Is there an association between psoriasis and inflammatory bowel disease?
This meta-analysis included 5 case-control or cross-sectional studies with 1 826 677 individuals; patients with psoriasis had 1.70-fold increased odds of Crohn disease and 1.75-fold increased odds for ulcerative colitis. The meta-analysis also included 4 cohort studies with 5 967 410 individuals; patients with psoriasis had a 2.53-fold increased risk of developing Crohn disease and a 1.71-fold increased risk of developing ulcerative colitis.
Psoriasis appears to be associated with inflammatory bowel disease; gastroenterology consultation may be indicated when patients with psoriasis present with bowel symptoms.
Patients with psoriasis may experience comorbidities involving cardiovascular diseases, chronic kidney disease, uveitis, psychiatric disturbances, and metabolic syndrome. However, the association between psoriasis and inflammatory bowel disease (IBD) has been largely unclear.
To investigate the association of psoriasis with IBD.
For this systematic review and meta-analysis, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched for relevant studies from inception to January 17, 2018.
Case-control, cross-sectional, or cohort studies that examined either the odds or risk of IBD in patients with psoriasis were included. No geographic or language limitations were used in the search.
Data Extraction and Synthesis
The PRISMA and MOOSE guidelines were followed for data extraction. The Newcastle-Ottawa Scale was used to evaluate the risk of bias of included studies. Crohn disease and ulcerative colitis were analyzed separately and random-effects model meta-analysis was conducted. A subgroup analysis was performed on psoriatic arthritis.
Main Outcomes and Measures
The risk and odds of IBD, Crohn disease, and ulcerative colitis in patients with psoriasis.
A total of 5 case-control or cross-sectional studies and 4 cohort studies with 7 794 087 study participants were included. Significant associations were found between psoriasis and Crohn disease (odds ratio, 1.70; 95% CI, 1.20-2.40) and between psoriasis and ulcerative colitis (odds ratio, 1.75; 95% CI, 1.49-2.05). Patients with psoriasis had an increased risk of Crohn disease (risk ratio, 2.53; 95% CI, 1.65-3.89) and ulcerative colitis (risk ratio, 1.71; 95% CI, 1.55-1.89).
Conclusions and Relevance
These findings suggest that psoriasis is significantly associated with IBD. Gastroenterology consultation may be indicated when patients with psoriasis present with bowel symptoms.
Psoriasis is a chronic systemic immune-mediated disorder affecting approximately 0.5% to 11.4% of adults and approximately 1.4% of children worldwide.1,2 Psoriasis has been characterized by sharply demarcated erythematous scaling plaques with a typical relapsing and remitting course.3,4 Even with proper treatments, psoriasis can only be controlled but cannot be cured.5 Genetic and environmental factors are considered involved in the possible causes of psoriasis.6 Previous genome-based analysis revealed that specific genes (eg, PSORS1 [OMIM 177900], IL12B [OMIM 161561], and IL23R [OMIM 607562]) are predisposing factors for psoriasis.7 Psoriasis has been linked with a variety of comorbidities including cardiovascular diseases, chronic kidney disease, uveitis, psychiatric disturbances, and metabolic syndrome and its relevant components (obesity, hypertension, dyslipidemia, and type 1 and 2 diabetes), resulting in impaired quality of life and shortening of life expectancy.8-18
Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the gastrointestinal tract that requires long-term management.19 Crohn disease (CD) and ulcerative colitis (UC) are the 2 main forms of IBD.20 During the past 2 decades, the incidence of IBD has increased in developing countries, with an annual increase of 11.1% for CD and an annual increase of 14.9% for UC.21 Accumulating evidence indicates that genetic susceptibility may play an essential role in the dysregulated inflammatory reaction of IBD.22,23 Crohn disease frequently causes the infiltration and destruction of all intestinal wall layers along the digestive tract, while UC primarily involves the colon and rectum, with mucosal and submucosal invasion.24 Patients with IBD often experience recurrent loss of appetite, vomiting, diarrhea, abdominal pain, rectal bleeding, and body weight loss.25-27
Previous studies have shown common genotypes, clinical course, and immunologic features shared by psoriasis and IBD.7 Genetic correlation between psoriasis and IBD, including chromosomal locus 6p21 and the IL23R and IL12B genes, has been identified.7,28-30 As to the shared immunologic features, increased levels of IL-17 were found in both IBD and psoriasis.31-33 However, the association between psoriasis and IBD was largely unclear. In this study, we aimed to systematically analyze the association of psoriasis with IBD.
We conducted a systematic review and meta-analysis of observational studies (including case-control, cross-sectional, and cohort studies) on the association of psoriasis with IBD. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)34 and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines.35
We searched MEDLINE, the Cochrane Central Register of Controlled Trials, and Embase from inception to January 17, 2018, for relevant studies. The search strategy is shown in the eTable in the Supplement. No language or geographic restrictions were imposed.
We included studies that met the following inclusion criteria: (1) observational studies examining the association of psoriasis with IBD, including cross-sectional, case-control, or cohort studies; (2) the study participants were humans; and (3) the case group was composed of patients with psoriasis and the control group was composed of individuals without psoriasis. Two of us (Y.F. and C.-H.L.) independently screened the search results and assessed their eligibility by scanning the titles and abstracts of citations. We checked the full text of potentially eligible studies and included studies that met the inclusion criteria. Disagreement was resolved by consulting another one of us (C.-C.C.).
Data Extraction and Risk of Bias Assessment
The following data were extracted from the included studies: first author, year of publication, country, study design, and quantitative estimates including odds ratio (OR) and risk ratio (RR) with 95% CIs on the association of psoriasis with IBD. We used the Newcastle-Ottawa Scale to assess the risk of bias of included studies.36 The following 8 domains were evaluated for included case-control studies: adequacy of case definition, representativeness of cases, selection of controls, definition of controls, comparability of cases and controls, ascertainment of exposure, same method of ascertainment for cases and controls, and nonresponse rate. The following 8 domains were evaluated for included cohort studies: the representativeness of exposed cohort, selection of nonexposed cohort, ascertainment of exposure, outcome of the interest not present at start of study, comparability of cohorts, assessment of outcome, follow-up duration, and adequacy of follow up of cohorts.
All analyses were conducted by using the Review Manager, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration). We calculated the pooled OR with 95% CI for included case-control and cross-sectional studies, and calculated the pooled RR with 95% CI for included cohort studies. If there were multiple risk estimates provided in the study report, we adopted the risk estimates with the most adjusted confounders. The statistical heterogeneity across the included studies was assessed by using the I2 statistic. We considered an I2 of greater than 50% to represent substantial heterogeneity. We adopted the random-effects model in conducting meta-analyses as we anticipated clinical heterogeneity. We conducted a subgroup analysis on patients with psoriatic arthritis.
Characteristic of Included Studies
The PRISMA study flowchart is shown in Figure 1. Our search identified 1109 records after removing duplicates. After scanning the titles and abstracts, 1083 citations were excluded. After examining the full text, 5 case-control or cross-sectional studies and 4 cohort studies with a total of 7 794 087 study participants were included in this study.37-45 The characteristics of the included case-control or cross-sectional studies are listed in Table 1,37-40,43 and the characteristics of the cohort studies are listed in Table 2.41,42,44,45
Risk of Bias of Included Studies
The risk of bias of included case-control and cohort studies was summarized in Figure 237-45 and Figure 3.37-45 Of 5 included case-control studies, 4 studies were rated with unclear risk in the domains of adequacy of case definition and ascertainment of exposure domains.38-40,43 The main reason for an unclear risk in the adequacy of case definition domain was that most studies defined the case group by using corresponding International Classification of Diseases diagnosis codes. Moreover, the reason for an unclear risk of bias in the ascertainment of exposure domain was that most studies used the medical record as their only reference for ascertainment of exposure. We rated the study by Augustin et al38 at high risk in the comparability of cases and controls domain because there was no controlling for confounders. All 4 included cohort studies were rated at low risk of bias in the adequacy of follow-up of cohorts domain, as the length of follow-up exceeded 1 year in all 4 studies.41,42,44,45 We rated the study by Li et al41 at high risk in the domain of representativeness of exposed cohort because the study participants were from a specific group limited to nurses. We also rated the study by Manos et al44 at high risk of bias in the domain of outcome of the interest not present at start of the study because the study did not report relevant information.
Association of Psoriasis With IBD
Except for the study by Tsai et al,39 all of the other 4 case-control studies demonstrated an increased odds of CD in association with psoriasis.37,38,40,43 We identified substantial statistical heterogeneity across these 5 studies (I2 = 92%). As shown in Figure 3A,37-40,43 the meta-analysis illustrates a significant association of psoriasis with CD (pooled OR, 1.70; 95% CI, 1.20-2.40).
Four included case-control studies provided data regarding the association of psoriasis with UC.37,38,40,43 Significant statistical heterogeneity was identified across the 4 studies (I2 = 54%). As illustrated in Figure 3B,37,38,40,43 the meta-analysis revealed a significant association of psoriasis with UC (pooled OR, 1.75; 95% CI, 1.49-2.05).
All 4 included cohort studies illustrated an increased risk of CD and UC in patients with psoriasis.41,42,44,45 The meta-analysis revealed that patients with psoriasis had a significantly increased risk of CD (pooled RR, 2.53; 95% CI, 1.65-3.89) (Figure 3C)41,42,44,45 and UC (pooled RR, 1.71; 95% CI, 1.55-1.89) (Figure 3D).41,42,44,45 Substantial statistical heterogeneity was found in the risk estimate for CD (I2 = 55%) (Figure 3C)41,42,44,45 but not for UC (I2 = 0%) (Figure 3D).41,42,44,45
Subgroup Analysis on Patients With Psoriatic Arthritis
One case-control study and 2 cohort studies investigated the association of psoriatic arthritis with CD and UC.43-45 The case-control study found significant associations of psoriatic arthritis with CD (OR, 2.20; 95% CI, 1.59-3.03) and UC (OR, 1.91; 95% CI, 1.21-3.00).43 As illustrated in Figure 3E,44,45 the meta-analysis on the 2 cohort studies demonstrated a significantly increased risk of CD (RR, 2.74; 95% CI, 1.41-5.32; I2 = 0%) and a nonsignificant increase in the risk of UC (RR, 1.74; 95% CI, 0.72-4.17; I2 = 34%) in patients with psoriatic arthritis.
To our knowledge, this study is the first meta-analysis to examine the association of psoriasis with IBD. We found that patients with psoriasis were prone to have comorbid IBD. The evidence from case-control studies indicates that patients with psoriasis had 1.70-fold increased odds of developing CD and 1.75-fold increased odds of developing UC when compared with controls. Meanwhile, the evidence from cohort studies revealed that patients with psoriasis had a 2.53-fold increased risk of developing CD and a 1.71-fold increased risk of developing UC when compared with controls. The subgroup analysis on patients with psoriatic arthritis showed similar results. Patients with psoriatic arthritis had a 2.74-fold risk of developing CD and a 1.74-fold risk of developing UC when compared with controls.
Only 1 case-control study evaluated the association of psoriasis with CD in Asians; it showed a negative association of psoriasis with CD in Asians (OR, 0.70; 95% CI, 0.52-0.94). By contrast, all the other studies were conducted in Western countries and Israel, and found a significant association of psoriasis with CD (pooled OR, 2.02; 95% CI, 1.84-2.22; I2 = 3%).
Most of the included studies were rated as low risk of bias according to the Newcastle-Ottawa Scale. Three included studies were rated as high risk of bias for the following reasons: no control for confounders,38 study participants from a specific group,41 and lack of relevant information on the outcome interest not present at the start of the study.44 These points in study design should be considered in future studies.
The possible explanations for the identified association of psoriasis with IBD include genetic abnormalities, immune dysfunction, systemic inflammation, and dysregulation of gut microbiota. A few studies have explored the genetic link between psoriasis and IBD. Chromosomal locus 6p21, an area encompassing the major compatibility complex (MHC)–related genes, is the most extensively studied genetic region.46 Psoriasis and IBD shared same the genetic susceptibility loci on chromosome 6p21, which corresponds to PSORS1 in psoriasis and IBD3 in IBD.7 Furthermore, genes not related to major compatibility complex, including IL23R and IL12B, have been identified in the pathogenesis of both psoriasis and IBD.28-30 The IL23R gene encodes a subunit of the IL-23 receptor and affects the binding capability of IL-23. Interleukin-23 is essential for the differentiation and activation of TH17 lymphocytes that produce IL-17. Binding of IL-17 to its receptor stimulates hyperproliferation and differentiation of keratinocytes, maturation of myeloid dendritic cells, and recruitment of neutrophils and macrophages in psoriatic lesions.31,32 In the gastrointestinal system, increased expression of IL-17 in the mucosa of the gut and serum in patients with IBD in comparison with healthy controls has been found.33 The evidence supports the possibility that IL-17 plays an important role in the pathogenesis of IBD. Moreover, the IL12B gene encodes the p40 subunit that participates in the signaling pathways of both IL-12 and IL-23.47 Therefore, IL-12B is an essential cytokine subunit in the pathogenesis of both psoriasis and IBD.
On the other hand, the skin and gut show similarities in IBD and psoriasis, including immense microbial diversity and bountiful blood supply.48 Microbiota affect the physiology and immune response of the epithelium of the skin and gut by regulating biological metabolites.49,50 In addition, the microbiota may lead to expression of antimicrobial particles, elevated cytokine levels, and, consequently, regulation of activity and differentiation of T cells.51 Therefore, microbiota dysfunction may cause systemic immune dysregulation. The emerging evidence supports the gut-skin axis theory that describes the close association between intestinal dysbiosis and cutaneous manifestations.52 Patients with psoriasis have been found to present with decreased diversity and abundance of gut microbiota that was similar to patients with IBD.53
This study has several limitations. First, we found that only 1 cohort study reported the association between different severity of psoriasis and IBD.42 Second, only 1 case-control study provided data on the association of psoriasis with IBD in Asians.39 More studies are warranted to confirm if psoriasis is inversely associated with IBD in this population. Third, owing to the variation in sample size across the included studies, the relative weight of studies varied in different subgroup analyses. Nevertheless, the overall direction of effects was consistent.
The evidence to date supports an association of psoriasis with IBD. Patients with psoriasis should be informed about the increased risk of IBD. Gastroenterology consultation is indicated for patients with psoriasis presenting with bowel symptoms.
Accepted for Publication: August 23, 2018.
Corresponding Author: Ching-Chi Chi, MD, MMS, DPhil, Department of Dermatology, Chang Gung Memorial Hospital, Linkou, 5, Fuxing St, Guishan District, Taoyuan 33305, Taiwan (firstname.lastname@example.org).
Published Online: October 24, 2018. doi:10.1001/jamadermatol.2018.3631
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: All authors.
Drafting of the manuscript: Fu, Lee.
Critical revision of the manuscript for important intellectual content: Chi.
Statistical analysis: All authors.
Administrative, technical, or material support: Chi.
Conflict of Interest Disclosures: None reported.
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