Autoimmune diseases involving skin and intestinal mucosa are more frequent in adolescents and young adults suffering from atopic dermatitis

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1 doi: / Journal of Dermatology 2017; 44: REVIEW ARTICLE Autoimmune diseases involving skin and intestinal mucosa are more frequent in adolescents and young adults suffering from atopic dermatitis Francesca CIPRIANI, Alice MARZATICO, Giampaolo RICCI Pediatric Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy ABSTRACT Evidence has emerged about the relationship between atopic dermatitis (AD) and autoimmune diseases, but the underlying mechanism of this association is complex and still unclear. Recent epidemiological data from the published work suggest a positive correlation. The aim of this review is to analyze the frequency of co-occurrence of AD and autoimmune diseases. Our systematic review included 22 articles from PubMed describing the reciprocal association between AD and autoimmune diseases. Although not all the studies achieved statistically significant results, patients suffering from autoimmune diseases involving skin and intestinal mucosa, such as vitiligo, alopecia areata, celiac disease and inflammatory bowel diseases, showed a higher risk to have AD as comorbidity. In contrast, patients with rheumatological autoimmune disorders did not show a significant correlation with AD. By analyzing the occurrence of autoimmune disorders in patients with AD, we confirmed a positive correlation between AD and autoimmune diseases involving skin and intestinal mucosa, but also with systemic lupus erythematosus, while the association between AD and type 1 diabetes, autoimmune thyroiditis and rheumatoid arthritis showed conflicting results. Further investigations are need to explain the mechanism underlying the observed comorbidity between AD and autoimmune diseases and to develop targeted prevention strategies and treatment. Key words: atopic dermatitis, autoimmune disease, autoimmunity, childhood, eczema. INTRODUCTION Atopic dermatitis (AD) is a chronic inflammatory disorder that affects up to 20% of pediatric population and 3% of adult population in Western countries. 1 Numerous systemic diseases have been reported to be associated with AD, including allergic comorbidities, cardiovascular diseases, cancer, inflammatory disorders, mental disorders, eosinophilic gastroenteritis and metabolic diseases. 1,2 There is an increasing evidence about the relationship between autoimmunity and AD, but the mechanism of this association is still unclear. An autoimmune mechanism involved in the pathogenesis of AD has been suggested by the evidence that AD patients frequently exhibit immunoglobulin (Ig)E autoreactivity to a variety of human proteins and the presence of IgE autoantibodies seems to be related to the severity and chronicity of the disease. 3,4 It is still not clear if the presence of serum autoreactive IgE has a pathogenic role or if it represents just an epiphenomenon in patients with AD. Furthermore, it is still unclear if genetic predisposition and/or environmental factors may elicit autoreactivity in AD patients. Some fungal and animal antigens share sequence homologies with human antigens and the fact that human IgE recognize both exogenous allergens and related human antigens supports the hypothesis of an autoimmune mechanism in AD pathogenesis. Autoreactivity seems to develop in early childhood, between 2 and 6 years of life, which represents the critical period for IgE autosensitization. 5 Authors hypothesized that the constant scratching of AD itching lesions may inflict cellular injury that leads to the release of intracellular autoantigens and to the progression through autoimmune mechanisms. 6 Dysfunction of skin barrier, mutations in the filaggrin gene and the persistent inflammation due to Staphylococcus aureus colonization of AD lesions represent all factors that may influence the disease course and the development of an aberrant IgE production. Evidence of co-occurrence of AD with autoimmune diseases has been recently reported. 6,7 As T-helper cells dysregulation plays a role in the physiopathology of both AD and autoimmune diseases, a positive correlation has been suggested. In the acute phase of AD, Th2 cells reactions predominate, while Th1 cell response characterizes the transit to the chronic phase. Autoimmune disorders comprise Th1-mediated diseases, such as type 1 diabetes and rheumatoid arthritis, Th2-mediated diseases such as systemic lupus erythematosus (SLE) and mixture of Th1/Th2-mediated disorders (i.e. inflammatory bowel diseases). 8 Furthermore, autoimmune disorders and AD share a chronic relapsing remitting pattern of the Correspondence: Giampaolo Ricci, M.D., Pediatric Unit, Department of Medical and Surgical Sciences, University of Bologna, S. Orsola-Malpighi Hospital, via Massarenti 11, Bologna, Italy. giampaolo.ricci@unibo.it Received 22 June 2017; accepted 6 August Japanese Dermatological Association 1341

2 F. Cipriani et al. disease, supporting the hypothesis of a pathogenic link between these two conditions. 6 In order to analyze the association between AD and autoimmune diseases, we performed a systematic review of the published work to evaluate the co-frequency of these disorders. SEARCH METHODS We searched PubMed for publications by using the terms atopic dermatitis/atopic eczema combined with autoimmune diseases and the different autoimmune diseases that may be associated with AD: vitiligo, alopecia areata, inflammatory bowel diseases, celiac disease, SLE, rheumatoid arthritis, type 1 diabetes and autoimmune thyroid disease. We considered only studies published from 2000 to 2016 reporting epidemiological data about the relationship between AD and at least one autoimmune disease. Case control studies, cohort studies, cross-sectional studies and case series studies were included in the analysis. We rejected review articles, metaanalysis and studies with irrelevant outcomes. Furthermore, we included in the analysis articles cited in the papers selected by online search. We excluded some studies after their full-text analysis if not yet rejected because of an inappropriate title or abstract. Among 956 articles identified, 22 were eligible for our systematic revision (Fig. 1). Six of these 22 articles reported data about the association between AD and autoimmune diseases, analyzing the incidence or prevalence of autoimmune diseases in AD patients compared with healthy controls (Table 1). Sixteen studies focused on the frequency of AD in patients with autoimmune diseases (Table 2). AD and vitiligo Five studies examined the relationship between AD and vitiligo. Two case control studies aimed to investigate the prevalence of vitiligo in AD patients compared with control subjects. 8,10 A recent study performed by Wu et al. 8 analyzed data from a nationwide database including patients with AD and age- and sex-matched controls without AD. The mean age of the study sample was years and coexistent autoimmune diseases (thyroid disease, vitiligo, SLE, rheumatoid arthritis, inflammatory bowel disease, pernicious anemia and type 1 diabetes mellitus) were studied, adjusting for age, sex, number of health-care visits and for different autoimmune diseases. 8 The prevalence of vitiligo was higher among patients with AD compared with healthy subjects, but this difference was not statistically significant (odds ratio [OR], 1.08; 95% confidence interval [CI], ). 8 Augustin et al. 10 enrolled 1.64 million patients (aged 0 18 years) in a case control study, including patients affected by AD as cases and individuals without AD as controls. The prevalence of autoimmune diseases such as vitiligo, alopecia areata and inflammatory bowel diseases were analyzed among AD patients and controls; they found a significantly higher prevalence of vitiligo in AD patients (prevalence ratio [PR], 3.26; 95% CI, ) than in controls. 10 Three articles analyzed the prevalence of AD among patients affected by vitiligo One retrospective case control study Ar cles extracted through Pubmed searching from 2000 to 2016 (n = 956) Review ar cles (n =288) Ar cles screened v (n = 668) Papers excluded (n = 646) Duplicated ar cles (n =26) Not in English (n = 69) Not addressing outcome of interest (n =551) Ar cles included in systema c review (n = 22) Figure 1. Selection of original studies included in the review by searching PubMed Japanese Dermatological Association

3 Atopic dermatitis and autoimmunity Table 1. Frequency of autoimmune diseases in AD patients References Study design Patients, n Age in years, mean/ range AD prevalence, % Autoimmune disorder Autoimmune disorder among patients with AD, % Autoimmune disorder among patients without AD, % Association between AD and comorbidity, 95% CI P Wu et al Case control study. Data from the Longitudinal Health Insurance Database between 1997 and 2010 Schmitt et al Retrospective cohort study. Data from German National Health Insurance collected between 2005 and 2011 Augustin et al Case control study. Prevalence data of patients up to 18 years in 2009 extracted from the Database of a German statutory health insurance company Wei et al Retrospective cohort study. Data from National Health Research Insurance Database from 2000 to SLE OR 1.94 ( ) <0.001 Vitiligo OR 1.08 ( ) IBD OR 0.74 ( ) Rheumatoid arthritis OR 0.89 ( ) <0.001 DM OR 1.00 ( ) <0.001 Autoimmune OR 0.93 ( ) thyroiditis Pernicious anemia OR 0.54 ( ) Crohn s disease RR 1.34 ( ) Ulcerative colitis RR 1.25 ( ) DM RR 0.80 ( ) Rheumatoid arthritis RR 1.72 ( ) million Vitiligo PR 3.26 ( ) <0.05 Alopecia areata PR 2.34 ( ) <0.05 Ulcerative colitis PR 1.75 ( ) <0.05 Crohn s disease PR 1.33 ( ) > <18 years 25 SLE HR 2.92 ( ) <0.001 Ress et al Case series Celiac disease 1.4 NA OR 4.18 ( ) NA Pedulla et al Case control study Autoimmune NA <0.05 thyroiditis AD, atopic dermatitis; DM1, diabetes mellitus type 1; HR, hazard ratio; IBD, inflammatory bowel disease; NA, not available; OR, odds ratio; PR, prevalence ratio; RR, relative risk; SLE, systemic lupus erythematosus Japanese Dermatological Association 1343

4 F. Cipriani et al. Table 2. Frequency of AD in patients affected by autoimmune diseases Autoimmune disorder References Study design Patients, n Age in years, mean/range Patients with autoimmune disorder, n AD and patients with autoimmune disorder, % AD and patients without autoimmune disorder, % Association between autoimmune disorder and AD OR/RR CI (95%) P Alopecia areata Celiac disease Chu et al Case control study 1 million Adult patients OR 2.24 ( ) <0.01 Barahmani OR 1.70 ( ) <0.001 et al controls Case control study cases, Ciacci et al Case control study 4114 Adult patients OR 3.17 ( ) <0.05 SLE Case control study OR 2.31 ( ) <0.001 Hsiao et al Sekigawa Case control study NA >0.05 et al DM1 Rosenbauer OR 0.71 ( ) Ankylosing spondylitis Rheumatoid arthritis Juvenile idiopathic arthritis et al controls Case control study cases, Olesen et al Retrospective case control study OR 0.68 ( ) < Meerwaldt et al Case control study OR 0.68 ( ) >0.05 Rudwaleit et al Cross-sectional study cases, NA > controls Karatay et al Case control study OR 0.60 ( ) >0.05 Rudwaleit et al Cross-sectional study cases, NA > controls Karatay et al Case control study OR 0.93 ( ) >0.05 Lin et al Case control study OR 1.51 ( ) >0.05 Chen et al control study Retrospective case OR 1.52 ( ) <0.05 Vitiligo Lee et al Case series NA NA RR 2.70 ( ) NA Silverberg et al Case series NA OR 1.71 ( )* <0.001* IBD Myrelid et al Case control study OR 1.98 ( ) Kim et al Cross-sectional study OR ( ) <0.05 *Self-reported body surface-area>76%. NA, not available. AD, atopic dermatitis; DM1, diabetes mellitus type 1; HR, hazard ratio; IBD, inflammatory bowel disease; NA, not available; OR, odds ratio; PR, prevalence ratio; RR, relative risk; SLE, systemic lupus erythematosus Japanese Dermatological Association

5 Atopic dermatitis and autoimmunity showed a significantly increased prevalence of AD in adult patients with vitiligo compared with controls without vitiligo (OR, 1.52; 95% CI, ). 25 Lee et al. 26 reported a higher prevalence of AD in vitiligo cases than in the general population (risk ratio [RR], 2.70; 95% CI, ). Silverberg et al. 27 enrolled 2645 adult patients (mean age, 40 years) affected by vitiligo and analyzed AD frequency comparing their results with adult patients from the general population. They observed a significantly higher prevalence of AD in patients with vitiligo involving at least 76% body surface area compared with adults from the general population (OR, 1.71; 95% CI, ). 27 The authors concluded that the pro-inflammatory status of AD may predispose toward melanocyte destruction and that constant itching and scratching could induce the Koebner effect in vitiligo. 26,27 Silverberg et al. 27 hypothesized a common genetic mutation predisposing to both AD and vitiligo. AD and alopecia areata Three studies analyzed the association between AD and alopecia areata. 10,14,15 Augustin et al. 10 reported a significant higher prevalence of alopecia areata in children with AD than in children without AD (PR, 2.34; 95% CI, ). Two case control studies showed an increased risk of comorbidity with AD in patients suffering from alopecia areata compared with patients without alopecia areata. 14,15 Chu et al. 14 conducted a case control study with 1 million adult patients and observed a significantly higher risk of developing AD among patients with alopecia areata (OR, 3.82; 95% CI, ). Barahmani et al. 15 performed a case control study involving 2613 individuals with alopecia areata and controls without alopecia areata (mean age, 38.5 years) and investigated the frequency of AD among patients. They found that a history of alopecia areata was associated with significantly higher risk of AD (OR, 1.70; 95% CI, ). 15 The limitation of this study could be the self-reported atopy. A common immune response shared by AD and alopecia areata could explain the association between these diseases. Both Th1 and Th2 cytokines are involved in animal models of alopecia areata and a biphasic pattern of Th response has been observed both in AD and alopecia areata. 15 One study reports that filaggrin mutations are more frequent among patients affected by alopecia areata with a history of AD. Furthermore, this study showed that the presence of filaggrin mutations correlates with a worse course of alopecia areata in patients with atopic diseases. The authors hypothesized that mutations in the filaggrin gene, a strong risk factor for AD, may also play a role in alopecia areata. 30 AD and inflammatory bowel diseases Three studies investigated the frequency of inflammatory bowel diseases in AD patients compared with control subjects without AD Augustin et al. 10 found a significantly higher prevalence of ulcerative colitis among AD patients than among controls (PR, 1.75; 95% CI, ) and a higher prevalence of Crohn s disease in AD patients, but in this case the association was not statistically significant (PR, 1.33; 95% 2017 Japanese Dermatological Association CI, ). Schmitt et al. 9 performed a retrospective cohort study collecting data from a nationwide database and including patients (mean age, 23 years) with and without AD. Authors reported that AD patients have an increased risk of developing ulcerative colitis (RR, 1.25; 95% CI, ) and Crohn s disease (RR, 1.34; 95% CI, ) if compared with controls without AD. 9 Another study showed a higher prevalence of inflammatory bowel diseases in AD patients than control subjects, even if not statistically significant (Table 1). 8 Myrelid et al. 28 reported that AD is significantly more frequent in Crohn s patients than in the general population (OR, 1.98; 95% CI, ). In this case control study 1238 patients were enrolled (age range, years) and AD frequency was investigated among patients with Crohn s disease compared with patients without Crohn s disease. Kim et al. 29 conducted a cross-sectional study involving individuals (age range, years) and found a significantly higher risk of developing AD in both Crohn s and ulcerative colitis patients (OR, 1.366; 95% CI, ). Atopic dermatitis and inflammatory bowel diseases are disorders due to a barrier dysfunction, so the common causes and some similarities evidenced in their pathophysiology could explain their frequent association. A dysregulation in Th1 and Th2 response and in regulatory T cell activities seems to be implicated in both inflammatory bowel disease and AD. 8,9 Tumor necrosis factor (TNF)-a and mast cells play an important role in atopic diseases, and TNF-a was also detected in mast cells of the ileal wall from patients with Crohn s disease. 28 Genome-wide studies showed that several susceptibility genes implicated in immune dysregulation in AD are also involved in other immune-mediated inflammatory disorders, such as inflammatory bowel diseases. 9 AD and celiac disease Ress et al. 12 analyzed the prevalence of celiac disease in 351 children with AD compared with a general pediatric population and showed a four-times greater risk of developing celiac disease in patient with AD (OR, 4.18; 95% CI, ). Ciacci et al. 16 conducted a case control study involving 4114 adult individuals with and without celiac disease and observed that AD was three-times more frequent in patients with celiac disease and two-times more frequent in their relatives than in their spouses (OR, 3.17; 95% CI, ). Few recent studies identified AD as a condition at risk for gluten-sensitive enteropathy. 12 One study reported a significantly higher risk for developing immune-mediated skin diseases among patients affected by celiac disease. 31 In this trial, 15 cases (5.3%) of AD were found among 1015 celiac subjects enrolled. The mucosal damage due to local immunological reactions to antigens, leading to mucosal inflammation and increased mucosal permeability, could represent a common pathogenesis in AD and celiac disease. The increased mucosal permeability may allow the passage of autoantigens through the intestinal wall and may lead to hyperactivation of the immune system. 12 Furthermore, AD and celiac disease could share a common genetic background

6 F. Cipriani et al. AD and SLE Two studies found a significantly increased risk for SLE in AD cases compared with a non-affected control group (Table 1). 8,11 In addition, two articles analyzed the risk for comorbidity with AD in SLE patients. 17,18 Hsiao et al. 17 analyzed data from a nationwide database involving 8365 adult individuals (mean age, 40.1 years) with and without SLE and noted that the frequency of AD was two-times more common in patients with SLE than in those without SLE (6.81% vs 3.06%) and this difference was statistically significant (OR, 2.31; 95% CI, ). Conversely, Sekigawa et al. 18 conducted a case control study including 104 adult patients (mean age, 33.6 years) with and without SLE and observed a lower prevalence of AD in SLE patients, even if the observed difference was not statistically significant; the limitations of this study was the little number of cases included and that the history of atopic diseases was investigated with a retrospective questionnaire. A Th2-mediated immune response and elevated levels of serum IgE were described in SLE patients; autoreactive IgE and activation of basophils seem to contribute to the disease pathogenesis. 32 The inflammation characterizing AD is also related to an IgE-mediated response, Th2 lymphocytes and Th2-related cytokines. 8,11 These immune dysregulations may lead to the production of Ig and autoantibodies both in SLE and in atopic diseases. Antinuclear antibodies, anti-ssa, anti- RNP and several autoantibodies have been detected in AD patients. 17 These findings suggest a physiopathological correlation between AD and SLE. AD and rheumatoid arthritis Two studies described a significantly higher frequency of rheumatoid arthritis among AD patients than controls, 8,9 while studies analyzing the prevalence of AD among patients with rheumatoid arthritis and healthy controls did not show significant difference (Table 2). 22,23 Rudwaleit et al. 22 conducted a cross-sectional study in 2008 adult individuals and analyzed AD frequency among patients affected by rheumatoid arthritis or ankylosing spondylitis and among non-affected controls. Another case control study on 935 adult individuals with rheumatoid arthritis and ankylosing spondylitis and among non-affected controls investigated the frequency of AD. 23 Although not statistically significant, the frequency of AD seems to be lower in patients with rheumatoid arthritis than in non-affected controls in both studies. Hence, the authors suggest that atopy may represent a protective factor against rheumatoid arthritis. 23 Conversely, Schmitt et al. 9 and Wu et al. 8 found an increased risk of developing rheumatoid arthritis in AD patients. The authors hypothesized that Th1 and Th17 responses contributing to the chronicity of rheumatoid arthritis also play a role in the transition to chronic inflammation in AD. Skin inflammation with increased Th1 and Th17 responses in AD subjects may lead to the development of rheumatic arthritis or other autoimmune diseases. 9 The conflicting results could be due to the use of a questionnaire method to assess atopic disease in these two articles, 22,23 while the other two studies 8,9 used data from a nationwide database. Furthermore, there is a relevant difference in the sample size among these studies. AD and type 1 diabetes Schmitt et al. 9 observed a significantly inverse correlation between AD and type 1 diabetes (RR, 0.72; 95% CI, ). In contrast with these results, Wu et al. 8 found a significantly higher prevalence of type 1 diabetes in AD cases compared with healthy controls (OR, 1.00; 95% CI, ). Two studies analyzed the prevalence of AD among patients with type 1 diabetes and in non-affected subjects (Table 2). 19,20 Rosenbauer et al. 19 included 2631 children with and without type 1 diabetes in a case control study and analyzed AD frequency among these patients which highlighted a significantly lower frequency of AD among patients with type 1 diabetes. The same result was found in a retrospective case control study on children aged 3 15 years with and without type 1 diabetes conducted by Olesen et al. 20 A lower prevalence of AD in diabetic patients was also observed Table 3. Summary of reciprocal correlation between AD and autoimmune disorders %AD in patients with autoimmune disorders % autoimmune disorders in patients with AD Alopecia areata X Ankylosing spondylitis +/ NA Autoimmune thyroiditis NA + Celiac disease ++ NA DM1 +/ Inflammatory bowel diseases X Juvenile idiopathic arthritis + NA Pernicious anemia NA = Rheumatoid arthritis + Systemic lupus erythematosus +/ ++ Vitiligo X Reciprocal correlation +, not significantly increased; +/, conflicting results; ++, significantly increased;, not significantly reduced; =, unrelated;, significantly reduced; AD, atopic dermatitis; DM1, diabetes mellitus type 1; NA, not assessed; X, yes Japanese Dermatological Association

7 Atopic dermatitis and autoimmunity in the case control study performed by Meerwaldt et al. 21 in a population of 1332 children with and without type 1 diabetes (age range, 1 19 years), even if the difference was not statistically significant. In this case, the quality of the studies did not seem to explain the conflicting results. However, most of the articles agree on the lower risk of type 1 diabetes in subjects with AD. An inverse relationship between atopic disease and diabetes was reported in previous studies, suggesting that atopic disorders could have a protective effect against the development of diabetes. 33 Rosenbauer et al. 19 conducted a case control study in preschool children, because they hypothesized that development of AD in early childhood could be protective against childhood type 1 diabetes; their results support the idea that an early Th2 immune response may reduce the risk of Th1-mediated diseases, like type 1 diabetes. Olesen et al. 20 hypothesized the existence of two subtypes of AD, a Th1-driven (intrinsic type) and a Th2-driven (extrinsic type); they suggested that AD developed before the onset of type 1 diabetes is associated with a predominant Th2 response. AD and autoimmune thyroid disease Association between AD and thyroid disease was investigated by two studies. 8,13 Wu et al. 8 found a higher prevalence of thyroid disease in AD patients than in control subjects (OR, 1.29; 95% CI, ), but the difference did not achieve statistical significance. Pedulla et al. 13 performed a case control study with 217 children (age range, years) and showed a significantly increased prevalence of thyroid autoimmunity in patients with AD compared with healthy controls. Furthermore, the authors described a significantly higher frequency of autoimmunity among patients with IgE-mediated AD than in subjects with non-ige-mediated AD, supporting the idea that the relationship of AD and thyroid autoimmunity could result from a similar immune dysregulation. DISCUSSION The relationship between AD and autoimmune diseases is a complex phenomenon. Case control studies performed in patients with AD showed a significant association and comorbidity with several autoimmune diseases. The relationship between AD and vitiligo has been confirmed by most of the studies analyzing that correlation. A consistent positive association between AD and alopecia areata has also emerged. Recently, two reports analyzed the risk of developing celiac disease among AD subjects, which showed higher frequency of co-occurrence of both diseases. The majority of the studies observed significant co-frequency of AD and inflammatory bowel diseases, in particular with ulcerative colitis. Conflicting results emerged from the analysis of the relationship between AD and rheumatoid arthritis, but two large-scale population-based studies demonstrated a significantly higher frequency of rheumatoid arthritis in AD patients. Evidence on the association between type 1 diabetes and AD is still conflicting; a meta-analysis reported a non-significant inverse association between both disorders Japanese Dermatological Association In summary, by analyzing the association from a double point of view, patients suffering from autoimmune diseases involving skin and intestinal mucosa, such as vitiligo, alopecia areata and inflammatory bowel diseases, showed a higher risk of having AD as a comorbidity; in contrast, patients with rheumatological autoimmune disorders and systemic autoimmune diseases (i.e. type 1 diabetes) did not show a significant correlation with AD (Table 3). The underlying mechanism responsible for the positive association with AD and autoimmune diseases needs further investigations. Both prevalence and severity of atopic diseases and autoimmune diseases could be influenced by environmental and/or genetic factors. 35 We suppose that conflicting findings could be due to difference in sample size among the studies, data collection methods, different age range or ethnicity of population. Further investigations in large cohort studies are needed to confirm these associations and to clarify these correlations. Understanding the physiopathology and the comorbidities of AD may allow the early detection of affected subjects predisposed to autoimmunity and the development of targeted preventive interventions or care models. CONFLICT OF INTEREST: None declared. REFERENCES 1 Darlenski R, Kazandjieva J, Hristakieva E et al. Atopic dermatitis as a systemic disease. Clin Dermatol 2014; 32: Deckert S, Kopkow C, Schmitt J. 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