FormalPara Key Summary Points

Although growing evidence has implicated a possible link between rosacea and inflammatory bowel disease (IBD), it remains unclear whether IBD increases the risk of rosacea and vice versa.

We performed a systematic review and meta-analysis to investigate the association between rosacea and IBD.

The prevalence of rosacea was higher in the IBD group than in the control group, with a pooled odds ratio (OR) of 1.86 (95% confidence interval [CI] 1.52–2.26). Both the Crohn’s disease and the ulcerative colitis groups had higher prevalences of rosacea than the control group, with ORs of 1.74 (95% CI 1.34–2.28) and 2.00 (95% CI 1.63–2.45), respectively. Compared with those in the control group, the risks of IBD, Crohn’s disease, and ulcerative colitis were significantly higher in the rosacea group, with incidence rate ratios of 1.37 (95% CI 1.22–1.53), 1.60 (95% CI 1.33–1.92), and 1.26 (95% CI 1.09–1.45), respectively.

IBD is bidirectionally associated with rosacea.

Introduction

Rosacea is a chronic inflammatory skin disorder commonly characterized by facial flushing, telangiectasia, and inflammatory papules and pustules [1]. Disease onset typically occurs after 30 years of age [2]. Caucasians have the highest risk of rosacea compared to other racial groups [3]. Rosacea can be triggered by multiple stimuli, including ultraviolet exposure, nutrition, extreme temperatures, hormonal changes, and psychological stress, and is developed by the activated innate immune system and dysregulated neurovascular system [4]. Rosacea is not limited to the skin, but is related to multiple systemic diseases, such as cardiovascular, gastrointestinal, and psychiatric diseases [5,6,7], suggesting that rosacea may be a cutaneous sign of systemic conditions [6].

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disorder of the gastrointestinal tract. It comprises two major distinct forms: Crohn’s disease (CD) and ulcerative colitis (UC) [8]. The onset of IBD mainly occurs in the second and third decades of life, and the majority of patients have relapsing and chronic disease courses [9]. Although the pathogenesis of IBD is poorly understood, it involves complex interactions between host genetic factors, microbiota, abnormal immune responses, and environmental factors [10]. Patients with IBD can experience abdominal pain, diarrhea, hematochezia, and fever. In addition, pat ients with IBD can have cutaneous manifestations, such as erythema nodosum, pyoderma gangrenosum, and Sweet’s syndrome [11,12,13].

Recently, growing evidence from various observational studies has implicated a possible link between IBD and rosacea [11, 14,15,16,17,18]. However, it remains unclear whether IBD increases the occurrence of rosacea and vice versa. In this study, we performed a systematic review and meta-analysis to elucidate the association between IBD and rosacea .

Materials and Methods

Data Sources and Search Strategy

The protocol was registered in PROSPERO (CRD42021276385) and the study was approved by an institutional review board of the Seoul Metropolitan Government—Seoul National University (SMG-SNU) Boramae Medical Center (approval #07-2021-35). This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

We searched the Ovid MEDLINE, Embase, and Cochrane Library databases from their inception to August 3, 2021, for published articles using the search terms “gastrointestinal diseases,” “inflammatory bowel disease,” “ulcerative colitis,” “Crohn’s disease,” and “rosacea.” The detailed search strategy is described in Supplemental Text 1.

Study Selection

Three authors (H.S.P., Y.K.J., and D.Y.) independently assessed the eligibility of all studies based on predetermined selection criteria. Studies that met the following eligibility criteria were included: (1) cohort, case–control, or cross-sectional studies; (2) studies containing the prevalence of rosacea in patients with IBD; and (3) studies written in English. The exclusion criteria were as follows: (1) non-human studies; (2) non-original articles such as reviews, editorials, expert opinions, letters, or case reports; and (3) studies that failed to provide raw numbers of patients. The authors evaluated each study according to the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines, which were revised in 2020. The title and abstract of each article were screened to select relevant studies after duplicates were removed. Full texts of the screened studies were reviewed in detail, and four eligible studies were identified. Two investigators (Y.K.J. and D.Y.) individually reviewed the selected articles. Disagreements between evaluators were resolved through discussion.

The investigators assessed the quality of the selected studies without bias in accordance with the Newcastle–Ottawa Scale (NOS) system (Table S1 in the Supplementary Information). The modified NOS system was used to assess cross-sectional studies.

Statistical Analysis

A meta-analysis was performed using the RevMan 5.4.1 software. Odds ratios (ORs), incidence rate ratios (IRRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. IRRs were chosen for the analysis because of the limited detailed information in the original articles. T2- and χ2-based Q statistics for statistical significance and I2 statistics for the degree of heterogeneity were used to estimate heterogeneity across studies. A p value < 0.10 or an I2 value ≥ 50% was considered to indicate substantial heterogeneity. Publication bias was evaluated using funnel plot asymmetry.

Results

The database search identified 644 studies (242 studies from Ovid Medline, 383 studies from EMBASE, and 19 studies from the Cochrane Library). After excluding 186 duplicates, 458 studies were screened according to their titles and abstracts. Among 458 studies, 416 were excluded based on titles: 375 were unrelated to rosacea and IBD; 34 were reviews, editorials, or guidelines; and 7 were case reports. Thirteen studies were excluded based on their abstracts because of irrelevance. Twenty-five studies were excluded after the full-length study review. Finally, eight eligible population-based studies [11, 14,15,16,17,18,19,20] were included in the meta-analysis (Fig. 1). The characteristics of the studies and the quality assessments using the NOS are summarized in Table 1. Five studies used health insurance databases and identified patients with IBD or rosacea through diagnosis based on the code of the International Classification of Diseases. There were no significant differences in age or sex composition among four of the studies using health insurance databases, whereas one of the studies did differ significantly. One study used databases from the Clinical Practice Research Datalink to collect primary care data, including medical diagnoses, drug prescriptions, and laboratory test results.

Fig. 1
figure 1

Flow diagram of study selection. n number; IBD inflammatory bowel disease

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Table 1 Main characteristics of all studies in the meta-analysis
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The results of the meta-analysis of the relationship between IBD and rosacea are shown in Figs. 2 and 3. The IBD group had a higher prevalence of rosacea than the control group, with a pooled OR of 1.86 (95% CI 1.52–2.26; Fig. 2a). The prevalence of rosacea was higher for both the CD and UC groups than for the control group, with ORs of 1.74 (95% CI 1.34–2.28; Fig. 2b) and 2.00 (95% CI 1.63–2.45; Fig. 2c), respectively. The rosacea group had a higher risk of IBD than the control group (IRR, 1.37; 95% CI 1.22–1.53; Fig. 3a). Separate analyses of the CD and UC groups yielded an IRR of 1.60 (95% CI 1.33–1.92) for CD (Fig. 3b) and an IRR of 1.26 (95% CI 1.09–1.45) for UC (Fig. 3c). According to the funnel plot, no significant publication bias was observed (Fig. S1 and S2).

Fig. 2
figure 2

Patients with a inflammatory bowel disease, b Crohn’s disease, and c ulcerative colitis had a higher prevalence of concomitant rosacea compared to controls. IBD inflammatory bowel disease; M–H Mantel–Haenszel; CI confidence interval; df degrees of freedom; CD Crohn’s disease; UC ulcerative colitis

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Fig. 3
figure 3

Relative risks of a inflammatory bowel disease, b Crohn’s disease, and c ulcerative colitis were significantly higher in the rosacea group than in the controls. IBD inflammatory bowel disease; SE standard error; CI confidence interval; df degrees of freedom; CD Crohn’s disease; UC ulcerative colitis

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Discussion

In this systematic review and meta-analysis, we found that patients with rosacea had a significantly higher probability of IBD, and patients with IBD might also have a high risk of rosacea. Moreover, we demonstrated an association between rosacea and each IBD type (CD and UC) using a consistent statistical method between the included studies. To our knowledge, this is the largest study examining the bidirectional association between rosacea and IBD.

To date, two previous meta-analyses [21, 22] have reported an association between rosacea and IBD. Wang et al. [21] demonstrated a one-way association, in which patients with rosacea had an increased risk of CD (OR, 1.30 [95% CI 0.99–1.69]; hazard ratio [HR], 1.58 [95% CI 1.14–2.20]) and UC (OR, 1.64 [95% CI 1.43–1.89]; HR, 1.18 [95% CI 1.01–1.37]). Han et al. [22] suggested a bidirectional association between IBD and rosacea (relative risk [RR] for IBD in rosacea patients, 1.32 [95% CI 1.18–1.49]; RR for rosacea in IBD patients, 1.66 [95% CI 1.50–1.84]). However, they did not differentiate prevalence from incidence in their meta-analysis. To overcome these limitations, we performed a bidirectional meta-analysis by separately analyzing the ORs for prevalence and the IRRs for incidence to obtain a consistent analysis of the included studies in different settings. Furthermore, as Han et al. [22] commented, the limitation of their analysis was that all the studies included in the meta-analysis were from Western countries. Instead, our study included a larger number of publications than the previous studies, including research from Asian countries.

The epidemiologic association between rosacea and IBD can be explained by the shared pathogenesis of the two diseases. First, recent genome-wide association studies provided evidence of a common genetic basis for rosacea and IBD [23,24,25]. The confirmed single-nucleotide polymorphism (SNP) variant rs763035 in rosacea is located around BTNL2 [23], which is associated with autoimmune diseases, including IBD [26, 27]. In addition, the rs77779142 variant found in rosacea is in high linkage disequilibrium with rs2231884, which is associated with IBD [24, 28]. The most recent study revealed that the rs11576518 variant may be the key linkage in the effect of IBD on rosacea, and suggested a causal relationship. Furthermore, glutathione S-transferases (GST) are important for photoprotection and cellular defense against reactive oxygen species (ROS) [29]. The prevalence of the GSTT1 null genotype has been reported to be significantly higher in rosacea patients [30] and has been associated with increased susceptibility to CD and UC [31]. The association between rosacea and IBD may be influenced by these common genetic factors. Second, as the gut and the skin are the interface between the external environment and the human body, IBD and rosacea have many commonalities. Changes in the innate and adaptive immune system are associated with both rosacea and IBD [32]. Innate immune system dysfunction may contribute to the development of chronic inflammation and vascular abnormalities. The inflammation in rosacea and IBD is exacerbated by the activation of macrophages and toll-like receptors (TLRs), the dysregulation of mast cells and fibroblasts, and the production of ROS, matrix metalloproteinases, tumor necrosis factor, and interleukin-1β [8, 9, 8, 9]. Regarding the adaptive immune system, the activation of the Th1/Th17 pathways through the production of interferon-gamma, tumor necrosis factor, interleukin-17, and multiple immunoglobulins is reportedly shared by rosacea and IBD [32, 34,35,36,37,38,39]. Third, gut dysbiosis is implicated in the pathogenesis of both diseases. Gut microbial composition changes in patients with IBD [40], and fecal microbiota transplantation is suggested to be a promising treatment for IBD [41]. The gut microbiome can play an important role in skin disorders, and the “gut–skin axis” is a recently highlighted concept [42]. An altered gut microbial composition is associated with rosacea [42,43,44], and the gut-active antibiotic rifaximin can bring the complete clearance of or a marked improvement in rosacea in patients with small-intestinal bacterial overgrowth [45, 46]. Therefore, rosacea and IBD can be seen as comorbidities that have similar pathophysiologies. However, further research is needed to elucidate the specific mechanisms of interaction between rosacea and IBD.

This study has some limitations. First, our study is limited by the small number of studies included and the lack of information on disease severity and treatment owing to the nature of the available database. Second, a causal relationship could not be determined in the included studies based on population-based databases. However, this research method that uses population-based studies has the advantage of reducing the likelihood of recall bias in individual patients. Our study also has several strengths. We provided a comprehensive review of the existing evidence on the bidirectional association between IBD and rosacea from Western and Asian countries. Our analysis included multiple studies that covered large databases, such as primary care data [14] or national health insurance databases [11, 17, 18], to enhance the reliability of our analysis in a real-world environment. We analyzed incidence and prevalence separately to ensure consistency between studies while including as many published studies as possible. Collectively, the consistent results between the included studies indicate a meaningful association between IBD and rosacea.

Conclusion

Our meta-analysis revealed a bidirectional association between rosacea and IBD. Based on our analysis, rosacea might be a comorbidity of IBD, and IBD might be a gastrointestinal manifestation in patients with rosacea. Further studies are required to reveal the exact mechanism of interaction between rosacea and IBD, and our study could be the cornerstone of future studies.