|Year : 2020 | Volume
| Issue : 3 | Page : 159-165
Association of atopic dermatitis with inflammatory bowel disease: A systematic review and meta-analysis
Chi-Hui Wang1, Yun Fu2, Ching-Chi Chi3
1 Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taoyuan; Department of Dermatology, Chang Gung Memorial Hospital, Keelung, Taiwan
2 Department of Dermatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
3 Department of Dermatology, Chang Gung Memorial Hospital, Linkou; College of Medicine, Chang Gung University, Taoyuan, Taiwan
|Date of Submission||21-Apr-2020|
|Date of Decision||08-May-2020|
|Date of Acceptance||12-May-2020|
|Date of Web Publication||10-Sep-2020|
Prof. Ching-Chi Chi
Department of Dermatology, Chang Gung Memorial Hospital, Linkou, No. 5, Fuxing St., Guishan, Taoyuan 33305
Source of Support: None, Conflict of Interest: None
Background: Altered microbiota of the gastrointestinal tract have been implicated in both atopic dermatitis (AD) and inflammatory bowel disease (IBD). However, the relationship between AD and IBD has been unclear. Objectives: The objective of this study was to systemically assess the evidence on the association of AD with IBD. Methods: We conducted a systematic review and meta-analysis of observational studies on the association of AD with IBD. We searched MEDLINE, Embase, CENTRAL, Web of Science, and Airiti Library from inception to May 24, 2019, for relevant studies. The outcomes were the odds and risk of Crohn's disease (CD) and ulcerative colitis (UC) in patients with AD. Results: We included five case–control studies and one cohort study. We identified significant associations of AD with prevalent CD (odds ratio [OR]: 1.55, 95% confidence interval [CI]: 1.11–2.15) and UC (OR: 2.49, 95% CI: 1.04–5.98). One Danish cohort study found no increased risk for incident CD (hazard ratio [HR]: 0.69, 95% CI: 0.34–1.30) and UC (HR: 0.94, 95% CI: 0.61–1.43) in patients with AD. Conclusion: The current limited evidence supports an association of AD with prevalent IBD. Digestive symptoms in patients with AD, for example, chronic diarrhea and abdominal pain, shall not be overlooked, and gastroenterology counseling may be needed.
Keywords: Atopic dermatitis, Crohn's disease, inflammatory bowel disease, meta-analysis, ulcerative colitis
|How to cite this article:|
Wang CH, Fu Y, Chi CC. Association of atopic dermatitis with inflammatory bowel disease: A systematic review and meta-analysis. Dermatol Sin 2020;38:159-65
|How to cite this URL:|
Wang CH, Fu Y, Chi CC. Association of atopic dermatitis with inflammatory bowel disease: A systematic review and meta-analysis. Dermatol Sin [serial online] 2020 [cited 2020 Sep 19];38:159-65. Available from: http://www.dermsinica.org/text.asp?2020/38/3/159/294707
| Introduction|| |
Atopic dermatitis (AD) is the most common chronic inflammatory skin disease with a prevalence of up to 25% in children and 7% among adults., AD typically presents with pruritus and eczematous lesions starting within the first 5 years of life and follows a relapsing–remitting nature. According to the World Health Organization 2010 Global Burden of Disease Survey, AD ranked first among common skin diseases with respect to disability-adjusted life years and years lived with a disease. Nowadays, immunologic aberrations, interactions between genetic mutations, skin barrier dysfunction, and microbiota are considered as the major pathogenesis of AD. AD has been associated with activation of T-cell subsets inducing immune deviations. Mutation of filaggrin (FLG) gene for defect in FLG synthesis is found in patients with AD, with resultant skin barrier impairment.,, A growing body of evidence has accumulated that AD can be accompanied by a variety of systemic diseases including cardiovascular diseases, autoimmune disorders, sleep disturbance, and metabolic abnormalities.,,,,
Inflammatory bowel disease (IBD) is a group of chronic inflammatory conditions of the intestine including Crohn's disease (CD) and ulcerative colitis (UC). Over the past decade, IBD has emerged as a public health challenge worldwide. Clinically, CD is characterized by transmural granulomatous inflammation and may affect the entire gastrointestinal tract but sparing the rectum; by contrast, UC typically presents as mucosal inflammation involving the colon and rectum., The pathogenesis of IBD is thought to be mediated by the microbiota of the intestinal lumen and inappropriate immune responses in genetically susceptible individuals.
As AD and IBD both involve chronic inflammation and alterations in microbiota, there may be a link between the two diseases. The objective of this study was to systemically assess the evidence on the association of AD with IBD.
| Materials and Methods|| |
We conducted a systematic review and meta-analysis of observational studies, including cross-sectional, case–control, and cohort studies, on the association of AD with IBD. This study was done following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology guidelines. We have registered the protocol with PROSPERO (CRD42018106852; see https://www.crd.york.ac.uk/PROSPERO/display_record.php&?RecordID = 106852).
Two authors (CW and CC) performed a literature search of electronic databases (MEDLINE, Embase, CENTRAL, Web of Science, and Airiti Library) from inception to May 24, 2019, for relevant studies. The search strategy is shown in [Table 1]. In addition, relevant published conference abstracts were tracked for full publications. No restrictions on language, publication status, or geographic regions were imposed.
Study selection and eligibility criteria
The eligibility criteria for articles to be included in this study were as follows: (1) observational studies investigating the association of AD with IBD, including case–control or cohort studies; (2) research of human subjects; and (3) the case group consisting of adults with AD and the control group consisting of adults without AD. We only included studies on adults because the peak incidence of CD and UC is in the 20–29-year and 20–39-year age group, respectively.
Review articles, case reports, case series, and comments were excluded. Titles, abstracts of citations, and contexts were independently screened and assessed by two authors (CH Wang and Y Fu). All three authors examined the full text of potentially eligible studies and determined which studies met the eligibility criteria.
Data extraction and risk of bias assessment
The relevant information extracted from the included studies was as follows: first author, year of publication, country of study, study design, sex of individuals, number of patients with AD and controls, and quantitative measures including odds ratio (OR) and hazard ratio (HR) with 95% confidence intervals (CIs) on the association of AD with IBD.
The risk of bias of included studies was assessed with the Newcastle–Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in systematic review and meta-analysis. Three broad perspectives were evaluated for included case–control studies: the selection of study groups, the comparability of study groups, and the ascertainment of study groups. Comparably, enrolled cohort studies were judged on three domains: the selection of study participants, the comparability of cohort, and the outcome of cohort. The details of NOS for assessing the quality are shown in [Table 2]. Data extraction and risks of bias were independently screened and assessed by two authors (CH Wang and Y Fu). Discrepancies during data extraction were resolved by consensus meetings of the authors.
|Table 2: Newcastle-Ottawa Quality Assessment Scale for case-control and cohort Studies|
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The Review Manager version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) was used for conducting the meta-analysis. The most fully adjusted OR and HR were used whenever provided. In case–control studies, if OR estimates were not available in the studies, crude ORs were calculated in accordance with the reported raw data. We calculated the pooled OR with 95% CI for included case–control studies, while HR with 95% CI was estimated for cohort studies. The statistical heterogeneity across the included studies was assessed using the I2 statistic. An I2 > 50% represents substantial heterogeneity. We performed a random-effects model meta-analysis due to the anticipated clinical variations of included studies.
| Results|| |
The PRISMA flowchart of study selection is shown in [Figure 1]. Our systematic literature search identified 3,842 records after removing duplicates, with 3,833 excluded after screening the titles and abstracts. For one relevant conference abstract, the full journal article was later obtained. After examining the full text, one study was excluded for duplicate data of study participants. Another study did not include adults and was thus excluded. We also excluded one study because the study participants were mainly children and adolescents. Eventually, 5 case–control studies,,,, and 1 cohort study with a total of 76,019,448 study participants were included in our study. The main characteristics of the included studies are summarized, respectively, in [Table 3]. Two case–control studies did not provide the respective data for CD and UC,, while one cohort study did not report the number of all IBD patients.
Risk of bias of included studies
The risk of bias assessment for included case–control and cohort studies are summarized in [Figure 2]a and [Figure 2]b, respectively. Three of five included case–control studies,, were rated as unclear risk in the “adequacy of case definition” taking account that these studies defined the case group according to the International Classification of Diseases (ICD) diagnosis codes. In addition, most of the case–control studies,,, were rated as uncertain risk for “ascertainment of exposure” because they used ICD diagnosis codes or medical records as the independent sources for assessing exposure ascertainment. In contrast, the 2004 study by Niwa et al. was rated as low risk of bias in adequate definition of the case group with established diagnosis of AD by fulfilling the Hanifin and Rajka criteria confirmed by one or more dermatologists and was rated as low risk for exposure ascertainment that the diagnosis of CD and UC was confirmed by colonoscopy examination and biopsy. We rated the Narla and Silverberg 2018 study at high risk in the “representativeness of cases” and “selection of controls” because of including only inpatients from the National Inpatient Sample database, which might have included a population with high disease severity.
|Figure 2:Risk of bias in included (a) case–control and (b) cohort studies|
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Odds of Crohn's disease in patients with atopic dermatitis in case–control studies
A total of three case–control studies provided data for this outcome. Exclusive of the 2004 study by Niwa et al., the other two case–control studies denoted an increased odds of CD associated with AD., As shown in [Figure 3], the meta-analysis of three studies identified significant associations of AD with prevalent CD (pooled OR: 1.55, 95% CI: 1.11–2.15), and the substantial statistical heterogeneity across the included studies was demonstrated (I2 = 69%).
|Figure 3:Associations of atopic dermatitis with inflammatory bowel disease in case–control studies|
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Odds of ulcerative colitis in patients with atopic dermatitis in case–control studies
Three included case–control studies,, illustrated an increased odds of UC in AD patients. A meta-analysis of these studies revealed a twofold increase of UC in AD patients (pooled OR: 2.49, 95% CI: 1.04–5.98), as shown in
[Figure 3]. There was high statistical heterogeneity across the included studies (I2 = 99%).
Odds of inflammatory bowel disease in patients with atopic dermatitis in case–control studies
Five case–control studies with a total of 72,424,442 individuals provided data for this outcome.,,,, As shown in [Figure 3], the meta-analysis illustrated an increased odds for prevalent IBD in relation to AD though not statistically significant (pooled OR: 1.46, 95% CI: 0.97–2.19). We identified substantial statistical heterogeneity across these five studies (I2 = 85%).
Risk of Crohn's disease and ulcerative colitis in patients with atopic dermatitis in a Cohort study
Only one Danish cohort study provided data for this outcome and demonstrated an adjusted overall HR of 0.69 (95% CI: 0.34–1.30) for incident CD and 0.94 (95% CI: 0.61–1.43) for incident UC in patients with AD.
| Discussion|| |
We identified evidence showing that AD patients are more likely to have prevalent IBD. The denotation of meta-analysis indicates that AD patients are associated with 1.55-fold odds to have prevalent CD and 2.49-fold odds to have prevalent UC compared to controls. In parallel, we found an increased odds for prevalent IBD in relation to AD though not statistically significant. Meanwhile, one cohort study did not detect an increase in the risk of incident IBD in AD patients; a causal link between AD and IBD needs further clarification.
The statistical heterogeneity found in the association of AD with CD in case–control studies may be attributed to the low number of events in the 2004 study by Niwa et al. Although we detected considerable statistical heterogeneity in the association of AD with UC in case–control studies, the overall association was consistent and thus did not affect our conclusion. The Wu 2014 study resulted in statistical heterogeneity found in the association of AD with IBD in case–control studies, which may be explained by the different roles of T helper (Th) 17 discussed below.
The potential explanations for the association of AD with IBD include immune dysfunction with activated systemic inflammation, shared genetic mutations, and dysregulation of microbiota.
Immunologically, both AD and IBD have been linked to dysregulation of Th2-mediated response., Imbalance of Th2 response promotes pro-infflammatory cytokines causing impaired epidermal integrity and activates keratinocytes to release pruritogenic mediators in AD; meanwhile, upregulation of Th2-mediated pathway leads to disruption of epithelial tight junctions and resultant chronic inflammation in UC., The latter phenomenon may explain the stronger association between AD and UC found in our meta-analysis.
AD shows heterogeneity in immune circuits across different phenotypes. Except for Japanese population, the activation of Th17 axis is involved in Asian AD patients.
Previous studies have demonstrated that Th17 cells and their related cytokines are crucial mediators in IBD; however, both pro-inflammatory and anti-inflammatory responses of intestinal Th17 cells have emerged under various situations. Notably, Th17-type cytokines including interleukin (IL)-17A and IL-22 have been reported to possess tissue-protective effects in the intestinal mucosa., The different actions of Th17 pathway activation may explain the decreasing trend of IBD in Taiwanese AD patients in the study by Wu et al.
Interestingly, as an important pro-inflammatory signaling, the Janus kinase and signal transducer and activator of transcription (JAK-STAT) pathway has been identified in the pathogenesis of both AD and IBD., The JAK-STAT pathway drives Th2 immunity and leads to increased downstream cytokines such as IL-4 and IL-13 in AD and contributes to dysregulated immune system and overexpression of multiple inflammatory cytokines including IL-6 and IL-12/IL-23 in IBD., Recently, the JAK inhibitor tofacitinib has been reported to have potential benefit in the treatment of recalcitrant AD and IBD.,,
The association between AD and IBD may be explained in part by shared common genetic abnormalities. A susceptibility locus for eczema has been identified on chromosome 11q13.5 with risk allele A of single-nucleotide polymorphism (SNP) rs7927894. In childhood AD, the significant association of rs7927894 was found to be independent of the well-established risk alleles of FLG and may be multiplicative in its effect. Furthermore, SNP rs7927894 has been identified as a susceptibility factor for CD. This common gene carrying susceptibility to epithelial infflammation may have analogous functions affecting both skin barrier in AD and intestinal mucosal epithelium in IBD.
It is noteworthy that the skin and gut have similarities including rich vascular supply, diverse microbial communities, and vital interfaces between the internal human body and the external environment. Gut microbiome alternation and low diversity of gut microbiota contribute to the development of allergic diseases such as AD. Intestinal microbial dysbiosis is also strongly associated with IBD. The gut-skin axis involves interactions between bacterial antigens and pattern recognition receptors expressed by host cells, with consequent triggering of cascades of innate and adaptive immune systems which participate in the pathophysiology of both AD and IBD.
Recently, Shi et al. published a similar systemic review on the association between IBD and AD and included three case–control studies and one cohort study. By contrast, our study included five case–control studies and one cohort study. Moreover, we have registered our protocol with PROSPERO.
There are a few limitations of our study. First, the majority of included studies were case–control and only one cohort study met our inclusion criteria. More cohort studies are warranted to clarify the risk of incident IBD in AD patients. Second, we rated two included studies with high risk of bias because of lacking adjustment for variables including sex, age, body mass index, and smoking habit, as well as study participants from a particular inpatient population. However, the direction of associations remained the same if we excluded the two studies with high risk of bias (data not shown). Third, considerable statistical heterogeneity was detected, as discussed previously.
| Conclusion|| |
The current limited evidence to date supports an association of AD with prevalent IBD. Prolonged digestive symptoms in AD patients, for example, chronic diarrhea and abdominal pain, shall not be overlooked, and gastroenterology counseling may be needed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]