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Contents lists available at ScienceDirect

Digestive and Liver Disease

journal homepage: www.elsevier.com/locate/dld

Meta-Analysis

Systematic review with meta-analysis: The prevalence, risk factors and

outcomes of upper gastrointestinal tract crohn’s disease
Yip Han Chin a,1,∗, Cheng Han Ng a,1, Snow Yunni Lin a, Sneha Rajiv Jain a, Gwyneth Kong a,
Jeffery Wei Heng Koh b, Darren Jun Hao Tan a, David Eng Hui Ong a,c,
Mark Dhinesh Muthiah a,c, Choon Seng Chong a,d, Fung Joon Foo e, Rupert Leong f,g,
Webber Pak Wo Chan h,∗
a
Yong Loo Lin School of Medicine, National University Singapore, Singapore, Singapore
b
Faculty of Science, National University Singapore, Singapore
c
Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital
d
Division of Colorectal Surgery, Department of Surgery, University Surgical Cluster, National University Hospital, Singapore, Singapore
e
Sengkang General Hospital, Singapore, Singapore
f
The University of Sydney, Sydney, New South Wales, Australia
g
Concord Repatriation General Hospital, Sydney, New South Wales, Australia
h
Department of Gastroenterology, Singapore General Hospital, Singapore, 20 College Road, Academia level 3, Singapore 169856

a r t i c l e i n f o a b s t r a c t

Article history: Aims: Upper gastrointestinal Crohn’s disease (UGI-CD) is an important subclassification of Crohn’s Disease
Received 27 April 2021 (CD). We performed a systematic review and meta-analysis to evaluate the prevalence, risk factors, and
Revised 28 June 2021
clinical outcomes associated with UGI-CD.
Accepted 21 July 2021
Methods: We searched Embase and Medline for articles reporting the clinical information of UGI-CD
Available online xxx
in CD patients, through 27 October 2020. Disease location and phenotype were coded according to the
Keywords: Montreal classification, and results were pooled with random effects by DerSimonian and Laird model.
Upper gastrointestinal Crohn’s disease Results: 26 articles were included. The prevalence of UGI-CD was 13%. UGI-CD was most commonly found
Crohn’s disease in the stomach (56%) and was associated with concurrent ileocolonic involvement (54%). Non-stricturing,
Epidemiology non-penetrating UGI-CD was the most common behavioral phenotype (61%). L4-jejunal disease was as-
Montreal classification sociated 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.
© 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Introduction Gottlieb et al. in 1937 [1], the prevalence of upper gastrointestinal

CD (UGI-CD) has been increasing, ranging from 3-4% in 1970–1980
Crohn’s disease (CD) is a chronic inflammatory disorder of the [2,3], to 11.3% in 2009–2016 [4], most likely due to improved diag-
gastrointestinal (GI) tract that with symptoms evolving in a re- nostic modalities. Upper GI tract involvement includes the esopha-
lapsing and remitting manner. CD can affect any part of the di- gus, stomach, duodenum, and jejunum, and proximal ileal disease,
gestive tract from the oral cavity to the anus, the most common which may occur as isolated disease location (Montreal Classifica-
being the terminal ileum and colon. Since its first description by tion L4) or co-exist with other CD locations (L1 to L3) [5].
Data regarding the disease course, risk factors, and clinical out-
come in UGI-CD are conflicting [4]. Earlier studies have reported
∗
Corresponding authors. UGI-CD as an important independent risk factor associated with
E-mail addresses: yiphan97@gmail.com (Y.H. Chin),
stricturing and penetrating behavioral phenotype [6], increased
webber.chan.p.w@singhealth.com.sg (W.P.W. Chan).
1
Equal Contribution, Yip Han Chin and Cheng Han Ng should be considered joint risk of disease recurrence, hospitalization [7], surgery, and post-
first author. operative recurrence [8,9]. In addition, recent findings from the

https://doi.org/10.1016/j.dld.2021.07.037
1590-8658/© 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Y.H. Chin, C.H. Ng, S.Y. Lin et al., Systematic review with meta-analysis: The prevalence, risk factors and
outcomes of upper gastrointestinal tract crohn’s disease, Digestive and Liver Disease, https://doi.org/10.1016/j.dld.2021.07.037
JID: YDLD
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Y.H. Chin, C.H. Ng, S.Y. Lin et al.
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 [10]. Prior studies have also found that disease behavior
at diagnosis significantly affected the prognosis of CD [11]. In
contrast, a population-based study concluded that involvement of
upper GI tract in CD did not result in a poorer outcome [4].
Advances in endoscopy, radiological imaging [4] and increased
use of biological treatments may have changed the epidemiology
and clinical outcomes of UGI tract involvement in CD [12,13]. Thus,
we performed a systematic review and meta-analysis to summa-
rize 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 [14].
2. Methods
2.1. Search strategy
Following the Preferred Reporting Items for Systematic Re-
views and Meta-Analyses (PRISMA) guidelines [15], 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 sub-
ject heading terms (MESH) were combined with the Boolean op-
erators “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 or-
der. Firstly, articles had to be original articles (cohort studies,
population-based studies, and cross-sectional studies), and stud-
ies that did not report primary data (reviews, conference presenta-
tions, meta-analyses, commentaries and editorials) were excluded
at this stage. Next, eligible articles had to be epidemiological arti-
cles with information on the prevalence, risk factors, clinical man-
ifestations and outcomes of UGI-CD. Finally, all full text articles
had to meet the following criteria: (1) articles classifying UGI-CD
utilizing the Montreal [5] or Vienna classification [16] for CD, (2)
diagnosis of UGI-CD established from endoscopy (gastroscopy, en-
teroscopy, capsule endoscopy.), radiological imaging (computed to-
mography, magnetic resonance imaging and barium studies) and/or
histology (micro and macroscopic findings on biopsy), and (3) arti-
cles written or translated into English language (4) studies orig-
inating 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 on-
set. 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 re-
liability [17].
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 arti-
cles. We also extracted data for the prevalence of UGI-CD, loca-
tion of the lesions, disease behavior, diagnostic methods used, risk
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factors, clinical manifestations, and outcomes of UGI-CD. Each arti-
cle 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 [5,16], 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 dis-
ease (p), where B1 refers to non-stricturing, non-penetrating dis-
ease, 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 [5].
2.3. Statistical analysis and quality assessment
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 [18]. A meta-analysis of proportions using a Freeman-Tukey
double arcsine transformation to stabilize the variance was under-
taken in the synthesis of the results [19]. The Freeman-Tukey dou-
ble arcsine transformation is one of the most common transforma-
tions used in the analysis of prevalence [20]. Cochran Q test, and
I2 statistics were used to analyze the heterogeneity of the analy-
sis, with an I2 value of 25%, 50% and 75% equating to small mod-
erate and large amounts of heterogeneity respectively [21]. Meta-
regression analysis was also conducted using a mixed effect model
to assess for prevalence over time. Where meta-analysis was con-
sidered 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 re-
moving articles with high selection bias. Further subgroup analy-
sis was also conducted based on the CD classification system used,
and the region of origin of the included studies. Studies were clas-
sified into Western and Asian regions of origin [22,23]. Publica-
tion 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 [24], which is a ten-item as-
sessment which addresses the internal (measurement and analy-
sis bias) and external (selection and nonresponse bias) validity of
the article, followed by a summary risk of bias assessment. The in-
cluded 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 to-
tal 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 vari-
ous countries such as China [25,26], Hong Kong [7,27,28], Taiwan
[29], Malaysia [30,31], Japan [32], South Korea [33], Sri Lanka [34],
Italy [35,36], Switzerland [4], The Netherland [37], Hungary [28,38],
Canada [10,39], USA [6,10,40,41], Denmark [42], Norway [43], New
Zealand [44], Saudi Arabia [45,46], Puerto Rico [10], and Brazil [47].
There were 2 multi-national studies, one involving Hungary and
Hong Kong [28], another involving USA, Canada, and Puerto Rico
[10]. Most studies were retrospective in nature (n=15), 2 were
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Y.H. Chin, C.H. Ng, S.Y. Lin et al.
Fig. 1. PRISMA flowchart.
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.
3.1. Prevalence of UGI-CD
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 inspec-
tion 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).
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
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in studies utilizing the Montreal Classification versus 10% (CI:6% -
18%; I2 = 92%; Fig. 2) that used the Vienna Classification. Sensitiv-
ity 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 remov-
ing an article with a slightly stricter inclusion criteria [42], 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
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Table 1
Summary of Included articles.

Author Year Country Region Total Sample Age (mean ± SD) % female Study Type Classification Diagnostic Methodology Risk of Bias
size used

Saadah et al 2020 Saudi Arabia Middle Eastern 78 17.2 ± 8.7 44.90 Retrospective study Montreal Endoscopic and histological methods Low
Classification
Sun et al 2019 China Asian 246 31.6 39.40 Retrospective study Montreal Clinical evaluation, endoscopic methods with Low
Classification biopsy
Mokhtar et al 2019 Malaysia Asian 132 27.4 ± 15.4 46.20 Retrospective study Montreal Clinical signs and symptoms, blood tests and Low

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Classification radiological methods
Maccioni et al 2019 Italy Western 118 - - Retrospective study Montreal Endoscopic and radiological methods Low
Classification
Mao et al 2018 Taiwan Asian 483 30.5 ± 12.3 33.30 Retrospective study Montreal Endoscopic and radiological methods Moderate
Classification
Greuter et al 2018 Switzerland Western 1638 27.7 ± 12.5 53.17 Retrospective study Montreal Clinical evaluation, endoscopic, radiological Low
Classification appearances and histological methods
Horjus Talabur Horje 2016 The Netherland Western 108 - 57.41 Prospective study Montreal Endoscopic and histological methods Low
et al Classification
4

Farkas et al 2016 Hungary and Asian 100 - 24.00 Prospective study Montreal Clinical evaluation, endoscopic, radiological Low
Hong Kong Classification appearances and histological methods
Western 80 29 36.25
De Felice et al 2015 USA Western 24 24.5 ± 11.8 63.00 Retrospective study Montreal Clinical evaluation, endoscopic methods Low
Classification
Sato et al 2015 Japan Asian 520 25.2 ± 10 29.42 Retrospective study Montreal Endoscopic and radiological methods Low
Classification
Aljebreen et al 2013 Saudi Arabia Middle Eastern 497 25 ± 14.0 59.00 Prospective study Montreal Endoscopic and histological methods Low
Classification
Zeng et al 2013 China Asian 17 27.5 ± 10.6 29.40 Prospective Montreal Clinical evaluation, endoscopic and Low
population-based Classification radiological methods
study
Park et al 2013 South Korea Asian 1403 32.4 ± 10.0 27.73 Retrospective study Montreal Endoscopic and radiological methods or Low
Classification surgical assessment.
Lazarev et al 2013 Canada, USA, Western 2,105 24.7 ± 12.3 52.35 Cross-sectional study Montreal Endoscopic and radiological methods or Low
Puerto Rico Classification surgical exploration
Annunziata et al 2012 Italy Western 119 40.25 ± 9.2 52.94 Prospective study Montreal Endoscopic and histological methods Low

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Classification
(continued on next page)

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Table 1 (continued)

Author Year Country Region Total Sample Age (mean ± SD) % female Study Type Classification Diagnostic Methodology Risk of Bias
size used

Lakatos et al 2011 Hungary Western 163 32.5 47.85 Prospective Montreal Endoscopic, radiological and histological Low
population-based Classification methods
study

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Jensen et al 2011 Denmark Western 50 43 ± 12.9 74.00 Prospective Montreal Endoscopic and radiological methods Low
population-based Classification
study
Niriella et al 2010 Sri Lanka Asian 55 - 50.91 Retrospective study Montreal Endoscopic and radiological methods Moderate
Classification
Thia et al 2010 USA Western 306 40.1 ± 14.5 51.00 Retrospective study Montreal Endoscopic and radiological methods Low
Classification
Chow et al 2008 Hong Kong Asian 132 32.7 ± 14.0 31.80 Prospective study Montreal Clinical evaluation, endoscopic, radiological Low
Classification appearances and histological methods
5

Tarrant et al 2008 New Zealand Western 715 - 59.00 Retrospective Montreal Clinical evaluation, endoscopic, radiological Low
population-based Classification appearances and histological methods
study
Solberg et al 2007 Norway Western 197 - 49.79 Prospective Vienna Clinical evaluation, endoscopic, radiological Low
population-based Classification appearances and histological methods
study
Santana et al 2007 Brazil Brazilian 65 37.3 ± 13.0 61.50 Cross-sectional study Vienna Clinical evaluation, endoscopic, radiological Low
Classification appearances and histological methods
Hilmi et al 2005 Malaysia Asian 34 29 ± 13.5 50.00 Retrospective study Vienna Clinical evaluation, endoscopic, radiological Low
Classification appearances and histological methods
Leong et al 2004 Hong Kong Asian 80 33.1 ± 14 29.00 Prospective study Vienna Clinical evaluation, endoscopic, radiological Low
Classification appearances and histological methods
Dorn et al 2003 USA Western 535 30.5 ± 10.8 51.02 Retrospective study Vienna Clinical evaluation, endoscopic, radiological Low
Classification appearances and histological methods
Freeman et al 2001 Canada Western 877 - 56.10 Retrospective study Vienna Endoscopic and histological or radiological Low
Classification methods

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Table 2
Summary 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.

Fig. 2. Prevalence of UGI-CD by Vienna and Montreal classification.

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Table 3
Analysis of meta-analysis by region.

Region statistics Asian Countries Western Countries Subgroup

Differences
Studies Sample Events Pooled Proportion I2 Studies Sample Events Pooled Proportion I2
(p-value)
Size at Size (95%)
Risk at Risk

Total L4 11 3202 755 15% (0.08 - 0.27) 98% 13 7011 900 11% (0.6 - 0.20) 98% 0.51
Type of Crohn’s Disease
B1 (Non-stricturing) 5 720 440 55% (0.37 - 0.72) 94% 3 251 141 75% (0.45 - 0.97) 89% 0.24
B2 (Stricturing) 5 720 191 27% (0.15 - 0.41) 90% 3 251 74 14% (0.00 - 0.40) 87% 0.26
B3 (Penetrating) 5 720 82 13% (0.07 - 0.20) 84% 3 251 36 13% (0.09 - 0.18) 0% 0.75
Concurrent Crohn’s Disease
location
L1 (Terminal Ileum) 8 747 179 29% (0.24 - 0.35) 47% 8 553 141 26% (0.22 - 0.31) 28% 0.65
L2 (Colon) 8 747 72 7% (0.01 - 0.17) 90% 8 553 61 9% (0.04 - 0.16) 0% 0.88
L3 (Ileocolon) 8 747 407 54% (0.41 - 0.66) 86% 8 553 256 56% (0.50 - 0.61) 25% 0.74

(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).
the stricturing phenotype and initial need for operation at diag-
nosis to be independently associated with UGI-CD [7]. Other no-
table 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 treat-
ment (OR:1.534, p=0.010) [4]. UGI-CD is also significantly associ-
ated with a shorter disease duration (OR:0.981 per year, p=0.016)
[4].

3.3. Influence of Different Regions of Study Population on UGI-CD 3.5. Outcomes: complications, hospitalization and surgery

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 re-
gion, and 11% (CI:6% - 20%) in the West(p=0.51; Table 3 and sup-
plementary material 4).
3.3.2. Location and Phenotype of UGI-CD
The location and phenotype of UGI-CD did not significantly dif-
fer between the Asian and Western regions (Table 3). The preva-
lence 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 preva-
lence of stricturing phenotype of 27% (CI:15% - 41%) whereas West-
ern 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 loca-
tion 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, smok-
ing, and UGI involvement was not clearly established in UGI-CD
(supplementary material 5) [7,35,45]. Greuter et al. [4] and Lazarev
et al. [9] identified UGI-CD to be more prevalent in younger pa-
tients, but 2 other studies did not find an association [35,45]. Sun
et al. [25] and Greuter et al. [4] observed that males were more
likely to develop UGI-CD, while 3 other studies did not find this
association [7,35,45]. Lazarev et al. [10] found that UGI-CD pa-
tients were less likely to be smokers, Saadah et al. [45] observed
that disease behavior did not differ significantly between the UGI-
CD and non-UGI-CD groups, whereas Chow et al. [7] found that
The complications of UGI-CD were assessed by multiple studies
but excluded from meta-analysis due to either an inadequate num-
ber of contributing studies or excessive heterogeneity. Sun et al.
reported that the most common complication of UGI-CD was re-
lapse, occurring in 36.3% of UGI-CD patients (supplementary ma-
terial 6). An intestinal obstruction rate of 11.3% and bowel perfo-
ration rate of 5% were found in UGI-CD. Two studies [29,33] re-
ported the rate of hospitalization ranged between 47.6% and 61.1%.
Eight studies [4,7,10,25,29,32,33,45] reported the prevalence of ab-
dominal 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 ob-
struction, abdominal abscess, intestinal fistula, and bowel perfora-
tion rates. Greuter et al. [4] and Saadah et al. [45] found no signif-
icant 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 [25]. There were 2 studies that
consistently showed that UGI-CD was associated with higher hos-
pitalization rates [7,33], while Mao et al. [29] found that there
was no significant differences between the 2 groups. Five stud-
ies reported that UGI-CD was a significant risk factor for surgery
(Table 4) [7,10,25,29,32]. Sato et al. [32] found that UGI-CD signif-
icantly increased the need for initial surgery (HR:1.37) but Greuter
et al., Park et al. and Saadah et al. did not [4,45].
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 [10,25], and L4-jejunal disease
usually had the highest rates of surgery (Table 4) [10,29]. 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)

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Table 4
Comparison 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 Non-Significant: No significant Median time until any
(composite of intestinal stenosis, associations was found between complications 6.17 (95% CI
perianal fistula, intestinal fistula, any UGI-CD and non-UGI-CD patients 5.67–7.41) versus 6.42 (95% CI
fistula, intestinal resection surgery, 5.00–13.01) years, log-rank test
and surgery for abscess or fistula) p = 0.341
Saadah et al 2012 Overall complications Non-Significant: No significant 6 (31.6%) vs 18 (30.5%), P = 1.0
(composite of intestinal/colonic associations were found for overall
strictures or bowel perforations) complications
Sun et al 2019 Overall complications Significant: UGI-CD was associated 8.4% vs 20.0%, p= 0.009
(composite of intestinal obstruction, with higher complications rate and - Intestinal obstruction (3.0% vs
abdominal abscess, intestinal fistula increased rates of intestinal 11.3%) p= 0.016
and bowel perforation) obstruction
- Intestinal Obstruction
Hospitalisations Chow et al 2009 3-year cumulative probability of Significant: UGI-CD is an HR:2.1 (95% CI: 1.3 to 3.5)
further hospitalization independent risk factor predicting p=0.004
further hospitalization
Park et al 2013 - 15-year cumulative probability of the Significant: UGI-CD is noted to - 15-year cumulative probability
first hospitalization increase the rates of cumulative of the first hospitalization (P=
- Higher incidence of hospitalisation probability of first hospitalisation 0.015).
- Longer duration of hospitalisations - 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 - 125 (42%) vs 88 (48%), p=0.226
differences were found when
comparing between L4 and non-L4
patients in number of
hospitalisations.
Surgery Chow et al 2009 - Surgery performed in the first month Significant: Patients in UGI-CD had - Surgery performed in the first
of diagnosis higher rates of major surgery month of diagnosis compared to
- 5-year cumulative probability of compared to non-UGI-CD patients non-UGI-CD patients (50.0%
major surgery 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 Significant: L4 diseases were more - L4 vs non-L4 (23% vs. 17 % ;
- L4 vs non-L4 disease likely to undergo multiple P = 0.007).
- L4-EGD disease vs. non-L4 disease operations. L4-jejunal having more - L4-EGD disease vs. non-L4
- L4-jejunal disease vs. non-L4 operations than L4-EGD disease. disease (35% vs. 47 % ;
disease Significant: L4-EGD disease has P = 0.003)
- L4-jejunal vs. L4-EGD disease lower rates compared to non-L4 - L4-jejunal disease vs. non-L4
disease 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 - L4-jejunal (HR 3.082; 95% CI
undergoing surgery if UGI-CD is 1.30- 7.31)
present - L4-proximal disease (HR 1.83;
95% CI 1.07–3.15)
Sun et al 2019 Predictor of abdominal surgery Significant: Increased odds of - Predictor of abdominal surgery
Proximal ileal disease vs EGD disease undergoing abdominal surgery (OR: 6.335) P<0.001
Jejunal disease vs EGD disease Significant: EGD had lowered rates - Proximal ileal disease vs EGD
of surgery compared to Proximal disease, (72.2% vs. 37.7%,
Ileal and jejunal disease 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 HR:1.37 (1.08–1.74), P<0.05
risk of initial surgery even after
controlling for age, sex, smoking,
and drinking
Greuter et al 2018 CD related surgery Non-Significant: No significant - OR:1.046 (0.785–1.394) 0.760
associations were found when
comparing between patients with
UGI-CD and patients with
non-UGI-CD
Park et al 2013 Major surgery rates Non-Significant: Proportion of - Jejunal (75/198, 37.9%) vs
patients undergoing major surgery non-jejunal (396/1205, 32.9%)
between jejunal and non-jejunal groups (P = 0.168).
patients were not significantly
different
Saadah et al 2012 Surgical Resection Rates Non-Significant: Comparable (2/19 (10.5%) vs. 5/59 (8.5%),
surgical resection rates P=1.00)
Anti-TNF – Anti-Tumour Necrosis Factor; EGD – Esophagogastroduodenal; HR – Hazard Ratio; OR – Odds Ratio; RR – Risk Ratio; UGI-CD – Upper Gastrointestinal Crohn’s
Disease.

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Y.H. Chin, C.H. Ng, S.Y. Lin et al.
Fig. 3. Graphical abstract depicting the summary of findings.
and jejunal disease (52% vs 37.7%, P=0.036) [25], while Lazarev
et al. found that L4-EGD disease had lower rates of surgery as com-
pared to L4-jejunal disease(14% vs 38%; P < 0.001) [10]. Lazarev
et al. and Mao et al. both found that L4-jejunal disease was associ-
ated with a higher risk of surgery compared to L4-proximal disease
[10].
4. Discussion
This systematic review and meta-analysis summarized the
prevalence of upper gastrointestinal involvement in CD, its risk fac-
tors, complications, and clinical outcomes (Fig. 3). In this system-
atic 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 Con-
sortium cohort of 16% [10]. Studies of UGI-CD in which diagnosis
was made by endoscopy revealed a prevalence of 23% (CI: 13% -
35%).
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 in-
creasing trend for the prevalence of UGI-CD by year, which coin-
cides 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 en-
tity. Moreover, we noted differences in the prevalence assessed by
9
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Digestive and Liver Disease xxx (xxxx) xxx
the Vienna versus the Montreal classifications [5,16]. Studies using
the Montreal Classification depicted a higher rate of UGI-CD (14%
vs 10%). The Montreal Classification, being the newer system, to-
gether with more advanced diagnostic tests, could have accounted
for the differences.
Our systematic review suggested that young male patients pre-
senting with erythema nodosum [4,10,25], aphthous ulcers and
stricturing-phenotype CD are associated with an increased risk of
development of UGI-CD [7]. UGI-CD patients usually have an initial
operation at diagnosis and receive anti-TNF therapy [4]. Some of
the factors, such as young age at diagnosis and stricturing pheno-
type, are identified as high-risk factors for an aggressive course of
CD [48]. Sun et al also showed that UGI-CD was associated with CD
relapse in 36% of UGI-CD patients [25]. The prevalence of abdomi-
nal surgery among UGI-CD was as high as 66.7%, which was higher
than CD overall surgical rate of 47% [49]. UGI-CD was also an in-
dependent risk factor for surgery, hospitalization, and overall com-
plications (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 aggres-
sively with modern treatment paradigms such as treat-to-target
and early treatment escalation, in order to prevent irreversible in-
testinal damage or surgical resections. Intestinal ultrasound and fe-
cal calprotectin would be additional tools that would assist in the
best-care of such patients [50].
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Y.H. Chin, C.H. Ng, S.Y. Lin et al.
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
[10,25,29]. The poorer prognosis associated with L4-jejunal dis-
ease 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 [51]. 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) [10,52]. 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. [29]. 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 [10,29].
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 sig-
nificance. Though our findings was statistically insignificant, differ-
ences 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) [53]. The reasons for differences in
prevalence found by Kim et al. may be due to genetic, environ-
mental 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 [54]. Other genes, how-
ever, such as the tumor necrosis factor superfamily 15 gene (TN-
FSF15) [55], were found to have a higher odds ratio in Asians
than in Caucasians. However, other factors such as smoking, pa-
tient and physician preferences to treatment procedures that af-
fect the prevalence of UGI-CD may have greater contribution to
the prevalence of UGI-CD and could have confounded our analy-
sis, leading to the insignificance of the results in our findings [14].
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 clas-
sifications. However, this meta-analysis also concedes some limita-
tions. 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 [56,57] with many meta-analysis
of prevalence depicting substantial heterogeneity of more than 90%
[58,59]. There is also a lack of representation of articles from the
African and South American regions, which further limits the gen-
eralizability of the paper. Next, most included articles were retro-
spective 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
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Digestive and Liver Disease xxx (xxxx) xxx
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 pre-
senting 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 concur-
rent ileocolonic disease and stricturing-phenotype compared with
Caucasians. Because UGI-CD may be subclinical, patients might re-
quire 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.
Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.dld.2021.07.037.
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