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Yong Loo Lin School of Medicine, National University Singapore, Singapore, SingaporeDivision of Gastroenterology and Hepatology, Department of Medicine, National University Hospital
Yong Loo Lin School of Medicine, National University Singapore, Singapore, SingaporeDivision of Gastroenterology and Hepatology, Department of Medicine, National University Hospital
Yong Loo Lin School of Medicine, National University Singapore, Singapore, SingaporeDivision of Colorectal Surgery, Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore
Upper gastrointestinal Crohn's disease (UGI-CD) is an important subclassification of Crohn's Disease (CD). We performed a systematic review and meta-analysis to evaluate the prevalence, risk factors, and clinical outcomes associated with UGI-CD.
Methods
We searched Embase and Medline for articles reporting the clinical information of UGI-CD in CD patients, through 27 October 2020. Disease location and phenotype were coded according to the Montreal classification, and results were pooled with random effects by DerSimonian and Laird model.
Results
26 articles were included. The prevalence of UGI-CD was 13%. UGI-CD was most commonly found in the stomach (56%) and was associated with concurrent ileocolonic involvement (54%). Non-stricturing, non-penetrating UGI-CD was the most common behavioral phenotype (61%). L4-jejunal disease was associated with the highest rates of surgery. Region of origin did not significantly influence the location and phenotype of UGI-CD. Young, male patients presenting with erythema nodosum, aphthous ulcers and stricturing-phenotype are more likely to have UGI-CD, which in turn is linked to increased risk of hospitalization and surgery.
Conclusion
UGI-CD is present in 13% of patients with CD, and patients with L4-jejunal disease are more likely to require surgery. Further studies examining the effect of ethnicity and region on UGI-CD are needed.
Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal (GI) tract that with symptoms evolving in a relapsing and remitting manner. CD can affect any part of the digestive tract from the oral cavity to the anus, the most common being the terminal ileum and colon. Since its first description by Gottlieb et al. in 1937 [
], most likely due to improved diagnostic modalities. Upper GI tract involvement includes the esophagus, stomach, duodenum, and jejunum, and proximal ileal disease, which may occur as isolated disease location (Montreal Classification L4) or co-exist with other CD locations (L1 to L3) [
Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.
The Clinical Characteristics and Prognosis of Crohn's Disease in Korean Patients Showing Proximal Small Bowel Involvement: Results from the CONNECT Study.
. In addition, recent findings from the inflammatory bowel disease (IBD) genetics consortium showed that jejunal disease was associated with a greater risk of multiple surgeries and stricturing disease compared with other UGI-CD locations [
Early anti-TNF/immunomodulator therapy is associated with better long-term clinical outcomes in Asian patients with Crohn's disease with poor prognostic factors.
. Thus, we performed a systematic review and meta-analysis to summarize the prevalence, risk factors and clinical outcomes of UGI-CD, as well as to compare the differences of UGI-CD between Asian and Western populations. The rising prevalence of IBD in Asia presents an opportunity for further analysis of the differences in UGI-CD presentation and outcomes [
], we conducted a comprehensive search of Medline and Embase databases from inception through 27th October 2020. We also manually searched through the references of the included manuscripts to identify studies missed by the electronic search. The following medical subject heading terms (MESH) were combined with the Boolean operators “AND” or “OR”: “Crohn's Disease”, “Upper Gastrointestinal” and “Prevalence”. The full terms used in the search strategy can be found in the supplementary material 1. Endnote X9 was used to remove duplicates. Sieving of the articles wase undertaken by three authors independently (YHC, CHN, SYL).
2.2 Inclusion criteria and extraction
The search process was conducted in the following order. Firstly, articles had to be original articles (cohort studies, population-based studies, and cross-sectional studies), and studies that did not report primary data (reviews, conference presentations, meta-analyses, commentaries and editorials) were excluded at this stage. Next, eligible articles had to be epidemiological articles with information on the prevalence, risk factors, clinical manifestations and outcomes of UGI-CD. Finally, all full text articles had to meet the following criteria: (1) articles classifying UGI-CD utilizing the Montreal [
Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.
] for CD, (2) diagnosis of UGI-CD established from endoscopy (gastroscopy, enteroscopy, capsule endoscopy.), radiological imaging (computed tomography, magnetic resonance imaging and barium studies) and/or histology (micro and macroscopic findings on biopsy), and (3) articles written or translated into English language (4) studies originating from the same center during the same time period, (5) studies with unclear definitions of the location of UGI-CD, and (6) studies involving pediatric population (younger than 18 years old), as UGI-CD has been significantly linked with younger age of onset. Thereafter, references of included articles were searched for relevant articles and also included into this paper. Discrepancies between the two authors (YHC, CHN) were resolved by the third author (SYL). The kappa statistic was used assess test interrater reliability [
Study characteristics including first author, publication year, source country (or countries), sample size, study design, ethnicity, and age of the patient population, were extracted from the articles. We also extracted data for the prevalence of UGI-CD, location of the lesions, disease behavior, diagnostic methods used, risk factors, clinical manifestations, and outcomes of UGI-CD. Each article was double coded blindly by either pair of authors (YHC, CHN or SNL, SRJ) to ensure accuracy in the coding. In accordance with the Vienna and Montreal classification [
Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.
, location of UGI-CD was classified into L1 to L4 where L1 refers to CD in the terminal ileum, L2 for disease in the colon, L3 for ileocolonic disease, and L4 for isolated upper GI disease(proximal to distal ileum). The disease behavior of CD was categorized into B1, B2 B3, and perianal disease (p), where B1 refers to non‐stricturing, non‐penetrating disease, B2 refers to stricturing disease, and B3 refers to penetrating disease Perianal disease (p) is a disease modifier that can be added to B1–B3 classification when concomitantly present [
Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.
Our primary outcomes of the study included the prevalence, disease behavior and location of UGI-CD. The secondary outcomes included risk factors and clinical outcomes of UGI-CD. All analysis were conducted using the DerSimonian and Laird random-effects model [
]. A meta-analysis of proportions using a Freeman-Tukey double arcsine transformation to stabilize the variance was undertaken in the synthesis of the results [
]. Cochran Q test, and I2 statistics were used to analyze the heterogeneity of the analysis, with an I2 value of 25%, 50% and 75% equating to small moderate and large amounts of heterogeneity respectively [
]. Meta-regression analysis was also conducted using a mixed effect model to assess for prevalence over time. Where meta-analysis was considered inappropriate, systematic review of the included studies was conducted to summarize the findings. All statistical analyses were conducted using STATA 16.1 and R (4.0.3).
For a more homogenous comparison, a sensitivity analysis was undertaken to include only UGI-CD diagnosed with endoscopic methods. Additional sensitivity analysis was undertaken after removing articles with high selection bias. Further subgroup analysis was also conducted based on the CD classification system used, and the region of origin of the included studies. Studies were classified into Western and Asian regions of origin [
. Publication bias was assessed through visual inspection of the funnel plot. The risk of bias was assessed by two authors independently using Hoy et al. tool for prevalence studies [
], which is a ten-item assessment which addresses the internal (measurement and analysis bias) and external (selection and nonresponse bias) validity of the article, followed by a summary risk of bias assessment. The included studies were thereafter grouped into low, moderate, or high risk of bias.
3. Results
In total, 937 citations were identified in the search. Of which a total of 95 full text articles were assessed for eligibility and 21 articles were included into the analysis. A further 6 articles were identified from the references of the search articles so a total of 27 articles were included into this study (Fig. 1). A total of 10,853 CD patients were screened. Kappa statistic was calculated and found to be 0.889. All included articles were assessed to be of low-to-moderate risk of bias. The articles originated from various countries such as China [
Incidence and clinical characteristics of inflammatory bowel disease in a developed region of Guangdong Province, China: a prospective population-based study.
Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?.
A four-decade analysis of the incidence trends, sociodemographic and clinical characteristics of inflammatory bowel disease patients at single tertiary centre, Kuala Lumpur, Malaysia.
Long-term course of Crohn's disease in Japan: Incidence of complications, cumulative rate of initial surgery, and risk factors at diagnosis for initial surgery.
]. Most studies were retrospective in nature (n=15), 2 were cross-sectional studies, and 10 were prospective studies, of which 4 were prospective population-based studies. A summary of these articles can be found in Table 1, and the risk of bias is attached as supplementary material 2.
Table 2 summarizes the results of the meta-analysis. A total of 1,783 patients were diagnosed with UGI-CD across all included papers comprising 10,853 patients. The overall pooled prevalence of UGI-CD was 13% (CI:9% - 19%; I2= 98%; Fig. 2). Visual inspection of the funnel plot revealed publication bias of the included articles (Supplementary material 3). Meta-regression analysis also found a non-significant increase in the prevalence of UGI-CD by year (β=0.040; CI:-0.044 - 0.124; p=0.35).
Table 2Summary of Meta-analysis.
No. of Studies
Events
Sample Size at Risk
I2
Pooled Proportion (95%CI)
Total UGI-CD
27
1783
10853
98%
13% (0.09 - 0.19)
Montreal classification studies only
20
1546
9065
99%
14% (0.09 - 0.22)
Vienna classification studies only
6
213
1788
92%
10% (0.06 - 0.18)
Endoscopic only
4
160
802
90%
23% (0.13 - 0.35)
Sensitivity Analysis
26
1748
10803
96%
12% (0.08% - 0.17)
Location of UGI-CD
Esophageal
2
11
99
0%
11% (0.05 - 0.18)
Stomach
3
47
118
93%
56% (0.17 - 0.92)
Duodenum
3
69
118
54%
55% (0.39 - 0.77)
Jejunum
4
247
667
95%
36% (0.18 - 0.55)
Proximal ileum
3
104
321
68%
32% (0.21 - 0.44)
Concurrent Location of CD
L1 (Terminal Ileum)
17
438
1555
55%
28% (0.24 - 0.33)
L2 (Colon)
17
176
1555
85%
10% (0.05 - 0.15)
L3 (Ileocolon)
17
839
1555
80%
54% (0.46 - 0.61)
No other Location
6
79
716
83%
10% (0.06 - 0.16)
Phenotype of CD
B1 (Non-stricturing)
10
748
1336
92%
61% (0.49 - 0.72)
B2 (Stricturing)
10
377
1336
88%
26% (0.19 - 0.34)
B3 (Penetrating)
10
227
1375
75%
16% (0.10 - 0.23)
Perianal
5
205
707
85%
28% (0.20 - 0.38)
CD – Crohn's Disease; UGI-CD – Upper Gastrointestinal Crohn's Disease.
In total, 21 articles utilized the Montreal and 6 used the Vienna Classifications. Though without statistical significance (p=0.409), the 14% (CI:9% - 22%; I2= 99%; Fig. 2) rate of UGI-CD was higher in studies utilizing the Montreal Classification versus 10% (CI:6% - 18%; I2= 92%; Fig. 2) that used the Vienna Classification. Sensitivity analysis of articles that used endoscopic procedures to diagnose UGI-CD found the prevalence to be 23% (CI:13% - 35%; I2= 90%) out of 802 CD patients. Additional sensitivity analysis after removing an article with a slightly stricter inclusion criteria [
], found no significant changes in prevalence of UGI-CD (12%; CI:8% - 17%).
3.2 Location and phenotype UGI-CD
UGI-CD was located in the stomach in 56% (CI:17% - 92%, I2= 93%), duodenum in 55% (CI:39% - 77%; I2= 54%), jejunum in 36%(CI:18 - 55%, I2= 95%) and proximal ileum in 32%(CI:21% - 44%; I2= 68%, Table 2). The esophagus was the least affected location in UGI-CD with a prevalence of 11% (CI:5% - 18%; I2= 0%).
Concurrent locations for CD were also analyzed. The ileocolonic region was most commonly associated with UGI-CD (L3+L4) with a prevalence of 54% (CI:46% - 61%), followed by terminal ileum (L1+L4) (28%,CI:24% - 33%), and colonic region (L2+L4) (10%,CI:5% - 15%). Only 10% (CI:6% - 16%) of UGI-CD was isolated (L4).
For the disease phenotype, B1 disease was the most common behavioral phenotype, accounting for 61% (CI:49% - 72%) of UGI-CD behavior, with the B2 phenotype at 26% (CI:19% - 34%) and B3 phenotype at 16% (CI:10% - 23%). Perianal disease was present in 28% (CI:20% - 38%) of UGI-CD patients. Substantial heterogeneity for all above analysis was observed by I2 analysis (Table 2).
3.3 Influence of Different Regions of Study Population on UGI-CD
3.3.1 Region and Prevalence of UGI-CD
The prevalence of UGI-CD by region of the study population was analyzed (Table 3). In total, 755 UGI-CD patients were from the Asian region and 538 UGI-CD patients were from the West. The pooled prevalence of UGI-CD was 15% (CI:8% - 27%) in the Asian region, and 11% (CI:6% - 20%) in the West(p=0.51; Table 3 and supplementary material 4).
The location and phenotype of UGI-CD did not significantly differ between the Asian and Western regions (Table 3). The prevalence of non-stricturing, non-penetrating phenotype of UGI-CD was 55% (CI:37% - 72%) in the Asian region compared to Western region studies of 75% (CI:45% - 97%). Asian region studies showed a prevalence of stricturing phenotype of 27% (CI:15% - 41%) whereas Western studies showed 14% (CI:0% - 40%). Penetrating phenotype was 13% from both Asian and Western region studies. Concurrent ileal location was 29% (CI:24% - 35%) in Asian region studies versus 26% (CI:22% - 31%) in Western region studies. Concurrent colonic location was 7% (CI:1% - 17%) in Asian region studies versus 9% (CI:4% - 16%) in Western studies. Concurrent ileocolonic location was 54% (CI:41% - 66%) in Asian region studies versus 56% (CI:50% - 61%) in Western region studies.
3.4 Risk Factors associated with UGI-CD
The association between age at diagnosis of CD, gender, smoking, and UGI involvement was not clearly established in UGI-CD (supplementary material 5) [
]. Other notable associations which increased the risk of UGI-CD included the presence of erythema nodosum (OR:1.793, p=0.019), aphthous ulcers (OR:1.838, p= 0.002) and requirement for anti-TNF treatment (OR:1.534, p=0.010) [
3.5 Outcomes: complications, hospitalization and surgery
The complications of UGI-CD were assessed by multiple studies but excluded from meta-analysis due to either an inadequate number of contributing studies or excessive heterogeneity. Sun et al. reported that the most common complication of UGI-CD was relapse, occurring in 36.3% of UGI-CD patients (supplementary material 6). An intestinal obstruction rate of 11.3% and bowel perforation rate of 5% were found in UGI-CD. Two studies [
Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?.
Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?.
Long-term course of Crohn's disease in Japan: Incidence of complications, cumulative rate of initial surgery, and risk factors at diagnosis for initial surgery.
reported the prevalence of abdominal surgery to range between 10.5% and 66.7% (supplementary material 6).
3.6 Comparison between UGI-CD patients and Non-UGI-CD patients
UGI-CD patients were compared against non-UGI-CD patients regarding clinical outcomes and risks of hospitalization and surgery (Table 4). The clinical outcomes included intestinal obstruction, abdominal abscess, intestinal fistula, and bowel perforation rates. Greuter et al. [
] found no significant differences in outcomes and surgical resection rates between the 2 groups. Sun et al. found UGI-CD was significantly associated with higher overall complication rates (8.4% vs 20.0%, p= 0.009) and intestinal obstruction rates (3.0% vs 11.3%, p= 0.016) possibly due to increased disease activity [
Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?.
] found that there was no significant differences between the 2 groups. Five studies reported that UGI-CD was a significant risk factor for surgery (Table 4) [
Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?.
Long-term course of Crohn's disease in Japan: Incidence of complications, cumulative rate of initial surgery, and risk factors at diagnosis for initial surgery.
Long-term course of Crohn's disease in Japan: Incidence of complications, cumulative rate of initial surgery, and risk factors at diagnosis for initial surgery.
Table 4Comparison of outcomes between UGI-CD patients and non-UGI-CD patients.
Outcomes
Author(s)
Year
Outcome Description
Further explanations
Summary estimates
Overall
Greuter et al
2018
Overall complications (composite of intestinal stenosis, perianal fistula, intestinal fistula, any fistula, intestinal resection surgery, and surgery for abscess or fistula)
Non-Significant: No significant associations was found between UGI-CD and non-UGI-CD patients
Median time until any complications 6.17 (95% CI 5.67–7.41) versus 6.42 (95% CI 5.00–13.01) years, log-rank test p = 0.341
Saadah et al
2012
Overall complications (composite of intestinal/colonic strictures or bowel perforations)
Non-Significant: No significant associations were found for overall complications
6 (31.6%) vs 18 (30.5%), P = 1.0
Sun et al
2019
Overall complications (composite of intestinal obstruction, abdominal abscess, intestinal fistula and bowel perforation) - Intestinal Obstruction
Significant: UGI-CD was associated with higher complications rate and increased rates of intestinal obstruction
8.4% vs 20.0%, p= 0.009 - Intestinal obstruction (3.0% vs 11.3%) p= 0.016
Hospitalisations
Chow et al
2009
3-year cumulative probability of further hospitalization
Significant: UGI-CD is an independent risk factor predicting further hospitalization
HR:2.1 (95% CI: 1.3 to 3.5) p=0.004
Park et al
2013
- 15-year cumulative probability of the first hospitalization - Higher incidence of hospitalisation - Longer duration of hospitalisations
Significant: UGI-CD is noted to increase the rates of cumulative probability of first hospitalisation
- 15-year cumulative probability of the first hospitalization (P= 0.015). - Higher incidence of all hospitalizations (RR: 1.40) - Longer total duration of hospitalizations (RR: 1.39)
Mao et al
2018
- Number of Hospitalisations
Non-Significant: No significant differences were found when comparing between L4 and non-L4 patients in number of hospitalisations.
- 125 (42%) vs 88 (48%), p=0.226
Surgery
Chow et al
2009
- Surgery performed in the first month of diagnosis - 5-year cumulative probability of major surgery
Significant: Patients in UGI-CD had higher rates of major surgery compared to non-UGI-CD patients
- Surgery performed in the first month of diagnosis compared to non-UGI-CD patients (50.0% versus 14.7%)(P = 0.0001). - Higher 5-year cumulative probability of major surgery without significance HR:1.3 (0.7 to 2.5) p=0.406
Lazarev et al
2013
Multiple surgery - L4 vs non-L4 disease - L4-EGD disease vs. non-L4 disease - L4-jejunal disease vs. non-L4 disease - L4-jejunal vs. L4-EGD disease
Significant: L4 diseases were more likely to undergo multiple operations. L4-jejunal having more operations than L4-EGD disease. Significant: L4-EGD disease has lower rates compared to non-L4 disease
- L4 vs non-L4 (23% vs. 17 % ; P = 0.007). - L4-EGD disease vs. non-L4 disease (35% vs. 47 % ; P = 0.003) - L4-jejunal disease vs. non-L4 disease (38% vs. 17 % ; P < 0.001) - L4-jejunal vs. L4-EGD disease (38 vs. 14 % ; P < 0.001)
Mao et al
2018
Cumulative probabilities of surgery
Significant: Increased risk of undergoing surgery if UGI-CD is present
- L4-jejunal (HR 3.082; 95% CI 1.30- 7.31) - L4-proximal disease (HR 1.83; 95% CI 1.07–3.15)
Sun et al
2019
Predictor of abdominal surgery Proximal ileal disease vs EGD disease Jejunal disease vs EGD disease
Significant: Increased odds of undergoing abdominal surgery Significant: EGD had lowered rates of surgery compared to Proximal Ileal and jejunal disease
- Predictor of abdominal surgery (OR: 6.335) P<0.001 - Proximal ileal disease vs EGD disease, (72.2% vs. 37.7%, P<0.001) - Jejunal disease vs EGD disease (52% vs 37.7%, P=0.036)
Sato et al
2015
Risk of initial surgery
Significant: Significantly higher risk of initial surgery even after controlling for age, sex, smoking, and drinking
HR:1.37 (1.08–1.74), P<0.05
Greuter et al
2018
CD related surgery
Non-Significant: No significant associations were found when comparing between patients with UGI-CD and patients with non-UGI-CD
- OR:1.046 (0.785–1.394) 0.760
Park et al
2013
Major surgery rates
Non-Significant: Proportion of patients undergoing major surgery between jejunal and non-jejunal patients were not significantly different
- Jejunal (75/198, 37.9%) vs non-jejunal (396/1205, 32.9%) groups (P = 0.168).
Outcomes according to different locations of UGI-CD were also explored by 3 included articles. L4-esophagogastroduodenal (EGD) disease generally had a lower surgical rate as compared to L4-jejunal or L4-proximal ileal diseases [
Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?.
. Sun et al. found that oesphagogastroduodenal (EGD) disease had lower rates of surgery as compared to proximal ileal (72.2% vs. 37.7%, P<0.001) and jejunal disease (52% vs 37.7%, P=0.036) [
This systematic review and meta-analysis summarized the prevalence of upper gastrointestinal involvement in CD, its risk factors, complications, and clinical outcomes (Fig. 3). In this systematic review we found that UGI-CD has an overall pooled prevalence of 13% (CI: 9% - 19%) amongst a population of 10,853 CD patients. This is similar to the prevalence reported by the IBD Genetics Consortium cohort of 16% [
Advances in and greater utilization of different diagnostic modalities in recent years may have increased the prevalence of UGI-CD. Our meta-regression analysis found a non-significant increasing trend for the prevalence of UGI-CD by year, which coincides with an era of more frequent use of MRI enterography and capsule endoscopy. Greater awareness of the poorer prognosis of UGI-CD might have also increased the vigilance of this disease entity. Moreover, we noted differences in the prevalence assessed by the Vienna versus the Montreal classifications [
Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.
. Studies using the Montreal Classification depicted a higher rate of UGI-CD (14% vs 10%). The Montreal Classification, being the newer system, together with more advanced diagnostic tests, could have accounted for the differences.
Our systematic review suggested that young male patients presenting with erythema nodosum [
]. UGI-CD was also an independent risk factor for surgery, hospitalization, and overall complications (Table 4). Our data also demonstrated a shorter duration of CD with the UGI-CD phenotype, suggesting that patients might be presenting with complications after years of subclinical disease. Therefore, patients with UGI-CD need to be managed more aggressively with modern treatment paradigms such as treat-to-target and early treatment escalation, in order to prevent irreversible intestinal damage or surgical resections. Intestinal ultrasound and fecal calprotectin would be additional tools that would assist in the best-care of such patients [
Differences in clinical outcomes were observed according to the location of UGI-CD : L4-esophagogastroduodenal (EGD), -jejunal, or -proximal ileal disease. L4-jejunal disease was associated with an increased risk for abdominal surgery versus other UGI-CD location [
Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?.
. The poorer prognosis associated with L4-jejunal disease could be due to its subclinical nature and therefore patients will likely present with established intestinal damage and need for surgery upon initial diagnosis or soon after [
]. Newer reiterations of CD location classification should recognise this poorer prognosis. The Paris classification of paediatric CD divides the L4 disease into L4a (proximal to ligament of Treitz) and L4b (ligament of Treitz to above distal ileum) [
. However, this is based upon paediatric assessment and may not be generalisable to adult UGI-CD, hence another option would be to divide the L4 disease further into L4-esophagogastroduodenal (EGD), -jejunal, or -proximal ileal disease as suggested by Mao et al. [
Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?.
]. This would allow physicians to better identify patients at risk for abdominal surgeries and take the appropriate steps to manage those patients. More studies analysing the differences in L4 disease should be done to consider whether the modification of the Montreal classification is necessary [
Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?.
During subgroup analysis according to regions of study, Asian studies were observed to have a higher rate of UGI-CD compared to Western countries (15% vs 11%), albeit without statistical significance. Though our findings was statistically insignificant, differences in prevalence were observed in a large retrospective analysis by Kim et al of pediatric CD (n=312 Asians, n=1221 Caucasians) with significantly higher UGI-CD involvement observed in Asians (74.4% vs. 46.2%, p < 0.001) [
]. The reasons for differences in prevalence found by Kim et al. may be due to genetic, environmental and microbiome differences between Asians and Caucasian patients. Genetic mutations of IBD in Asians differ from that seen in Caucasians. For example, the nucleotide oligomerization domain (NOD)-2 gene variants associated with the development of CD in Western patients, were absent in Asians [
], were found to have a higher odds ratio in Asians than in Caucasians. However, other factors such as smoking, patient and physician preferences to treatment procedures that affect the prevalence of UGI-CD may have greater contribution to the prevalence of UGI-CD and could have confounded our analysis, leading to the insignificance of the results in our findings [
]. Further studies on the potential differences in Asians and Western UGI-CD are needed to confirm the findings.
4.1 Strength and limitations
Our study has certain strengths and limitations. Firstly, to our knowledge, this is the first meta-analysis and systematic review that summarizes the prevalence, epidemiological association, and outcomes of UGI-CD. Next, this meta-analysis included studies with standard definitions of UGI-CDs according to the Montreal and Vienna Classification systems, thereby reducing heterogeneity of the included studies. The L4 definition is the same in both classifications. However, this meta-analysis also concedes some limitations. Firstly, our paper found substantial heterogeneity in most of our analysis (I2>75%), however, the I2 can be influenced by sample sizes and thus can be misleading [
. There is also a lack of representation of articles from the African and South American regions, which further limits the generalizability of the paper. Next, most included articles were retrospective in nature, this may have led to some bias in the collected data. Also, there were few articles examining the risk factors of UGI-CD, this limits the generalizability of our findings, and further research should be done to ascertain the risk factors of UGI-CD. Lastly, certain disease phenotypes were excluded in a few of the included articles, and this could have led to some discrepancies in the data collected.
5. Conclusion
In conclusion, our meta-analysis suggested that UGI-CD is present in 13% of patients with CD. Young, male patients presenting with erythema nodosum, aphthous ulcers and stricturing-phenotype of CD are more likely to have UGI-CD, which is linked to increased risk for anti-TNF treatment, hospitalization, and surgery. The prevalence of surgery in UGI-CD is about 45%. The L4-jejunal subtype is associated with the highest risk of surgery compared with other location subtypes. Asian patients may have a higher prevalence of UGI-CD and were more likely to present with concurrent ileocolonic disease and stricturing-phenotype compared with Caucasians. Because UGI-CD may be subclinical, patients might require more frequent follow up and be managed more aggressively to avoid progression to stricturing or penetrating disease.
Conflict of interest
The authors declare that there is no conflict of interest.
Acknowledgements
None.
Data availability statement
The articles included in this article are available on the search databases.
Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology.
The Clinical Characteristics and Prognosis of Crohn's Disease in Korean Patients Showing Proximal Small Bowel Involvement: Results from the CONNECT Study.
Early anti-TNF/immunomodulator therapy is associated with better long-term clinical outcomes in Asian patients with Crohn's disease with poor prognostic factors.
Incidence and clinical characteristics of inflammatory bowel disease in a developed region of Guangdong Province, China: a prospective population-based study.
Different clinical outcomes in Crohn's disease patients with esophagogastroduodenal, jejunal, and proximal ileal disease involvement: is L4 truly a single phenotype?.
A four-decade analysis of the incidence trends, sociodemographic and clinical characteristics of inflammatory bowel disease patients at single tertiary centre, Kuala Lumpur, Malaysia.
Long-term course of Crohn's disease in Japan: Incidence of complications, cumulative rate of initial surgery, and risk factors at diagnosis for initial surgery.
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