CENTRAL indicates Cochrane Central Register of Controlled Trials; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses.
The Newcastle-Ottawa Scale was used to access the risk of bias. A green dot denotes low risk of bias; yellow, unclear risk of bias.
Data were pooled separately by study design using random-effects model; the inverse variance (IV) technique was used for pooling of measures of effects. OR indicates odds ratio; SE, standard error.
eTable. Search strategy
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Chen W, Chi C. Association of Hidradenitis Suppurativa With Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. JAMA Dermatol. Published online July 10, 2019155(9):1022–1027. doi:10.1001/jamadermatol.2019.0891
Is hidradenitis suppurativa associated with inflammatory bowel disease?
This systematic review and meta-analysis included 5 case-control studies, 2 cross-sectional studies, and 1 cohort study with a total of 93 601 unique participants with hidradenitis suppurativa who had 2.12-fold increased odds for Crohn disease and 1.51-fold increased odds for ulcerative colitis. One cohort study found a 5.6-fold increased risk of inflammatory bowel disease in patients with hidradenitis suppurativa.
Gastrointestinal tract symptoms, such as recurrent abdominal pain and chronic diarrhea, should not be overlooked in patients with hidradenitis suppurativa, and consultation with gastroenterologists should be sought.
Hidradenitis suppurativa (HS) and inflammatory bowel disease (IBD) are inflammatory diseases that share common genetic susceptibility and immunologic features. However, the link between HS and IBD has been largely unclear.
To conduct a meta-analysis to investigate the association between HS and IBD.
A search of the MEDLINE, Cochrane Central Register of Controlled Trials, and Embase databases yielded 397 relevant studies from inception to June 10, 2018. Two additional studies were supplied by one of the investigators.
Case-control, cross-sectional, or cohort studies that examined the odds or risk of IBD in patients with HS were included. No geographic or language limitations were imposed.
Data Extraction and Synthesis
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The Newcastle-Ottawa Scale was used to assess the risk of bias of included studies. Crohn disease and ulcerative colitis were analyzed separately, and a random-effects model meta-analysis was conducted.
Main Outcomes and Measures
The odds ratios (ORs) and hazard ratios (HRs) of IBD, Crohn disease, and ulcerative colitis in association with HS.
Five case-control studies, 2 cross-sectional studies, and 1 cohort study with a total of 93 601 unique participants were included. The meta-analysis of case-control and cross-sectional studies showed significant associations of HS with Crohn disease (pooled OR, 2.12; 95% CI, 1.46-3.08) and ulcerative colitis (pooled OR, 1.51; 95% CI, 1.25-1.82). Two case-control studies found significant association of HS with IBD (ORs, 2.16 [95% CI, 1.40-3.34] and 10.00 [95% CI, 1.94-51.50]). One cohort study found an increased risk of IBD in patients with HS (HR, 5.6; 95% CI not reported; P < .002).
Conclusions and Relevance
The evidence to date supports an association of HS with IBD. These results suggest that consultation with gastroenterologists should be sought when patients with HS present with recurrent abdominal pain, chronic diarrhea, bloody stool, and body weight loss.
Hidradenitis suppurativa (HS) or acne inversa is defined as “a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland–bearing areas of the body, most commonly the axillary, inguinal, and anogenital regions” (Dessau definition).1(p619) The etiology is largely unclear, but dysregulated inflammatory response of cytokines, follicular occlusion, obstruction and dilatation of the pilosebaceous unit, and altered microbiota may be involved in the pathogenesis of HS.2-5
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestinal tract. Inflammatory bowel disease consists of 2 predominant types: Crohn disease (CD) and ulcerative colitis (UC).6 Accumulating evidence indicates that genetic susceptibility to dysregulated inflammatory reaction and altered microbiota may play crucial roles in the pathogenesis of IBD.7-9
Hidradenitis suppurativa shares common clinical manifestations, genetic susceptibility, and immunologic features with IBD.5,10 Both diseases have similar clinical manifestations in the skin and gut, characterized by sterile abscesses in the perineal and inguinal areas, scarring, and sinus tract formation.1,7,11,12 Hidradenitis suppurativa and IBD have been associated with an increased prevalence of spondyloarthropathy, and both diseases respond well to tumor necrosis factor inhibitors.1,13-17 Moreover, smoking and obesity are known common risk factors for HS and IBD.18-21
Although some studies have suggested a link between HS and IBD,22-25 data on the association remain inconsistent and unclear. For example, one recent study26 failed to find a significant association between HS and CD, whereas another study27 did not detect a significant increase of UC in patients with HS. In this study, we aimed to systematically examine the evidence of an association of HS with IBD.
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline,28 we conducted a meta-analysis of observational studies on the association of HS with IBD. The types of eligible studies included case-control, cross-sectional, and cohort studies.
The MEDLINE, Cochrane Central Register of Controlled Trials, and Embase databases were searched for relevant studies from the respective inception of these databases to June 10, 2018. We did not impose any language or geographic restrictions. Our search strategy is listed in the eTable in the Supplement.
Studies that met the following inclusion criteria were included: (1) observational studies examining the association of HS with IBD, including cross-sectional, case-control, or cohort studies; (2) human study participants; and (3) a case group consisting of patients with HS and a control group composed of people without HS. Both authors independently selected relevant studies by scanning the titles and abstracts of search results. The full text of potential studies was obtained and examined for eligibility. Disagreement was resolved by discussion.
We extracted the following data from the included studies: study design, first author, year of publication, country, and risk estimates, including odds ratios (ORs) and hazard ratios (HRs) with corresponding 95% CIs on the association of HS with IBD. We used the Newcastle-Ottawa Scale to assess the risk of bias of included studies.29
We used Review Manager software, version 5.3 (Nordic Cochrane Centre, Cochrane Collaboration), to conduct meta-analyses when at least 3 studies provided usable data for 1 outcome.30 We calculated a pooled OR with 95% CI for case-control and cross-sectional studies and a pooled HR with 95% CI for cohort studies. The I2 statistic was calculated for examining statistical heterogeneity across the included studies. An I2 of greater than 50% was considered substantial heterogeneity.31 The random-effects model was chosen for meta-analyses because clinical heterogeneity was anticipated.
The PRISMA study flow diagram is shown in Figure 1. After removing duplicates, 397 records were identified by our search. Two additional relevant studies were provided by 1 author (C.-C.C.).26,32 We excluded 375 citations after scanning the titles and abstracts. After examination of the full text, we included 5 case-control studies,26,33-36 2 cross-sectional studies,27,32 and 1 cohort study37 with a total of 93 601 unique study participants. One study was conducted in Asia,26 and the other 7 were conducted in the West.27,32-37 The characteristics of the included case-control studies are shown in Table 1.
The risk of bias among included case-control and cohort studies is summarized in Figure 2. No studies were rated with a high risk of bias in any item. As to the adequacy of case definition, 5 studies26,32-34,36 were rated with an unclear risk of bias because only codes from the International Classification of Diseases, Eighth Revision, and Ninth Revision, and Tenth Revision were used for identification of cases. Five case-control and cross-sectional studies26,33-36 and 1 cohort study37 were rated with an unclear risk of bias in the comparability of cases and controls or cohorts because the analyses controlled for age and sex but not body mass index and smoking. As to ascertainment of exposure, 6 case-control and cross-sectional studies26,32-36 and 1 cohort study37 were rated with an unclear risk of bias because only International Classification of Diseases codes were used.
Five studies with a combined 91 917 study participants, including 2 cross-sectional studies27,32 and 3 case-control studies,26,34,35 provided data on the association of HS with CD. Substantial statistical heterogeneity was found across these studies (I2 = 92%). As illustrated in Figure 3A, the meta-analysis illustrated a significantly increased odds of CD in patients with HS (pooled OR, 2.12; 95% CI, 1.46-3.08).
Four studies with a combined 39 497 study participants, including 1 cross-sectional study27 and 3 case-control studies,26,34,35 provided data on the association of HS with UC. We found no substantial statistical heterogeneity across these studies (I2 = 28%). As demonstrated in Figure 3B, the meta-analysis showed a significantly increased odds of UC in patients with HS (pooled OR, 1.51; 95% CI, 1.25-1.82).
Two case-control studies33,36 with a combined 1642 study participants provided data on the association of HS with IBD and found significantly increased odds of IBD in subjects with HS (ORs, 2.16 [95% CI, 1.40-3.34] and 10.00 (95% CI, 1.94-51.50]). One cohort study37 with 14 136 study participants found an increased risk of IBD in patients with HS (HR, 5.6; 95% CI not reported; P < .002).
To the best of our knowledge, this study is the first meta-analysis to illustrate a significant association of HS with IBD. The evidence from case-control studies indicates that patients with HS had 2.12-fold odds of CD and 1.51-fold odds of UC when compared with controls. Meanwhile, the evidence from 1 cohort study37 reveals that patients with HS had a 5.6-fold HR of IBD when compared with controls.
Hidradenitis suppurativa and IBD share many characteristics, including clinical manifestations, genetic susceptibility, and immunologic features. There are several explanations of the link between HS and IBD. First, genetic susceptibility loci shared by HS and IBD have been found. Certain genes, for example SULT1B1 (OMIM 608436) and SULT1E1 (OMIM 600043), have been associated with HS as well as IBD.5,38,39 Second, emerging studies have shown that HS and IBD are diseases of immune dysregulation. Cytokine abnormalities, such as elevation of interleukin 1 (IL-1), IL-6, IL-17, IL-23, and tumor necrosis factor, are involved in HS and IBD.40-42 Third, altered microbiota with dysregulated immune responses may play an important role in HS and IBD.5,43 Microbiota affect the immunologic and physiologic homeostasis of the epithelia of skin and mucosa of gut by activation of toll-like receptors to recognize pathogens and repair damage.44-46 However, a variety of environmental factors can alter microbial balance with a resultant decrease in microbial diversity.7 Such alterations of microbiota may cause immune dysregulation and susceptibility to diseases, including HS and IBD.47 Altered microbiota have been found in the lesional and nonlesional skin of patients with HS when compared with healthy control individuals.48 Increasing evidence shows that altered intestinal microbiota may be involved in the pathogenesis of IBD, with decreases in specific Firmicutes species and a concomitant increase in Bacteroidetes species and facultative anaerobes such as Enterobacteriaceae.49 The alterations of microbiota may lead to systemic immune impairment. Such a close interplay between alterations of microbiota, cytokines, and dermatoses has been proposed as the gut-skin axis theory.50
We detected high statistical heterogeneity for the association of HS with CD (I2 = 92%) (Figure 3A). However, no significant statistical heterogeneity was present when we excluded 3 studies26,34,35 that did not control for body mass index and smoking habit (I2 = 47%; P = .17). Therefore, uncontrolled confounding may account for the high statistical heterogeneity detected in Figure 3A.
This study has some limitations. First, no studies examined the association between different severity of HS and IBD. Second, most of the included studies were from Western countries (United States and Europe),27,32-37 with only 1 from Asia.26 More studies are warranted to confirm whether HS is associated with IBD in Asian or other racial/ethnic groups.
The evidence to date supports an association of HS with IBD. Patients with HS should be informed about the increased risk of IBD. Consultation with gastroenterologists should be sought when patients with HS present with recurrent abdominal pain, chronic diarrhea, bloody stool, and body weight loss.
Accepted for Publication: March 22, 2019.
Corresponding Author: Ching-Chi Chi, MD, MMS, DPhil, Department of Dermatology, Chang Gung Memorial Hospital, Linkou, 5, Fuxing St, Guishan District, Taoyuan 33305, Taiwan (email@example.com).
Published Online: July 10, 2019. doi:10.1001/jamadermatol.2019.0891
Author Contributions: Dr Chi had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Chi.
Acquisition, analysis, or interpretation of data: Both authors.
Drafting of the manuscript: Chen.
Critical revision of the manuscript for important intellectual content: Both authors.
Statistical analysis: Both authors.
Administrative, technical, or material support: Both authors.
Conflict of Interest Disclosures: None reported.
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