Microsoft Word - systemic AD.doc SKIN Copyright 2017 The National Society for Cutaneous Medicine 8 IN-DEPTH REVIEWS Systemic Manifestations of Atopic Dermatitis: A Systematic Review L. Bonomoa, A.J. Ramos-Rodriguez, MDb, and E. Guttman-Yassky, MD, PhDa,c aIcahn School of Medicine at Mount Sinai, Department of Dermatology, New York, NY bIcahn School of Medicine at Mount Sinai, Department of Medicine, New York, NY cLaboratory for Investigative Dermatology, The Rockefeller University, New York, NY A Atopic dermatitis (AD) is known to be associated with other allergic diseases. These conditions include asthma, food allergy, and allergic rhinoconjunctivitis1. AD typically occurs in early childhood with allergic comorbidities developing later in life in a serial fashion. This progression is termed the “atopic march” and is July 2017 Volume I Issue I Background: Atopic dermatitis (AD) is known to be associated with other allergic diseases, which often develop later in life in a serial fashion. This progression is termed the “atopic march” and is considered the classical presentation of atopic disease. However, recent evidence suggests that this paradigm may not hold true for a significant portion of patients with these conditions. Not only is the timing of development likely more complex than previously believed, the comorbidities associated with AD are possibly more numerous and varied. Methods: This two-step systematic review involved a targeted search of PubMed and EMBASE with an additional hand search of key journals. The terms “atopic dermatitis” and “atopic eczema” were searched in conjunction with multiple keywords representing the concept of systemic nature of disease. All titles and abstracts were subsequently screened for relevance to the research question. Results: This review’s evidence supports an association between AD and other atopic diseases. However, it also suggests that the classical paradigm of the “atopic march” does not apply to all patients with atopic dermatitis. There appears to be a significant association between AD and multiple neuro-psychiatric comorbidities, particularly ASD and ADHD. Additional themes supported by lower-level evidence are increased risk of cardiovascular disease, decreased risk of type I diabetes, and increased risk of multiple malignancies in patients with AD. Conclusion: There is likely a diversity of phenotypes for patterns of allergic disease. Both positive and negative associations identified in this systematic review suggest that AD is condition with varied systemic manifestations. ABSTRACT BACKGROUND SKIN considered the classical presentation of atopic disease2. However, recent evidence suggests that this paradigm may not hold true for a significant portion of patients with these conditions3. Not only is the timing of development likely more complex than previously believed, the comorbidities associated with AD are possibly more numerous and varied4. Because AD is an inflammatory disease characterized by ongoing T-cell activation and cytokine production, it stands to reason that its mediators could have an effect on multiple extracutaneous organ systems. If the mechanisms underlying atopic disease do indeed play a role in the development of non-atopic comorbidities, it would support the notion put forth by Brunner et al. (2016) that AD should be regarded as a systemic disease. The body of evidence behind this idea is rapidly expanding, with associations between AD and autoimmune, infectious, cardiovascular, neuro-psychiatric, and gastrointestinal disease becoming more well defined. However, there has not been a systematic review on this topic to date. We conducted a two-part systematic search of the literature on AD and extracutaneous disease. The first part involved a targeted search of PubMed (MEDLINE + Cochrane Library) and EMBASE. In both of these databases “atopic dermatitis” and “atopic eczema” were searched in conjunction with various keywords representing the concept of systemic nature of disease (Table 1). The second part of the systematic search process was a hand search of all recent abstracts accepted by the AAD and EADV and abstracts published in 5 key journals (Journal of the American Academy of Dermatology, Journal of the European Academy of Dermatology and Venereology, British Journal of Dermatology, American Journal of Clinical Dermatology, and the Journal of Allergy and Clinical Immunology) within the past 2 years. All hits returned by both parts of the search process were screened for possible inclusion. Narrative reviews, single-case studies, animal studies, editorials, non-English articles, and articles published prior to 1996 (greater than 20 years old) were excluded in a first review. Next, titles and abstracts were screened for relevance to the research question. Finally, all included articles were rated for quality of evidence with a Newcastle-Ottowa score5. This scale was chosen because the majority of included articles were case-control or cohort studies. The numbers of references obtained after each step of the search process are detailed in Table 2. The final yield of the two-step, systematic search was 65 articles. These consisted of 41 case-control studies (63.1%), 19 cohort studies (29.2%), and 5 meta-analyses (7.7%). Mean star ratings on the Newcastle Ottowa scale for case-control studies were: Selection 2.44, Comparability 1.56, and Exposure 2.21. For cohort studies, mean ratings were 3.26, 1.63, and 2.37, respectively. Non-atopic comorbidities identified in these studies included autoimmune disease, cardiovascular disease, gastrointestinal disease, neuro- psychiatric disease, infectious disease, and malignancy. All distinct associated conditions identified during the search process are discussed below; when multiple studies revealed a positive association with a comorbidity, those with the highest Newcastle Ottowa score were cited. July 2017 Volume I Issue I Copyright 2017 The National Society for Cutaneous Medicine 9 METHODS RESULTS Copyright 2017 The National Society for Cutaneous Medicine 10 SKIN Concept Keywords/Phrases Atopic dermatitis Atopic dermatitis Atopic eczema Systemic nature of disease Systemic, inflammat* Epidemiology, etiology Comorbid* Autoimmun*, immun*, cytokine activation Atopic march, food allergy, asthma Cardiovascular, gastrointestinal, neuro-psychiatric, malignancy Table 1. Keywords used in systematic search process. Truncation symbols are represented by asterisk. July 2017 Volume I Issue I Figure 1. Eczema herpeticum. This vesicular eruption is caused by viral infection, typically HSV, of pre- existing atopic dermatitis. FIGURES/TABLES SKIN July 2017 Volume I Issue I Copyright 2017 The National Society for Cutaneous Medicine 11 Results obtained in this review support the notion that the development of various allergic diseases is a dynamic process. There are numerous studies that describe the relationship among AD, asthma, food allergy, hay fever, allergic rhinitis, and atopic ophthalmic disease. While the “atopic march” pattern is prevalent, there is evidence that it may represent only one particular phenotype of allergic disease6. Additionally, development of one allergic disease does not dictate which additional diseases might develop or when7. This apparent variability of phenotypes is worth mentioning before any discussion of non-atopic comorbidities, as it is possible that each one produces distinct extracutanous disease. Autoimmune Disease: The most well studied autoimmune disease investigated with AD is type I diabetes mellitus. The great majority of the evidence, including the study with the highest Newcastle Ottowa score, supports an inverse relationship between AD and type I diabetes8. In other words, children with insulin-dependent diabetes are less likely to suffer from eczema. This is thought to be due to negative interaction between Th1 and Th2 subsets9. Interestingly, no association was shown between diabetes and asthma or hay fever. There is less data available on the association between AD and other autoimmune diseases. Two studies provide conflicting evidence on its relationship with lupus erythematosus10, 11, although the study showing a positive association is both more recent and higher quality by Newcastle Ottowa score. Finally, there is one cohort study suggesting that AD may be a risk factor for rheumatoid arthritis12. Cardiovascular Disease: The data on cardiovascular disease and risk factors in the AD population are more heterogeneous. Evidence was mixed on the association between AD and increased BMI or hypertension. However, one study demonstrated an increased prevalence of coronary artery disease in AD patients using CT angiography13. The highest-scoring study related to cardiovascular disease demonstrated an increased risk of adverse cardiovascular outcomes in a cohort of 145,372 patients, including myocardial infarction, ischemic stroke, and cardiovascular death14. A possibly related comorbidity, erectile dysfunction, was observed in a case-control study to occur more frequently in AD patients15. Interestingly, one study showed an association between AD and IgA vasculitis in children16. For all of these cardiovascular conditions, further studies are needed to clarify the role of lifestyle and psychosocial factors in their development. Gastrointestinal Disease: There is extensive literature on the relationship between AD and food allergy, as discussed above. However, less information is available on non-allergic gastrointestinal disease. One case-control study examined various gastrointestinal symptoms in the pediatric AD population and found an increased incidence of vomiting, regurgitation, and diarrhea17. There is also emerging evidence supporting the role of the intestinal microbiome in the development of AD and the possibility of probiotic use in therapy18. There is one case-control study showing that children with AD are predisposed to develop fatty liver, but further investigation is needed19. Finally, the cohort study mentioned above suggests that, in addition to being a risk factor for rheumatoid arthritis, AD might also be a risk factor for inflammatory bowel disease12. Neuro-Psychiatric Disease: There is a significant body of evidence supporting an association between AD and autism spectrum and attention deficit hyperactivity disorders (ASD, ADHD). One retrospective cohort study DISCUSSION SKIN July 2017 Volume I Issue I Copyright 2017 The National Society for Cutaneous Medicine 12 of 21,756 patients demonstrated that AD occurring before the age of 3 increased the risk of developing both of these conditions20. Additionally, increased rates of depression, anxiety, somatization, and injury requiring medical attention have been observed in multiple case-control studies21-23. These associations are often positively correlated with severity of AD. One possible explanation for these phenomena is sleep disturbance in AD patients. A case-control study found that inadequate sleep persists even when patients are in clinical remission24. Malignancy: Multiple high-quality studies analyze the risk of cancer in patients with AD. There is consistent evidence that AD patients are at increased risk for lymphoma, squamous cell carcinoma, and basal cell carcinoma25-27. However, a case-control study of 13,687 patients found that the increased risk of lymphoma was correlated with length of treatment with topical corticosteroids27. Further studies are therefore needed to disentangle the effects of disease and the effects of treatment on skin cancer risk. There is conflicting evidence regarding other types of cancer. For instance, there is low-quality evidence of both increased and decreased risk of central nervous system malignancy in the AD population28, 29. A meta-analysis focusing on leukemia noted that available data were also quite heterogeneous30. It did, however, find a significant inverse relationship between AD and ALL. Future high-quality cohort studies are needed to evaluate the risk of these malignancies. Infectious Disease: It is well documented that patients with AD are at increased risk for certain cutaneous infections due to the compromised barrier function of the skin. These classically include Staphylococcus aureus, herpesvirus (Fig. 1), and cocksackivirus. However, studies identified in this literature review also provided evidence for association with warts, molluscum, otitis media, and dental caries31-34. It is worth noting a case series that did not meet inclusion criteria for this review, which described an increased incidence of infectious endocarditis in AD patients35. Because of the severity of this possible comorbidity, a case control or cohort study is recommended. The results of this systematic review support the notion that atopic dermatitis is strongly associated with other atopic diseases, including asthma, hay fever, and allergic rhinoconjunctivitis. However, it also suggests that the classical paradigm of the “atopic march” does not apply to all patients with atopic dermatitis. There is likely a diversity of phenotypes for patters of allergic disease. Our analysis supports a significant association between AD and multiple neuro- psychiatric comorbidities, particularly ASD and ADHD. Additional themes supported by lower-level evidence are increased risk of cardiovascular disease, decreased risk of type I diabetes, and increased risk of multiple malignancies in patients with AD. In conclusion, the systemic manifestations of AD are likely multifactorial, resulting from both the inflammatory disease itself and associated lifestyle factors. Conflict of Interest Disclosures: Dr. Emma Guttman-Yassky has served on advisory boards for AbbVie, Anaco, Celgene, Demira, Galderma, Glenmark, Leo Pharmaceuticals, Medimmune, Novartis, Pfizer, Regeneron, Sanofi, Stiefel/GlaxoSmithKline, Vitae, Mitsubishi Tanabe, Eli Lilly, Asana Biosciences, Kiowa Kirin, and Almirall Corresponding Author: Dr. Emma Guttman-Yassky Address: 5 East 98th Street, 5th Floor, New York, NY 10029 Phone: 212-241-9728 Fax: 212-987-1197 Email: Emma.Guttman@mountsinai.org CONCLUSIONS SKIN July 2017 Volume I Issue I Copyright 2017 The National Society for Cutaneous Medicine 13 References: 1. Leung DY. Atopic dermatitis: new insights and opportunities for therapeutic intervention. Journal of Allergy and Clinical Immunology. 2000 May 31;105(5):860-76. 2. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. Journal of Allergy and Clinical Immunology. 2003 Dec 31;112(6):S118-27. 3. Belgrave DC, Granell R, Simpson A, Guiver J, Bishop C, Buchan I, Henderson AJ, Custovic A. Developmental profiles of eczema, wheeze, and rhinitis: two population-based birth cohort studies. PLoS Med. 2014 Oct 21;11(10):e1001748. 4. Brunner PM, Silverberg JI, Guttman-Yassky E, Paller AS, Kabashima K, Amagai M, Luger TA, Deleuran M, Werfel T, Eyerich K, Stingl G. Increasing Comorbidities Suggest that Atopic Dermatitis Is a Systemic Disorder. Journal of Investigative Dermatology. 2017 Jan 31;137(1):18-25. 5. Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 6. Illi S, von Mutius E, Lau S, Nickel R, Gruber C, Niggemann B, et al. The natural course of atopic dermatitis from birth to age 7 years and the association with asthma. The Journal of allergy and clinical immunology. 2004;113(5):925-31. 7. Barberio G, Pajno GB, Vita D, Caminiti L, Canonica GW, Passalacqua G. Does a 'reverse' atopic march exist? Allergy: European Journal of Allergy and Clinical Immunology. 2008;63(12):1630-2. 8. Decreased prevalence of atopic diseases in children with diabetes. The EURODIAB Substudy 2 Study Group. The Journal of pediatrics. 2000;137(4):470-4. 9. Olesen AB, Juul S, Birkebaek N, Thestrup-Pedersen K. Association between atopic dermatitis and insulin- dependent diabetes mellitus: a case-control study. Lancet (London, England). 2001;357(9270):1749-52. 10. Sekigawa I, Yoshiike T, Iida N, Hashimoto H, Ogawa H. Allergic disorders in systemic lupus erythematosus: Prevalence and family history. Lupus. 2002;11(7):426-9. 11. Sekigawa I, Yoshiike T, Iida N, Hashimoto H, Ogawa H. Allergic disorders in systemic lupus erythematosus: Prevalence and family history. Lupus. 2002;11(7):426-9. 12. Schmitt J, Schwarz K, Baurecht H, Hotze M, Folster-Holst R, Rodriguez E, 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. The Journal of allergy and clinical immunology. 2016;137(1):130-6. 13. Hjuler KF, Bottcher M, Vestergaard C, Deleuran M, Raaby L, Botker HE, et al. Increased Prevalence of Coronary Artery Disease in Severe Psoriasis and Severe Atopic Dermatitis. The American journal of medicine. 2015;128(12):1325-34.e2. 14. Andersen YM, Egeberg A, Gislason GH, Hansen PR, Skov L, Thyssen JP. Risk of myocardial infarction, ischemic stroke, and cardiovascular death in patients with atopic dermatitis. The Journal of allergy and clinical immunology. 2016;138(1):310-2.e3. 15. Chung SD, Keller JJ, Lin HC. Association of erectile dysfunction with atopic dermatitis: a population-based case-control study. The journal of sexual medicine. 2012;9(3):679-85. 16. Wei CC, Lin CL, Shen TC, Li TC, Chen AC. Atopic Dermatitis and Association of Risk for Henoch- Schonlein Purpura (IgA Vasculitis) and Renal Involvement Among Children: Results From a Population-Based Cohort Study in Taiwan. Medicine. 2016;95(3):e2586. 17. Caffarelli C, Cavagni G, Deriu FM, Zanotti P, Atherton DJ. Gastrointestinal symptoms in atopic eczema. Archives of disease in childhood. 1998;78(3):230-4. 18. Penders J, Gerhold K, Stobberingh EE, Thijs C, Zimmermann K, Lau S, et al. Establishment of the intestinal microbiota and its role for atopic dermatitis in early childhood. The Journal of allergy and clinical immunology. 2013;132(3):601-7.e8. 19. Kimata H. Fatty liver in atopic dermatitis. Allergy. 2001 May 1;56(5):460. 20. Chen MH, Su TP, Chen YS, Hsu JW, Huang KL, Chang WH, Chen TJ, Pan TL, Bai YM. Is atopy in early childhood a risk factor for ADHD and ASD? A longitudinal study. Journal of psychosomatic research. 2014 Oct 31;77(4):316-21. 21. Garg N, Silverberg JI. Association between childhood allergic disease, psychological comorbidity, and injury requiring medical attention. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2014;112(6):525-32. SKIN July 2017 Volume I Issue I Copyright 2017 The National Society for Cutaneous Medicine 14 22. Garg N, Silverberg JI. Association between childhood allergic disease, psychological comorbidity, and injury requiring medical attention. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2014;112(6):525-32. 23. Schmitt J, Apfelbacher C, Chen CM, Romanos M, Sausenthaler S, Koletzko S, et al. Infant-onset eczema in relation to mental health problems at age 10 years: results from a prospective birth cohort study (German Infant Nutrition Intervention plus). The Journal of allergy and clinical immunology. 2010;125(2):404-10. 24. Reuveni H, Chapnick G, Tal A, Tarasiuk A. Sleep fragmentation in children with atopic dermatitis. Archives of pediatrics & adolescent medicine. 1999;153(3):249-53. 25. Jensen AO, Svaerke C, Farkas DK, Olesen AB, Kragballe K, Sørensen HT. Atopic Dermatitis and Risk of Skin Cancer. American journal of clinical dermatology. 2012 Feb 1;13(1):29-36. 26. Arana A, Wentworth CE, Fernández-Vidaurre C, Schlienger RG, Conde E, Arellano FM. Incidence of cancer in the general population and in patients with or without atopic dermatitis in the UK. British Journal of Dermatology. 2010 Nov 1;163(5):1036-43. 27. Arellano FM, Arana A, Wentworth CE, Fernández- Vidaurre C, Schlienger RG, Conde E. Lymphoma among patients with atopic dermatitis and/or treated with topical immunosuppressants in the United Kingdom. Journal of Allergy and Clinical Immunology. 2009 May 31;123(5):1111-6. 28. Hwang CY, Chen YJ, Lin MW, Chen TJ, Chu SY, Chen CC, Lee DD, Chang YT, Wang WJ, Liu HN. Cancer risk in patients with allergic rhinitis, asthma and atopic dermatitis: a nationwide cohort study in Taiwan. International journal of cancer. 2012 Mar 1;130(5):1160-7. 29. Deckert S, Kopkow C, Schmitt J. Nonallergic comorbidities of atopic eczema: an overview of systematic reviews. Allergy. 2014 Jan 1;69(1):37-45. 30. Linabery AM, Jurek AM, Duval S, Ross JA. The association between atopy and childhood/adolescent leukemia: a meta-analysis. American journal of epidemiology. 2010 Apr 1;171(7):749-64. 31. Silverberg JI, Silverberg NB. Childhood atopic dermatitis and warts are associated with increased risk of infection: a US population-based study. Journal of Allergy and Clinical Immunology. 2014 Apr 30;133(4):1041-7. 32. Hayashida S, Furusho N, Uchi H, Miyazaki S, Eiraku K, Gondo C, Tsuji G, Hachisuka J, Fukagawa S, Kido M, Nakahara T. Are lifetime prevalence of impetigo, molluscum and herpes infection really increased in children having atopic dermatitis?. Journal of dermatological science. 2010 Dec 31;60(3):173-8. 33. Ibáñez MD, Valero AL, Montoro J, Jauregui I, Ferrer M, Dávila I, Bartra J, Cuvillo A, Mullol J, Sastre J. Analysis of comorbidities and therapeutic approach for allergic rhinitis in a pediatric population in Spain. Pediatric Allergy and Immunology. 2013 Nov 1;24(7):678-84. 34. Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: A US population–based study. Journal of Allergy and Clinical Immunology. 2013 Nov 30;132(5):1132-8. 35. Fukunaga N, Okada Y, Konishi Y, Murashita T, Koyama T. Pay attention to valvular disease in the presence of atopic dermatitis. Circulation Journal. 2013;77(7):1862-6.