Portal de Periódicos da CAPES

Comorbidities of atopic dermatitis—what does the evidence say?

2023; Elsevier BV; Volume: 151; Issue: 5 Linguagem: Inglês

10.1016/j.jaci.2022.12.002

1097-6825

Jacob P. Thyssen, Anne‐Sofie Halling, Peter Schmid‐Grendelmeier, Emma Guttman‐Yassky, Jonathan I. Silverberg,

Allergic Rhinitis and Sensitization

Atopic dermatitis (AD) is a common disease that is associated with atopic and nonatopic comorbidities. There has been a growing interest in this area of AD, because presence or risk of comorbidities can in many ways impact the management of patients with AD. Thus, some treatments for AD may improve its comorbidities as well, whereas others may increase their risk. In this review article, we discuss various comorbidities of AD mostly on the basis of the results of recent multiple systematic reviews and meta-analyses to update readers about this rapidly developing area of dermatology. We emphasize the important information provided by studies presenting both relative risk and absolute risk, and show that AD is associated with, among others, atopic comorbidities such as asthma, rhinitis, and food allergy, nonatopic comorbidities such as ocular, psychiatric, infectious, endocrine, autoimmune, and cardiovascular diseases, and certain cancers. Clinicians need to be aware of these and be cognizant about positive and negative effects of existing and new treatments for AD. Atopic dermatitis (AD) is a common disease that is associated with atopic and nonatopic comorbidities. There has been a growing interest in this area of AD, because presence or risk of comorbidities can in many ways impact the management of patients with AD. Thus, some treatments for AD may improve its comorbidities as well, whereas others may increase their risk. In this review article, we discuss various comorbidities of AD mostly on the basis of the results of recent multiple systematic reviews and meta-analyses to update readers about this rapidly developing area of dermatology. We emphasize the important information provided by studies presenting both relative risk and absolute risk, and show that AD is associated with, among others, atopic comorbidities such as asthma, rhinitis, and food allergy, nonatopic comorbidities such as ocular, psychiatric, infectious, endocrine, autoimmune, and cardiovascular diseases, and certain cancers. Clinicians need to be aware of these and be cognizant about positive and negative effects of existing and new treatments for AD. Atopic dermatitis (AD) is a common disease affecting about one-fifth of young children at some point and 3% to 5% of adults.1Barbarot S. Auziere S. Gadkari A. Girolomoni G. Puig L. Simpson E.L. et al.Epidemiology of atopic dermatitis in adults: results from an international survey.Allergy. 2018; 73: 1284-1293Crossref PubMed Scopus (419) Google Scholar Patients with AD typically experience itch, skin pain, and sleep problems, leading to an impaired quality of life.2Langan S.M. Irvine A.D. Weidinger S. Atopic dermatitis.Lancet. 2020; 396: 345-360Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar Childhood AD may either persist or resolve by adulthood.3Thyssen J.P. Corn G. Wohlfahrt J. Melbye M. Bager P. Retrospective markers of paediatric atopic dermatitis persistence after hospital diagnosis: a nationwide cohort study.Clin Exp Allergy. 2019; 49: 1455-1463Crossref PubMed Scopus (6) Google Scholar, 4Kim J.P. Chao L.X. Simpson E.L. Silverberg J.I. Persistence of atopic dermatitis (AD): a systematic review and meta-analysis.J Am Acad Dermatol. 2016; 75: 681-687.e11Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 5Margolis J.S. Abuabara K. Bilker W. Hoffstad O. Margolis D.J. Persistence of mild to moderate atopic dermatitis.JAMA Dermatol. 2014; 150: 593-600Crossref PubMed Scopus (200) Google Scholar, 6Wan J. Mitra N. Hoffstad O.J. Yan A.C. Margolis D.J. Longitudinal atopic dermatitis control and persistence vary with timing of disease onset in children: a cohort study.J Am Acad Dermatol. 2019; 81: 1292-1299Abstract Full Text Full Text PDF PubMed Google Scholar, 7Abuabara K. Ye M. Margolis D.J. McCulloch C.E. Mulick A.R. Silverwood R.J. et al.Patterns of atopic eczema disease activity from birth through midlife in 2 British birth cohorts.JAMA Dermatol. 2021; 157: 1191-1199Crossref PubMed Scopus (5) Google Scholar Onset or recurrence of AD commonly occurs in adulthood.8Silverberg J.I. Adult-onset atopic dermatitis.J Allergy Clin Immunol Pract. 2019; 7: 28-33Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 9Abuabara K. Yu A.M. Okhovat J.P. Allen I.E. Langan S.M. The prevalence of atopic dermatitis beyond childhood: a systematic review and meta-analysis of longitudinal studies.Allergy. 2018; 73: 696-704Crossref PubMed Scopus (132) Google Scholar, 10Lee H.H. Patel K.R. Singam V. Rastogi S. Silverberg J.I. A systematic review and meta-analysis of the prevalence and phenotype of adult-onset atopic dermatitis.J Am Acad Dermatol. 2019; 80: 1526-1532.e7Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar Several disease trajectories may occur in children with AD.11Paternoster L. Savenije O.E.M. Heron J. Evans D.M. Vonk J.M. Brunekreef B. et al.Identification of atopic dermatitis subgroups in children from 2 longitudinal birth cohorts.J Allergy Clin Immunol. 2018; 141: 964-971Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 12Ziyab A.H. Mukherjee N. Zhang H. Arshad S.H. Karmaus W. Sex-specific developmental trajectories of eczema from infancy to age 26 years: a birth cohort study.Clin Exp Allergy. 2022; 52: 416-425Crossref PubMed Scopus (4) Google Scholar, 13Irvine A.D. Mina-Osorio P. Disease trajectories in childhood atopic dermatitis: an update and practitioner's guide.Br J Dermatol. 2019; 181: 895-906Crossref PubMed Scopus (0) Google Scholar Some of these are associated with higher rates of atopic comorbidities such as food allergy, asthma, and rhinitis (Christensen et al, unpublished data, 2022).14Haider S. Fontanella S. Ullah A. Turner S. Simpson A. Roberts G. et al.Evolution of eczema, wheeze and rhinitis from infancy to early adulthood: four birth cohort studies.Am J Respir Crit Care Med. 2022; 206: 950-960Crossref PubMed Google Scholar,15Belgrave D.C. Granell R. Simpson A. Guiver J. Bishop C. Buchan I. et al.Developmental profiles of eczema, wheeze, and rhinitis: two population-based birth cohort studies.PLoS Med. 2014; 11e1001748Crossref PubMed Scopus (178) Google Scholar There is a growing interest in the comorbidities of AD, which in many ways can impact the management of patients with AD. In some patients, a cross-specialty approach should be encouraged, wherein the overall burden of AD and its atopic and nonatopic comorbidities are diagnosed and treated in the same setting. Old and new treatments for moderate to severe AD may improve not only the signs and symptoms of AD but also comorbid atopic/allergic and autoimmune conditions. Some of these improvements are frequently observed in patients with AD (eg, cyclosporin may improve conjunctivitis and dupilumab may improve asthma), whereas others are infrequently observed (eg, methotrexate and baricitinib may improve RA and baricitinib may improve AA). Comorbid conditions of AD may in turn affect treatment selection. Moreover, adverse risk (in this context, comorbidities) from some newer systemic AD treatments, such as conjunctivitis, viral infections, and cardiovascular disease (CVD), may be particularly increased in patients with more severe disease, either because they are more often treated with these systemics or because they tend to have, for example, more cardiovascular risk factors or suffer from more severe inflammatory diseases of, for example, the eyes.16Egeberg A. Andersen Y.M. Gislason G.H. Skov L. Thyssen J.P. Prevalence of comorbidity and associated risk factors in adults with atopic dermatitis.Allergy. 2017; 72: 783-791Crossref PubMed Scopus (57) Google Scholar This narrative review article updates the reader on the comorbidities of AD. Selected association data presented in Fig 1 provide an overview of overall effect sizes from large systematic reviews (SRs) and meta-analyses. Guidelines are beginning to recommend that health care providers address nonatopic comorbidities also in their patients.17Davis D.M.R. Drucker A.M. Alikhan A. Bercovitch L. Cohen D.E. Darr J.M. et al.American Academy of Dermatology Guidelines: awareness of comorbidities associated with atopic dermatitis in adults.J Am Acad Dermatol. 2022; 86: 1335-1336.e18Abstract Full Text Full Text PDF PubMed Google Scholar When interpreting data from various epidemiological studies as well as SRs and meta-analyses, it is important to acknowledge that inherent limitations exist. The quality of an SR is based on the quality of the included studies ("garbage in–garbage out"); for example, ascertainment bias in the underlying clinical and survey studies of an SR may affect the outcome of the meta-analysis; that is, some members of a target population are more likely than others to be selected in a sample. Moreover, in some studies, severity categorization of patients with AD is based on clinical observation, whereas in other studies, it is based on medication use. Relative risk (RR) estimates show the ratio of a given outcome in the exposed group (patients with AD) in comparison with that in an unexposed group (controls). RR estimates allow for comparison across different studies because these estimates are stable across various populations with different baseline risk estimates. RR estimates are often presented as odds ratios in cross-sectional studies and as hazard ratios in prospective studies and are useful in meta-analyses. As RR estimates cannot discriminate between large and small absolute differences, studies should preferably also present absolute risk (AR) estimates. These are particularly important for clinicians because these can be used to assess how frequently they may come across a given comorbidity in their patients. Although one cannot extrapolate AR estimates in 1 study, combining AR and RR can allow clinicians to calculate the risk in their own patient population. For example, an RR of 2 is calculated not only if an event occurs in 2 of 100 in the case group and 1 of 100 in the control group but also if the event occurs in 200 of 100 in the case group and 100 of 100 in the control group. Therefore, absolute numbers are also needed for proper interpretation of overall risk. An illustrative example of the fundamental difference between AR and RR can be seen in a nicely conducted UK study that showed significantly increased RR of CVD in patients with severe AD.18Silverwood R.J. Forbes H.J. Abuabara K. Ascott A. Schmidt M. Schmidt S.A.J. et al.Severe and predominantly active atopic eczema in adulthood and long term risk of cardiovascular disease: population based cohort study.BMJ. 2018; 361: k1786Crossref PubMed Scopus (87) Google Scholar News media reported this novel finding widely, but when analyzing the AR in the UK data set, it was apparent that it was very low, and that clinicians would need to see thousands of patients with AD each year to come across the 1 patient in whom AD was responsible for myocardial infarction.19Thyssen J.P. Egeberg A. Cardiovascular disease and atopic dermatitis: epidemiological strengths and limitations.Br J Dermatol. 2018; 179: 1014-1015Crossref PubMed Scopus (2) Google Scholar Clinicians should be wary of statistically significant differences between groups in large data sets that have low AR or clinical significance. SRs often do not provide AR estimates, so it is often possible to get such data only from looking into individual studies. In this article, we therefore refer to low AR from specific articles, but acknowledge that AR is dependent on AD severity of the source population as well as age, ethnicity, and many other factors. Efforts were recently made to identify the best search terms algorithms for AD research using SRs, because this may profoundly impact the number of articles retrieved and hence the outcome of a meta-analysis.20Ayasse M.T. Ahmed A. Espinosa M.L. Walker C.J. Yousaf M. Thyssen J.P. et al.What are the highest yielding search strategy terms for systematic reviews in atopic dermatitis? A systematic review.Arch Dermatol Res. 2021; 313: 737-750Crossref PubMed Scopus (1) Google Scholar The number of languages used during the screening, the number of databases included, as well as their origin are key to ensure broad inclusion of studies from all around the world. The diagnostic criteria for AD are important because these may dramatically impact risk estimates (as in a Danish survey on CVD risk).21Andersen Y.M.F. Egeberg A. Hamann C.R. Skov L. Gislason G.H. Skaaby T. et al.Poor agreement in questionnaire-based diagnostic criteria for adult atopic dermatitis is a challenge when examining cardiovascular comorbidity.Allergy. 2018; 73: 923-931Crossref PubMed Scopus (17) Google Scholar When possible, stratification for clinical characteristics, most notably, disease severity, disease activity, and lifestyle factors, should be done because these will impact the risk of having or developing comorbidities. Recent comprehensive SRs and meta-analyses informed in detail about the overlap between AD and atopic conditions. In individuals with AD, the overall pooled prevalence of rhinitis, asthma, or both is 40.5%, 25.7%, and 14.2%, respectively.22Ravnborg N. Ambikaibalan D. Agnihotri G. Price S. Rastogi S. Patel K.R. et al.Prevalence of asthma in patients with atopic dermatitis: a systematic review and meta-analysis.J Am Acad Dermatol. 2021; 84: 471-478Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,23Knudgaard M.H. Andreasen T.H. Ravnborg N. Bieber T. Silverberg J.I. Egeberg A. et al.Rhinitis prevalence and association with atopic dermatitis: a systematic review and meta-analysis.Ann Allergy Asthma Immunol. 2021; 127: 49-56.e1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In adults with AD, 28.6% and 24.1% have food sensitivity and food allergy, and even higher proportions were observed in children with AD (Christensen et al, unpublished data, 2022). Food challenge–proven food allergy is also common in children and adults; egg was found to be the most common allergen. Patients with AD have 3- to 4-fold increased odds of having an atopic disease (Christensen et al, unpublished data, 2022),22Ravnborg N. Ambikaibalan D. Agnihotri G. Price S. Rastogi S. Patel K.R. et al.Prevalence of asthma in patients with atopic dermatitis: a systematic review and meta-analysis.J Am Acad Dermatol. 2021; 84: 471-478Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,23Knudgaard M.H. Andreasen T.H. Ravnborg N. Bieber T. Silverberg J.I. Egeberg A. et al.Rhinitis prevalence and association with atopic dermatitis: a systematic review and meta-analysis.Ann Allergy Asthma Immunol. 2021; 127: 49-56.e1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar which in part is explained by shared genetics.24Ferreira M.A. Vonk J.M. Baurecht H. Marenholz I. Tian C. Hoffman J.D. et al.Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology.Nat Genet. 2017; 49: 1752-1757Crossref PubMed Scopus (285) Google Scholar Furthermore, more severe AD is associated with increased likelihood of atopic comorbidities, including asthma (Christensen et al, unpublished data, 2022).22Ravnborg N. Ambikaibalan D. Agnihotri G. Price S. Rastogi S. Patel K.R. et al.Prevalence of asthma in patients with atopic dermatitis: a systematic review and meta-analysis.J Am Acad Dermatol. 2021; 84: 471-478Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,23Knudgaard M.H. Andreasen T.H. Ravnborg N. Bieber T. Silverberg J.I. Egeberg A. et al.Rhinitis prevalence and association with atopic dermatitis: a systematic review and meta-analysis.Ann Allergy Asthma Immunol. 2021; 127: 49-56.e1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,25Li H. Dai T. Liu C. Liu Q. Tan C. Phenotypes of atopic dermatitis and the risk for subsequent asthma: a systematic review and meta-analysis.J Am Acad Dermatol. 2022; 86: 365-372Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Importantly, AD is associated with both allergic and nonallergic forms of asthma and rhinitis defined from specific IgE measurements and skin prick tests.22Ravnborg N. Ambikaibalan D. Agnihotri G. Price S. Rastogi S. Patel K.R. et al.Prevalence of asthma in patients with atopic dermatitis: a systematic review and meta-analysis.J Am Acad Dermatol. 2021; 84: 471-478Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,23Knudgaard M.H. Andreasen T.H. Ravnborg N. Bieber T. Silverberg J.I. Egeberg A. et al.Rhinitis prevalence and association with atopic dermatitis: a systematic review and meta-analysis.Ann Allergy Asthma Immunol. 2021; 127: 49-56.e1Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Little is currently known about the overlap between AD and other conditions characterized by type 2 inflammation, such as nasal polyposis and eosinophilic esophagitis. These disorders are less common overall, but are more common in patients with AD.26Halling A.S. van Hauen M. Eggers-Lura V.H. Knudgaard M.H. Loft N. Thyssen J.P. Association between atopic dermatitis and nasal polyposis: what is the evidence?.J Eur Acad Dermatol Venereol. 2021; 35: e290-e293Crossref PubMed Scopus (2) Google Scholar,27Paller A.S. Mina-Osorio P. Vekeman F. Boklage S. Mallya U.G. Ganguli S. et al.Prevalence of type 2 inflammatory diseases in pediatric patients with atopic dermatitis: real-world evidence.J Am Acad Dermatol. 2022; 86: 758-765Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Clinicians should consider screening their patients with AD for gastrointestinal and respiratory atopic symptoms because this may impact treatment selection. Anterior subcapsular cataract, keratoconus, and recurrent conjunctivitis are minor Hanifin and Rajka criteria for AD, emphasizing that ocular disease is a part of the AD syndrome.28Hanifin J.M. Rajka G. Diagnostic features of atopic dermatitis.Acta Derm Venereol. 1980; 92: 44-47Crossref Google Scholar The high prevalence of ocular adverse events, including conjunctivitis and blepharitis, secondary to inhibitors of IL-13 and IL-4 signaling in patients with AD, led to renewed interest in ocular comorbidity of AD.29Halling A.S. Loft N. Silverberg J.I. Guttman-Yassky E. Thyssen J.P. Real-world evidence of dupilumab efficacy and risk of adverse events: a systematic review and meta-analysis.J Am Acad Dermatol. 2021; 84: 139-147Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar An SR showed that the prevalence of conjunctivitis was 31.7% in patients with AD and 13.3% in controls, the most common subtypes in patients with AD being allergic conjunctivitis, whereas atopic keratoconjunctivitis and infectious conjunctivitis were much less common.30Ravn N.H. Ahmadzay Z.F. Christensen T.A. Larsen H.H.P. Loft N. Rævdal P. et al.Bidirectional association between atopic dermatitis, conjunctivitis, and other ocular surface diseases: a systematic review and meta-analysis.J Am Acad Dermatol. 2021; 85: 453-461Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Blepharitis affected 22.0%, dry eye disease 9.1%, and keratitis 1.4%, whereas keratoconus affected less than 1%. Clinicians should ask about ocular symptoms and perform clinical examinations when relevant to reduce the burden of comorbid ocular disease. Some ocular comorbidities may indirectly worsen underlying AD, such as eye pruritus from allergic conjunctivitis leading to chronic rubbing around the eyes and secondary eczematization. The impact of AD on mental health can be substantial. The AR of psychiatric comorbidity is high in both pediatric and adult patients with AD31Patel K.R. Immaneni S. Singam V. Rastogi S. Silverberg J.I. Association between atopic dermatitis, depression, and suicidal ideation: a systematic review and meta-analysis.J Am Acad Dermatol. 2019; 80: 402-410Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar and should be considered by clinicians in clinical practice. Among all the SRs and meta-analyses, there were 2 that examined the relationship of AD with depression, suicidality, and/or anxiety.31Patel K.R. Immaneni S. Singam V. Rastogi S. Silverberg J.I. Association between atopic dermatitis, depression, and suicidal ideation: a systematic review and meta-analysis.J Am Acad Dermatol. 2019; 80: 402-410Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar,32Rønnstad A.T.M. Halling-Overgaard A.S. Hamann C.R. Skov L. Egeberg A. Thyssen J.P. 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: 448-456.e30Abstract Full Text Full Text PDF PubMed Google Scholar The first included 23, 13, and 6 studies in the meta-analyses of depression, anxiety, and suicidality, respectively, and found significantly higher odds of AD with depression and anxiety in adults, depression in children, and suicidality in adults and adolescents.32Rønnstad A.T.M. Halling-Overgaard A.S. Hamann C.R. Skov L. Egeberg A. Thyssen J.P. 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: 448-456.e30Abstract Full Text Full Text PDF PubMed Google Scholar Risk of depression and anxiety was increased 2-fold, and risk of suicidal ideation 4-fold.32Rønnstad A.T.M. Halling-Overgaard A.S. Hamann C.R. Skov L. Egeberg A. Thyssen J.P. 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: 448-456.e30Abstract Full Text Full Text PDF PubMed Google Scholar The second included 36 studies with sufficient data for meta-analysis and found that 20.1% (1 in 5 persons) with AD had depression compared with only 14.8% of controls.31Patel K.R. Immaneni S. Singam V. Rastogi S. Silverberg J.I. Association between atopic dermatitis, depression, and suicidal ideation: a systematic review and meta-analysis.J Am Acad Dermatol. 2019; 80: 402-410Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Adult patients with AD had significantly higher rates of clinical depression (14.9% vs 12.6%), numerically higher rates of antidepressant use (29.3% vs 20.3%), and significantly higher rates of suicidality (12.2% vs 6.4%).31Patel K.R. Immaneni S. Singam V. Rastogi S. Silverberg J.I. Association between atopic dermatitis, depression, and suicidal ideation: a systematic review and meta-analysis.J Am Acad Dermatol. 2019; 80: 402-410Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Depression occurred particularly in patients with moderate to severe AD.31Patel K.R. Immaneni S. Singam V. Rastogi S. Silverberg J.I. Association between atopic dermatitis, depression, and suicidal ideation: a systematic review and meta-analysis.J Am Acad Dermatol. 2019; 80: 402-410Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Depression and antidepressant use particularly occurred in adults.31Patel K.R. Immaneni S. Singam V. Rastogi S. Silverberg J.I. Association between atopic dermatitis, depression, and suicidal ideation: a systematic review and meta-analysis.J Am Acad Dermatol. 2019; 80: 402-410Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Children with AD also had higher prevalence of parental depression compared with children without AD (29.3% vs 20.3%).31Patel K.R. Immaneni S. Singam V. Rastogi S. Silverberg J.I. Association between atopic dermatitis, depression, and suicidal ideation: a systematic review and meta-analysis.J Am Acad Dermatol. 2019; 80: 402-410Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Two SRs showed that suicidal ideation risk was increased 1.5 times and suicidal attempt was also significantly increased.33Sandhu J.K. Wu K.K. Bui T.L. Armstrong A.W. Association between atopic dermatitis and suicidality: a systematic review and meta-analysis.JAMA Dermatol. 2019; 155: 178-187Crossref PubMed Scopus (66) Google Scholar,34Pompili M. Bonanni L. Gualtieri F. Trovini G. Persechino S. Baldessarini R.J. Suicidal risks with psoriasis and atopic dermatitis: systematic review and meta-analysis.J Psychosom Res. 2021; 141110347Crossref PubMed Scopus (15) Google Scholar An SR specifically in children confirmed the association between AD and psychiatric disease.35Xie Q.W. Dai X. Tang X. Chan C.H.Y. Chan C.L.W. Risk of mental disorders in children and adolescents with atopic dermatitis: a systematic review and meta-analysis.Front Psychol. 2019; 10: 1773Crossref PubMed Scopus (38) Google Scholar It is currently unclear whether AD has a causative genetic effect on depression.36Qi H.J. Li L.F. Association of atopic dermatitis with depression and suicide: a two-sample Mendelian randomization study.Biomed Res Int. 2022; 20224084121Crossref Scopus (2) Google Scholar, 37Cao H. Li S. Baranova A. Zhang F. Shared genetic liability between major depressive disorder and atopic diseases.Front Immunol. 2021; 12665160Crossref Scopus (4) Google Scholar, 38Baurecht H. Welker C. Baumeister S.E. Weidnger S. Meisinger C. Leitzmann M.F. et al.Relationship between atopic dermatitis, depression and anxiety: a two-sample Mendelian randomization study.Br J Dermatol. 2021; 185: 781-786Crossref PubMed Scopus (2) Google Scholar AD was also associated with attention deficit/hyperactivity disorder and with its severity.35Xie Q.W. Dai X. Tang X. Chan C.H.Y. Chan C.L.W. Risk of mental disorders in children and adolescents with atopic dermatitis: a systematic review and meta-analysis.Front Psychol. 2019; 10: 1773Crossref PubMed Scopus (38) Google Scholar,39Chuang Y.C. Wang C.Y. Huang W.L. Wang L.J. Kuo H.C. Chen Y.C. et al.Two meta-analyses of the association between atopic diseases and core symptoms of attention deficit hyperactivity disorder.Sci Rep. 2022; 12: 3377Crossref PubMed Scopus (4) Google Scholar,40Tsai T.Y. Chao Y.C. Hsieh C.Y. Huang Y.C. Association between atopic dermatitis and autism spectrum disorder: a systematic review and meta-analysis.Acta Derm Venereol. 2020; 100adv00146Crossref Scopus (4) Google Scholar Four studies in the aforementioned SR31Patel K.R. Immaneni S. Singam V. Rastogi S. Silverberg J.I. Association between atopic dermatitis, depression, and suicidal ideation: a systematic review and meta-analysis.J Am Acad Dermatol. 2019; 80: 402-410Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar found that different topical, oral systemic, or biologic treatment regimens for AD improved depression and/or depressive symptoms.41Kataoka Y. Nakajima S. Is coping of atopic dermatitis patients originated from their own character or secondarily remodeled by disease suffering? Obvious improvement of coping and psychiatric symptoms after "tight eczema control.".Acta Derm Venereol. 2017; 97: 880-881Google Scholar, 42Vinnik T. Kirby M. Bairachnaya M. Koman I. Tarkina T. Sadykova G. et al.Seasonality and BDNF polymorphism influences depression outcome in patients with atopic dermatitis and psoriasis.World J Biol Psychiatry. 2017; 18: 604-614Crossref PubMed Scopus (12) Google Scholar, 43Simpson E.L. Bieber T. Eckert L. Wu R. Ardeleanu M. Graham N.M. et al.Patient burden of moderate to severe atopic dermatitis (AD): insights from a phase 2b clinical trial of dupilumab in adults.J Am Acad Dermatol. 2016; 74: 491-498Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 44Kawana S. Kato Y. Omi T. Efficacy of a 5-HT1a receptor agonist in atopic dermatitis.Clin Exp Dermatol. 2010; 35: 835-840Crossref PubMed Scopus (28) Google Scholar These studies suggest that depressive symptoms occurring in AD may be directly related to AD severity and modifiable with reduced AD severity. A Danish registry study showed that the risk of being hospitalized for clinical depression or anxiety is similar to that of the general population.45Vittrup I. Andersen Y.M.F. Droitcourt C. Skov L. Egeberg A. Fenton M.C. et al.Association between hospital-diagnosed atopic dermatitis and psychiatric disorders and medication use in childhood.Br J Dermatol. 2021; 185: 91-100Crossref PubMed Scopus (8) Google Scholar Recent AD guidelines from the American Academy of Dermatology recognize that AD in adults is associated with clinician-diagnosed depression and anxiety (moderate-quality evidence) and may be associated with suicide (low-quality evidence).17Davis D.M.R. Drucker A.M. Alikhan A. Bercovitch L. Cohen D.E. Darr J.M. et al.American Academy of Dermatology Guidelines: awareness of comorbidities associated with atopic dermatitis in adults.J Am Acad Dermatol. 2022; 86: 1335-1336.e18Abstract Full Text Full Text PDF PubMed Google Scholar The odds ratio of alopecia areata (AA) in patients with AD is increased up to 10-fold, and similar to atopic comorbidities, the association is bidirectional.46Mohan G.C. Silverberg J.I. Association of vitiligo and alopecia areata with atopic dermatitis: a systematic review and meta-analysis.JAMA Dermatol. 2015; 151: 522-528Crossref PubMed Scopus (118) Google Scholar,47Lu Z. Zeng N. Cheng Y. Chen Y. Li Y. Lu Q. et al.Atopic dermatitis and risk of autoimmune diseases: a systematic review and meta-analysis.Allergy Asthma Clin Immunol. 2021; 17: 96Crossref PubMed Scopus (7) Google Scholar AA may be more severe in the context of AD and in the presence of filaggrin gene mutations.48Betz R.C. Pforr J. Flaquer A. Redler S. Hanneken S. Eigelshoven S. 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: 2539-2543Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar Large studies showed increased risk of developing AA in patients with atopic conditions, with the risk increasing with each additional atopic condition.49Kridin K. Renert-Yuval Y.