Atopic Dermatitis Is Associated with Dermatitis Herpetiformis and Celiac Disease in Children

Atopic dermatitis (AD) is an eczematous inflammatory skin disease that confers increased risk for several atopic, somatic, and psychiatric comorbidities (Brunner et al., 2017Brunner P.M. Silverberg J.I. Guttman-Yassky E. Paller A.S. Kabashima K. Amagai M. al.Increasing suggest atopic a systemic disorder.J Invest Dermatol. 2017; 137: 18-25Abstract Full Text PDF PubMed Scopus (224) Google Scholar, Kauppi 2019Kauppi S. Jokelainen J. Timonen Tasanen Huilaja L. Adult patients with eczema have high burden of disease: Finnish Nationwide Registry study.Acta Derm Venereol. 2019; 99: 647-651Crossref (15) Scholar). Recent epidemiologic data AD are at autoimmune diseases (Narla Silverberg, 2019Narla Association between disorders in US adults children: cross-sectional study.J Am Acad 80: 382-389Abstract (37) Celiac (CD) which dietary gluten intake induces enteropathy (Collin 2017Collin P. Salmi T.T. Hervonen Kaukinen Reunala T. Dermatitis herpetiformis: cutaneous manifestation coeliac disease.Ann Med. 49: 23-31Crossref (68) herpetiformis (DH) extraintestinal CD presenting intensely pruritic vesicles on specific areas Studies analyzing the children adolescents found contradictory results Ress 2014Ress Annus Putnik U. Luts Uibo R. O. dermatitis.Pediatr 2014; 31: 483-488Crossref (35) Because highest reported national prevalence DH was from study conducted Finland (Salmi 2011Salmi Kautiainen H. Collin Prevalence incidence 40-year prospective Finland.Br J 2011; 165: 354-359Crossref (103) Scholar), we designed present retrospective nationwide hospital register-based to examine risks AD. Study control populations (Table 1), databases used, statistical analyses presented Supplementary Materials Methods online. We significant association (OR = 10.42, 95% confidence interval [CI] 6.56–16.55) as well 2.28, CI 2.07–2.52) pediatric population compared individuals. After adjusting healthcare utilization, associations remained similar 2). Despite ORs presented, it important take into account rarity when interpreting because difference 0.099% (95% 0.073–0.124). In small Estonian 351 AD, four times greater than general 4.18, 1.12–15.64) (Ress contrast, large cohort 9,290 adult 10,196 United States, not statistically 2.90, 0.88–9.54) relatively rare, needed fully elucidate its Moreover, both Scholar) may impacted our findings. The stratified by sex shown Tables S1 S2. sexes among mean age diagnosis 6.3 years 6.8 versus 5.8 girls boys, respectively. No seen onset or groups (Supplementary Table S3).Table 1Subject Characteristics Cases ControlsGroupADControlTotal96,060228,642Study population, n (%)64,975 (100.0)1Including those cases least two recorded diagnoses register.228,642 (100.0) Girls31,137 (47.92)108,568 (47.5) Boys33,190 (51.08)120,074 (52.5)Abbreviation: dermatitis.1 Including register. Open table new tab 2OR Diagnoses Patients Adjusted Healthcare UtilizationDiseaseGroupTotaln (%)OR CI)Adjusted OR CI)DHAD64,97571 (0.1)1A total 1 71 group 3 24 had only once.10.42 (6.56–16.55)9.80 (6.15–15.62)Control228,64224 (0.01)1A once.ReferenceReferenceCDAD64,975648 (1.0)2.28 (2.07–2.52)1.92 (1.73–2.13)Control228,6421,005 (0.4)ReferenceReferenceAbbreviations: dermatitis; CD, celiac disease; CI, interval; DH, herpetiformis.1 A once. Abbreviation: dermatitis. Abbreviations: herpetiformis. pathogenesis begins gut where ingested immune-mediated genetically susceptible individuals, but still unclear why proportion develops (Reunala 2018Reunala common disease.Nutrients. 2018; 10: 602Crossref (52) usually latent asymptomatic leads prolonged inflammation gut. This over time lead production antibodies against transglutaminase (TG)3 through epitope spreading cross-reactivity tissue TG2 TG3 (Kárpáti 2018Kárpáti Sárdy Németh Mayer B. Smyth N. Paulsson al.Transglutaminases inherited diseases: phenomena functional compensation.Exp 27: 807-814Crossref (33) It suggested autoimmunity formation circulating IgA–TG3 immunocomplexes deposit dermis Scratching itchy lesions injury, release intracellular autoantigens thus, activation immune mechanisms (Tang 2012Tang T.S. Bieber Williams H.C. Does "autoreactivity" play role dermatitis?.J Allergy Clin Immunol. 2012; 129: 1209-1215.e2Abstract (115) Considering revealed face significantly higher possible damage predispose DH. Our line previous studies showing carry heightened (Andersen 2017Andersen Y.M. Egeberg A. Gislason G.H. Skov Thyssen J.P. Autoimmune dermatitis.J 76: 274-280.e1Abstract (69) Narla growing body evidence suggests autoreactivity plays has also been atopy be linked mucosal resulting (Ciacci 2004Ciacci C. Cavallaro Iovino Sabbatini F. Palumbo Amoruso D. al.Allergy disease.J 2004; 113: 1199-1203Abstract (62) There substantial overlap genetic backgrounds diseases. 31 genomic regions associated Most these loci roles responses implicated other (Paternoster 2015Paternoster Standl Waage Baurecht Hotze Strachan D.P. al.Multi-ancestry genome-wide 21,000 95,000 controls identifies dermatitis.Nat Genet. 2015; 47: 1449-1456Crossref (329) HLA-DQ2 -DQ8 haplotypes susceptibility (Spurkland 1997Spurkland Ingvarsson G. Falk E.S. Knutsen I. Sollid L.M. Thorsby primarily HLA-DQ (alpha 1∗0501, beta 1∗02) 1∗03, 1∗0302) heterodimers.Tissue Antigens. 1997; 29-34Crossref (125) 2002Kaukinen Partanen Mäki typing disease.Am Gastroenterol. 2002; 97: 695-699Crossref no detected HLA types However, best knowledge, genetics concomitant yet studied, so unknown whether any bearing major strength random, representative sample group. register optimal source studying link particularly weakness limited setting do contain information about lifestyle factors detailed clinical information. this registry-based study, misclassification cannot excluded. summary, report adolescents. daily practice, dermatologists recognize especially symptoms obscured although overall low. Further determine potential underlying CD. Care Register Health (former name: Hospital Discharge Register) maintained National Institute Welfare. According laws regulations, social welfare health care registers documents confidential. Welfare can, case-by-case basis, grant permission use purposes scientific research. More research authorization applications can https://www.thl.fi/en/web/thlfi-en/statistics/information-for-researchers. Saana Kauppi: http://orcid.org/0000-0003-3609-8874 Jari Jokelainen: http://orcid.org/0000-0003-4629-0560 Markku Timonen: http://orcid.org/0000-0002-9624-6544 Kaisa Tasanen: http://orcid.org/0000-0001-8056-5949 Laura Huilaja: https://orcid.org/0000-0002-7597-4323 SK received educational grants Novartis, Leo Pharma, Sanofi Genzyme, AbbVie, Janssen-Cilag honoraria Genzyme speaking. KT Novartis Pfizer Janssen-Cilag, Eli Lilly consulting LH Shire, LeoPharma UCB Pharma speaking investigator AbbVie. remaining authors state conflict interest. Conceptualization: SK, MT, KT, LH; Formal Analysis: JJ, Methodology: Supervision: Writing - Original Draft Preparation: SK; Review Editing: LH. study. All hospitals January 1987 December 2016 were eligible inclusion if patient aged <18 diagnosis. Patient records obtained (CRHC), CRHC covers all in-patient visits outpatient 1998 onward. Records selected (code 6918B World Organization International Classification Diseases [ICD]-9 code L20.0 ICD-10). Finland, ICD-9 used 1995 ICD-10 since 1996. As controls, collected random individuals >18 Population Centre. Information System contains basic residents, every individual recognized personal identity code. AD-diagnosed excluded Those without avoid bias having undiagnosed groups, gathered numbers (codes 6940A 6942A L13.0 ICD-10) 5790 K90.0 before 18 years. characteristics proportions means. evaluated using logistic regression model intervals. performed SAS software package (version 9.4, Institute, Cary, NC) two-sided P-values < 0.05 considered significant. search database returned 151,822 who 96,060 under final 64,975 formed including increase validity Of 500,000 sample, 228,642 one registered identified controls. 1.Supplementary S1OR Stratified By SexDiseaseGroupTotalGirlsBoysn CI)n CI)DHAD64,97532 (0.1)8.48 (4.45–16.16)39 (0.1)12.74 (6.53–24.88)Control228,64213 (0.0)Reference11 (0.0)ReferenceCDAD64,975394 (0.6)2.21 (1.95–2.51)254 (0.4)2.36 (2.01–2.77)Control228,642617 (0.6)Reference388 (0.3)ReferenceAbbreviations: S2OR Utilization (%)Adjusted (0.1)8.63 (4.77–15.64)39 (0.1)11.26 (5.95–21.29)Control228,64213 (0.6)1.51 (1.35–1.70)254 (0.4)2.75 (2.42–3.13)Control228,642617 S3Age Diagnosis ControlsDiseaseGroupAge diagnosis, Mean (SD)ADAD6.3 (4.5)ControlNADHAD9.6 (3.9)Control7.8 (4.1)CDAD8.2 (4.1)Control7.9 (4.0)Abbreviations: herpetiformis; NA, applicable.