Meta-analysis of the association between appendiceal orifice inflammation and appendectomy and ulcerative colitis

Peng Deng¹ and Junchao Wu²

Departments of ¹Emergency and ²Digestive Internal Medicine. West China Hospital. Chengdu, China

The authors thank West China Hospital for Excellent Technical Support.

Correspondence

Objective: This study aimed to investigate the relationship between appendiceal orifice inflammation (AOI) and appendectomy and ulcerative colitis (UC) by a meta-analysis.
Methods: Databases were thoroughly searched for studies on AOI and UC up to January 2016. Three comparisons were performed: a) whether the previous appendectomy was a risk factor of UC; b) influence of appendectomy on UC courses; c) influence of AOI on UC severity. Odds ratios (ORs) and 95% confidence intervals (CIs) were the effects sizes. The merging of results and publication bias assessment were performed by using RevMan 5.3. Sensitivity analysis was conducted using Stata 12.0.
Results: Nineteen studies were selected in the present study. Results of comparison I showed that appendectomy was a protective factor of UC (OR = 0.44; 95% CI [0.30, 0.64]). Comparison II indicated appendectomy had no significant influence in the courses of UC (proctitis: OR = 1.03, 95% CI [0.74, 1.42]; left-sided colitis: OR = 1.01, 95% CI [0.73, 1.39]; pancolitis: OR = 0.92, 95% CI [0.59, 1.43]; colectomy: OR = 1.38, 95% CI [0.62, 3.04]). Comparison III indicated UC combined with AOI did not affect the courses of UC (proctitis: OR = 1.15, 95% CI [0.67, 1.98]; left-sided colitis: OR = 1.14, 95% CI [0.24, 5.42]; colectomy: OR = 0.36, 95% CI [0.10, 1.23]). Sensitivity analysis confirmed the robust of the results in the present study.
Conclusion: In conclusion, this meta-analysis indicated appendectomy can reduce the risk of UC. But appendectomy or AOI had no influence on the severity of the disease and the effect of surgical treatment.

Key words: Appendiceal orifice. Punctiform erosion. Ulcerative colitis.

Introduction

Ulcerative colitis (UC) is one of the inflammatory bowel diseases (IBD), including UC and Crohn's disease (CD), that affect 8 to 246 per 100,000 individuals (1,2). The classic characteristics are continuous and dispersive inflammation extending proximally from the rectum (3). The rectum, the rectosigmoid area, the left colon and the entire colon are common anatomic UC locations (4). It has been found that the number of patients with UC is on the rise year by year in our country, and UC contributes to developing cancers such as colorectal cancer (1). Extensive epidemiology studies on IBD have been conducted and its risk factors, such as familial aggregation, smoking habits and appendectomy, have been identified (5-7).

Cecal appendix has been repeatedly implicated in the pathogenesis and clinical course of UC (8). Appendectomy is strongly correlated with a decreased incidence of UC (9-12), indicating that appendicitis may have a relationship with UC. Furthermore, other studies showed that 71-88% of children with extensive UC had active inflammation in the appendiceal orifice (13,14). All these studies seem to draw attention to this skip-lesion change in UC. The clinical significance of appendiceal orifice inflammation (AOI) in UC has been extensively elucidated (15-17).

In this study, we systematically retrieved the databases to identify the relevant studies. Then, we completed a meta-analysis with three comparisons to explore the relationship between AOI and UC.

Material and methods

This meta-analysis was presented in accordance with the guidelines of PRISMA.

Search strategy

PubMed, Embase and Cochrane Library bibliographic databases were thoroughly searched up to January 2016. Manual document tracing was also conducted for relevant studies. The key words were ulcerative colitis (UC), appendiceal orifice inflammation (AOI), and appendectomy. The search strategy was ((ulcerative colitis) OR UC) AND ((appendiceal orifice inflammation) OR appendectomy). There was no restriction on the language.

Study selection

Two investigators (A and B) independently selected the study according to the inclusion criteria. In case of disagreement, a third investigator (C) was induced for discussion. The inclusion criteria were as follows: a) studies related to appendicitis and ulcerative colitis; b) the subjects were adults; and c) studies contained at least one of the outcomes. The exclusion criteria were as follows: a) duplicates; and b) studies whose outcome measures could not be obtained. The exclusion criteria were as follows: a) duplicates were excluded; and b) studies whose outcome measures could not be obtained were also excluded.

In addition, manual searching of the printed literature, reference lists of reviews and included studies were also performed for obtaining more relevant studies for the meta-analysis.

Authors A and B independently extracted the data, including first author, publication year, study type, country, patients (including time, groups, number and age of the subjects), and outcomes. Any disagreement was resolved by discussion with author C. Newcastle-Ottawa Scale (NOS) (21) was used for quality assessment, which was conducted by author B and C

Statistical analysis

There were three comparisons in this meta-analysis:

- Comparison I: UC patients vs. healthy control; outcome: previous appendectomy.

- Comparison II: UC patients under appendectomy vs. no appendectomy; outcomes: disease extent (proctitis, left-sided colitis, pancolitis), colectomy.

- Comparison III: UC patients AOI positive vs. AOI negative; outcomes: disease extent (proctitis, left-sided colitis), surgical therapy.

Odds ratios (ORs) and 95% confidence intervals (CIs) were used as effect sizes. Cochran's Q test and I² test (22) were used to assess heterogeneity among studies, with p < 0.05 or I² > 50% indicating significant heterogeneity, and the random effects model was used for data merge; otherwise the fixed effect model was used. Publication bias was assessed by the funnel plot. All the statistical analyses were performed by using RevMan 5.3 software (Nordic Cochrane Centre, Copenhagen, Denmark).

Sensitivity analysis was conducted by removing one study each time. Stata 12.0 software was used for this process.

Study selection

The procedures for the study selection are displayed in figure 1. We firstly found 639 studies (PubMed: 211; Embase: 424; Cochrane Library: 4). After removing 133 duplicates, 506 studies remained. Then, 321 completely unrelated studies and 140 reviews, letters or abstracts were excluded, and 45 articles remained. By screening of the full text, 19 studies were finally included in the present meta-analysis (5-7,15-17,19,23-34). The basic information of the selected studies is listed in tables I, II and III. All the studies had high quality with NOS 6-8.

The results of comparison I: appendectomy was a protective factor of UC

Comparison I was conducted among 11 studies (5-7,19,25,27,28,30-32,34) with 10,889 subjects (UC patients: 4,673; healthy control: 6,216).

There was significant heterogeneity (I²= 82%, p < 0.0001) among studies, thus the random effects model was chosen. The merged OR was 0.44 (95% CI [0.30, 0.64], p < 0.0001) (Fig. 2A), indicating that appendectomy was a protective factor against UC.

The results of comparison II: appendectomy did not affect the severity of UC

We further conducted comparison II to investigate the effects of appendectomy on the UC clinical course. Six studies (23,24,26,28,31,33) were involved in comparison II with 4,994 subjects (appendectomy: 434; no appendectomy: 4,560). These results were displayed in figure 3. There was no significant heterogeneity among studies on other outcomes of disease severity (proctitis, left sided colitis, pancolitis), excepting colectomy (I² = 72%, p = 0.003). No significant differences were found in disease courses between UC patients with appendectomy and those without appendectomy (proctitis: OR = 1.03, 95% CI [0.74, 1.42], p = 0.87; left sided colitis: OR = 1.01, 95% CI [0.73, 1.39], p = 0.97; pancolitis: OR = 0.92, 95% CI [0.59, 1.43], p = 0.70; colectomy: OR = 1.38, 95% CI [0.62, 3.04], p = 0.43). This fact indicated that appendectomy did not affect the severity of UC.

Besides, subgroup analysis by the different time for appendectomy was performed (Table IV). The results showed that appendectomy before or after UC diagnosis did not statistically affect the severity of UC (p > 0.05); however, there was a report for both before/after UC diagnosis (33) showing a significant difference (p = 0.003).

Results of comparison III: combined AOI did not affect the severity and surgical treatment rate of UC patients

The results of comparison III were shown in figure 4. The influence of combined AOI in the severity of UC was studied in four articles (15-17,29) including 436 subjects (AOI positive: 123; AOI negative: 313). There was significant heterogeneity among studies for left-sided colitis and the random effects model was used for merging of the effect sizes, while no heterogeneity was found among the studies for proctitis and the fixed effect model was used. Pooled results showed that there were no statistical significance in severity of UC between patients combined with AOI and those not combined with AOI (proctitis: OR = 1.15, 95% CI [0.67, 1.98], p = 0.61; left-sided colitis: OR = 1.14, 95% CI [0.24, 5.42], p = 0.87). Meanwhile, there was also no significant difference in surgical treatment rate for UC patients (OR = 1.36, 95% CI [0.10, 1.23], p = 0.10). These results indicate that combined AOI did not affect the severity and surgical treatment rate.

Sensitivity analysis and publication bias

No reverse occurred after removing any of the studies (data not shown), which indicates that the present results were robust.

The funnel plot of comparison I showed that there was no significant publication bias (Fig. 2B). Publication bias for other comparisons was not performed because of the limited amount of literature.

Discussion

This meta-analysis including 19 case-control studies comprehensively compared the influences of appendectomy and AOI in risk and severity of UC. The strengths of this study were the comprehensive analysis, the high quality of the studies included (NOS 6-8) and its robust results (sensitivity analysis). The results showed that appendectomy reduced the risk of UC but, as well as AOI, it did not affect its courses.

Firstly, comparison I confirmed that appendectomy was a protective factor of UC (OR = 0.44 [95% CI: 0.30-0.64], p < 0.0001). This is not consistent with the previous meta-analysis which indicated that the risk of CD, another IBD, significantly increased in the early years after appendectomy (RR = 1.99) (35). This disparity might be caused by the different mechanisms of the disease and the heterogeneity among studies. Heterogeneity in comparison I mainly comes from the study of Ko 2015a, which was performed among Middle Eastern migrants who were in a specific environment (19). Thus, we can still speculate that appendectomy or AOI may relate to the development of UC.

The influence of time between appendectomy and IBD diagnosis should be taken into account (35). In this study, subgroup analysis by appendectomy time was conducted and the results showed that appendectomy before or after UC diagnosis did not statistically affect the severity of UC. However, we did not stratify the time after UC diagnosis as the study conducted by Kaplan et al. did (35) due to the limited data, which is one of the disadvantages of the present study.

A long-term outcome study of Naves et al. (29) indicated that patients with AOI tend to present a mild course, and the chance to develop proximal progression of disease extent or colectomy was reduced. We finally analyzed the courses of UC in patients with AOI positive and AOI negative in comparison III. The meta-analysis of four studies, including the study by Naves et al. (2011) (29), indicated that there was no significant association between AOI and the extent of UC patient to develop proctitis, left-sided colitis and pancolitis, and the need of colectomy.

However, interpretation of the results in comparison III should be cautious due to the following reasons. First, the small sample size in comparisons II and III may influence the study conclusions; thus, it needs support from large-scale studies. Second, there were heterogeneities among studies for colectomy in comparison II and for left-sided colitis in comparison III. The possible sources, the difference in age when appendectomy was performed, the difference in subtypes of UC and the difference in nursing levels among diverse areas could affect the clinical courses and treatment of UC. Though the random effects model was used for merging effect sizes, there might also be influences in the observations.

In conclusion, this meta-analysis confirmed that appendectomy can reduce the risk of UC. But AOI or appendectomy had no influence on the severity of the UC disease and the effect of surgical treatment.

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Correspondence:
Junchao Wu.
Department of Digestive Internal Medicine.
West China Hospital.
Guoxue lane, 37.
610000 Wuhou District. Chengdu, China
e-mail: nojunchao@163.com

Received: 20-12-2015
Accepted: 05-02-2016