Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2025;15(3):5064 1 Atopic Dermatitis and Autoimmune Connective Tissue Diseases: Systematic Review and Meta-Analysis Somaia Naassan1, Misbah Noshela Ghazanfar1, Simon Francis Thomsen1,2, Zarqa Ali1 1 Department of Dermato-Venereology & Wound Healing Centre, Bispebjerg Hospital, Copenhagen, Denmark 2 Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark Key words: Atopic dermatitis, Autoimmune connective tissue diseases, Sjögren syndrome, Systemic lupus erythematosus, Rheumatoid arthritis Citation: Naassan S, Ghazanfar MN, Thomsen SF, et al. Atopic Dermatitis and Autoimmune Connective Tissue Diseases: Systematic Review and Meta-Analysis. Dermatol Pract Concept. 2025;15(3):5064. DOI: https://doi.org/10.5826/dpc.1503a5064 Accepted: March 23, 2025; Published: July 2025 Copyright: ©2025 Naassan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: With no relation to the present manuscript, Simon Francis Thomsen has received research support from Janssen, LEO Pharma, Novartis, Sanofi, and UCB and has been a speaker/consultant for Abbvie, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Novartis, Pfizer, Sanofi, Symphogen, UCB, and Union Therapeutics. The other authors have nothing to declare. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Somaia Naassan, Department of Dermato-Venereology & Wound Healing Centre, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV, Denmark. Orcid ID: 0009-0009-2612-5307. E-mail: somaia_n@hotmail.com Introduction: The association between atopic dermatitis (AD) and autoimmune connective tissue diseases (ACTD) is not well investigated. Objective: We aimed to conduct a systematic review and meta-analysis to assess the association be- tween AD and ACTD. Methods: A comprehensive literature search was performed on PubMed, Embase, Cochrane Library, and Web of Science to identify relevant studies, which included those providing original data on the prevalence, incidence, or risk of ACTD in people with AD. Pooled point prevalence and odds ratio (OR) with 95% confidence intervals (CI) were estimated using a random effect inverse variance method. Results: Twenty-one studies were included in the systematic review, of which 18 were included in the meta-analysis. The pooled ORs were statistically significant overall for ACTD, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren syndrome (SS), and polymyositis (PM)/dermato- myositis (DM), but not for ankylosing spondylitis (AS) or systemic scleroderma (SSc): any ACTD 1.76 (95% CI: 1.57–1.97, I2 =94%, P<0.01), RA 1.40 (95% CI: 1.23–1.58, I2 = 97%, P<0.01), SLE 1.92 (95% CI: 1.66–2.23, I2 = 86%, P<0.01), SS 2.08 (95% CI: 1.48–2.94, I2 = 92%, P<0.01), AS 1.75 (95% CI: 1.32–2.33, I2 = 47%, P=0.13), PM/DM 2.37 (95% CI: 1.54–3.67, I2 = 73%, P<0.01), and SSc 2.75 (95% CI: 1.44–5.27, I2 = 60%, P=0.06). Conclusion: AD is associated with a significantly increased risk of ACTD, particularly RA, SLE, SS, and PM/DM, while no significant association was observed with AS or SSc. ABSTRACT 2 Review | Dermatol Pract Concept. 2025;15(3):5064 Introduction Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by dry skin, recurrent eczematous lesions, and intense itching. AD typically manifests during early childhood [1], affecting up to 20% of children and up to 10% of adults [2]. With over 230 million people affected worldwide, AD is a significant global health concern [3]. The burden of AD extends beyond its cutaneous manifestations; it negatively impacts quality of life by imposing lifestyle limitations, reducing social interactions, and affecting daily activities [4]. The etiology of AD stems from a complex and multi- factorial interaction between genetic predisposition, skin barrier abnormalities, immune dysregulation, and environ- mental and lifestyle factors  [1]. The co-occurrence of AD and autoimmune disorders has been widely investigated, and there is growing evidence suggesting that AD is a systemic disease [5-6]. While the coexistence of AD and other atopic disorders, e.g., asthma and allergic rhinoconjunctivitis, is a well-established phenomenon  [7], the potential association between AD and ACTD represents a novel and quite unex- pected finding. Objectives The aim of this study was to systematically investigate the existing literature to elucidate whether individuals with AD have an increased risk of autoimmune diseases affecting con- nective tissue, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren syndrome (SS), anky- losing spondylitis (AS), polymyositis/dermatomyositis (PM/ DM), systemic scleroderma (SSc), and mixed connective tis- sue disease (MCTD). Methods The protocol for this systematic review and meta-analysis was registered in PROSPERO (CRD42024519053). This study was conducted in accordance with the Preferred Re- porting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines [8] (Figure 1). Literature Search PubMed, Embase, Cochrane Library, and Web of Science were searched to identify the existing literature related to the association between AD and ACTD from March to June 2024. The search strategy consisted of terms related to AD and ACTD (Table S1). No language or date restric- tion was applied to the database searches. All references were imported into Covidence, an online software tool that streamlines the production of systematic and other literature reviews [9]. Covidence was utilized to remove duplicates and assess the references while blinding the reviewers. Screening and Study Selection Two reviewers (SN and MNG) independently screened all titles identifying studies meeting the inclusion criteria. Full text articles were retrieved and screened to confirm eligibil- ity. Any discrepancy in eligibility between the two review- ers was resolved through discussion. Studies were excluded if they were non-English, non-original papers, reviews, or study population with fewer than 100 AD patients. Data Extraction Data from the studies were extracted manually by SN and The Newcastle-Ottawa Scale (NOS)  [10], a validated tool, was used to evaluate the quality of included studies. NOS assesses the quality of cohort and case-control studies based on eight items in three domains: selection (four items), com- parability (one item), and outcome/exposure (three items). Each item can be graded with one point, except comparabil- ity, which can be graded with two points, with the highest possible score being nine points. Cross-sectional studies were assessed through an adapted version of NOS, with the high- est possible score of ten points. Studies receiving an NOS score of ≥7 were considered as high quality. Statistical Analysis The association between AD and ACTD was analyzed us- ing random effects models with the inverse variance method. Separate analyses were conducted for each ACTD, reporting an estimated pooled point prevalence and odds ratio (OR) with 95% confidence interval (CI). If point prevalence or OR was not reported, but the necessary data were available, we calculated the crude estimators with 95% CI. Study hetero- geneity was assessed using Sidik-Jonkman, as an estimator for τ2, and the I2 statistics, where heterogeneity levels were categorized as low >25%, moderate >50%, or high >75%. Funnel plots were used to visually assess publication bias. All statistical analyses were performed using R version 4.3.2. Results The database search identified 8013 studies (PubMed: 1361, Embase: 4733, Cochrane Library: 224, Web of Science: 1695). Additionally, one study was identified through review of references. Covidence removed 1939 duplicates, resulting in 6075 for title and abstract screening. A total of 58 studies were retrieved for full text screening. Ultimately, 21 studies met the inclusion criteria and were included in the review. Eighteen studies provided quantitative results and were in- cluded in the meta-analyses (Figure 1). Review | Dermatol Pract Concept. 2025;15(3):5064 3 Figure 1. PRISMA flow diagram of the search strategy. Characteristics of Included Studies The details of the included studies are listed in Table 1. The publication year ranged from 2014 to 2024, and the major- ity of the studies were from Europe and North America. The predominant study designs were cohort studies [11-22] and cross-sectional studies [23-28]. The population sizes varied across studies, with the smallest population being 48,672 [23] and the largest population being 87,053,155 [26]. The age distribution of study populations is summarized in Table 1. The studies primarily assessed AD and ACTD through ICD-9 or 10 coding  [11,14-15,17-19,22-23,26-31], but medical records  [13,16,21], physician diagnosis, clinical laboratory testing, and self-reported questionnaires  [24,32] were also used. However, six studies did not specify their source of information for AD and/or ACTD  [12,14-15,20,25,33]. Thirteen studies reported the point prevalence of ACTD in AD  [12-13,16,18-19,21-23,26-27,29-31] and nine studies reported ORs [15,23-29,31], while nine studies provided the necessary data to calculate ORs manually [12-13,16-19,21- 22,30]. Quality assessment using the Newcastle-Ottawa Scale was conducted on a total of 13 studies  [11,13,15- 17,19,22-23,26-29,31], which reported the association be- tween AD and ACTD as primary outcome. The remaining studies were either not primary articles or not observational studies, or they reported the association between AD and ACTD as cohort baseline characteristics. All assessed stud- ies were considered of high quality, with a NOS score ≥7 (Table S2). Despite the comprehensive search, no study investigating the association between AD and MCTD was identified. Association Between Atopic Dermatitis and Any Autoimmune Connective Tissue Disease To estimate the prevalence of any ACTD, we combined 36 reported point prevalence estimates from 13 distinct stud- ies  [12-13,16,18-19,21-23,26-27,29-31]. The prevalence of any ACTD was estimated to be 0.17% (Figure 2A). Forty-five ORs, extracted from 18 individual studies [12-13,15-19,21-31], were pooled to estimate an overall esti- mate. The combined odds of any ACTD in patients with AD were estimated to be 1.76 (95% CI: 1.57–1.97, I2 = 94%, P <0.01) (Figure 3A). Association Between Atopic Dermatitis and Rheumatoid Arthritis Eighteen studies investigated the association between AD and RA  [12-13,15-21,23-27,29,31-33]. Eleven studies re- ported the point prevalence of RA in AD  [12-13,16,18- 19,21,23,26-27,29,31], and the pooled point prevalence was estimated to 0.43% (Figure 2B). The OR was reported in 15 studies  [12-13,15-19,21,23-27,29,31]; 13 studies identified a statistically significant association  [12-13,15- 18,21,23-27,29], while two did not  [19,31]. The me- ta-analysis estimated the pooled OR to be 1.40 (95% CI: 1.23–1.58, I2 = 97%, P <0.01) (Figure 3B). Narla et al. [26] detected a significant association in adults (OR 1.37, 95% 4 Review | Dermatol Pract Concept. 2025;15(3):5064 T ab le 1 . C ha ra ct er is ti cs o f In cl ud ed S tu di es . A ut ho r (y ea r) C ou nt ry D es ig n ST U D Y P O PU L A T IO N A T O PI C D E R M A T IT IS A SS O C IA T IO N C on cl us io n N O S R ec ru it m en t si te A ge D efi ni ti on T ot al , n A C T D n (% ) O R ( 95 % C I) D efi ni ti on Pr im ar y ou tc om e A le xa nd er et a l. (2 01 9) U ni te d K in gd om C oh or t R oy al C ol le ge o f G en er al P ra ct it io ne rs R es ea rc h an d Su rv ei lla nc e C en tr e da ta ba se N /A N /A 47 0 24 0 R A 28 21 ( 0. 6) 1. 50 ( 1. 44 – 1 .5 7) N /A Y es A D is a ss oc ia te d w it h an in cr ea se d ri sk o f su bs eq ue nt R A N /A A nd er se n et a l. (2 01 6) D en m ar k C S T he D an is h N at io na l Pa ti en t R eg is tr y ≥ 18 y ea rs IC D -1 0 co de : L 20 81 12 A S R A SS c SS SL E 27 ( 0. 33 ) 12 6 (1 .5 5) 16 ( 0. 20 ) 41 ( 0. 51 ) 29 ( 0. 36 ) 2. 33 ( 1. 42 -3 .8 3) 1. 61 ( 1. 29 -2 .0 1) 2. 42 ( 1. 26 -4 .6 4) 3. 74 ( 2. 41 -5 .8 2) 2. 65 ( 1. 63 -4 .3 1) IC D -1 0 co de s Y es A D w as si gn ifi ca nt ly as so ci at ed w it h A S, R A , S Sc , S S an d SL E 8 Sc hm it t et a l. (2 01 5) G er m an y C oh or t A llg em ei ne O rt sk ra nk en ka ss e Sa xo ny d at ab as e ≤ 40 y ea rs ≥ 2 IC D -1 0 co de : L 20 49 8 47 R A 21 ( 0. 04 ) 0. 87 ( 0. 56 -1 .3 6) IC D -1 0 co de Y es A D p at ie nt s ar e at a s ig ni fic an tl y in cr ea se d ri sk t o de ve lo p R A t ha n pa ti en ts w it ho ut A D ( si gn ifi ca nt R R ), w hi le O R w as n ot f ou nd t o be s ig ni fic an t. 9 de L us ig na n et a l. (2 02 2) U ni te d K in gd om C oh or t O xf or d- R oy al C ol le ge o f G en er al Pr ac ti ti on er s R es ea rc h an d Su rv ei lla nc e C en tr e pr im ar y ca re da ta ba se A ll ag es 2 A D re co rd s (e it he r di ag no se s or tr ea tm en ts ) ap pe ar in g w it hi n an y 1- ye ar pe ri od 17 3 70 9 A S R A SS SL E 32 ( 0. 02 % ) 34 2 (0 .2 0% ) 67 ( 0. 04 % ) 37 ( 0. 02 % ) 1. 58 ( 1. 05 -2 .3 8) 1. 72 ( 1. 51 -1 .9 5) 2. 39 ( 1. 77 -3 .2 4) 1. 85 ( 1. 25 -2 .7 3) C lin ic al co de s us in g or p re vi ou sl y va lid at ed de fin it io ns Y es A D is a ss oc ia te d w it h in cr ea se d od ds f or A S, R A , SS a nd S L E A D is a ss oc ia te d w it h in cr ea se d ri sk f or R A , S S, bu t no t A S an d SL E 9 D en g et a l. (2 02 2) In te rn at io na l C oh or t T ri N et X , in te rn at io na l he al th ca re n et w or k w it h m ed ic al r ec or ds ≥ 18 y ea rs ≥ 2 IC D -1 0 co de : L 28 92 4 59 SL E N /A N /A N /A Y es Pa ti en ts w it h A D ha d an e le va te d ri sk o f SL E N /A H ou e t al . (2 02 1) U SA C S 20 12 N at io na l H ea lt h In te rv ie w Su rv ey N /A Se lf - re po rt ed N /A R A SL E N /A 1. 76 ( 1. 36 –2 .2 9) 3. 02 ( 1. 54 –5 .9 3) Se lf -r ep or te d Y es In cr ea se d ri sk o f R A a nd S L E in A D in dv id ua ls N /A Review | Dermatol Pract Concept. 2025;15(3):5064 5 Iv er t et a l. (2 02 1) Sw ed en C C Sw ed is h na ti on al he al th ca re r eg is te rs ≥ 15 y ea rs IC D -1 0 co de : L 20 .0 – L 20 .9 o r IC D -9 co de : 6 91 or I C D -8 co de : 69 1. 00 10 4 83 2 A S D M PM R A SS c SL E 27 8 (0 .3 ) 34 ( 0. 03 ) 21 ( 0. 02 ) 89 6 (0 .9 ) 64 ( 0. 1) 21 4 (0 .2 ) 1. 46 ( 1. 29 –1 .6 6) 2. 80 ( 1. 91 –4 .1 0) 1. 35 ( 0. 86 –2 .1 4) 1. 44 ( 1. 34 –1 .5 4) 1. 87 ( 1. 43 –2 .4 4) 1. 65 ( 1. 42 –1 .9 0) IC D -8 o r IC D -9 o r IC D -1 0 co de s Y es A D w as si gn ifi ca nt ly as so ci at ed w it h A S, D M , R A , S Sc an d SL E b ut n ot PM 8 K ri sh na et a l. (2 01 9) U ni te d K in gd om C oh or t T he H ea lt h Im pr ov em en t N et w or k A ll ag es R ea d C od es (c ur re nt an d pa st ) 1 39 3 57 0 R A SS SL E 69 33 ( 0. 50 ) 69 3 (0 .0 5) 14 45 ( 0. 10 ) 1. 05 ( 1. 02 -1 .0 8) 1. 33 ( 1. 20 -1 .4 7) 1. 40 ( 1. 30 -1 .5 0) R ea d C od es (c ur re nt a nd pa st ) Y es T he lo ng - te rm r is ks o f au to im m un e di so rd er s ar e si gn ifi ca nt ly hi gh er in p at ie nt s w it h al le rg ic di se as es 9 K uo e t al . (2 01 6) Ta iw an C C T he N at io na l H ea lt h In su ra nc e R es ea rc h D at ab as e of T ai w an ≤ 20 y ea rs IC D -9 co de : 6 91 , 69 1. 8 31 2 37 SL E 49 ( 0. 2) 2. 00 ( 1. 42 -2 .8 2) C om or bi di ty N o T he r es ul ts sh ow ed t ha t SL E w as a ss oc ia te d A D N /A L ai e t al . (2 01 5) Ta iw an C oh or t T he N at io na l H ea lt h In su ra nc e R es ea rc h D at ab as e of T ai w an ≥ 20 y ea rs ≥ 3 IC D -9 co de : 6 91 , 69 1. 8 18 9 07 R A N /A 1. 64 ( 1. 12 -2 .3 9) IC D -9 c od e Y es R is k of de ve lo pi ng R A m ar gi na l a m on g pa ti en ts w it h A D 9 N ar la et a l. (2 01 8) U SA C S U SA N at io nw id e In pa ti en t Sa m pl e N /A IC D -9 c od e W ei gh te d fr eq ue nc y: A du lt s: 4 4 60 5 C hi ld re n: 48 4 96 A du lt s A S PM R A SS c SS SL E C hi ld re n R A SS c SL E 47 ( 0. 1) 29 ( 0. 1) 68 8 (1 .5 ) 82 ( 0. 2) 63 ( 0. 1) 37 0 (0 .8 ) 24 ( 0. 05 ) 19 ( 0. 04 ) 44 ( 0. 09 ) 2. 63 ( 1. 31 -5 .2 7) 2. 04 ( 0. 72 -5 .7 3) 1. 37 ( 1. 11 -1 .6 9) 2. 32 ( 1. 35 -3 .9 8) 1. 63 ( 0. 85 -3 .1 3) 1. 80 ( 1. 38 -2 .3 4) 1. 09 ( 0. 35 -3 .4 0) 9. 35 ( 2. 97 -2 9. 44 ) 1. 27 ( 0. 58 -2 .8 0) IC D -9 c od es Y es Si gn ifi ca nt as so ci at io ns w it h A S, R A , SS c an d SL E a nd no s ig ni fic an t as so ci at io ns w it h PM a nd S S in ad ul ts Si gn ifi ca nt as so ci at io ns w it h SS c an d no s ig ni fic an t as so ci at io ns w it h R A o r SL E in ch ild re n 8 Ta bl e 1 (c on ti nu ed ) 6 Review | Dermatol Pract Concept. 2025;15(3):5064 A ut ho r (y ea r) C ou nt ry D es ig n ST U D Y P O PU L A T IO N A T O PI C D E R M A T IT IS A SS O C IA T IO N C on cl us io n N O S R ec ru it m en t si te A ge D efi ni ti on T ot al , n A C T D n (% ) O R ( 95 % C I) D efi ni ti on Pr im ar y ou tc om e R oh e t al . (2 02 1) U SA C S M ar ke tS ca n C om m er ci al C la im s da ta ba se 18 –6 4 ye ar s ≥ 2 IC D -1 0 co de : L 20 39 7 79 PM /D M SS SL E N /A 3. 54 ( 2. 47 –5 .0 8) 2. 17 ( 1. 86 -2 .5 3) 2. 46 ( 2. 17 -2 .7 8) IC D -1 0 co de s Y es A D p at ie nt s ha d a hi gh er li ke lih oo d of P M /D M , S S an d SL E 8 Sy ed e t al . (2 02 1) U ni te d K in gd om C oh or t T he H ea lt h Im pr ov em en t N et w or k A ll ag es N /A A du lt s: 62 5 08 3 C hi ld re n: 40 9 43 1 R A N /A N /A N /A Y es O ve ra ll in cr ea se d ri sk o f R A in pa ti en ts w it h A D N /A W ei e t al . (2 01 4) Ta iw an C oh or t T he N at io na l H ea lt h In su ra nc e R es ea rc h D at ab as e of T ai w an < 18 y ea rs ≥ 3 IC D -9 co de : 6 91 19 2 35 7 SL E 32 ( 0. 02 ) 2. 91 ( 1. 85 -4 .5 9) IC D -9 co de a nd co nfi rm at io n by R eg is tr y fo r C at as tr op hi c Il ln es s Pa ti en t D at ab as e Y es Si gn ifi ca nt ly in cr ea se d in ci de nc e ra te o f JS L E in c hi ld re n w it h A D 9 W u et a l. (2 01 4) Ta iw an C C T he N at io na l H ea lt h In su ra nc e R es ea rc h D at ab as e of T ai w an A ll ag es ≥ 2 IC D -9 co de : 69 1. 8 41 9 50 R A SL E 20 0 (0 .4 8% ) 97 ( 0. 23 % ) 0. 89 ( 0. 74 –1 .0 6) 1. 94 ( 1. 48 –2 .5 4) IC D -9 c od es Y es Pa ti en ts w it h A D ha ve a h ig he r ri sk of S L E , a nd n o re la ti on sh ip w it h R A 8 Fu xe nc h et a l. (2 02 3) U SA C oh or t O pt um C lin fo rm at ic s D at a M ar t da ta ba se N /A IC D c od es 60 1 78 3 R A N /A 1. 70 ( 1. 60 -1 .8 1) N /A Y es In di vi du al s w it h A D h av e an in cr ea se d ri sk of R A 8 R ad tk e et a l. (2 01 7) G er m an y C S G er m an n at io nw id e st at ut or y he al th in su ra nc e G m ue nd er E rs at zk as se ≥ 18 y ea rs IC D -1 0 co de : L 20 48 1 40 R A 16 4 (0 .3 4) 1. 20 ( 1. 04 –1 .4 1) IC D -1 0 co de Y es In cr ea se d pr ev al en ce o f R A a m on g A D p at ie nt s co m pa re d to th os e w it ho ut A D 7 T ab le 1 . C ha ra ct er is ti cs o f In cl ud ed S tu di es . ( co nt in ue d) Review | Dermatol Pract Concept. 2025;15(3):5064 7 M ey er s et a l. (2 02 1) U SA C oh or t IB M W at so n M ar ke tS ca n C om m er ci al C la im s an d E nc ou nt er s, M ed ic ar e Su pp le m en ta l, an d M ed ic ai d da ta ba se s ≥ 18 y ea rs IC D -9 co de : 69 1. 8 or IC D -1 0 co de : L 20 .0 , L 20 .8 x, L 20 .9 19 8 68 5 R A SL E 20 62 ( 1. 0) 45 0 (0 .2 ) 1. 44 ( 1. 38 -1 .5 0) 1. 72 ( 1. 56 -1 .8 9) C om or bi di ty N o C oh or t ch ar ac te ri st ic s N /A W ar re n et a l. (2 02 3) U ni te d K in gd om , W al es a nd Sc ot la nd C oh or t O pt im um P at ie nt C ar e R es ea rc h D at ab as e ≥ 18 y ea rs R ea d an d SN O M E D C T c od es an d tw o or m or e A D tr ea tm en ts pr es cr ib ed on di ff er en t da te s 15 0 97 5 R A 12 19 ( 0. 8) 1. 16 ( 1. 09 -1 .2 4) C om or bi di ty N o C oh or t ch ar ac te ri st ic s N /A Jo o et a l. (2 01 7) K or ea C S K or ea n N at io na l H ea lt h an d N ut ri ti on E xa m in at io n Su rv ey N /A N /A N /A R A N /A 2. 22 ( 1. 81 -2 .7 3) N /A Y es A D w as p os it iv el y as so ci at ed w it h R A N /A A hn e t al . (2 02 4) K or ea C oh or t T he N at io na l H ea lt h In su ra nc e Se rv ic e < 18 y ea rs ≥ 5 IC D -1 0 co de L 20 .9 an d ≥ 2 pr es cr ip tio ns of A D tr ea tm en t 39 8 32 A S SL E SS PM /D M N /A N /A IC D -1 0 co de s Y es A D w as si gn ifi ca nt ly as so ci at ed w it h an in cr ea se d ri sk of A S, S L E , S S, an d PM /D M . 9 A bb re vi at io ns : A C T D , a ut oi m m un e co nn ec ti ve t is su e di se as es ; A D , a to pi c de rm at it is ; A S, a nk yl os in g sp on dy lit is ; C C , c as e– co nt ro l; C I, co nf id en ce in te rv al ; C S, c ro ss -s ec ti on al ; P M , p ol ym yo si ti s; D M , d er m at o- m yo si ti s; O R , o dd s ra ti o; S S, S jö gr en ’s s yn dr om e; S L E , s ys te m ic lu pu s er yt he m at os us ; S Sc , s ys te m ic s cl er od er m a; R A , r he um at oi d ar th ri ti s; N O S, N ew ca st le -O tt aw a Sc al e; N /A , n ot a va ila bl e. 8 Review | Dermatol Pract Concept. 2025;15(3):5064 Figure 2. Forest plot for the meta-analysis of the pooled point prevalence of ACTD in AD. (A) Any autoimmune connective tissue diseases. (B) Rheumatoid arthritis. (C) Systemic lupus erythematosus. (D) Sjögren syndrome. (E) Ankylosing spondylitis. (F) Polymyositis/dermatomyositis. (G) Systemic scleroderma. (AD, atopic dermatitis; ACTD, autoimmune connective tissue diseases; CI, confidence interval.) Review | Dermatol Pract Concept. 2025;15(3):5064 9 Figure 2. (Continued) 10 Review | Dermatol Pract Concept. 2025;15(3):5064 Figure 3. Forest plot for the meta-analysis of the pooled OR of ACTD in AD. (A) Any autoimmune connective tissue diseases. (B) Rheumatoid arthritis. (C) Systemic lupus erythematosus. (D) Sjögren syndrome, (E) Ankylosing spondyli- tis. (F) Polymyositis/dermatomyositis. (G) Systemic scleroderma. (AD, atopic dermatitis; ACTD, autoimmune connec- tive tissue diseases; OR, odds ratio; CI, confidence interval.) Review | Dermatol Pract Concept. 2025;15(3):5064 11 Figure 3. (Continued) 12 Review | Dermatol Pract Concept. 2025;15(3):5064 Figure 3. (Continued) CI: 1.11–1.69) when compared to controls, but not in chil- dren (OR 1.09, 95% CI: 0.35–3.40). Among the associa- tions not included in the meta-analysis due to the absence of ORs, six cohort studies examined the risk of RA in AD patients compared to controls. Five of them found a sig- nificantly increased risk: Alexander et al. [12] reported an hazard ratio (HR) of 1.41 (95% CI: 1.32–1.51), Schmitt et al. [19] reported an relative risk (RR) of 1.72 (95% CI: 1.25–2.37), de Lusignan et al. [13] reported an HR of 1.38 (95% CI: 1.21–1.57), Krishna et al. [16] reported an RR of 1.28 (95% CI: 1.22–1.34), Syed et al. [34] reported an HR of 1.18 (95% CI: 1.13–1.22) for adults and an HR of 1.38 (95% CI: 1.14–1.67) for children. However, Lai et al. [17] did not find a significant association, reporting an HR of 1.41 (95% CI: 0.98–2.02). Association Between Atopic Dermatitis and Systemic Lupus Erythematosus Fourteen studies examined the association between AD and SLE  [11,13-14,16,18,22-24,26,28-31,33]. Eight studies re- ported a point prevalence of SLE in AD  [13,16,18,23,26, 29-31]; the pooled point prevalence was estimated to be 0.17% (Figure 2C). Eleven studies compared the odds of SLE in AD and controls, with all reporting a statistically significant OR [13,16,18,22-24,26,28-31]. However, Narla et al.  [26] only found the association to be significant in adults (OR 1.80, 95% CI: 1.38–2.34) but not children (OR 1.27, 95% CI: 0.58–2.80). We estimated the pooled OR to 1.92 (95% CI: 1.66–2.23, I2 = 86%, P <0.01) (Figure 3C). Addition- ally, four cohort studies, for which the reported association could not be pooled in the meta-analysis due to the absence Review | Dermatol Pract Concept. 2025;15(3):5064 13 of ORs, identified a significant increased risk of SLE in AD patients, as Deng et al. [14] reported an RR of 1.29 (95% CI: 1.06–1.57), Krishna et al. [16] reported an RR of 1.86 (95% CI: 1.66–2.09), and Wei et al. [22] reported a higher HR of 2.92 (95% CI: 1.85–4.60), while Ahn et al. [11] reported an HR of 1.43 (95% CI: 1.04–1.95) in children. Conversely, de Lusignan et al.  [13] reported an insignificant increased risk of SLE in AD compared to controls (HR 1.44, 95% CI: 0.97–2.13). Association Between Atopic Dermatitis and Sjögren Syndrome Six studies investigated the association between AD and SS  [11,13,16,23,26,28], four of which reporting the point prevalence of SS in AD [13,16,23,26]; the pooled point prev- alence was estimated to be 0.11% (Figure 2D). Five of the studies provided data on the odds of SS in AD compared to controls; four found a statistically significant associa- tion [13,16,23,28], while one did not [26]. The meta- analysis estimated a pooled OR of 2.08 (95% CI: 1.48–2.94, I2 = 92%, P<0.01) (Figure 3D). Three cohort studies, whose re- ported association could not be pooled in the meta-analysis due to the lack of ORs, similarly identified an increased risk of SS among AD patients compared to controls: de Lusignan et al.  [13] reported an HR of 1.83 (95% CI: 1.34–2.48), Krishna et al. [16] reported an RR of 1.48 (95% CI: 1.30– 1.69), and Ahn et al. [11] reported an HR of 1.40 (95% CI: 1.01-1.94) in children. Association Between Atopic Dermatitis and Ankylosing Spondylitis Six of the identified studies investigated the association be- tween AD and AS [11,13,23,26,29,33], with four reporting the point prevalence [13,23,26,29]; the pooled point preva- lence was estimated to be 0.11% (Figure 2E). A statistically significant increased odds for comorbid AS in AD patients was reported in four studies  [13,23,26,29], with a pooled OR estimated to be 1.75 (95% CI: 1.32 –2.33, I2 = 47%, P=0.13) (Figure 3E). One cohort study, which could not be included in the meta-analysis due to the absence of ORs, found an increased risk of AS in children: Ahn et al.  [11] reported an HR of 1.41 (95% CI: 1.02-1.94). However, de Lusignan et al. [13] reported a non-significant increased risk of AS in AD patients compared to controls (HR 1.33, 95% CI: 0.87–2.01). Association Between Atopic Dermatitis and Polymyositis/Dermatomyositis The association between AD and PM was reported in two studies  [26,29], one study investigated the association be- tween AD and DM  [29], and two studies reported on the association between AD and PM/DM [11,28], with the point prevalence reported in two   [26,29]; the combined preva- lence of PM/DM in AD was estimated to 0.04% (Figure 2F). Three studies reported an OR, which were significant for DM and PM/DM. However, none of the studies reporting an OR for the association between AD and PM was significant. The combined OR of the association between AD and PM/ DM was estimated to be 2.37 (95% CI: 1.54–3.67, P<0.01) (Figure 3F). Ahn et al. [11], whose reported association could not be pooled in the meta-analysis, identified an increased risk of PM/DM, with an HR of 1.59 (95% CI: 1.03–2.45). Association Between Atopic Dermatitis and Systemic Scleroderma Three studies investigated the association between AD and SSc  [23,26,29], with all reporting both a point prevalence and an OR. The pooled point prevalence was estimated to be 0.1% (Figure 2G). All the studies found a statistically significant association, with a pooled OR of 2.75 (95% CI: 1.44–5.27, I2 = 60%, P=0.06) (Figure 3G). Publication Bias Publication bias was assessed using funnel plots. The funnel plot for the association between AD and any ACTD showed an almost symmetrical distribution, indicating little to no publication bias (Figure 4A). The funnel plot for RA showed symmetry, indicative of no publication bias (Figure  4B), while the funnel plot for SLE was somewhat asymmetric, indicating potential publication bias (Figure 4C). Due to the limited numbers of studies of SS, AS, PM/DM, and SSc, fun- nel plots were not constructed for these associations. Discussion Main Findings In this systematic review and meta-analysis, we estimated the prevalence of any ACTD at 0.17%, RA at 0.43%, SLE at 0.17%, SS at 0.11%, AS at 0.11%, PM/DM at 0.04%, and SSc at 0.1% among patients with AD. Additionally, AD had an overall significant association with any ACTD; the esti- mated ORs for the association between AD and the ACTD were statistically significant for RA, SLE, SS, and PM/DM. However, the association with AS and SSc was not statisti- cally significant. The association between AD and MCTD could not be investigated due to the absence of studies avail- able on this topic. Interpretation Our results are consistent with previous research, sup- porting the evidence for the potential association between AD and systemic autoimmune diseases. Previous reviews based on relatively fewer studies reported positive associa- tions between AD and RA [35-38] and SLE [35-36,39-41]. 14 Review | Dermatol Pract Concept. 2025;15(3):5064 Figure 4. Funnel plots of the meta-analyses. (A) Any autoimmune connective tissue diseases. (B) Rheumatoid arthritis. (C) Systemic lupus erythematosus. (AD, atopic dermatitis; ACTD, auto- immune connective tissue diseases; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.) Review | Dermatol Pract Concept. 2025;15(3):5064 15 conditions. In clinical practice, early detection of ACTD in AD patients can be facilitated through screening protocols, including standardized questionnaires with short and simple questions, to assess symptoms such as joint swelling, muscle pain, stiffness, and dryness of the eyes, mouth, and skin. At- risk patients may benefit from additional serological testing, such as ANA, rheumatoid factor, and anti-CCP antibodies, to detect early signs of autoimmunity. Emerging systemic treatments for AD, such as dupilumab and Janus kinase (JAK) inhibitors, have shown significant ef- ficacy in managing the condition. However, their long-term impact on autoimmune disease risk remains an area of on- going research. Clinicians should carefully consider individual patient profiles, including the presence of autoimmune comor- bidities and family history, when selecting treatment options. Limitations This systematic review and meta-analysis investigated the association between AD and ACTD, which included RA, SLE, SS, AS, PM/DM, and SSc. However, several limitations should be acknowledged. Given the relatively low incidence and prevalence of ACTD, the number of available studies was limited. Furthermore, the availability of data varied across the studies, including discrepancies in the reporting of prevalence and risk estimates of ACTD in AD. Moderate-to-high levels of heterogeneity were ob- served in some analyses, which can be attributed to several factors. Different study designs were included, with varia- tions in recruitment methods, sample sizes, and population characteristics, including sex and age distribution. The as- sessment of AD varied across studies, and diagnosis varied from physician-verified to self-reports, introducing potential recall bias and misclassification. Furthermore, studies were conducted in different geographic regions, and with AD having geographic variation in prevalence [60], this may contribute to the heterogeneity. These factors may influence the interpretation and comparison of the pooled estimates. We extracted and analyzed the adjusted effects with 95% CI when available. However, inconsistencies in confounder adjustment were observed across included studies. Due to the nature of the meta-analysis, we were unable to account for these variations, which may have introduced bias and affected the pooled results. Given that studies were conducted across Europe, North America, and Asia, with only one study being international, with Africa not being represented, it is important to note that the result do not reflect a global perspective. Conclusion AD was significantly associated with an increased risk of any ACTD, especially RA, SLE, SS, and PM/DM. However, the Additionally, Chester et al.  [40] similarly reported positive associations between AD and SS, AS, and SSc. Our study in- vestigates the association between AD and RA, SLE, SS, AS, PM/DM, and SSc. While research has uncovered associations between AD and autoimmune diseases, further supporting that AD ex- tends beyond cutaneous manifestations [5-6], the underlying pathophysiological mechanism connecting AD and these con- ditions remains unclear. AD is characterized by a dysregulated innate immune response with an immunological T helper 2 (Th2) cell reaction characterized by the release of proin- flammatory cytokines such as interleukin (IL)-4, IL-5, and IL-13, and subsequent increased levels of immunoglobulin E (IgE) [42]. While Th1 and Th17 are well-recognized contribu- tors to autoimmune diseases [43], emerging evidence suggests their involvement in the pathogenesis of AD as well [44-46]. This proinflammatory response might not be limited to the skin. One possible explanation is the activation of common immunologic pathways, resulting in increased autoreactiv- ity [47] and risk of subsequent autoimmune diseases. These conditions are characterized by a dysregulated immune re- sponse, leading to pathological autoimmunity and ultimately tissue damage [48]. The positive association between AD and ACTD could potentially be attributed to shared immunologic dysregulation in T cell activity. Th1 and Th17 are widely rec- ognized as contributors to the pathogenesis of RA  [43,49]. Similarly, SS has gained interest in recent research, and both experimental and clinical evidence suggest that both Th1 and Th17 play a crucial role in the development and progression of SS [50]. SLE has long been considered a Th1- and Th17- mediated disease. However, more recent insight suggest that Th2 cells also play an active role in its pathogenesis, eventually resulting in elevated levels of IgE [51-52]. Additionally, regu- latory T cells (Treg), which play an essential role in immune suppression and self-tolerance, thereby preventing autoim- munity, have been found to be dysfunctional in AD [53], RA, SLE [54], and SS [50], potentially resulting in the formation of autoantigens, and thus promoting autoreactivity. Interest- ingly, antinuclear antibody (ANA), a cluster of autoantibod- ies targeting nuclear cellular components strongly associated with ACTD, especially SLE, SS, SSc, PM, and DM, but also RA [55-56], has been detected in patients with AD [57-59]. These similarities in pathophysiological mechanism strongly indicate a correlation between AD and ACTD. Our findings underscore the need for future studies in- vestigating the association between AD and ACTD. Given the potential association between AD and ACTD, dermatologists should be aware of their possible coexistence and the challenges this may present in differential diagno- sis. 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