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Manuscript Doi: 10.

1093/ecco-jcc/jjad038

Diagnosis and Clinical Features of Perianal Lesions in Newly Diagnosed Crohn’s

Disease: Subgroup Analysis from Inception Cohort Registry Study of Patients with

Crohn's Disease (iCREST-CD)

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Takayuki Yamamoto,a Hiroshi Nakase,b Kenji Watanabe,c Shinichiro Shinzaki,c,d Noritaka

Takatsu,e Toshimitsu Fujii,f Ryuichi Okamoto,f Katsuyoshi Matsuoka,g Akihiro Yamada,g

Reiko Kunisaki,h Minoru Matsuura,i Hisashi Shiga,j Shigeki Bamba,k Yohei Mikami,l

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Takahiro Shimoyama,a Satoshi Motoya,m Takehiro Torisu,n Taku Kobayashi,o Naoki

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Ohmiya,p Masayuki Saruta,q Koichiro Matsuda,r Takayuki Matsumoto,s Atsuo Maemoto,t

Yoko Murata,u Shinichi Yoshigoe,u Shinya Nagasaka,u Tsutomu Yajima,v Tadakazu

Hisamatsu,i,* iCREST-CD Study Group


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an
a
Department of Surgery and Inflammatory Bowel Disease Centre, Yokkaichi Hazu Medical
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Centre, 10-8 Hazuyama-cho Yokkaichi, Mie, Japan


b
Department of Gastroenterology and Hepatology, Sapporo Medical University School of
d

Medicine, 16-291 South-1 jo-nishi, Chuo-ku, Sapporo, Hokkaido, Japan


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c
Centre for Inflammatory Bowel Disease, Division of Gastroenterology and Hepatology,
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Department of Internal Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan


d
Department of Gastroenterology and Hepatology, Osaka University Graduate School of
c

Medicine, Suita, Osaka, Japan


Ac

e
Department of Inflammatory Bowel Disease Centre, Fukuoka University Chikushi Hospital,

1-1-1 Zokumyoin Chikushino Fukuoka, Japan


f
Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-

5-45 Yushima, Bunkyo-ku, Tokyo, Japan

© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License
(https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction
in any medium, provided the original work is properly cited. For commercial re-use, please contact
[email protected]
Manuscript Doi: 10.1093/ecco-jcc/jjad038

g
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho

University Sakura Medical Centre, 564-1 Shimoshizu, Sakura, Chiba, Japan


h
Inflammatory Bowel Disease Centre, Yokohama City University Medical Centre, 4 -57

Urafune-cho, Minami-ku, Yokohama, Kanagawa, Japan

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i
Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, 6-

20-2 Shinkawa, Tokyo, Japan

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ip
j
Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1 -1 Seyro-

machi, Aoba-ku, Sendai, Miyagi, Japan

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k
Division of Digestive Endoscopy, Shiga University of Medical Science, Seta Tsukinowa-

cho, Otsu, Shiga, Japan


l us
an
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio

University, 35 Shinanomachi, Shinjiku-ku, Tokyo, Japan


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m
IBD Centre, Hokkaido Preventive Welfare Federation of Agricultural Cooperative,

Sapporo-Kosei General Hospital, 8-5 Kita-3 johigashi, Chuo-ku, Sapporo, Hokkaido, Japan
d

n
Department of Medicine and Clinical Science, Graduate School of Medical Sciences,
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Kyushu University, Fukuoka, Japan, 3-1-1, Maidashi, Higashi-ku, Fukuoka, Fukuoka, Japan
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o
Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute

Hospital, 5-9-1, Shirokane, Minato-ku, Tokyo, Japan


c

p
Ac

Department of Advanced Endoscopy, Fujita Health University School of Medicine, 1 -98

Dengakukubo, Kutsukake-Cho, Toyoake, Aichi, Japan


q
Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei

University School of Medicine, 3-19-18 Nishi- shinbashi, Minato-ku, Tokyo, Japan


r
Department of Gastroenterology, Toyama Preventive Central Hospital, 2 -2 -78, Nishinagae,

Toyama, Japan
Manuscript Doi: 10.1093/ecco-jcc/jjad038

s
Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate

Medical University, 10 -1, Uchimaru, Morioka, Iwate, Japan


t
IBD Centre, Sapporo Higashi Tokushima Hospital, 3-1, Kita 33 Higashi 14, Higashiku,

Sapporo, Hokkaido, Japan

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u
Immunology, Medical Affairs Division, Janssen Pharmaceuticals K.K., 3-5-2 Nishi-Kanda,

Chiyoda-ku, Tokyo, Japan

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v
Statistics and Decision Sciences (SDS), Janssen Pharmaceuticals K.K., 3-5-2 Nishi-Kanda,

Chiyoda-ku, Tokyo, Japan

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Collaborators: iCREST-CD Study Group

• Masakazu Nagahori, Department of Gastroenterology and Hepatology, Tokyo


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Medical and Dental University

• Tatsu Yukawa, Inflammatory Bowel Disease Centre Yokohama City University


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Medical Centre

• Daisuke Saito, Department of Gastroenterology and Hepatology, Kyorin University


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School of Medicine

• Mikio Kawai, Department of Intestinal Inflammation Research, Hyogo College of


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Medicine
c

• Atsushi Masamune, Division of Gastroenterology, Tohoku University Graduate


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School of Medicine

• Mitsuo Nagasaka, Department of Gastroenterology, Fujita Health University School

of Medicine

• Tomoe Kazama, Department of Gastroenterology and Hepatology, Sapporo Medical

University School of Medicine


Manuscript Doi: 10.1093/ecco-jcc/jjad038

Abbreviations

BMI: body mass index

CD: Crohn's disease

CT: Computed Tomography

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CRP: C-reactive protein

EIM: extra-intestinal manifestation

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HBI: Harvey-Bradshaw Index

IBD: inflammatory bowel disease

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ICF: informed consent form

IEC: Independent Ethics Committee


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MHLW: Ministry of Health, Labour and Welfare

MRI: Magnetic Resonance Imaging


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QoL: quality of life

RBC: red blood cell


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SIBDQ: Short Inflammatory Bowel Disease Questionnaire


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WBC: white blood cell


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Corresponding author: Tadakazu Hisamatsu, Department of Gastroenterology and

Hepatology, Kyorin University School of Medicine, Tokyo, Japan, 6-20-2 Shinkawa, Mitaka,
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Tokyo 181–8611, Japan. Tel.: 81-422-47-5511; Fax: 81-422-44-0655; Email:

[email protected]

Conference presentations: Poster presentation at the 12th annual meeting of the Japan

Society for Inflammatory Bowel Disease, November 26-27, 2021, Japan.


Manuscript Doi: 10.1093/ecco-jcc/jjad038

Abstract

Background and Aims: Perianal lesion is a refractory phenotype of Crohn's disease (CD)

with significantly diminished quality of life. We evaluated the clinical characteristics of

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perianal lesions in newly diagnosed CD patients and the impact of perianal lesions on the

quality of life in Japanese patients with CD.

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Methods: Patients newly diagnosed with CD after June 2016 were included between

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December 2018 and June 2020 from the Inception Cohort Registry Study of Patients with CD

(iCREST-CD).
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Results: Perianal lesions were present in 324 (48.2%) of 672 patients with newly diagnosed
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CD. 71.9% (233/324) were male. The prevalence of perianal lesions was higher in patients

aged <40 years versus ≥40 years, and it decreased with age. Perianal fistula (59.9%) and
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abscess (30.6%) were the most common perianal lesions. In multivariate analyses, male sex,
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age <40 years, and ileocolonic disease location were significantly associated with a high
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prevalence of perianal lesions, whereas stricturing behaviour and alcohol intake were

associated with low prevalence. Fatigue was more frequent (33.3% vs 21.6%) and, work
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productivity and activity impairment-work time missed (36.3% vs 29.5%) and activity

impairment (51.9% vs 41.1%) were numerically higher in patients with than those without

perianal lesions.

Conclusions: At the time of CD diagnosis, approximately half of the patients had perianal

lesions; perianal abscesses and perianal fistulas were the most common. Young age, male

sex, disease location, and behaviour are significantly associated with the presence of perianal
Manuscript Doi: 10.1093/ecco-jcc/jjad038

lesions. The presence of perianal lesion was associated with fatigue and impairment of daily

activities.

Clinical trials registry: University Hospital Medical Information Network Clinical Trials

Registry System (UMIN-CTR, UMIN000032237)

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Keywords (3 words): Crohn's disease; Patient-reported outcomes; Perianal lesion

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Manuscript Doi: 10.1093/ecco-jcc/jjad038

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Graphical abstract

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Manuscript Doi: 10.1093/ecco-jcc/jjad038

1. INTRODUCTION

Crohn‟s disease (CD) is a chronic transmural inflammatory bowel disease (IBD).1-3 The

incidence of perianal lesions in patients with CD has been reported to be in the range of 20–

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40% worldwide,4,5 with a higher incidence of 30.3–58.8% in Asian countries.6, 7 An estimated

26% of patients with CD develop perianal fistula within two decades of the diagnosis.4 The

natural course of perianal CD may be affected by the location of the disease, age at diagnosis,

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type of intestinal fistula, and the presence of abscesses and intestinal strictures.8, 9
The

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retrospective Crohn's Disease Clinical Network and Cohort (CONNECT) study from Korea

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reported a significant association of perianal fistula with young age, male gender, diagnosis

of CD at primary care centres, and ileocolonic involvement.7


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Perianal lesions, especially perianal fistula in patients with CD are a marker of chronic,

debilitating, and aggressive disease, which can cause pain, swelling, and discharge in the
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perianal region.10 This condition has a major negative effect on the health-related quality of
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life (HRQoL) through increased morbidity, resulting from sphincter and perineal tissue
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destruction, physical disability, and a weakened sexual and psychological state.5, 11, 12 Studies

have demonstrated the association of perianal fistula with greater disease burden, adversely
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affected HRQoL, and high healthcare costs.13


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The diagnosis and treatment of perianal lesions, however, are challenging; an accurate
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understanding of the clinical features and the natural course of perianal CD is paramount in

providing the most appropriate therapeutic strategy.13 The Inception Cohort Registry Study of

Patients with Crohn's Disease (iCREST-CD), is an ongoing large-scale, multicentre,

prospective registry in Japan that is aimed at investigating the onset, diagnosis, and treatment

of newly diagnosed patients with CD. An interim analysis of the iCREST-CD study revealed

the demographics and disease characteristics of newly diagnosed CD patients and


Manuscript Doi: 10.1093/ecco-jcc/jjad038

demonstrated that the disease phenotype varied between patients <40 years and ≥40 years of

age.14

In this current report, we present a subgroup analysis of the iCREST-CD study to understand

the natural history and clinical characteristics of perianal lesions of CD, to provide an

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understanding of the diagnostic and clinical aspects of perianal lesions, and to assess their

impact on the activities of daily living in newly diagnosed patients with CD. This study

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comprehensively and thoroughly evaluates the clinical features of perianal lesions associated

with newly diagnosed CD using the nationwide registry database.

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2. MATERIALS AND METHODS

2.1 Study Design


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As aforementioned, the iCREST-CD is a prospective cohort study being conducted
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at 19 tertiary centres in Japan, with an observation period until June 2024. The

details of the study design have been described in the primary publication of the
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iCREST-CD study.14 The present study is a subgroup analysis using a prospectively


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maintained database (iCREST-CD) to investigate the impacts of perianal lesions on


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the clinical features of patients with newly diagnosed CD.

2.2 Study Population


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Male and female patients, newly diagnosed with CD as per the Japanese diagnostic

criteria (including suspected diagnosis)15-17 after 1st June 2016, aged ≥16 years at the

time of informed consent, were enrolled from December 17, 2018 to June 30, 2020.

Patients with an unknown date of diagnosis of CD and/or those who had used a

biologic agent indicated for autoimmune disease prior to the diagnosis of CD were

excluded.
Manuscript Doi: 10.1093/ecco-jcc/jjad038

2.3 Data Collection

Patients were identified from the medical records, and the data prospectively collected

from the day of informed consent were obtained. The data on activities of daily living

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and quality of life (QoL) were self-reported by patients. Patient-completed

questionnaires were recorded into the study database through an internet-based

application by patients‟ smartphone or tablet terminals and were considered as source

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data. Patients will be prospectively followed up for 4 years during the observation

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period; additionally, retrospective data will be collected. Data such as patient

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demographics, clinical characteristics, and imaging tests from the initial diagnosis

until the enrolment were retrospectively collected. An interim analysis of the


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iCREST-CD study was conducted on Japanese patients registered in this study. The

current interim analysis of the iCREST-CD study describes the clinical characteristics
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of patients with perianal involvement at the time of diagnosis of CD. The longitudinal

perianal data after the diagnosis of CD will be analysed in our future studies.
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2.4 Study Investigations


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The study investigations included the patient demographics, clinical characteristics,

clinical evaluation, and patient-reported outcomes (PROs). The patient demographic


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and clinical characteristic data included age, gender, age at disease onset, CD
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characteristics, body mass index (BMI), extra-intestinal complications, history of

hospitalisation, and occupation. Other clinical observations included the types of

perianal lesions observed at the definitive diagnosis of CD, the implementation rate of

imaging tests (colonoscopy, small bowel follow-through, balloon-assisted endoscopy,

small bowel capsule endoscopy, bowel ultrasonography, computed tomography [CT]


Manuscript Doi: 10.1093/ecco-jcc/jjad038

enterography, and magnetic resonance [MR] enterography), and the sites of intestinal

involvement associated with perianal lesions at diagnosis of CD.

The characteristics of intestinal lesions by perianal lesion type at the diagnosis of CD

were determined by (i) the location and type of intestinal lesions, (ii) the location and

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behaviour of intestinal lesions through the modified Montreal system of

classification,18 and (iii) the types of fistula and abscesses in the intestinal lesions.

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Clinical evaluation was performed using the imaging findings and the Harvey-

Bradshaw Index (HBI). Disease activity in patients with perianal lesions at the

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diagnosis of CD was determined using HBI, patient general well-being, abdominal

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pain, and the number of liquid/soft stools at diagnosis.
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For PROs of lifestyle survey, health status, and QoL, data were collected using an

internet-based application for patients who provided written informed consent at the
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time of study enrolment (December 17, 2018 to June 30, 2020). The baseline PROs

could not be collected from patients who were already diagnosed with CD prior to this
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period. The health status of patients was determined by their general condition and
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abdominal pain.
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Quality of life was measured through the impairment of daily living activities using

the Functional Assessment of Chronic Illness Therapy-Fatigue scale version 4


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(FACIT-Fatigue),19, 20
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Work Productivity and Activity Impairment Questionnaire-

General Health version 2.2 (WPAI-GH),21, 22


and Short-form Inflammatory Bowel

Disease QoL (SIBDQ).23 The lifestyle survey evaluated the frequency of meals,

smoking and drinking history, amount of exercise, sleep, and work status.
Manuscript Doi: 10.1093/ecco-jcc/jjad038

2.5 Statistical Analysis

This subgroup analysis from the interim data of the iCREST-CD study was performed

after the last patient was enrolled. Data at the time of CD diagnosis were taken from

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the data closest to the date of diagnosis within 3 months before and after CD

diagnosis. The statistical analysis was performed on SAS System version 9.4 (SAS,

Japan). Summary statistics, frequency, and proportion were calculated for the patient

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characteristics at the time of CD diagnosis. Age-wise and gender-wise distribution of

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the prevalence of perianal lesions was reported. The distribution of location and

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behaviour of intestinal CD in patients with and without perianal lesions was compared

using the Fisher‟s exact test. The difference in the types of perianal lesions was also
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evaluated in the male and female patient subgroups using the Fisher's exact test.

Differences in patient characteristics at the diagnosis of CD were assessed using the


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chi-square test (age at diagnosis – modified Montreal classification, smoking history,

alcohol history, and social background), Fisher's exact test (gender, age at diagnosis –
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Vienna classification, diagnosis of CD) and Student t-test (mean age at diagnosis,

BMI). The chi-square test was conducted to compare differences in the disease
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activity classification, well-being status, abdominal pain, and episodes of liquid stools
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according to the Bristol Scale. The Student t-test was used for the differences in the
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mean HBI scores between patients with/without perianal lesions. To determine the

presence of significant associations between risk factors and perianal lesions in

patients with CD, logistic regression analysis was performed. The univariate analysis

included sex, age, BMI, family history, disease location, disease behaviour, extra-

intestinal manifestation (EIM), smoking history, and alcohol intake as covariates; all

patients observed for each item were included. Subsequently, multivariate analysis
Manuscript Doi: 10.1093/ecco-jcc/jjad038

was performed to determine the dependent variables; only patients with data available

for all covariates (sex, age, BMI, family history, disease location, disease behaviour,

EIM, smoking history, and alcohol intake) were included. Fischer‟s exact test was

carried out to compare significant differences in the FACIT-Fatigue score categories

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(<30 vs. ≥30). To detect significant differences in the WPAI-GH and SIBDQ scores

between subgroups, a Student t-test and/or a Wilcoxon rank sum test was performed.

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P<0.05 was considered statistically significant.

3. RESULTS

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3.1 Eligibility for the Study and the Summary of the Eligible Patients

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A total of 673 newly diagnosed patients with CD were enrolled, of which, 672
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patients (male: 458, female: 214; the mean age at diagnosis of CD: 29.4 years) were

eligible for the interim analysis. One patient did not meet the diagnosis (probable)
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criteria; the subsequent re-diagnosis was ulcerative colitis. This patient was excluded

from the analysis. The detailed information for the patient baseline characteristics of
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the 672 patients is presented in Table 1.


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3.2 Prevalence of Perianal Lesions


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Perianal lesions were present in 48.2% of patients (324/672) and absent in 50.3% of

patients (338/672); data not available for the remaining 10 patients. In patients with
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perianal lesions, 94.4% (306/324) had a definitive diagnosis of CD, whereas 5.6% (18

patients) had a suspected diagnosis. Only two of the 324 patients (0.6%) showed

Crohn‟s perianal lesions without involvement of intestine (perianal fistula for both

patients). The majority (71.9%; 233/324) of patients with perianal lesions were male,

and the mean±standard deviation (SD) age at diagnosis was 25.6±9.3 years (Table 1).

Perianal lesions were more common in younger patients (<40 years), and the

prevalence of perianal lesions decreased with age (Table 1, Figure 1A). The
Manuscript Doi: 10.1093/ecco-jcc/jjad038

proportion of patients younger than 40 years was significantly higher in patients with

perianal lesions as compared with those without perianal lesions (92% [298/324] vs.

70.1% [237/338]; P<0.001; Table 1). Patients younger than 16 years of age had the

highest prevalence of perianal lesions (63%), while elderly patients over 75 years of

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age did not have perianal lesions (Figure 1A). With respect to the subgroups of age

(<40 years vs. ≥40 years) and sex (male vs. female), the prevalence of perianal lesions

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was the highest in young males (aged <40 years) as compared with those older than

40 years, or female patients (Figures 1A, 1B, 1C). The mean BMI was not

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significantly different between patients with and without perianal lesions (Table 1).

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The proportion of patients with and without perianal lesions having a history
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(current/past) of smoking (31.9% vs. 31.8%) and current alcohol intake (59.7% vs.

56.1%) was comparable. In the social background, there was a significant difference
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between patients with and without perianal lesions across the different categories

(P=0.004, Table 1).


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[Insert Table 1 here]


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[Insert Figure 1 here]


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3.3 Types of Perianal Lesions

In a total of 672 patients, the most common type of perianal lesion observed at the
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time of CD diagnosis was perianal fistula (59.9%), followed by perianal abscess

(30.6%), skin tag (19.1%), perianal fissure (18.5%), ulcer (11.1%), stenosis (4.6%),

and others (3.7%) (Table 2). 58 (58.6%) of 99 patients with perianal abscess had an

underlining fistula. In both males and females, perianal fistulas were the most

common type of perianal lesions (66.5% and 42.9%, respectively). The second most

common type of lesion observed was perianal abscess (32.6%) in males and skin tag

(36.3%) in females (Table 2). The prevalence of both perianal fistulas and abscesses
Manuscript Doi: 10.1093/ecco-jcc/jjad038

was numerically higher in males. Skin tags were more commonly observed in females

(36.3% vs. 12.4% in males, P<0.001), and the prevalence of ulcers were numerically

higher in females (15.4% vs. 9.4% in males, P=0.167). The prevalence of fissure and

stenosis was similar between males and females.

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[Insert Table 2 here]

3.4 Disease Activity

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At the diagnosis of CD, the mean HBI score was similar in patients with and without

perianal lesions (Table 3), although the disease activity was affected not only by

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perianal lesions but also by coexisting intestinal lesions and EIMs. There was no

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difference between patients with and without perianal lesions based on the severity of
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disease activity, the status of general well-being, and abdominal pain. Overall, the

patients with EIMs were low (24/672; 3.6%, Table 4). The prevalence of EIMs was
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similar between patients with vs. without perianal lesions (4.0% vs 3.0%), with

erythema nodosum being the most frequent complication in patients with (3.4%) or
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without (2.1%) perianal lesions. The levels of laboratory markers including white
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blood cells (WBC), platelets, and erythrocyte sedimentation rate (ESR) were
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significantly higher in patients with perianal lesions at the diagnosis of CD

(Supplementary Table 1).


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[Insert Table 3 here]

[Insert Table 4 here]

3.5 Location and Behaviour of Coexisting Intestinal CD

The distribution of intestinal location and disease behaviour in patients with and

without perianal lesions is shown in Figure 2. The most common location was L3

(ileocolonic), followed by L1 (ileal) and L2 (colonic) in both patients with and

without perianal lesions (Figure 2A). Ileocolonic disease location was significantly
Manuscript Doi: 10.1093/ecco-jcc/jjad038

higher and ileal location was significantly lower in patients with perianal lesions

compared to those without (both P<0.001). The most common behaviour was B1

(inflammatory), followed by B2 (stricturing) and B3 (penetrating), in patients with

and without perianal lesions (Figure 2B). The proportion of inflammatory CD was

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significantly higher in patients with perianal lesions (68.2% vs. 57.7%, respectively;

P=0.006), while stricturing CD was significantly lower in patients with perianal

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lesions compared to those without (19.1% vs. 32.2%, respectively; P<0.001). Details

of behaviour and location of intestinal CD in patients with each type of perianal lesion

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are presented in Supplementary Table 2.

[Insert Figure 2 here]


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3.6 Clinical Factors Associated with Presence of Perianal Lesions at the

Diagnosis of CD
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In univariate analyses, sex, age, ileocolonic location (L3 vs. L1), stricturing behaviour

(B2 vs. B1), history of smoking, and alcohol intake were found to be significantly
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(P<0.05) associated with the presence of perianal lesions, while no association was
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found with colonic location (L2 vs. L1), positive EIMs, BMI, family history, and
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penetrating disease behaviour (B3 vs. B1). Multivariate multiple regression analyses

(odds ratio, OR [95% confidence interval]) further confirmed that male sex (1.566
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[1.029-2.384], P=0.037), age <40 years (4.181 [2.288-7.639, P<0.001), and

ileocolonic location L3 (2.259 [1.379-3.700]; P=0.001 vs. L1) were significantly and

independently associated with a high prevalence of perianal lesions (Table 5). In

contrast, stricturing behaviour B2 (0.544 [0.345-0.856]; P=0.009 vs. B1) and a history

of alcohol intake (0.589 [0.376-0.922]; P=0.020) were significantly and independently

associated with a low prevalence of perianal lesions (Table 5).

[Insert Table 5 here]


Manuscript Doi: 10.1093/ecco-jcc/jjad038

3.7 Impacts on Activities of Daily Living

Participation in daily activity questionnaires was encouraged but not mandatory. The

data on activities of daily living were available in 138 patients (72 in patients with

perianal lesions and 66 in those without perianal lesions). The proportion of patients

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experiencing fatigue (FACIT-Fatigue <30) was higher in patients with vs. without

perianal lesions (29.2% vs. 21.6%; P=0.465); however, the difference was not

t
ip
significant (Figure 3A). Patients with perianal lesions had numerically higher WPAI

scores on missing work time “absenteeism” (36.3% vs. 29.5%; P=0.645), impairment

cr
at work “presenteeism” (35.6% vs. 31.5%; P=0.610), overall work productivity loss

us
(33.0% vs. 30.0%; P=0.683), and activity impairment (51.9% vs. 41.1%; P=0.102)
an
when compared with patients without perianal lesions (Figure 3B). The mean SIBDQ

total score did not significantly differ in patients with perianal lesions vs. without
M

perianal lesions (48.2 vs. 49.8; P=0.581). Similarly, the SIBDQ systemic, social,

bowel, and emotional sub scores were not significantly different between the two
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groups (Figure 3C).


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[Insert Figure 3 here]


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4. DISCUSSION

Perianal lesion, particularly perianal fistula, is an aggressive disease phenotype that can have
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Ac

a substantial detrimental impact on QoL of patients with CD. Crohn‟s perianal fistulas exert a

heavy negative physical and emotional impact on patients. The natural history of perianal CD

remains poorly described and is mostly based on retrospective studies from referral centres.

Our prospective cohort study comprehensively and thoroughly investigated patients with

various types of perianal lesions at the diagnosis of CD. The impacts of demographic and

habitual parameters along with disease presentation of coexisting intestinal CD and EIM on

the prevalence of perianal lesions were evaluated based on univariate and multivariate
Manuscript Doi: 10.1093/ecco-jcc/jjad038

statistical analyses. To our knowledge, no previous research has assessed harmful effects of

perianal lesions on the health status and QoL of patients at the diagnosis of CD. To resolve

this issue, we prospectively collected the PRO data using three types of questionnaire surveys

such as FACIT-Fatigue, WPAI-GH, and SIBDQ.

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In a Western cohort study from Olmsted county in Minnesota, the cumulative incidence of

perianal fistula was 21% at 10 years and 26% at 20 years after the diagnosis of CD.4 A cohort

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study from Stockholm county reported that anorectal fistulas occurred in 13.7% of 1293

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patients before or after the diagnosis of CD.24 In a recent French cohort study, at the time of

diagnosis of CD, 116 (4%) of 2906 patients had fistulizing perianal CD.25 The prevalence of

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perianal lesions in Asian patients with CD appears to be much higher than that of Western
an
countries. Consistent with the high prevalence reported among the Asian population (30.3–

58.8%), perianal lesions were present in 48.2% of the patients included in the iCREST
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study.6, 7 The multicentre, retrospective CONNECT study showed the prevalence of perianal

fistula in 39% (n=465) of patients with CD.7 The results from the Hong Kong territory-wide
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IBD Registry (HKIBDR) showed perianal involvement at diagnosis in 42.4% of patients. 26

Male sex was more prevalent in the population of patients with perianal lesions (71.9%) and
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in the overall study population (68%); this is also in line with the results reported by Zhu et
c

al. (76.9%) in their single-centre study in Chinese patients,27 and the CONNECT (73.8%)7
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and the HKIBDR studies (78.8%).26 Furthermore, the HKIBDR study showed that the male

gender was significantly associated with the development of perianal CD.26

In our study, perianal lesions are more prevalent in patients with disease onset between 17-40

years of age. The CONNECT study also showed a significant association between perianal

lesions with a younger age at diagnosis.7 Similar to our study, most of the patients aged 17–

40 years in the CONNECT study7 had perianal lesions present (82.7% and 81.1%,
Manuscript Doi: 10.1093/ecco-jcc/jjad038

respectively). In the HKIBDR study, younger age at diagnosis of CD was associated with the

development of perianal lesions.26 A decrease in the proportion of both male and female

patients with perianal lesions with increasing age was noted in our study. The higher

prevalence of perianal fistulas in male and young CD patients was also confirmed in the

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Western cohort studies.4,24,25 The reason for the high prevalence of perianal lesions in young

and male patients with CD remains unknown, although the role of genetic, microbiological,

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and immunological factors has been investigated in the pathogenesis of perianal CD.28

Our results showed that perianal fistulas and perianal abscesses were the most common types

cr
of perianal lesions (59.9% and 30.6%, respectively). These are corroborated by the results of

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Zhu et al. and HKIBDR studies, wherein the majority of patients with perianal lesions had

anal fistula followed by perianal abscess.26,27 In our study, the prevalence of both perianal
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fistulas and abscesses were numerically higher in males than in females. In contrast, skin tag
M

was more commonly observed in females (36.3% vs. 12.4% in males) and the prevalence of

the ulcer was only numerically higher in females (15.4% vs. 9.4% in males).
d

Our multivariate analyses found that in addition to male sex and age <40 years, increased
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prevalence of perianal lesions was significantly associated with ileocolonic disease location,
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whereas stricturing CD and alcohol intake were associated with decreased prevalence of

perianal lesions. The presence of perianal lesions was reported to be associated with
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coexisting intestinal CD.29,30 Ileocolonic involvement was present in 69.1% of patients in our
Ac

study, while the same was reported in 51.9% of patients by Zhu et al.,27 44.9% of patients in

the HKIBDR study,26 and 69.7% of patients in the CONNECT study.7 In another study, the

rectum and sigmoid colon are the most frequently involved regions; the more distal the

intestinal site of CD, the higher the risk of perianal CD.30 The impact of the location of

intestinal CD on perianal lesions needs to be further investigated. The inflammatory disease

behaviour in 68.2% of patients in our study is also in line with findings of the HKIBDR study
Manuscript Doi: 10.1093/ecco-jcc/jjad038

(56.5%)26 and Zhu et al. (75.0%).27 Non-perianal fistulas and intra-abdominal abscesses were

significantly more common in CD patients with perianal lesions compared to those without in

the CONNECT study.7 In our study, the prevalence of the penetrating type in intestinal CD

was 11.4% in patients with perianal lesions. This prevalence data of penetrating type lesions,

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though lower than expected, may be appropriate since we studied the patients at the diagnosis

of CD, and it will increase with time. Additionally, it is interesting to see the prevalence of

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stricturing CD is significantly lower in patients with vs. without perianal lesions. The present

study investigated patients at the diagnosis of CD and therefore, the majority of the patients

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had inflammatory behaviour of intestinal CD. The prevalence of stricturing behaviour will

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increase with time along with penetrating disease behaviour. The change in disease behaviour
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of intestinal CD after the diagnosis of perianal lesions should be further investigated with a

longer observation time. In our study, alcohol intake was associated with a low prevalence of
M

perianal lesions. However, patients with perianal symptoms might quit the consumption of

alcohol before the diagnosis of CD. The impacts of smoking and alcohol consumption on the
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occurrence and progression of perianal lesions should be re-investigated with a longer


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observational period.
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Previous studies have reported that compared to healthy individuals, patients with CD usually

feel fatigued.31-34 The FACIT-Fatigue scale is a generic PRO instrument to assess and
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Ac

compare the degree of fatigue regardless of any disease, with higher scores indicating lesser

fatigue. Complications or conditions other than perianal lesions or CD may affect the findings

of fatigue. In this study, the proportion of patients experiencing fatigue (FACIT-Fatigue <30)

was numerically higher in patients with vs. without perianal lesions (29.2% vs. 21.6%).

Fatigue has been associated with work productivity loss and reduced health-related QoL.35

The presence of active perianal disease was a predictor of work productivity loss in the

WORK-IBD study.35 The WPAI questionnaire is a validated PRO tool to evaluate work
Manuscript Doi: 10.1093/ecco-jcc/jjad038

productivity impairment due to perianal CD as impaired work time resulted from both

absenteeism (work time missed) and presenteeism (impairment while working);22,36 higher

scores indicate severe impairment. In the present study, patients with perianal lesions had

numerically higher WPAI scores on missing work time (absenteeism: 36.3% vs. 29.5%),

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impairment at work (presenteeism: 35.6% vs. 31.5%), overall work productivity loss (33.0%

vs. 30.0%), and activity impairment (51.9% vs. 41.1%) as compared with those without

t
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perianal lesions. Particularly, activity impairment was more frequently observed in the

presence of perianal lesions. In our study, patients with perianal lesions frequently presented

cr
with fatigue and impairment of work productivity and daily activities; however, the

us
differences between patients with and without perianal lesions were not statistically
an
significant, probably because the data on activities of daily living were available in limited

patients.
M

Disease severity is correlated with poor QoL in CD patients.37, 38


SIBDQ is a simplified

version of the IBDQ, with higher scores indicating better QoL. In our study, there was no
d

significant difference in the SIBDQ total score and subscores (systemic, social, bowel, and
te

emotional subscores) between patients with and without perianal lesions. A cross-sectional
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prospective study showed similar mean SIBDQ scores in patients with vs. without perianal

lesions (49.53 vs. 48.71).39 The overall higher SIBDQ score reported in our study suggests
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Ac

improved QoL and is reflective of the disease severity which was “mild” or “in remission” in

the majority of patients. The lowest score was obtained for the systemic symptoms domain

(subscore) and the highest score was observed for the bowel symptoms domain, similar to the

findings reported by Parra et al. in their observational study.36 The SIBDQ is an index

evaluated mainly to determine the deterioration of QoL caused by intestinal symptoms. 23

Hence, deterioration of QoL caused by perianal lesions cannot be properly reflected by this

index. Data from future studies using the newly developed and validated PRO measure, the
Manuscript Doi: 10.1093/ecco-jcc/jjad038

Crohn's Anal Fistula Quality of Life (CAF-QoL) scale40, may provide valuable insights on

the impact on QoL due to perianal CD.

There are no established and validated methods to timely and accurately diagnose perianal

CD in clinical practice. The morphology, anatomy, and activity of perianal CD are varied and

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changeable. Therefore, it is challenging to obtain a precise diagnosis of perianal CD and

accurately determine its prevalence. In addition, the clinical evaluation of patients with CD

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with perianal lesions is affected by the presence of coexisting intestinal lesions; only a few

patients with CD with perianal lesions did not display the presence of intestinal lesions.

cr
Further, the data on activities of daily living were available in only a limited number of

us
patients since the survey was not mandatory; this may have led to statistically non-significant
an
results. As this study presents the data on perianal lesions at the early stage of CD diagnosis,

further studies are warranted to ascertain these findings in the later stages of the disease.
M

At the time of CD diagnosis, nearly half of the patients had perianal lesions with a higher

prevalence observed in males and younger patients. Additionally, perianal abscess/fistula


d

tended to be more common than other types of lesions. Patients with perianal lesions
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frequently experienced fatigue and impairment of daily activities, including missing work
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time, impairment at work, and work productivity loss. The 4-year follow-up data from this

registry study will provide robust evidence on the characteristics of perianal disease in newly
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Ac

diagnosed patients with CD in a real-world clinical setting.


Manuscript Doi: 10.1093/ecco-jcc/jjad038

Funding

This study was funded by Janssen Pharmaceutical K.K., Tokyo, Japan. Janssen

Pharmaceutical K.K. contributed to the study design, data collection, analysis and

interpretation and writing, reviewing, and approval of the final version.

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Acknowledgments

The authors thank the collaborators to enrol patients. Collaborators of the iCREST-CD Study

t
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Group are listed. The authors would also like to thank the Japanese Society for Inflammatory

Bowel Disease for support of the study. Writing assistance for this manuscript was provided

cr
by Priyanka Sharma, M. Pharm and Uma Kundu, M. Pharm (SIRO Clinpharm Pvt. Ltd.,

us
India). This study was conducted in collaboration with JSIBD. Janssen Pharmaceutical K.K.'s
an
Amano. M and Matsuda. M contributed to the study operation and Takano. T contributed to

data management. EPS Corporation contributed to the statistical analysis. This study was
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operated by EP Cruise Co., Ltd., and expenses were paid by Janssen Pharmaceutical K.K.

Janssen Pharmaceutical K.K. was responsible for the research cost, operational cost, and
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editorial and submission costs for the preparation of the paper.


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Author Contributions
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All authors participated in the interpretation of study results, drafting, critical revision, and
c

approval of the final version of the manuscript.


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Ethics approval

The iCREST-CD study was approved by the ethics committee of Kyorin University, the

principal medical institution. The study protocol and informed consent form were approved

by the ethics committee or institutional review board of each study site, and the study was

conducted in accordance with „Ethical Guidelines for Medical and Health Research Involving
Manuscript Doi: 10.1093/ecco-jcc/jjad038

Human patients (December 22, 2014, Ministry of Education, Culture, Sports, Science and

Technology and Ministry of Health, Labour and Welfare, partially revised on February 28,

2017)‟ and „World Medical Association Declaration of Helsinki (WMA Fontaleza general

meeting revised in October 2013)‟. All patients who participated in this study provided

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written informed consent. This study was registered in the University Hospital Medical

Information Network Clinical Trials Registry System (UMIN-CTR, UMIN000032237) in

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April 2018.

Conflicts of interest

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Yoko Murata, Shinichi Yoshigoe, Shinya Nagasaka, and Tsutomu Yajima are employees of

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Janssen Pharmaceutical K.K. and may hold stock or stock options of Johnson & Johnson.
an
Kenji Watanabe reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grants from EA Pharma,
M

Takeda and EP CRSU and payment or honoraria for lectures, presentations, speakers bureaus,

manuscript writing or educational events from JIMRO, EA Pharma, Takeda and Abbvie
d
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Japan, and held leadership or fiduciary roles in the Finance Committee of JSIBD, Japan

Small Intestine Society, The Japanese Society of Mucosal Immunology and Public Relations
ep

Committee of The Japanese Society for Mucosal Immunology. Tadakazu Hisamatsu reports
c

no conflict of interest for the submitted manuscript. Outside this publication during the past
Ac

36 months, he has received research grants from Janssen Pharmaceutical K.K, Alfresa, EA

Pharma, Mitsubishi Tanabe, AbbVie GK, JIMRO, Zeria, Daiichi-Sankyo,Kyorin. Nippon

Kayaku, Takeda, Pfizer Inc., and Mochida; consulting fees for advisory boards from Janssen

Pharmaceutical K.K, AbbVie GK, Takeda, Pfizer Inc., and Gilead; payment or honoraria for

lectures, presentations, speakers bureaus, manuscript writing or educational events from

Janssen Pharmaceutical K.K, EA Pharma, Mitsubishi Tanabe, AbbVie GK, JIMRO, Kyorin,
Manuscript Doi: 10.1093/ecco-jcc/jjad038

Takeda, Pfizer Inc., Mochida, and Gilead; and held leadership or fiduciary roles in MHLW,

Grant-in-Aid for Scientific Research on Intractable Diseases, “Research on Intractable

Inflammatory Bowel Disorders”, JSIBD, Japan Small Intestine Society, The Japanese Society

for Mucosal Immunology, and The Japanese Society of Clinical Immunology.

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Ryuichi Okamoto reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grants from Mitsubishi

t
ip
Tanabe, Zeria, Mochida, and Takeda; and held leadership or fiduciary roles in the Research

cr
Grant Committee of JSIBD and International Exchange Committee of JSIBD.

us
Katsuyoshi Matsuoka reports no conflict of interest for the submitted manuscript. Outside

this publication during the past 36 months, he has received research grants from AbbVie, EA
an
Pharma, Mitsubishi Tanabe Pharma, Mochida, Kyorin, Kissei, JIMRO, and Nippon Kayaku;
M

payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or

educational events from AbbVie, EA Pharma, Mochida, Kyorin, Kissei, Janssen, JIMRO,
d

Gilead Sciences, Pfizer, Takeda, Zeria, Miyarisan, Nippon Kayaku, Celltrion Healthcare, Eli
te

Lilly, and Mitsubishi Tanabe Pharma; and held leadership or fiduciary roles in the Clinical
ep

Epidemiology Committee of JSIBD, The Japanese Society for Mucosal Immunology,

International Exchange Committee of The Japanese Society for Mucosal Immunology,


c

AOCC Governing Board, Japan Small Intestine Society, and MHLW, Grant-in-Aid for
Ac

Scientific Research on Intractable Diseases, “Research on Intractable Inflammatory Bowel

Disorders”.

Shigeki Bamba reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grants from AbbVie GK;

payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or


Manuscript Doi: 10.1093/ecco-jcc/jjad038

educational events from AbbVie GK, Mitsubishi Tanabe, Kyorin, Janssen, Mochida and EA

Pharma; and held leadership or fiduciary roles in the Japan Small Intestine Committee, The

Japanese Society for Mucosal Immunology The Conflict of Interest and Ethics Committee of

The Japanese Society for Mucosal Immunology.

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Toshimitsu Fujii reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grants from Janssen

t
ip
Pharmaceutical K.K, AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, EA Pharma,

cr
Kissei, Takeda, Alfresa Corporation, Celgene, Eli Lilly, Gilead Sciences, and Sekisui

us
Medical; payment or honoraria for lectures, presentations, speakers bureaus, manuscript

writing or educational events from Janssen Pharmaceutical K.K, AbbVie, Boehringer


an
Ingelheim, Bristol-Myers Squibb, EA Pharma, Kissei, Kyorin, Mitsubishi Tanabe, Mochida,

Nichiiko, Nippon Kayaku, Takeda and Zeria; and held leadership or fiduciary roles in the
M

Clinical Epidemiology Committee of JSIBD and Specialist system Committee of JSIBD.


d

Reiko Kunisaki reports no conflict of interest for the submitted manuscript. Outside this
te

publication during the past 36 months, he has received research grants from Janssen
ep

Pharmaceutical K.K, AbbVie GK, EA Pharma, Kissei, Mitsubishi Tanabe, Takeda, Zeria,

Ajinomoto, Eli Lilly and Pfizer Inc.; payment or honoraria for lectures, presentations,
c

speakers bureaus, manuscript writing or educational events from Janssen Pharmaceutical


Ac

K.K, AbbVie GK, EA Pharma, Kissei, Kyorin, Nippon Kayaku, Mitsubishi Tanabe, Takeda

and Zeria; and held leadership or fiduciary role in the Committee on Public Information of

JSIBD.

Koichiro Matsuda reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received payment or honoraria (received by his
Manuscript Doi: 10.1093/ecco-jcc/jjad038

Institution) for lectures, presentations, speakers bureaus, manuscript writing or educational

events from Jansen Pharmaceutical K.K, Mitsubishi Tanabe Pharma Corporation, Takeda

Pharmaceutical Co.,Ltd., AbbVie Inc.,Eli Lilly Japan K.K.; participated in the Data Safety

Monitoring Board or Advisory Board of Jansen Pharmaceutical K.K.; and holds stock or

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stock options of Gilead Sciences, Inc.

Minoru Matsuura reports no conflict of interest for the submitted manuscript. Outside this

t
ip
publication during the past 36 months, he has received payment or honoraria (received by his

cr
Institution) for lectures, presentations, speakers bureaus, manuscript writing or educational

us
events from Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., AbbVie GK,

Takeda Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical
an
Co., Ltd., Viatris Inc., Sandoz AG, Nippon Kayaku Co., Ltd., JIMRO Co., Ltd., EA Pharma

Co., Ltd., ZERIA Pharmaceutical Co.,Ltd.; and held leadership or fiduciary role in the
M

Clinical epidemiology committee of JSIBD, The Japanese Society for Mucosal Immunology,

Committee on Public Information of the Japanese Society for Mucosal Immunology, and
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Japan Small Intestine Society.


ep

Yohei Mikami reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grant from Janssen
c

Pharmaceutical K.K., and held leadership or fiduciary role in the Clinical Epidemiology
Ac

Committee of JSIBD, Research Grant Committee of JSIBD, and The Japanese Society for

Mucosal Immunology.

Satoshi Motoya reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grants from AbbVie GK,

Takeda, Janssen, Pfizer Japan Inc., and EA Pharma; payment or honoraria (received by his
Manuscript Doi: 10.1093/ecco-jcc/jjad038

Institution) for lectures, presentations, speakers bureaus, manuscript writing or educational

events from Mitsubishi Tanabe, AbbVie GK, Mochida, Takeda, and Janssen; held leadership

or fiduciary role in the Public Relations Committee of JSIBD, Clinical Epidemiology

Committee of JSIBD, and Japan Small Intestine Society.

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Naoki Ohmiya reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grants from Abbvie GK,

t
ip
Daiichi Sankyo, Bristol-Myers Squibb, Takeda, Eli Lilly, Mitsubishi Tanabe, and Nippon

cr
Kayaku; payment or honoraria (received by his Institution) for lectures, presentations,

us
speakers bureaus, manuscript writing or educational events from EA Pharma and Janssen;

held leadership or fiduciary role in the Japan Small Intestine Society.


an
Hisashi Shiga reports no conflict of interest for the submitted manuscript. Outside this
M

publication during the past 36 months, he has received research grants from Janssen

Pharmaceutical K.K., payment or honoraria (received by his Institution) for lectures,


d

presentations, speakers bureaus, manuscript writing or educational events from Mitsubishi


te

Tanabe Pharma, EA Pharma Co. Ltd., Takeda Pharmaceutical Co. Ltd., AbbVie Inc., Janssen
ep

Pharmaceutical K.K., Pfizer Inc.; held leadership or fiduciary role in the Education

Committee of JSIBD and Specialist System Committee of JSIBD.


c
Ac

Takahiro Shimoyama reports no conflict of interest for the submitted manuscript and outside

this publication during the past 36 months.

Shinichiro Shinzaki reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grants from Sekisui Medical;

consulting fees from Abbvie Inc., Janssen Pharmaceutical K.K., Takeda Pharmaceutical;

payment or honoraria (received by his Institution) for lectures, presentations, speakers


Manuscript Doi: 10.1093/ecco-jcc/jjad038

bureaus, manuscript writing or educational events from Alfresa Pharma Corporation, Astra

Zeneka K.K., EA Pharma, Eisai, Gilead Sciences, Kissei, Kyorin, Janssen Pharmaceutical

K.K., JIMRO, Mitsubishi-Tanabe Pharma, Mochida, Nippon Kayaku, Pfizer, Sekisui

Medical, Takeda, Zeria; held leadership or fiduciary role in the International Exchange

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Committee of JSIBD, Clinical Epidemiology Committee of JSIBD, The Japanese Society of

Gastroenterological Immunology, Board of education of The Japanese Society for Mucosal

t
ip
Immunology.

cr
Noritaka Takatsu reports no conflict of interest for the submitted manuscript and outside this

us
publication during the past 36 months.

Takehiro Torisu reports no conflict of interest for the submitted manuscript and outside this
an
publication during the past 36 months.
M

Takayuki Yamamoto reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grants from Janssen
d

Pharmaceutical K.K., held leadership or fiduciary role in the International exchange


te

committee of JSIBD and Clinical Epidemiology Committee of JSIBD.


ep

Taku Kobayashi reports no conflict of interest for the submitted manuscript. Outside this
c

publication during the past 36 months, he has received research grants (paid to his institution)
Ac

from Abbie GK, Activaid, Alfresa Pharma Corporation, JMDC Inc., Gilead Sciences, Inc.,

Nippon Kayaku Co., Ltd., Eli Lilly Japan K.K., Mochida Pharmaceutical Co., Ltd., Janssen

Pharmaceutical K.K., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Bristol-Myers

Squibb, Mitsubishi Tanabe Pharma, Zeria Nippon Kayaku Co., Ltd., Otsuka Holdings, EA

Pharma, JIMRO, Kyorin and Google Asia Pacific Pte.Ltd.; payment or honoraria (received

by his Institution) for lectures, presentations, speakers bureaus, manuscript writing or


Manuscript Doi: 10.1093/ecco-jcc/jjad038

educational events from Takeda Pharmaceutical Co., Ltd., Activaid, Alfresa Pharma

Corporation, Zeria, Kyorin, Nippon Kayaku Co., Ltd., Mitsubishi Tanabe Pharma

Corporation, Abbie GK, Pfizer Japan Inc., Janssen Pharmaceutical K.K., Thermo Fisher

Diagnostics K.K., JIMRO, and Galapagos; payment for expert testimony from Janssen

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Pharmaceutical K.K., EA Pharma Co., Ltd., KISSEI Pharmaceutical Co., Ltd., Takeda

Pharmaceutical Co., Ltd., Activaid, Pfizer Japan Inc., Nippon Kayaku Co., Ltd., Alfresa

t
ip
Pharma Corporation, Kyorin Pharmaceutical Co., Ltd., Abbie GK, Mochida Pharmaceutical

Co., Ltd., and Mitsubishi Tanabe Pharma Corporation; held leadership or fiduciary role in the

cr
MHLW, Grant-in-Aid for Scientific Research on Intractable Diseases, “Research on

us
Intractable Inflammatory Bowel Disorders”, International Exchange Committee of JSIBD,
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The Japanese Society for Mucosal Immunology, International Exchange Committee of the

Japanese Society for Mucosal Immunology.


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Atsuo Maemoto reports no conflict of interest for the submitted manuscript and outside this

publication during the past 36 months.


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Takayuki Matsumoto reports no conflict of interest for the submitted manuscript. Outside this
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publication during the past 36 months, he has received research grants from Janssen

Pharmaceutical K.K., and Mitsubishi Tanabe; payment or honoraria for lectures,


c

presentations, speakers bureaus, manuscript writing or educational events from Janssen


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Pharmaceutical K.K., Tanabe Mitsubishi Pharmaceutical, EA Pharma, Abbvie, and Takeda

Pharmaceutical; held leadership or fiduciary role in the MHLW, Grant-in-Aid for Scientific

Research on Intractable Diseases, “Research on Intractable Inflammatory Bowel Disorders”,

JSIBD, General Affairs Committee of JSIBD, Japan Small Intestine Society, The Japanese

gastroenterological association, and Japanese Gastroenterological Endoscopy Society.


Manuscript Doi: 10.1093/ecco-jcc/jjad038

Hiroshi Nakase reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grants from Hoya Group

Pentax Medical, Boehringer Ingelheim GmbH, and Bristol-Myers Squibb; payment or

honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational

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events from Janssen Pharmaceutical K.K.; held leadership or fiduciary role in the MHLW,

Grant-in-Aid for Scientific Research on Intractable Diseases, “Research on Intractable

t
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Inflammatory Bowel Disorders”, JSIBD, JSIBD, International Exchange Committee, Bulletin

editorial committee of JSIBD, Japan Small Intestine Society, The Japanese Society for

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Mucosal Immunology, Finance committee of the Japanese Society for Mucosal Immunology,

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Society Steering Committee of the Japanese Society for Mucosal Immunology, Board of
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Academic and Board Certified Physicians of The Japanese Society of Clinical Immunology,

Certified Physician/Guideline Subcommittee of The Japanese Society of Clinical


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Immunology, and The Japanese Society of Gastroenterology.

Masayuki Saruta reports no conflict of interest for the submitted manuscript. Outside this
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publication during the past 36 months, he has received research grants from Mochida

Pharmaceutical Co.,Ltd., Zeria Pharma Co., Ltd., EA Pharma Co., Ltd., Kissei
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Pharmaceutical Co., Ltd., and EPS Corporation; payment or honoraria for lectures,
c

presentations, speakers bureaus, manuscript writing or educational events from Abbvie GK,
Ac

Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Ltd., Takeda Pharmaceutical

Co., Ltd., EA Pharma Co., Ltd., and Gilead Sciences K.K., held leadership or fiduciary role

in the MHLW, Grant-in-Aid for Scientific Research on Intractable Diseases, “Research on

Intractable Inflammatory Bowel Disorders”, General Affairs Committee of JSIBD, AOCC,

Japan Small Intestine Society, The Japanese Society for Mucosal Immunology, and Officer

Selection Committee of The Japanese Society for Mucosal Immunology.


Manuscript Doi: 10.1093/ecco-jcc/jjad038

Akihiro Yamada reports no conflict of interest for the submitted manuscript. Outside this

publication during the past 36 months, he has received research grants (paid to institution)

from Abbie GK, Mitsubishi Tanabe, EA Pharma, and Mochida.

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Data availability

The datasets generated and/or analysed during the current study are not publicly available due

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to the confidentiality clauses signed with the participating medical institutions.

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Manuscript Doi: 10.1093/ecco-jcc/jjad038

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with Crohn's disease. Dig. Liver Dis. 2021;53:661-665.

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28. Tozer PJ, Whelan K, Phillips RKS, et al. Etiology of perianal Crohn's disease: Role of

genetic, microbiological, and immunological factors. Inflamm. Bowel Dis. 2009;15:1591-

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29. Oostenbrug LE, van Dullemen HM, te Meerman GJ et al. Clinical outcome of Crohn's

disease according to the Vienna classification: disease location is a useful predictor of disease

course. Eur. J Gastroenterol Hepatol. 2006;18:255-261.


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30. Kaur M, Panikkath D, Yan X et al. Perianal Crohn's Disease is Associated with Distal

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Variation in the JAK-STAT Pathway. Inflamm. Bowel Dis. 2016;22:862-869.

31. van Langenberg DR, Della Gatta P, Warmington SA et al. Objectively measured

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muscle fatigue in Crohn's disease: Correlation with self-reported fatigue and associated

factors for clinical application. J Crohn Colitis 2014;8:137-146.

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32. Vogelaar L, van't Spijker A, van Tilburg AJ, et al. Determinants of fatigue in Crohn's

disease patients. Eur. J Gastroenterol Hepatol. 2013;25:246-251.

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33. Piche T, Ducrotté P, Sabate JM et al. Impact of functional bowel symptoms on quality

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of life and fatigue in quiescent Crohn disease and irritable bowel syndrome.
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Neurogastroenterol. Motil. 2010;22:626-e174.

34. Truyens M, De Ruyck E, Gonzales GB et al. Prevalence of Fatigue and Unrecognized


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Depression in Patients with Inflammatory Bowel Disease in Remission under

Immunosuppressants and Biologicals. J Clin. Med 2021; 10: 4107.


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35. van Gennep S, Evers SW, Rietdijk ST et al. High Disease Burden Drives Indirect
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Costs in Employed Inflammatory Bowel Disease Patients: The WORK-IBD Study. Inflamm.
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Bowel Dis. 2021; 27: 352-363.

36. Parra RS, Chebli JMF, Amarante HMBS et al. Quality of life, work productivity
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impairment and healthcare resources in inflammatory bowel diseases in Brazil. World J

Gastroenterol 2019;25: 5862-5882.

37. Blondel-Kucharski F, Chircop C, Marquis P et al. Health-related quality of life in

Crohn's disease: a prospective longitudinal study in 231 patients. Am. J. Gastroenterol.

2001;96:2915-2920.
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38. Gibson PR, Weston AR, Shann A et al. Relationship between disease severity, quality

of life and health-care resource use in a cross-section of Australian patients with Crohn's

disease. J. Gastroenterol. Hepatol. 2007;22:1306-1312.

39. Trad D. Impacts of Perianal Crohn's Disease on Quality of Life and Work

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Productivity. Acta Sci. Gastron. Disord. 2021;4:38-44.

40. Adegbola SO, Dibley L, Sahnan K et al. Development and initial psychometric

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validation of a patient-reported outcome measure for Crohn's perianal fistula: the Crohn's

Anal Fistula Quality of Life (CAF-QoL) scale. Gut 2021;70:1649-1656.

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Manuscript Doi: 10.1093/ecco-jcc/jjad038

Figure legends

Figure 1. Prevalence of perianal lesions by (A) age group, and by age group in (B) male and

(C) female patients.

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Figure 2. The distribution of (A) location and (B) behaviour of intestinal Crohn's disease in

patients with and without perianal lesions.

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Fischer exact test was carried out to compare significant differences in the proportion of disease

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location and behaviour (L1, L2, L3, B1, B2, and B3) in patients with and without perianal lesions. P

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values shown in * signifies P<0.05.

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Figure 3. Impairment of activities of daily living (A) FACIT-Fatigue, (B) WPAI-GH, and

(C) SIBDQ subscore.


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P values were calculated using: Fisher's exact test for FACIT-Fatigue; Student t-test for WPAI-GH
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and SIBDQ subscore. FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy-Fatigue

scale; SIBDQ, Short-form Inflammatory Bowel Disease Questionnaire; WPAI-GH, Work


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Productivity and Activity Impairment Questionnaire-General Health.


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Manuscript Doi: 10.1093/ecco-jcc/jjad038

Table 1. Characteristics of patients with/without perianal lesions at the diagnosis of Crohn's

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disease

Parameters Patients with Patients P-Value

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perianal lesions without

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(N=324), perianal

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n (%) lesions

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n (%)
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Gender Male 233 (71.9) 219 (64.8) P=0.055
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Female 91 (28.1) 119 (35.2)

Age at Mean (SD) 25.6 (9.3) 32.9 (15.1) P<0.001*


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diagnosis of Median (min-max) 23.0 (13–73) 28.0 (14–86)


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CD ≤16 years 30 (9.3) 28 (8.3) P<0.001*


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≥17 to <40 years 268 (82.7) 209 (61.8)

≥40 to <65 years 25 (7.7) 86 (25.4)


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≥65 years 1 (0.3) 15 (4.4)


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<40 years 298 (92.0) 237 (70.1) P<0.001*

≥40 years 26 (8.0) 101 (29.9)

Diagnosis of Definite 306 (94.4) 312 (92.3) P=0.348

CD Suspected 18 (5.6) 25 (7.4)

BMI (kg/m2) Number of patients 259 258


Manuscript Doi: 10.1093/ecco-jcc/jjad038

Mean±SD 20.41±3.63 20.67±3.36 P=0.396

Smoking Number of patients 72 66

history# No history of smoking 49 (68.1) 45 (68.2) P=0.947

Current smoker 11 (15.3) 9 (13.6)

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Has smoked in the past 12 (16.7) 12 (18.2)

Alcohol Number of patients 72 66

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history# Did not drink/stopped 29 (40.3) 29 (43.9) P=0.609

drinking

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Hardly drink 28 (38.9) 19 (28.8)

Occasional
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11 (15.3) 14 (21.2)
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Drinks frequently 4 (5.6) 4 (6.1)

Social Student 124 (38.3) 76 (22.5) P=0.004*


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background Company employee 142 (43.8) 165 (48.8)

Corporate Officer 4 (1.2) 6 (1.8)


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Officers and employees of 2 (0.6) 2 (0.6)


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private organizations
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Civil servants 6 (1.9) 11 (3.3)

Faculty member 3 (0.9) 3 (0.9)


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Self-employed 8 (2.5) 10 (3.0)

Housewife 14 (4.3) 25 (7.4)

Others 10 (3.1) 23 (6.8)

Unemployed 11 (3.4) 15 (4.4)

Unknown/not specified 0 (0.0) 2 (0.6)

Abbreviations: BMI, body mass index; CD, Crohn‟s disease; SD, standard deviation
Manuscript Doi: 10.1093/ecco-jcc/jjad038

Details on perianal lesion were unknown for 10 patients, which are not included here.

All data are presented as n (%) unless otherwise stated. Denominator for the proportion of patients with or

without perianal lesion includes all patients.

P-values are calculated using chi-square test (age at diagnosis – Modified Montreal classification, smoking

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history, alcohol history, social background), Fisher's exact test (gender, age at diagnosis - Vienna classification,

diagnosis of CD), and t-test (mean age at diagnosis, BMI).


#
At informed consent - however, data were collected within 3 months from the diagnosis of CD.

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P values shown in * signifies P<0.05.

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Manuscript Doi: 10.1093/ecco-jcc/jjad038

Table 2. Percentage of males and females with types of perianal lesions observed at the

diagnosis of Crohn's disease

Parameter Patients with Males Females P-value

perianal lesions (N=233), (N=91),

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(N=372), n (%) n (%)

n (%)

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Perianal fistula 194 (59.9) 155 (66.5) 39 (42.9) P<0.001*

Perianal abscess 99 (30.6) 76 (32.6) 23 (25.3) P=0.228

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Skin tag 62 (19.1) 29 (12.4) 33 (36.3) P<0.001*

Perianal fissure 60 (18.5) 44 (18.9)


us 16 (17.6) P=0.874
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Ulcer 36 (11.1) 22 (9.4) 14 (15.4) P=0.167

Stenosis 15 (4.6) 10 (4.3) 5 (5.5) P=0.769


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Others 12 (3.7) 6 (2.6) 6 (6.6) P=0.103

P-values are calculated using Fisher's exact test.


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P values shown in * signifies P<0.05.


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Manuscript Doi: 10.1093/ecco-jcc/jjad038

Table 3. Disease activity in patients with/without perianal lesions at the diagnosis of Crohn's

disease

Parameter Patients with Patients P-Value

perianal without

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lesions perianal lesions

(N=324) (N=338)

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HBI Number of patients 108 114

Mean±SD 5.8±4.8 5.1±5.0 P=0.256

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Disease activity Number of patients 108 114

Remission
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47 (43.5) 63 (55.3) P=0.059
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Mild activity 36 (33.3) 20 (17.5)

Moderate activity 23 (21.3) 29 (25.4)


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Severe activity 2 (1.9) 2 (1.8)

General Number of patients 117 121


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well-being 0: Good 39 (33.3) 51 (42.1) P=0.673


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1: Slightly poor 36 (30.8) 35 (28.9)


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2: Poor 22 (18.8) 17 (14.0)

3: Very Poor 14 (12.0) 12 (9.9)


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4: Very Poor 6 (5.1) 6 (5.0)

Abdominal pain Number of patients 120 126

0: None 42 (35.0) 57 (45.2) P=0.352

1: Mild 55 (45.8) 48 (38.1)

2: Moderate 19 (15.8) 19 (15.1)

3: Severe 4 (3.3) 2 (1.6)


Manuscript Doi: 10.1093/ecco-jcc/jjad038

Number of watery Number of patients 114 121

or muddy stools 0 to <3 episodes 61 (53.5) 71 (58.7) P=0.030*

per day according ≥3 to <6 episodes 39 (34.2) 24 (19.8)

to the Bristol Scale ≥6 to <10 episodes 9 (7.9) 21 (17.4)

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≥10 episodes 5 (4.4) 5 (4.1)

Abbreviations: HBI, Harvey-Bradshaw Index; SD, standard deviation.

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Remission: HBI <5, mild activity: 5 ≤ HBI ≤ 7, moderate activity: 8 ≤ HBI ≤ 16, and severe activity: 16 <HBI.

All data are presented as n (%) unless otherwise stated. P-values are calculated using:

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chi-square test (disease activity, general well-being, abdominal pain, number of episodes of muddy stools), t-test

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(HBI).

P values shown in * signifies P<0.05.


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Manuscript Doi: 10.1093/ecco-jcc/jjad038

Table 4. Prevalence and proportion of patients with extra-intestinal manifestations

Complications Number of patients (%)

Patients with perianal Patients without

lesions (N=324) perianal lesions (N=338)

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Overall 13 (4.0) 10 (3.0)

Iritis 2 (0.6) 1 (0.3)

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Uveitis 1 (0.3) 0

Ankylosing spondylitis 0 1 (0.3)

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Sacroiliitis 1 (0.3) 2 (0.6)

Erythema nodosum 11 (3.4)


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Pyoderma gangrenosum 2 (0.6) 1 (0.3)

Venous thrombosis 0 0
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Primary sclerosing cholangitis 0 0

Statistical comparisons were not conducted because of low prevalence of extra-intestinal manifestation
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Table 5. Clinical factors associated with presence of perianal lesions at the diagnosis of CD

Parameter Univariate analysis Multivariate analysis

N Patients OR (95% P-Value N Patients OR (95% P-Value

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with CI) with CI)

perianal perianal

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lesions lesions

n (%) n (%)

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Sex Female 210 91 167 73

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(43.3) (43.7)

Male 452 233 1.391 343 182 1.566 P=0.037*

(51.5) (1.001;
an P=0.049* (53.1) (1.029;

1.934) 2.384)
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Age ≧40 127 26 96 18

(20.5) (18.8)
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< 40 535 298 4.884 414 237 4.181 P<0.001*


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(55.7) (3.072; P<0.001* (57.2) (2.288;


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7.765) 7.639)

BMI <20.53 300 157 296 154


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(52.3) (52.0)
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≧20.53 217 102 0.808 214 101 0.960 P=0.837

(47.0) (0.569; P=0.232 (47.2) (0.652;

1.146) 1.414)

Family No 626 306 485 242

history (48.9) (49.9)


Manuscript Doi: 10.1093/ecco-jcc/jjad038

Yes 34 18 1.176 25 13 0.859 P=0.736

(52.9) (0.589; P=0.645 (52.0) (0.356;

2.349) 2.075)

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Disease L1 150 51 117 38

location (34.0) (32.5)

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L2 108 45 1.386 P=0.210 77 33 1.450 P=0.273

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(41.7) (0.832; (42.9) (0.746;

2.310) 2.818)

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L3 396 224 2.528 P<0.001* 316 184 2.259 P=0.001*

(56.6) (1.708; an (58.2) (1.379;

3.741) 3.700)

Disease B1 416 221 310 171


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behaviour (53.1) (55.2)
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B2 171 62 0.502 P<0.001* 140 53 0.544 P=0.009*


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(36.3) (0.348; (37.5) (0.345;

0.724) 0.856)
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B3 71 37 0.960 P=0.874 60 31 1.258 P=0.470

(52.1) (0.580; (51.7) (0.675;


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1.589) 2.344)
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EIM No 639 311 490 244

(48.7) (49.8)

Yes 23 13 1.371 P=0.461 20 11 1.282 P=0.620

(56.5) (0.593; (55.0) (0.480;

3.172) 3.422)
Manuscript Doi: 10.1093/ecco-jcc/jjad038

Smoking No 447 237 345 188

history#1 (53.0) (54.5)

Yes 213 87 0.612 P=0.004* 165 67 0.951 P=0.832

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(40.8) (0.440; (40.6) (0.600;

0.851) 1.507)

t
ip
Alcohol No 479 250 372 199

cr
intake#2 (52.2) (53.5)

Yes 180 74 0.639 P=0.012* 138 56 0.589 P=0.020*

us
(41.1) (0.452; (40.6) (0.376;

0.905) an 0.922)

Abbreviations: BMI, body mass index; CI, confidence interval; EIM, extra-intestinal manifestations. OR,

odds ratio.
M
#1
Smoking history "Yes" is the total of "I am smoking now" and "I have smoked in the past".
#2
Alcohol intake “Yes” is the total of “sometimes drink” and “drink often”, and “no” is the total of “do not
d

drink / stop” and “almost never drink”.


te

Logistic regression analysis with sex, age, BMI, family history, disease location, disease behaviour, extra-
ep

intestinal manifestation (EIM), smoking history, and alcohol intake as covariates.

P values shown in * signifies P<0.05.


c
Ac
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ip
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Manuscript Doi: 10.1093/ecco-jcc/jjad038

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Figure 1

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d
te
ep c
Ac
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ip
cr
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Manuscript Doi: 10.1093/ecco-jcc/jjad038

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Figure 2

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ep c
Ac
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ip
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Manuscript Doi: 10.1093/ecco-jcc/jjad038

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Figure 3

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ep c
Ac

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