disease comorbidities in patients with atopic dermatitis: a nationwide case-control study in Taiwan. Pediatr Allergy Immunol 2014; 25: 586–92.
Wei C-C, Lin C-L, Tsai J-D, Shen T-C, Sung F-C. Increased incidence of juvenile onset systemic lupus erythematosus in children with atopic dermatitis. Lupus 2014; 23: 1494–9.
Hsiao YP, Tsai JD, Muo CH, et al. Atopic diseases and systemic lupus erythematosus: an epidemiological study of the risks and correlations. Int J Environ Res Public Health 2014; 11: 8112–22.
Schmitt J, Schwarz K, Baurecht H, et al. Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes. J Allergy Clin Immunol 2016; 137: 130–6.
Kim M, Choi KH, Hwang SW, Lee YB, Park HJ, Bae JM. Inflammatory bowel disease is associated with an increased risk of inflammatory skin diseases: a population-based cross-sectional study. J Am Acad Dermatol 2017; 76: 40–8.
Ress K, Annus T, Putnik U, Luts K, Uibo R, Uibo O. Celiac disease in children with atopic dermatitis. Pediatr Dermatol 2014; 31: 483–8.
Silverberg JI, Greenland P. Eczema and cardiovascular risk factors in 2 US adult population studies. J Allergy Clin Immunol 2015; 135: 721–8.e6.
Egeberg A, Andersen YMF, Gislason GH, Skov L, Thyssen JP. Prevalence of comorbidity and associated risk factors in adults with atopic dermatitis. Allergy 2017; 72: 783–91.
Zhang A, Silverberg JI. Association of atopic dermatitis with being overweight and obese: a systematic review and metaanalysis. J Am Acad Dermatol 2015; 72: 606–16.e4.
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: 144–52.
Su VY-F, Chen T-J, Yeh C-M, et al. Atopic dermatitis and risk of ischemic stroke: a nationwide population-based study. Ann Med 2014; 46: 84–9.
Hjuler KF, Böttcher M, Vestergaard C, et al. Increased prevalence of coronary artery disease in severe psoriasis and severe atopic dermatitis. Am J Med 2015; 128: 1325–34.e2.
Silverberg JI. Association between adult atopic dermatitis, cardiovascular disease, and increased heart attacks in three population-based studies. Allergy 2015; 70: 1300–8.
Andersen YMF, Egeberg A, Gislason GH, Hansen PR, Skov L, Thyssen JP. Risk of myocardial infarction, ischemic stroke, and cardiovascular death in patients with atopic dermatitis. J Allergy Clin Immunol 2016; 138: 310–2.e3.
Thyssen JP, Skov L, Hamann CR, Gislason GH, Egeberg A. Assessment of major comorbidities in adults with atopic dermatitis using the Charlson comorbidity index. J Am Acad Dermatol 2017; 76: 1088–92.e1.
Drucker AM, Qureshi AA, Dummer TJB, Parker L, Li W-Q. Atopic dermatitis and risk of hypertension, type 2 diabetes, myocardial infarction and stroke in a cross-sectional analysis from the Canadian Partnership for Tomorrow Project. Br J Dermatol 2017; 177: 1043–51.
Drucker AM, Li W-Q, Cho E, et al. Atopic dermatitis is not independently associated with non-fatal myocardial infarction or stroke among US women. Allergy 2016; 71: 1496–500.
Standl M, Tesch F, Baurecht H, et al. Association of atopic dermatitis with cardiovascular risk factors and diseases. J Invest Dermatol 2017; 137: 1074–81.
Marshall VD, Moustafa F, Hawkins SD, Balkrishnan R, Feldman SR. Cardiovascular disease outcomes associated with three major inflammatory dermatologic diseases: a propensity-matched case control study. Dermatol Ther (Heidelb) 2016; 6: 649–58.
Thyssen JP, Halling-Overgaard AS, Andersen YMF, Gislason G, Skov L, Egeberg A. The association with cardiovascular disease and type 2 diabetes in adults with atopic dermatitis: a systematic review and meta-analysis. Br J Dermatol 2018; 178: 1272–9.
Balma-Mena A, Lara-Corrales I, Zeller J, et al. Colonization with community-acquired methicillin-resistant Staphylococcus aureus in children with atopic dermatitis: a cross-sectional study. Int J Dermatol 2011; 50: 682–8.
Suh L, Coffin S, Leckerman KH, Gelfand JM, Honig PJ, Yan AC. Methicillin-resistant Staphylococcus aureus colonization in children with atopic dermatitis. Pediatr Dermatol 2008; 25: 528–34.
Hayashida S, Furusho N, Uchi H, et al. Are lifetime prevalence of impetigo, molluscum and herpes infection really increased in children having atopic dermatitis? J Dermatol Sci 2010; 60: 173–8.
Peng WM, Jenneck C, Bussmann C, et al. Risk factors of atopic dermatitis patients for eczema herpeticum. J Invest Dermatol 2007; 127: 1261–3.
Beck LA, Boguniewicz M, Hata T, et al. Phenotype of atopic dermatitis subjects with a history of eczema herpeticum. J Allergy Clin Immunol 2009; 124: 260–9.e7.
Gao PS, Rafaels NM, Hand T, et al. Filaggrin mutations that confer risk of atopic dermatitis confer greater risk for eczema herpeticum. J Allergy Clin Immunol 2009; 124: 507–13.e7.
Leung DYM, Gao PS, Grigoryev DN, et al. Human atopic dermatitis complicated by eczema herpeticum is associated with abnormalities in IFN-γ response. J Allergy Clin Immunol 2011; 127: 965–73.e5.
Manti S, Amorini M, Cuppari C, et al. Filaggrin mutations and Molluscum contagiosum skin infection in patients with atopic dermatitis. Ann Allergy Asthma Immunol 2017; 119: 446–51.
Silverberg JI, Silverberg NB. Childhood atopic dermatitis and warts are associated with increased risk of infection: a US populationbased study. J Allergy Clin Immunol 2014; 133: 1041–7.
Strom MA, Silverberg JI. Association between atopic dermatitis and extracutaneous infections in US adults. Br J Dermatol 2017; 176: 495–7.
Narla S, Silverberg JI. Association between childhood atopic dermatitis and cutaneous, extracutaneous and systemic infections. Br J Dermatol 2018; 178: 1467–8.
Narla S, Silverberg JI. Association between atopic dermatitis and serious cutaneous, multiorgan and systemic infections in US adults. Ann Allergy Asthma Immunol 2018; 120: 66–72.e11.
Chang YS, Chiang BL. Sleep disorders and atopic dermatitis: a 2-way street? J Allergy Clin Immunol} 2018; 142: 1033–40.
Ronnstad ATM, Halling-Overgaard AS, Hamann CR, Skov L, Egeberg A, Thyssen JP. Association of atopic dermatitis with depression, anxiety, and suicidal ideation in children and adults: a systematic review and meta-analysis. J Am Acad Dermatol 2018; 79: 448–56.e30.
Bender BG, Ballard R, Canono B, Murphy JR, Leung DYM. Disease severity, scratching, and sleep quality in patients with atopic dermatitis. J Am Acad Dermatol 2008; 58: 415–20.
Silverberg JI, Garg NK, Paller AS, Fishbein AB, Zee PC. Sleep disturbances in adults with eczema are associated with impaired overall health: a US population-based study. J Invest Dermatol 2015; 135: 56–66.
Schmitt J, Chen CM, Apfelbacher C, et al. Infant eczema, infant sleeping problems, and mental health at 10 years of age: the prospective birth cohort study LISAplus. Allergy 2011; 66: 404–11.
Schmitt J, Romanos M, Pfennig A, Leopold K, Meurer M. Psychiatric comorbidity in adult eczema. Br J Dermatol 2009; 161: 878–83.
Yaghmaie P, Koudelka CW, Simpson EL. Mental health comorbidity in patients with atopic dermatitis. J Allergy Clin Immunol 2013; 131: 428–33.
Shin J, Choi Y, Park E-C, et al. Psychiatry outpatient visits by atopic dermatitis patients varying in the complexity of their prescriptions. Medicine (Baltimore) 2016; 95: e5411.
Yu SH, Silverberg JI. Association between atopic dermatitis and depression in US adults. J Invest Dermatol 2015; 135: 3183–6.
Cheng CM, Hsu JW, Huang KL, et al. Risk of developing major depressive disorder and anxiety disorders among adolescents and adults with atopic dermatitis: a nationwide longitudinal study. J Affect Disord 2015; 178: 60–5.
Shyu CS, Lin HK, Lin CH, Fu LS. Prevalence of attentiondeficit/ hyperactivity disorder in patients with pediatric allergic disorders: a nationwide, population-based study. J Microbiol Immunol Infect 2012; 45: 237–42.
Lee S, Shin A. Association of atopic dermatitis with depressive symptoms and suicidal behaviors among adolescents in Korea: the 2013 Korean Youth Risk Behavior Survey. BMC Psychiatry 2017; 17: 3.
Halvorsen JA, Lien L, Dalgard F, Bjertness E, Stern RS. Suicidal ideation, mental health problems, and social function in adolescents with eczema: a population-based study. J Invest Dermatol 2014; 134: 1847–54.
Patel KR, Immaneni S, Singam V, Rastogi S, Silverberg JI. Association between atopic dermatitis, depression and suicidal ideation: a systematic review and meta-analysis. J Am Acad Dermatol 2019; 80: 402–10.
Schmitt J, Romanos M, Schmitt NM, Meurer M, Kirch W. Atopic eczema and attention-deficit/hyperactivity disorder in a population-based sample of children and adolescents. JAMA 2009; 301: 724–6.
Chen MH, Su TP, Chen YS, et al. Is atopy in early childhood a risk factor for ADHD and ASD? A longitudinal study. J Psychosom Res 2014; 77: 316–21.
Tsai JD, Chang SN, Mou CH, Sung FC, Lue KH. Association between atopic diseases and attention-deficit/hyperactivity disorder in childhood: a population-based case-control study. Ann Epidemiol 2013; 23: 185–8.
Riis JL, Vestergaard C, Deleuran MS, Olsen M. Childhood atopic dermatitis and risk of attention deficit/hyperactivity disorder: a cohort study. J Allergy Clin Immunol 2016; 138: 608–10.
Liao TC, Lien YT, Wang S, Huang SL, Chen CY. Comorbidity of atopic disorders with autism spectrum disorder and attention deficit/hyperactivity disorder. J Pediatr 2016; 171: 248–55.
Maksimović N, Janković S, Marinković J, Sekulović LK, Živković Z, Spirić VT. Health-related quality of life in patients with atopic dermatitis. J Dermatol 2012; 39: 42–7.
Kwak Y, Kim Y. Health-related quality of life and mental health of adults with atopic dermatitis. Arch Psychiatr Nurs 2017; 31: 516–21.
Eckert L, Gupta S, Amand C, Gadkari A, Mahajan P, Gelfand JM. Impact of atopic dermatitis on health-related quality of life and productivity in adults in the United States: an analysis using the National Health and Wellness Survey. J Am Acad Dermatol 2017; 77: 274–9.e3.
Silverberg JI, Gelfand JM, Margolis DJ, et al. Patient burden and quality of life in atopic dermatitis in US adults: a populationbased cross-sectional study. Ann Allergy Asthma Immunol 2018; 121: 340–7.
Garg N, Silverberg JI. Association between childhood allergic disease, psychological comorbidity, and injury requiring medical attention. Ann Allergy Asthma Immunol 2014; 112: 525–32.
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Disclosure. Financial support: none. Conflicts of interest: Clara Oliveira has no conflict of interest. Tiago Torres has received consulting fees, speaking fees, and honoraria from AbbVie, Lilly, Pfizer, and Sanofi.
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Oliveira, C., Torres, T. More than skin deep: the systemic nature of atopic dermatitis. Eur J Dermatol 29, 250–258 (2019). https://doi.org/10.1684/ejd.2019.3557
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DOI: https://doi.org/10.1684/ejd.2019.3557