Article Search
검색
검색 팝업 닫기

Metrics

Help

  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

  • 2. Editorial Board

    Editor-in-Chief + MORE

    Editor-in-Chief
    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

    Deputy Editor

    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
  • 3. Editorial Office
  • 4. Articles
  • 5. Instructions for Authors
  • 6. File Download (PDF version)
  • 7. Ethical Standards
  • 8. Peer Review

    All papers submitted to Gut and Liver are reviewed by the editorial team before being sent out for an external peer review to rule out papers that have low priority, insufficient originality, scientific flaws, or the absence of a message of importance to the readers of the Journal. A decision about these papers will usually be made within two or three weeks.
    The remaining articles are usually sent to two reviewers. It would be very helpful if you could suggest a selection of reviewers and include their contact details. We may not always use the reviewers you recommend, but suggesting reviewers will make our reviewer database much richer; in the end, everyone will benefit. We reserve the right to return manuscripts in which no reviewers are suggested.

    The final responsibility for the decision to accept or reject lies with the editors. In many cases, papers may be rejected despite favorable reviews because of editorial policy or a lack of space. The editor retains the right to determine publication priorities, the style of the paper, and to request, if necessary, that the material submitted be shortened for publication.

Search

Search

Year

to

Article Type

Original Article

Split Viewer

Clinical Characteristics and Long-term Outcomes of Pediatric Ulcerative Colitis: A Single-Center Experience in Korea

Jooyoung Jang1 , Sung Hee Lee1 , In Sook Jeong1 , Jinmin Cho1 , Hyun Jin Kim2 , Seak Hee Oh1 , Dae Yeon Kim3 , Ho-Su Lee4 , Sang Hyoung Park5 , Byong Duk Ye5 , Suk-Kyun Yang5 , Kyung Mo Kim1

1Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, 2Department of Pediatrics, Chungnam National University Hospital, Daejeon, 3Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 4Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, and 5Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence to: Kyung Mo Kim
ORCID https://orcid.org/0000-0001-7896-6751
E-mail kmkim@amc.seoul.kr

Received: November 1, 2019; Revised: May 6, 2021; Accepted: May 17, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2022;16(2):236-245

Published online July 12, 2021, Published Date March 15, 2022 https://doi.org/10.5009/gnl20337

Copyright © Gut and Liver.

Background/Aims: Although pediatric ulcerative colitis (UC) has a different phenotype and clinical course than adult UC, its clinical features and outcomes are poorly defined, especially in Asian populations. This study investigated the clinical features and long-term outcomes of pediatric UC in a Korean population.
Methods: We retrospectively analyzed 208 patients aged <18 years diagnosed with UC between 1987 and 2013. The patient characteristics at diagnosis according to the Paris classification and the clinical course were analyzed.
Results: The male-to-female ratio was 1.3:1, and the median patient age was 15.5 years. At diagnosis, 28.8% of patients had proctitis (E1), 27.8%, left-sided colitis (E2); 5.2%, extensive colitis (E3); and 38.2%, pancolitis (E4). The cumulative probabilities of extension after 5, 10, 15, and 20 years were 32.7%, 40.4%, 52.5%, and 65.8%, respectively. Eighteen patients underwent colectomy, and three patients had colorectal cancer. The cumulative probabilities of colectomy after 5, 10, 15, and 20 years were 7.1%, 8.9%, 12.6%, and 15.6%, and those of colorectal cancer after 10, 15, and 20 years were 0%, 2.1%, and 12.0%, respectively. The disease extent, Pediatric Ulcerative Colitis Activity Index severity, and systemic corticosteroid therapy were significant risk factors for colectomy. The development of primary sclerosing cholangitis was significantly associated with colorectal cancer.
Conclusions: This study provides detailed information on the disease phenotype and long-term clinical outcomes in a large cohort of Korean children with UC. They have extensive disease at diagnosis, a high rate of disease extension, and a low rate of cumulative colectomy.

Keywords: Pediatrics, Colitis, ulcerative, Outcome, Colectomy, Colorectal neoplasms

Ulcerative colitis (UC) is a chronic and relapsing inflammatory bowel disorder localized to the colon, extending proximally from the rectum. The incidence of UC is increasing worldwide;1,2 rapid increase in the incidence was reported in Korea and other parts of Asia, despite Asia being previously considered a low incidence area.3-7

Unlike Crohn’s disease, UC is localized to the colon. Surgery is a treatment option. As UC may be complicated with the development of colorectal cancer, understanding the natural history of UC important. In Western countries, 10% to 25% adult UC patients undergo colectomy within the first 10 years after diagnosis. The relative risk of colorectal cancer is higher in UC patients than in the general population.8 Some clinical features of pediatric UC differed from those of adult UC in Western studies.9-11 In Europe and North America, pediatric UC is characterized by extensive and severe disease activity at diagnosis and an overall high disease extension rate at follow-up.9-11 Approximately 25% to 30% of pediatric UC patients are corticosteroid-dependent by 1-year,12,13 and its aggressiveness is associated with a high early colectomy rate.14

Limited data are available regarding the long-term prognosis of pediatric UC patients in Asia. This study aimed to investigate the clinical characteristics and long-term outcomes of pediatric UC patients at a single tertiary center in Korea and evaluate the risk of cumulative colectomy and colorectal cancer and the factors associated with pediatric UC in Korea.

1. Patients

UC patients aged <18 years diagnosed between March 1987 and December 2013 were enrolled and registered at the Inflammatory Bowel Disease (IBD) Center and the Children’s Hospital of the Asan Medical Center, a tertiary-care referral hospital. The diagnosis was based on conventional clinical, upper and lower endoscopic, radiological, and histological criteria. Indeterminate colitis, infections, or other recognized causes of intestinal inflammation were excluded.15 Patients who met the Pediatric Inflammatory Bowel Disease-class 1 features of the revised Porto classification were diagnosed with Crohn’s disease and were also excluded.16

2. Study design

All data were collected from the IBD registry of the Asan Medical Center or obtained by retrospective medical record review. Baseline patient demographic and clinical characteristics, including age, sex, age at diagnosis, time between symptom onset and UC diagnosis, family history of IBD, extraintestinal manifestations (EIMs), and location, were recorded.

To evaluate long-term disease outcomes, we also noted the initiation of various medications, changes in disease extent, and cumulative probabilities of colectomy and colorectal cancer and analyzed the risk factors for colectomy and development of colorectal cancer. Additionally, to evaluate changes in baseline characteristics, treatment policies, and prognosis of UC, we divided the patients into three sequential subcohorts based on the date of diagnosis (subcohorts: 1, 1986–2000; 2, 2001–2005; and 3, 2006–2013), as used in our previous study on pediatric Crohn’s disease patients.17 Age at diagnosis was divided into three groups (A1a, 0–9 years; A1b, 10–16 years; and A2, ≥17 years) according to Paris classification.18 Baseline and clinical characteristics were compared among the groups.

The disease extent was assessed using the Paris classification: proctitis (E1, disease limited to the rectum), left-sided colitis (E2, disease distal to the splenic flexure), extensive colitis (E3, disease with distal hepatic flexure), and pancolitis (E4, disease proximal to the hepatic flexure). We assessed the disease activity at diagnosis using the Pediatric Ulcerative Colitis Activity Index (PUCAI).19

This retrospective analysis was approved by the Institutional Review Board of Asan Medical Center (IRB number: 2015-0125). We received informed consents from all patients enrolled.

3. Statistical analysis

We used the chi-square or the Fisher exact tests to compare the binominal variables. The cumulative risks of disease extension, colectomy, and colorectal cancer were calculated using the Kaplan-Meier method. Differences between the Kaplan-Meier curves were compared using log-rank tests. Hazard ratios could not be obtained and multivariate analysis could not be performed owing to the small numbers of incident cases. p-values <0.05 were considered statistically significant. Statistical analysis was performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY, USA).

1. Basic patient characteristics and clinical features

From 1986 to 2013, we identified 208 UC patients (119 males [57.2%] and 89 females [42.8%], male-to-female ratio=1.3:1). The median age at diagnosis was 15.5 years (range, 1.3 to 17.9 years). The median follow-up duration was 6.5 years (range, 0.3 to 29.3 years), and the median interval from symptom onset to diagnosis was 2.3 months (range, 0 to 91 months). Nearly half of the patients (43.8%) were diagnosed within 2 months, and 25.0% had a diagnostic delay exceeding 6 months after symptom onset. The predominant symptoms at diagnosis were rectal bleeding (n=194), diarrhea (n=159), and abdominal pain (n=136). Anorexia (n=38), nausea (n=26), fever (n=14), weight loss (n=64), and EIMs (n=7) were also reported (Fig. 1). Twenty-three patients (11.1%) had a family history of IBD, including first-, second-, and third-degree relatives in 16 (7.7%), six (2.9%), and one (0.5%) patient, respectively. Five (2.4%), 158 (76.0%), and 45 (21.6%) patients were aged >10 years (A1a), 10 to 17 years (A1b), and >17 years (A2), respectively. EIMs were detected in seven patients (3.3%) at diagnosis and in 31 patients (14.9%) at follow-up, including primary sclerosing cholangitis (PSC; n=12), arthralgia (n=9), peripheral arthritis (n=2), erythema nodosum (n=7), pyoderma gangrenosum (n=2), and iritis (n=2) (Fig. 2). Three patients had three EIMs (arthralgia and erythema nodosum, erythema nodosum and iritis, and erythema nodosum and PSC). Two patients with PSC underwent liver transplantation. The subcohort analysis showed no significant differences in the sex ratio, age, family history, PUCAI at diagnosis, UC extent at diagnosis or follow-up, or colectomy rate among the three subcohorts. EIMs were more frequent in cohort 1 (p=0.045), and all three colorectal cancer patients were in cohort 1 (p=0.023) (Table 1). In age group analysis, group A1b had a higher proportion of moderate to severe PUCAI (p=0.024) than the other groups, as well as the highest rate of systemic corticosteroid use (p=0.003). All three cancer patients were in group A1b (Supplementary Table 1).

Table 1. Baseline and Clinical Characteristics of the 208 Pediatric Patients with Ulcerative Colitis According to the Year of Diagnosis

VariableTotal
(1986–2013)
Subcohort 1
(1986–2000)
Subcohort 2
(2001–2005)
Subcohort 3
(2006–2013)
p-value
No. of patients208 (100)51 (24.5)44 (21.2)113 (54.3)
Male sex119 (57.2)30 (58.8)25 (56.8)64 (56.6)0.982
Age at diagnosis, yr15.5 (1.3–17.9)15.1 (11.0–17.9)15.4 (4.0–17.9)15.1 (1.3–17.9)0.985
Time between onset of symptoms and UC diagnosis, mo2.3 (0–91.0)3.0 (0–40.0)2 (0–70.0)2.1 (0–91.0)0.543
Follow-up period, yr6.5 (0.3–29.3)18.1 (1.3–29.3)9.5 (0.3–15.0)4.0 (0.4–8.4)
Age at diagnosis0.723
A1a (0–9 yr)5 (2.4)01 (2.3)4 (3.5)
A1b (10–16 yr)158 (76.0)41 (78.4)32 (72.7)86 (76.1)
A2 (≥17 yr)45 (21.6)11 (21.6)11 (25.0)23 (20.4)
Family history of IBD23 (11.1)7 (13.7)5 (11.4)11 (25.0)0.731
PUCAI score at diagnosis0.344
Remission5 (2.6)01 (2.4)4 (3.6)
Mild75 (38.5)21 (50.0)12 (28.6)42 (37.8)
Moderate87 (44.6)18 (42.9)22 (52.4)47 (42.3)
Severe28 (14.3)3 (7.1)7 (16.7)18 (16.2)
Extent at diagnosis (n=191)0.931
Ulcerative proctitis (E1)55 (28.8)13 (31.0)10 (25.0)32 (29.4)
Left-sided colitis (E2)53 (27.8)13 (31.0)10 (25.0)30 (27.5)
Extensive colitis (E3)10 (5.2)1 (2.4)3 (7.5)6 (5.5)
Pancolitis (E4)73 (38.2)15 (35.7)17 (42.5)41 (37.6)
Maximum extent during follow-up (n=191)0.625
Ulcerative proctitis (E1)32 (16.8)5 (11.9)5 (12.5)22 (20.2)
Left-sided colitis (E2)41 (21.5)11 (26.2)6 (15.0)24 (22.0)
Extensive colitis (E3)15 (7.8)4 (9.5)4 (10.0)7 (6.4)
Pancolitis (E4)103 (53.9)22 (52.4)25 (62.5)56 (51.4)
Appendiceal orifice inflammation36 (17.3)6 (11.8)12 (27.3)18 (15.7)0.127
Backwash ileitis14 (6.8)3 (5.9)3 (6.8)9 (8.0)0.955
Extraintestinal manifestations31 (14.9)13 (25.5)6 (13.6)12 (10.6)0.045
Systemic corticosteroid144 (69.2)36 (70.6)35 (79.5)73 (64.6)0.185
Colectomy18 (8.7)7 (13.7)5 (11.4)6 (5.3)0.179
Colorectal cancer3 (1.4)3 (5.9)000.023

Data are presented as number (%) or median (range).

UC, ulcerative colitis; IBD, inflammatory bowel disease; PUCAI, Pediatric Ulcerative Colitis Activity Index.



Figure 1.Clinical manifestations at diagnosis.
EIM, extraintestinal manifestation.

Figure 2.Extraintestinal manifestations.
EIM, extraintestinal manifestation; PSC, primary sclerosing cholangitis.

2. Medical treatment

The proportions of patients who used systemic corticosteroids, thiopurines, and anti-tumor necrosis factor (TNF) agents at diagnosis or during the follow-up were 69.2% (n=144), 34.6% (n=72), and 9.6% (n=20), respectively. The median intervals from the diagnosis of UC to the initiation of systemic corticosteroids, thiopurines, and anti-TNF agents were 0.1 months (range, 0 to 203.6 months), 43.4 months (range, 0 to 247.5 months), and 15.9 months (range, 0.4 to 133.7 months), respectively. The cumulative probabilities of medication use at 1, 5, 10, and 15 years after diagnosis were 54.6%, 64.8%, 70.4%, and 77.1%, respectively, for corticosteroids; 19.3%, 30.1%, 35.8%, and 38.9%, respectively, for thiopurines; and 3.9%, 7.8%, 11.3%, and 12.8%, respectively, for anti-TNF agents (Fig. 3). The cumulative probability of prescription of systemic corticosteroids did not differ significantly between the subcohorts. The cumulative probability of thiopurine prescription was the lowest in subcohort 1 (p<0.001). The cumulative probability of prescription of anti-TNF agents increased over time from subcohort 1 to subcohort 3 (p<0.001). Some patients received other immunomodulators, such as cyclosporine (n=7) and tacrolimus (n=2). Almost all patients (n=198) took 5-aminosalicylates and probiotics, but the exact rate of probiotics usage could not be determined.

Figure 3.Cumulative probability of medication uses in all 208 pediatric patients with ulcerative colitis (UC) and in the three subcohorts from the time of diagnosis. (A) Systemic corticosteroids. (B) Thiopurines. (C) Anti-tumor necrosis factor agents.

3. Disease extent

The most common Paris classification grade for extent at diagnosis among 191 patients with known extent at diagnosis was E4 (n=73, 38.2%). Fifty-five (28.8%), 53 (27.8%), and 10 (5.2%) patients had E1, E2, and E3, respectively. With respect to the maximum extent during follow-up, 32 patients (16.8%) had E1, 41 (21.5%) had E2, 15 (7.8%) had E3, and 103 (53.9%) had E4 (Supplementary Fig. 1). The cumulative probabilities of extension rates (except for the E4 group) after 5, 10, 15, 20 years were 32.7%, 40.4%, 52.5%, and 65.8%, respectively. Among patients with E1 at diagnosis, the cumulative probabilities of extension after 5, 10, 15, and 20 years were 36.6%, 44.6%, 59.0%, and 79.5%, respectively. Among patients with E2, the cumulative probabilities of extension after 5, 10, 15, and 20 years were 29.2%, 42.5%, 48.3%, and 55.7%, respectively. Among patients with E3, the cumulative probability of extension after 5, 10, 15, and 20 years was 25.9%. With respect to disease extension, there were no significant differences among patients with E1, E2, and E3 (Fig. 4).

Figure 4.Cumulative probability of disease extension in 109 patients with E1/E2 ulcerative colitis and three subcohorts classified according to the date of diagnosis. (A) Cumulative probability of extension in E1, E2 groups. (B) Cumulative extension rate in three subcohorts based on the date of diagnosis.
NS, not significant.

4. Colectomy

Eighteen patients (8.7%) underwent colectomy soon after diagnosis or during follow-up: 13 patients underwent total proctocolectomy with ileal pouch-anal anastomosis and five patients underwent total colectomy with ileostomy. The cumulative probabilities of colectomy were 7.1%, 8.9%, 12.6%, and 15.6%, at 5, 10, 15, and 20 years after diagnosis, respectively (Fig. 5). There were no significant differences in the probability of colectomy among the three subcohorts. Disease extent at diagnosis (p=0.007), maximum extent during follow-up (p=0.002), PUCAI (p<0.001), and use of systemic corticosteroids (p=0.028) were significant risk factors for colectomy, based on the log-rank tests. Age at diagnosis, sex, family history, antineutrophil cytoplasmic antibody, PSC, EIM, and use of anti-TNF-α agents were not associated with the risk of colectomy (Table 2).

Table 2. Risk of Colectomy in 208 Pediatric Patients with Ulcerative Colitis Analyzed by the Log-Rank Test

VariableNo. of patientsColectomyp-value
Age group0.385
A1a (0–9 yr)51
A1b (10–16 yr)15815
A2 (≥17 yr)452
Sex0.794
Male11911
Female897
Family history of IBD0.352
No18517
Yes231
Extent at diagnosis0.007
Ulcerative proctitis (E1)552
Left-sided colitis (E2)532
Extensive colitis (E3) 100
Pancolitis (E4)7312
Maximum extent during follow-up0.002
Ulcerative proctitis (E1)320
Left-sided colitis (E2)410
Extensive colitis (E3)150
Pancolitis (E4)10316
ANCA0.268
Negative928
Positive1015
PSC0.549
Negative19616
Positive122
EIM0.835
Negative17415
Positive313
PUCAI at diagnosis<0.001
Remission50
Mild751
Moderate878
Severe288
AOI0.336
Negative17217
Positive361
Systemic corticosteroid0.028
Negative641
Positive14417
Immunosuppressant0.273
Negative13210
Positive728
Anti-TNF-α0.155
Negative18815
Positive203

IBD, inflammatory bowel disease; ANCA, antineutrophil cytoplasmic antibody; PSC, primary sclerosing cholangitis; EIM, extraintestinal manifestation; PUCAI, Pediatric Ulcerative Colitis Activity Index; AOI, appendiceal orifice inflammation; TNF, tumor necrosis factor.



Figure 5.Cumulative risk of colectomy in 208 pediatric patients with ulcerative colitis.

5. Colorectal cancer

Three patients were diagnosed with colorectal cancer, which developed 12.4, 18.4, and 19.7 years after the diagnosis of UC, respectively. The cumulative risks of colorectal cancer after 10, 15, and 20 years were 0%, 2.1%, and 12%, respectively. No significant differences were observed in the cumulative probabilities of colorectal cancer among the three cohort groups (Fig. 6). Two cancer patients had PSC. Based on the log-rank tests, only PSC was observed to be significantly associated with colorectal cancer (p=0.002) (Table 3).

Table 3. Risk of Colorectal Cancer in 208 Pediatric Patients with Ulcerative Colitis Analyzed by the Log-Rank Test

VariableNo. of patientsColorectal
cancer
p-value
Age groupNC
A1a (0–9 yr)50
A1b (10–16 yr)1583
A2 (17 yr)450
Sex0.759
Male1192
Female891
Family history of IBD0.410
No1853
Yes230
Extent at diagnosisNC
Ulcerative proctitis (E1)550
Left-sided colitis (E2)530
Extensive colitis (E3)100
Pancolitis (E4)733
Maximum extent during follow-up0.302
Ulcerative proctitis (E1)320
Left-sided colitis (E2)410
Extensive colitis (E3)150
Pancolitis (E4)1033
ANCA0.642
Negative922
Positive1011
PSC0.002
Negative1961
Positive122
EIM0.113
Negative1742
Positive311
PUCAI at diagnosisNC
Remission50
Mild751
Moderate878
Severe288
AOI0.579
Negative1723
Positive360
Systemic corticosteroid0.359
Negative640
Positive1443
Immunosuppressant0.594
Negative1322
Positive721
Anti-TNF-α NC
Negative1883
Positive200

IBD, inflammatory bowel disease; ANCA, antineutrophil cytoplasmic antibody; PSC, primary sclerosing cholangitis; EIM, extraintestinal manifestation; PUCAI, Pediatric Ulcerative Colitis Activity Index; AOI, appendiceal orifice inflammation; TNF, tumor necrosis factor; NC, not calculable.



Figure 6.Cumulative probability of colorectal cancer in 208 pediatric patients with ulcerative colitis.

6. Mortality

By the last follow-up, four patients had died: one of colorectal cancer and one of sepsis after azathioprine-induced neutropenia; the other two causes of death were not related to UC.

This report on a large, single-center study applying Paris classifications to an Asian pediatric UC population provides detailed information on the disease phenotype and long-term clinical course. Disease extent at diagnosis, EIMs, and progression of UC extent were similar to the findings reported in Western studies, while the cumulative colectomy rate was lower than that reported previously.10,20-22

Recent studies have reported on the association between pediatric UC and higher proportions of pancolitis.23-25 In our study, 65.8% of patients without pancolitis had extension during follow-up and pancolitis became the most predominant type. Pediatric UC patients have more extensive disease, are more frequently treated with immunomodulators, have a higher frequency of steroid dependency, and have a more severe disease course than adult UC patients.23 The presence of EIMs and high PUCAI scores at diagnosis are related to disease extension.11,24 A family history of IBD and diagnostic delays >6 months are also associated with colonic extension.11,25 A recent meta-analysis reported that 10% to 20% of pediatric patients experienced EIMs and that PSC was observed in 5% to 12% of patients,22 similar to the rates of EIMs (16.3%) and PSC (5.8%) noted in our study. EIMs have been identified as a marker of poor prognosis because they are associated with increased immunogenicity and severity and extension of UC.26,27 The reported prevalence of PSC among adult Korean UC patients is 1.1%,28 lower than the 5.8% reported in our study on pediatric UC patients. Seven of the 12 PSC patients had PSC at initial diagnosis. Asan Medical Center is the leading hospital for liver transplantation in South Korea; thus, many patients with liver disease are transferred to this institution, which may have increased the frequency of PSC in pediatric UC patients.

The cumulative probability of colectomy in our study was lower than reported in previous studies that estimated that approximately 20% of patients undergo operations after 10 years of follow-up.22 Higher PUCAI scores at diagnosis and male sex are associated with an increased risk of colectomy.9,29 The colectomy rate is also associated with the presence of EIMs at diagnosis and is higher among patients with disease extension.11 Our study revealed a similar prevalence of EIMs and disease extent; however, the cumulative probability of colectomy was lower than that reported in Western studies, suggesting that Korean UC children tend to experience a more benign clinical course than children in the Western populations.

Lee et al.30 reported that the proportions of E1, E2, and E3 disease extent at diagnosis were 44.8%, 25.9%, and 29.3%, respectively, among adult Korean UC patients, and the overall colectomy rate was 7.5%. The cumulative probabilities of colectomy at 10 and 20 years after diagnosis were 7.8% and 14.2%, respectively, in adult-onset UC, which are lower than 8.9% and 15.6% reported in our study. Our patients had a lower rate of proctitis and a high proportion of extensive disease at diagnosis than those reported previously in patients with adult-onset UC; however, they had similar cumulative colectomy rates at 20 years. The administration rates for corticosteroids, thiopurines, and anti-TNF agents were higher in our pediatric cohort than those reported for Korean adults. The median interval from the diagnosis of UC to the start of medication in children was shorter than that in adults. These results suggest that the disease course is more aggressive in pediatric UC patients than in adult UC patients in Korea.

The cumulative probability of medication uses in our three subcohorts revealed the frequent early administration of immunomodulators and anti-TNF agents in the most recent subcohort; however, the risks of colectomy and colorectal cancer did not differ significantly among the subcohorts. Moreover, it is difficult to confirm the effects of these medications on the decreasing rates of surgery or colorectal cancer because immunomodulators and anti-TNF agents are used in patients with severe disease activity.

During follow-up, three patients were diagnosed with colorectal cancer and two patients died from disease-related causes. The crude cancer rate was 1.4%, while the disease-related mortality was 0.96%, similar to rates reported previously. A population-based study reported a mortality rate of 0.84% among pediatric UC patients, which did not differ from that in the reference population. The reported crude cancer was 1.3%, with a significant three-fold increased risk of cancer, and the cumulative probability of cancer was 3.7% after 17 years of follow-up.25 In a study of adults conducted at our center, 18 patients developed colorectal cancer among 2,798 UC patients during 22,272 person-years of follow-up.31 In a Swiss IBD cohort study, approximately 4% of UC patients had PSC, which was associated with considerable long-term morbidity and mortality. Significantly more patients with UC and PSC developed colorectal cancer than UC patients without PSC. Extensive disease and pancolitis increased the risk of PSC development.32 Our results indicate that PSC is a strong risk factor for the development of colorectal cancer.

This study has several limitations. First, it was performed in a single tertiary center; therefore, the findings may not reflect the general prevalence and prognosis of all Korean pediatric UC patients. Second, we did not use the revised Porto criteria15 to diagnose UC; therefore, we could not distinguish between UC, atypical UC, and IBD-unclassified.16 Further studies applying the Porto criteria are needed to describe pediatric UC in our context. Finally, this study included results from an era before the introduction of biologic therapy as the first-line treatment. Thus, we could not evaluate the effect of medications on the long-term outcomes of pediatric UC. Further well-designed prospective studies are warranted to confirm the effects of drugs on the natural history of pediatric UC.

In conclusion, pediatric UC at our center was characterized by extensive disease at diagnosis and a high rate of disease extension at follow-up. The cumulative colectomy rate was lower in our Korean cohort than in Western children. Disease extent, severe PUCAI, and systemic steroid treatment were associated with a higher probability of colectomy. PSC was determined as a significant risk factor for the development of colorectal cancer.

No potential conflict of interest relevant to this article was reported.

Study design: J.J., K.M.K., S.H.L., I.S.J., J.C., H.J.K., S.H.O. Data analysis: J.J., K.M.K., S.H.L., I.S.J., J.C., H.J.K., S.H.O., D.Y.K., H.S.L., S.H.P., B.D.Y., S.K.Y. Writing - original draft: J.J., K.M.K. Writing - review & editing: S.K.Y.

  1. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46-54.
    Pubmed CrossRef
  2. Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011;17:423-439.
    Pubmed CrossRef
  3. Yang SK, Yun S, Kim JH, et al. Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, 1986-2005: a KASID study. Inflamm Bowel Dis 2008;14:542-549.
    Pubmed CrossRef
  4. Ishige T, Tomomasa T, Hatori R, et al. Temporal trend of pediatric inflammatory bowel disease: analysis of national registry data 2004 to 2013 in Japan. J Pediatr Gastroenterol Nutr 2017;65:e80-e82.
    Pubmed CrossRef
  5. Wang XQ, Zhang Y, Xu CD, et al. Inflammatory bowel disease in Chinese children: a multicenter analysis over a decade from Shanghai. Inflamm Bowel Dis 2013;19:423-428.
    Pubmed CrossRef
  6. Ong C, Aw MM, Liwanag MJ, Quak SH, Phua KB. Rapid rise in the incidence and clinical characteristics of pediatric inflammatory bowel disease in a South-East Asian cohort in Singapore, 1994-2015. J Dig Dis 2018;19:395-403.
    Pubmed CrossRef
  7. Kim S, Lee J, Kwak G, et al. P804 Temporal trends and the influence of regional and socioeconomic status on the incidence of inflammatory bowel disease: using National Health Insurance Service Database in Korea, 2005-2017. J Crohns Colitis 2020;14(Suppl_1):S629-S630.
    CrossRef
  8. Wanderås MH, Moum BA, Høivik ML, Hovde Ø. Predictive factors for a severe clinical course in ulcerative colitis: results from population-based studies. World J Gastrointest Pharmacol Ther 2016;7:235-241.
    Pubmed KoreaMed CrossRef
  9. Aloi M, D'Arcangelo G, Pofi F, et al. Presenting features and disease course of pediatric ulcerative colitis. J Crohns Colitis 2013;7:e509-e515.
    Pubmed CrossRef
  10. Moon JS. Clinical aspects and treatments for pediatric inflammatory bowel disease. Intest Res 2019;17:17-23.
    Pubmed KoreaMed CrossRef
  11. Gower-Rousseau C, Dauchet L, Vernier-Massouille G, et al. The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol 2009;104:2080-2088.
    Pubmed CrossRef
  12. Markowitz J, Hyams J, Mack D, et al. Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn's disease. Clin Gastroenterol Hepatol 2006;4:1124-1129.
    Pubmed CrossRef
  13. Moore JC, Thompson K, Lafleur B, et al. Clinical variables as prognostic tools in pediatric-onset ulcerative colitis: a retrospective cohort study. Inflamm Bowel Dis 2011;17:15-21.
    Pubmed CrossRef
  14. Hyams JS, Davis P, Grancher K, Lerer T, Justinich CJ, Markowitz J. Clinical outcome of ulcerative colitis in children. J Pediatr 1996;129:81-88.
    Pubmed CrossRef
  15. Levine A, Koletzko S, Turner D, et al. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr 2014;58:795-806.
    Pubmed CrossRef
  16. Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, part 1: ambulatory care-an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;67:257-291.
    Pubmed CrossRef
  17. Kim HJ, Oh SH, Kim DY, et al. Clinical characteristics and long-term outcomes of paediatric Crohn's disease: a single-centre experience. J Crohns Colitis 2017;11:157-164.
    Pubmed CrossRef
  18. Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis 2011;17:1314-1321.
    Pubmed CrossRef
  19. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007;133:423-432.
    Pubmed CrossRef
  20. Hochart A, Gower-Rousseau C, Sarter H, et al. Ulcerative proctitis is a frequent location of paediatric-onset UC and not a minor disease: a population-based study. Gut 2017;66:1912-1917.
    Pubmed CrossRef
  21. Lovasz BD, Lakatos L, Horvath A, et al. Incidence rates and disease course of paediatric inflammatory bowel diseases in Western Hungary between 1977 and 2011. Dig Liver Dis 2014;46:405-411.
    Pubmed CrossRef
  22. Fumery M, Duricova D, Gower-Rousseau C, Annese V, Peyrin-Biroulet L, Lakatos PL. Review article: the natural history of paediatric-onset ulcerative colitis in population-based studies. Aliment Pharmacol Ther 2016;43:346-355.
    Pubmed CrossRef
  23. Jakobsen C, Bartek J Jr, Wewer V, et al. Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease: a population-based study. Aliment Pharmacol Ther 2011;34:1217-1224.
    Pubmed CrossRef
  24. Rinawi F, Assa A, Hartman C, et al. Long-term extent change of pediatric-onset ulcerative colitis. J Clin Gastroenterol 2018;52:326-332.
    Pubmed CrossRef
  25. Peneau A, Savoye G, Turck D, et al. Mortality and cancer in pediatric-onset inflammatory bowel disease: a population-based study. Am J Gastroenterol 2013;108:1647-1653.
    Pubmed CrossRef
  26. Ditisheim S, Fournier N, Juillerat P, et al. Inflammatory articular disease in patients with inflammatory bowel disease: result of the Swiss IBD cohort study. Inflamm Bowel Dis 2015;21:2598-2604.
    Pubmed CrossRef
  27. Isene R, Bernklev T, Høie O, et al. Extraintestinal manifestations in Crohn's disease and ulcerative colitis: results from a prospective, population-based European inception cohort. Scand J Gastroenterol 2015;50:300-305.
    Pubmed CrossRef
  28. Ye BD, Yang SK, Boo SJ, et al. Clinical characteristics of ulcerative colitis associated with primary sclerosing cholangitis in Korea. Inflamm Bowel Dis 2011;17:1901-1906.
    Pubmed CrossRef
  29. Rinawi F, Assa A, Eliakim R, et al. Risk of colectomy in patients with pediatric-onset ulcerative colitis. J Pediatr Gastroenterol Nutr 2017;65:410-415.
    Pubmed CrossRef
  30. Lee HS, Park SH, Yang SK, et al. Long-term prognosis of ulcerative colitis and its temporal change between 1977 and 2013: a hospital-based cohort study from Korea. J Crohns Colitis 2015;9:147-155.
    Pubmed CrossRef
  31. Lee HS, Park SH, Yang SK, et al. The risk of colorectal cancer in inflammatory bowel disease: a hospital-based cohort study from Korea. Scand J Gastroenterol 2015;50:188-196.
    Pubmed CrossRef
  32. Fraga M, Fournier N, Safroneeva E, et al. Primary sclerosing cholangitis in the Swiss Inflammatory Bowel Disease Cohort Study: prevalence, risk factors, and long-term follow-up. Eur J Gastroenterol Hepatol 2017;29:91-97.
    Pubmed CrossRef

Article

Original Article

Gut and Liver 2022; 16(2): 236-245

Published online March 15, 2022 https://doi.org/10.5009/gnl20337

Copyright © Gut and Liver.

Clinical Characteristics and Long-term Outcomes of Pediatric Ulcerative Colitis: A Single-Center Experience in Korea

Jooyoung Jang1 , Sung Hee Lee1 , In Sook Jeong1 , Jinmin Cho1 , Hyun Jin Kim2 , Seak Hee Oh1 , Dae Yeon Kim3 , Ho-Su Lee4 , Sang Hyoung Park5 , Byong Duk Ye5 , Suk-Kyun Yang5 , Kyung Mo Kim1

1Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, 2Department of Pediatrics, Chungnam National University Hospital, Daejeon, 3Department of Pediatric Surgery, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 4Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, and 5Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence to:Kyung Mo Kim
ORCID https://orcid.org/0000-0001-7896-6751
E-mail kmkim@amc.seoul.kr

Received: November 1, 2019; Revised: May 6, 2021; Accepted: May 17, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims: Although pediatric ulcerative colitis (UC) has a different phenotype and clinical course than adult UC, its clinical features and outcomes are poorly defined, especially in Asian populations. This study investigated the clinical features and long-term outcomes of pediatric UC in a Korean population.
Methods: We retrospectively analyzed 208 patients aged <18 years diagnosed with UC between 1987 and 2013. The patient characteristics at diagnosis according to the Paris classification and the clinical course were analyzed.
Results: The male-to-female ratio was 1.3:1, and the median patient age was 15.5 years. At diagnosis, 28.8% of patients had proctitis (E1), 27.8%, left-sided colitis (E2); 5.2%, extensive colitis (E3); and 38.2%, pancolitis (E4). The cumulative probabilities of extension after 5, 10, 15, and 20 years were 32.7%, 40.4%, 52.5%, and 65.8%, respectively. Eighteen patients underwent colectomy, and three patients had colorectal cancer. The cumulative probabilities of colectomy after 5, 10, 15, and 20 years were 7.1%, 8.9%, 12.6%, and 15.6%, and those of colorectal cancer after 10, 15, and 20 years were 0%, 2.1%, and 12.0%, respectively. The disease extent, Pediatric Ulcerative Colitis Activity Index severity, and systemic corticosteroid therapy were significant risk factors for colectomy. The development of primary sclerosing cholangitis was significantly associated with colorectal cancer.
Conclusions: This study provides detailed information on the disease phenotype and long-term clinical outcomes in a large cohort of Korean children with UC. They have extensive disease at diagnosis, a high rate of disease extension, and a low rate of cumulative colectomy.

Keywords: Pediatrics, Colitis, ulcerative, Outcome, Colectomy, Colorectal neoplasms

INTRODUCTION

Ulcerative colitis (UC) is a chronic and relapsing inflammatory bowel disorder localized to the colon, extending proximally from the rectum. The incidence of UC is increasing worldwide;1,2 rapid increase in the incidence was reported in Korea and other parts of Asia, despite Asia being previously considered a low incidence area.3-7

Unlike Crohn’s disease, UC is localized to the colon. Surgery is a treatment option. As UC may be complicated with the development of colorectal cancer, understanding the natural history of UC important. In Western countries, 10% to 25% adult UC patients undergo colectomy within the first 10 years after diagnosis. The relative risk of colorectal cancer is higher in UC patients than in the general population.8 Some clinical features of pediatric UC differed from those of adult UC in Western studies.9-11 In Europe and North America, pediatric UC is characterized by extensive and severe disease activity at diagnosis and an overall high disease extension rate at follow-up.9-11 Approximately 25% to 30% of pediatric UC patients are corticosteroid-dependent by 1-year,12,13 and its aggressiveness is associated with a high early colectomy rate.14

Limited data are available regarding the long-term prognosis of pediatric UC patients in Asia. This study aimed to investigate the clinical characteristics and long-term outcomes of pediatric UC patients at a single tertiary center in Korea and evaluate the risk of cumulative colectomy and colorectal cancer and the factors associated with pediatric UC in Korea.

MATERIALS AND METHODS

1. Patients

UC patients aged <18 years diagnosed between March 1987 and December 2013 were enrolled and registered at the Inflammatory Bowel Disease (IBD) Center and the Children’s Hospital of the Asan Medical Center, a tertiary-care referral hospital. The diagnosis was based on conventional clinical, upper and lower endoscopic, radiological, and histological criteria. Indeterminate colitis, infections, or other recognized causes of intestinal inflammation were excluded.15 Patients who met the Pediatric Inflammatory Bowel Disease-class 1 features of the revised Porto classification were diagnosed with Crohn’s disease and were also excluded.16

2. Study design

All data were collected from the IBD registry of the Asan Medical Center or obtained by retrospective medical record review. Baseline patient demographic and clinical characteristics, including age, sex, age at diagnosis, time between symptom onset and UC diagnosis, family history of IBD, extraintestinal manifestations (EIMs), and location, were recorded.

To evaluate long-term disease outcomes, we also noted the initiation of various medications, changes in disease extent, and cumulative probabilities of colectomy and colorectal cancer and analyzed the risk factors for colectomy and development of colorectal cancer. Additionally, to evaluate changes in baseline characteristics, treatment policies, and prognosis of UC, we divided the patients into three sequential subcohorts based on the date of diagnosis (subcohorts: 1, 1986–2000; 2, 2001–2005; and 3, 2006–2013), as used in our previous study on pediatric Crohn’s disease patients.17 Age at diagnosis was divided into three groups (A1a, 0–9 years; A1b, 10–16 years; and A2, ≥17 years) according to Paris classification.18 Baseline and clinical characteristics were compared among the groups.

The disease extent was assessed using the Paris classification: proctitis (E1, disease limited to the rectum), left-sided colitis (E2, disease distal to the splenic flexure), extensive colitis (E3, disease with distal hepatic flexure), and pancolitis (E4, disease proximal to the hepatic flexure). We assessed the disease activity at diagnosis using the Pediatric Ulcerative Colitis Activity Index (PUCAI).19

This retrospective analysis was approved by the Institutional Review Board of Asan Medical Center (IRB number: 2015-0125). We received informed consents from all patients enrolled.

3. Statistical analysis

We used the chi-square or the Fisher exact tests to compare the binominal variables. The cumulative risks of disease extension, colectomy, and colorectal cancer were calculated using the Kaplan-Meier method. Differences between the Kaplan-Meier curves were compared using log-rank tests. Hazard ratios could not be obtained and multivariate analysis could not be performed owing to the small numbers of incident cases. p-values <0.05 were considered statistically significant. Statistical analysis was performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, NY, USA).

RESULTS

1. Basic patient characteristics and clinical features

From 1986 to 2013, we identified 208 UC patients (119 males [57.2%] and 89 females [42.8%], male-to-female ratio=1.3:1). The median age at diagnosis was 15.5 years (range, 1.3 to 17.9 years). The median follow-up duration was 6.5 years (range, 0.3 to 29.3 years), and the median interval from symptom onset to diagnosis was 2.3 months (range, 0 to 91 months). Nearly half of the patients (43.8%) were diagnosed within 2 months, and 25.0% had a diagnostic delay exceeding 6 months after symptom onset. The predominant symptoms at diagnosis were rectal bleeding (n=194), diarrhea (n=159), and abdominal pain (n=136). Anorexia (n=38), nausea (n=26), fever (n=14), weight loss (n=64), and EIMs (n=7) were also reported (Fig. 1). Twenty-three patients (11.1%) had a family history of IBD, including first-, second-, and third-degree relatives in 16 (7.7%), six (2.9%), and one (0.5%) patient, respectively. Five (2.4%), 158 (76.0%), and 45 (21.6%) patients were aged >10 years (A1a), 10 to 17 years (A1b), and >17 years (A2), respectively. EIMs were detected in seven patients (3.3%) at diagnosis and in 31 patients (14.9%) at follow-up, including primary sclerosing cholangitis (PSC; n=12), arthralgia (n=9), peripheral arthritis (n=2), erythema nodosum (n=7), pyoderma gangrenosum (n=2), and iritis (n=2) (Fig. 2). Three patients had three EIMs (arthralgia and erythema nodosum, erythema nodosum and iritis, and erythema nodosum and PSC). Two patients with PSC underwent liver transplantation. The subcohort analysis showed no significant differences in the sex ratio, age, family history, PUCAI at diagnosis, UC extent at diagnosis or follow-up, or colectomy rate among the three subcohorts. EIMs were more frequent in cohort 1 (p=0.045), and all three colorectal cancer patients were in cohort 1 (p=0.023) (Table 1). In age group analysis, group A1b had a higher proportion of moderate to severe PUCAI (p=0.024) than the other groups, as well as the highest rate of systemic corticosteroid use (p=0.003). All three cancer patients were in group A1b (Supplementary Table 1).

Table 1 . Baseline and Clinical Characteristics of the 208 Pediatric Patients with Ulcerative Colitis According to the Year of Diagnosis.

VariableTotal
(1986–2013)
Subcohort 1
(1986–2000)
Subcohort 2
(2001–2005)
Subcohort 3
(2006–2013)
p-value
No. of patients208 (100)51 (24.5)44 (21.2)113 (54.3)
Male sex119 (57.2)30 (58.8)25 (56.8)64 (56.6)0.982
Age at diagnosis, yr15.5 (1.3–17.9)15.1 (11.0–17.9)15.4 (4.0–17.9)15.1 (1.3–17.9)0.985
Time between onset of symptoms and UC diagnosis, mo2.3 (0–91.0)3.0 (0–40.0)2 (0–70.0)2.1 (0–91.0)0.543
Follow-up period, yr6.5 (0.3–29.3)18.1 (1.3–29.3)9.5 (0.3–15.0)4.0 (0.4–8.4)
Age at diagnosis0.723
A1a (0–9 yr)5 (2.4)01 (2.3)4 (3.5)
A1b (10–16 yr)158 (76.0)41 (78.4)32 (72.7)86 (76.1)
A2 (≥17 yr)45 (21.6)11 (21.6)11 (25.0)23 (20.4)
Family history of IBD23 (11.1)7 (13.7)5 (11.4)11 (25.0)0.731
PUCAI score at diagnosis0.344
Remission5 (2.6)01 (2.4)4 (3.6)
Mild75 (38.5)21 (50.0)12 (28.6)42 (37.8)
Moderate87 (44.6)18 (42.9)22 (52.4)47 (42.3)
Severe28 (14.3)3 (7.1)7 (16.7)18 (16.2)
Extent at diagnosis (n=191)0.931
Ulcerative proctitis (E1)55 (28.8)13 (31.0)10 (25.0)32 (29.4)
Left-sided colitis (E2)53 (27.8)13 (31.0)10 (25.0)30 (27.5)
Extensive colitis (E3)10 (5.2)1 (2.4)3 (7.5)6 (5.5)
Pancolitis (E4)73 (38.2)15 (35.7)17 (42.5)41 (37.6)
Maximum extent during follow-up (n=191)0.625
Ulcerative proctitis (E1)32 (16.8)5 (11.9)5 (12.5)22 (20.2)
Left-sided colitis (E2)41 (21.5)11 (26.2)6 (15.0)24 (22.0)
Extensive colitis (E3)15 (7.8)4 (9.5)4 (10.0)7 (6.4)
Pancolitis (E4)103 (53.9)22 (52.4)25 (62.5)56 (51.4)
Appendiceal orifice inflammation36 (17.3)6 (11.8)12 (27.3)18 (15.7)0.127
Backwash ileitis14 (6.8)3 (5.9)3 (6.8)9 (8.0)0.955
Extraintestinal manifestations31 (14.9)13 (25.5)6 (13.6)12 (10.6)0.045
Systemic corticosteroid144 (69.2)36 (70.6)35 (79.5)73 (64.6)0.185
Colectomy18 (8.7)7 (13.7)5 (11.4)6 (5.3)0.179
Colorectal cancer3 (1.4)3 (5.9)000.023

Data are presented as number (%) or median (range)..

UC, ulcerative colitis; IBD, inflammatory bowel disease; PUCAI, Pediatric Ulcerative Colitis Activity Index..



Figure 1. Clinical manifestations at diagnosis.
EIM, extraintestinal manifestation.

Figure 2. Extraintestinal manifestations.
EIM, extraintestinal manifestation; PSC, primary sclerosing cholangitis.

2. Medical treatment

The proportions of patients who used systemic corticosteroids, thiopurines, and anti-tumor necrosis factor (TNF) agents at diagnosis or during the follow-up were 69.2% (n=144), 34.6% (n=72), and 9.6% (n=20), respectively. The median intervals from the diagnosis of UC to the initiation of systemic corticosteroids, thiopurines, and anti-TNF agents were 0.1 months (range, 0 to 203.6 months), 43.4 months (range, 0 to 247.5 months), and 15.9 months (range, 0.4 to 133.7 months), respectively. The cumulative probabilities of medication use at 1, 5, 10, and 15 years after diagnosis were 54.6%, 64.8%, 70.4%, and 77.1%, respectively, for corticosteroids; 19.3%, 30.1%, 35.8%, and 38.9%, respectively, for thiopurines; and 3.9%, 7.8%, 11.3%, and 12.8%, respectively, for anti-TNF agents (Fig. 3). The cumulative probability of prescription of systemic corticosteroids did not differ significantly between the subcohorts. The cumulative probability of thiopurine prescription was the lowest in subcohort 1 (p<0.001). The cumulative probability of prescription of anti-TNF agents increased over time from subcohort 1 to subcohort 3 (p<0.001). Some patients received other immunomodulators, such as cyclosporine (n=7) and tacrolimus (n=2). Almost all patients (n=198) took 5-aminosalicylates and probiotics, but the exact rate of probiotics usage could not be determined.

Figure 3. Cumulative probability of medication uses in all 208 pediatric patients with ulcerative colitis (UC) and in the three subcohorts from the time of diagnosis. (A) Systemic corticosteroids. (B) Thiopurines. (C) Anti-tumor necrosis factor agents.

3. Disease extent

The most common Paris classification grade for extent at diagnosis among 191 patients with known extent at diagnosis was E4 (n=73, 38.2%). Fifty-five (28.8%), 53 (27.8%), and 10 (5.2%) patients had E1, E2, and E3, respectively. With respect to the maximum extent during follow-up, 32 patients (16.8%) had E1, 41 (21.5%) had E2, 15 (7.8%) had E3, and 103 (53.9%) had E4 (Supplementary Fig. 1). The cumulative probabilities of extension rates (except for the E4 group) after 5, 10, 15, 20 years were 32.7%, 40.4%, 52.5%, and 65.8%, respectively. Among patients with E1 at diagnosis, the cumulative probabilities of extension after 5, 10, 15, and 20 years were 36.6%, 44.6%, 59.0%, and 79.5%, respectively. Among patients with E2, the cumulative probabilities of extension after 5, 10, 15, and 20 years were 29.2%, 42.5%, 48.3%, and 55.7%, respectively. Among patients with E3, the cumulative probability of extension after 5, 10, 15, and 20 years was 25.9%. With respect to disease extension, there were no significant differences among patients with E1, E2, and E3 (Fig. 4).

Figure 4. Cumulative probability of disease extension in 109 patients with E1/E2 ulcerative colitis and three subcohorts classified according to the date of diagnosis. (A) Cumulative probability of extension in E1, E2 groups. (B) Cumulative extension rate in three subcohorts based on the date of diagnosis.
NS, not significant.

4. Colectomy

Eighteen patients (8.7%) underwent colectomy soon after diagnosis or during follow-up: 13 patients underwent total proctocolectomy with ileal pouch-anal anastomosis and five patients underwent total colectomy with ileostomy. The cumulative probabilities of colectomy were 7.1%, 8.9%, 12.6%, and 15.6%, at 5, 10, 15, and 20 years after diagnosis, respectively (Fig. 5). There were no significant differences in the probability of colectomy among the three subcohorts. Disease extent at diagnosis (p=0.007), maximum extent during follow-up (p=0.002), PUCAI (p<0.001), and use of systemic corticosteroids (p=0.028) were significant risk factors for colectomy, based on the log-rank tests. Age at diagnosis, sex, family history, antineutrophil cytoplasmic antibody, PSC, EIM, and use of anti-TNF-α agents were not associated with the risk of colectomy (Table 2).

Table 2 . Risk of Colectomy in 208 Pediatric Patients with Ulcerative Colitis Analyzed by the Log-Rank Test.

VariableNo. of patientsColectomyp-value
Age group0.385
A1a (0–9 yr)51
A1b (10–16 yr)15815
A2 (≥17 yr)452
Sex0.794
Male11911
Female897
Family history of IBD0.352
No18517
Yes231
Extent at diagnosis0.007
Ulcerative proctitis (E1)552
Left-sided colitis (E2)532
Extensive colitis (E3) 100
Pancolitis (E4)7312
Maximum extent during follow-up0.002
Ulcerative proctitis (E1)320
Left-sided colitis (E2)410
Extensive colitis (E3)150
Pancolitis (E4)10316
ANCA0.268
Negative928
Positive1015
PSC0.549
Negative19616
Positive122
EIM0.835
Negative17415
Positive313
PUCAI at diagnosis<0.001
Remission50
Mild751
Moderate878
Severe288
AOI0.336
Negative17217
Positive361
Systemic corticosteroid0.028
Negative641
Positive14417
Immunosuppressant0.273
Negative13210
Positive728
Anti-TNF-α0.155
Negative18815
Positive203

IBD, inflammatory bowel disease; ANCA, antineutrophil cytoplasmic antibody; PSC, primary sclerosing cholangitis; EIM, extraintestinal manifestation; PUCAI, Pediatric Ulcerative Colitis Activity Index; AOI, appendiceal orifice inflammation; TNF, tumor necrosis factor..



Figure 5. Cumulative risk of colectomy in 208 pediatric patients with ulcerative colitis.

5. Colorectal cancer

Three patients were diagnosed with colorectal cancer, which developed 12.4, 18.4, and 19.7 years after the diagnosis of UC, respectively. The cumulative risks of colorectal cancer after 10, 15, and 20 years were 0%, 2.1%, and 12%, respectively. No significant differences were observed in the cumulative probabilities of colorectal cancer among the three cohort groups (Fig. 6). Two cancer patients had PSC. Based on the log-rank tests, only PSC was observed to be significantly associated with colorectal cancer (p=0.002) (Table 3).

Table 3 . Risk of Colorectal Cancer in 208 Pediatric Patients with Ulcerative Colitis Analyzed by the Log-Rank Test.

VariableNo. of patientsColorectal
cancer
p-value
Age groupNC
A1a (0–9 yr)50
A1b (10–16 yr)1583
A2 (17 yr)450
Sex0.759
Male1192
Female891
Family history of IBD0.410
No1853
Yes230
Extent at diagnosisNC
Ulcerative proctitis (E1)550
Left-sided colitis (E2)530
Extensive colitis (E3)100
Pancolitis (E4)733
Maximum extent during follow-up0.302
Ulcerative proctitis (E1)320
Left-sided colitis (E2)410
Extensive colitis (E3)150
Pancolitis (E4)1033
ANCA0.642
Negative922
Positive1011
PSC0.002
Negative1961
Positive122
EIM0.113
Negative1742
Positive311
PUCAI at diagnosisNC
Remission50
Mild751
Moderate878
Severe288
AOI0.579
Negative1723
Positive360
Systemic corticosteroid0.359
Negative640
Positive1443
Immunosuppressant0.594
Negative1322
Positive721
Anti-TNF-α NC
Negative1883
Positive200

IBD, inflammatory bowel disease; ANCA, antineutrophil cytoplasmic antibody; PSC, primary sclerosing cholangitis; EIM, extraintestinal manifestation; PUCAI, Pediatric Ulcerative Colitis Activity Index; AOI, appendiceal orifice inflammation; TNF, tumor necrosis factor; NC, not calculable..



Figure 6. Cumulative probability of colorectal cancer in 208 pediatric patients with ulcerative colitis.

6. Mortality

By the last follow-up, four patients had died: one of colorectal cancer and one of sepsis after azathioprine-induced neutropenia; the other two causes of death were not related to UC.

DISCUSSION

This report on a large, single-center study applying Paris classifications to an Asian pediatric UC population provides detailed information on the disease phenotype and long-term clinical course. Disease extent at diagnosis, EIMs, and progression of UC extent were similar to the findings reported in Western studies, while the cumulative colectomy rate was lower than that reported previously.10,20-22

Recent studies have reported on the association between pediatric UC and higher proportions of pancolitis.23-25 In our study, 65.8% of patients without pancolitis had extension during follow-up and pancolitis became the most predominant type. Pediatric UC patients have more extensive disease, are more frequently treated with immunomodulators, have a higher frequency of steroid dependency, and have a more severe disease course than adult UC patients.23 The presence of EIMs and high PUCAI scores at diagnosis are related to disease extension.11,24 A family history of IBD and diagnostic delays >6 months are also associated with colonic extension.11,25 A recent meta-analysis reported that 10% to 20% of pediatric patients experienced EIMs and that PSC was observed in 5% to 12% of patients,22 similar to the rates of EIMs (16.3%) and PSC (5.8%) noted in our study. EIMs have been identified as a marker of poor prognosis because they are associated with increased immunogenicity and severity and extension of UC.26,27 The reported prevalence of PSC among adult Korean UC patients is 1.1%,28 lower than the 5.8% reported in our study on pediatric UC patients. Seven of the 12 PSC patients had PSC at initial diagnosis. Asan Medical Center is the leading hospital for liver transplantation in South Korea; thus, many patients with liver disease are transferred to this institution, which may have increased the frequency of PSC in pediatric UC patients.

The cumulative probability of colectomy in our study was lower than reported in previous studies that estimated that approximately 20% of patients undergo operations after 10 years of follow-up.22 Higher PUCAI scores at diagnosis and male sex are associated with an increased risk of colectomy.9,29 The colectomy rate is also associated with the presence of EIMs at diagnosis and is higher among patients with disease extension.11 Our study revealed a similar prevalence of EIMs and disease extent; however, the cumulative probability of colectomy was lower than that reported in Western studies, suggesting that Korean UC children tend to experience a more benign clinical course than children in the Western populations.

Lee et al.30 reported that the proportions of E1, E2, and E3 disease extent at diagnosis were 44.8%, 25.9%, and 29.3%, respectively, among adult Korean UC patients, and the overall colectomy rate was 7.5%. The cumulative probabilities of colectomy at 10 and 20 years after diagnosis were 7.8% and 14.2%, respectively, in adult-onset UC, which are lower than 8.9% and 15.6% reported in our study. Our patients had a lower rate of proctitis and a high proportion of extensive disease at diagnosis than those reported previously in patients with adult-onset UC; however, they had similar cumulative colectomy rates at 20 years. The administration rates for corticosteroids, thiopurines, and anti-TNF agents were higher in our pediatric cohort than those reported for Korean adults. The median interval from the diagnosis of UC to the start of medication in children was shorter than that in adults. These results suggest that the disease course is more aggressive in pediatric UC patients than in adult UC patients in Korea.

The cumulative probability of medication uses in our three subcohorts revealed the frequent early administration of immunomodulators and anti-TNF agents in the most recent subcohort; however, the risks of colectomy and colorectal cancer did not differ significantly among the subcohorts. Moreover, it is difficult to confirm the effects of these medications on the decreasing rates of surgery or colorectal cancer because immunomodulators and anti-TNF agents are used in patients with severe disease activity.

During follow-up, three patients were diagnosed with colorectal cancer and two patients died from disease-related causes. The crude cancer rate was 1.4%, while the disease-related mortality was 0.96%, similar to rates reported previously. A population-based study reported a mortality rate of 0.84% among pediatric UC patients, which did not differ from that in the reference population. The reported crude cancer was 1.3%, with a significant three-fold increased risk of cancer, and the cumulative probability of cancer was 3.7% after 17 years of follow-up.25 In a study of adults conducted at our center, 18 patients developed colorectal cancer among 2,798 UC patients during 22,272 person-years of follow-up.31 In a Swiss IBD cohort study, approximately 4% of UC patients had PSC, which was associated with considerable long-term morbidity and mortality. Significantly more patients with UC and PSC developed colorectal cancer than UC patients without PSC. Extensive disease and pancolitis increased the risk of PSC development.32 Our results indicate that PSC is a strong risk factor for the development of colorectal cancer.

This study has several limitations. First, it was performed in a single tertiary center; therefore, the findings may not reflect the general prevalence and prognosis of all Korean pediatric UC patients. Second, we did not use the revised Porto criteria15 to diagnose UC; therefore, we could not distinguish between UC, atypical UC, and IBD-unclassified.16 Further studies applying the Porto criteria are needed to describe pediatric UC in our context. Finally, this study included results from an era before the introduction of biologic therapy as the first-line treatment. Thus, we could not evaluate the effect of medications on the long-term outcomes of pediatric UC. Further well-designed prospective studies are warranted to confirm the effects of drugs on the natural history of pediatric UC.

In conclusion, pediatric UC at our center was characterized by extensive disease at diagnosis and a high rate of disease extension at follow-up. The cumulative colectomy rate was lower in our Korean cohort than in Western children. Disease extent, severe PUCAI, and systemic steroid treatment were associated with a higher probability of colectomy. PSC was determined as a significant risk factor for the development of colorectal cancer.

SUPPLEMENTARY MATERIALS

Supplementary materials can be accessed at https://doi.org/10.5009/gnl20337.

gnl-16-2-236-supple.pdf

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

AUTHOR CONTRIBUTIONS

Study design: J.J., K.M.K., S.H.L., I.S.J., J.C., H.J.K., S.H.O. Data analysis: J.J., K.M.K., S.H.L., I.S.J., J.C., H.J.K., S.H.O., D.Y.K., H.S.L., S.H.P., B.D.Y., S.K.Y. Writing - original draft: J.J., K.M.K. Writing - review & editing: S.K.Y.

Fig 1.

Figure 1.Clinical manifestations at diagnosis.
EIM, extraintestinal manifestation.
Gut and Liver 2022; 16: 236-245https://doi.org/10.5009/gnl20337

Fig 2.

Figure 2.Extraintestinal manifestations.
EIM, extraintestinal manifestation; PSC, primary sclerosing cholangitis.
Gut and Liver 2022; 16: 236-245https://doi.org/10.5009/gnl20337

Fig 3.

Figure 3.Cumulative probability of medication uses in all 208 pediatric patients with ulcerative colitis (UC) and in the three subcohorts from the time of diagnosis. (A) Systemic corticosteroids. (B) Thiopurines. (C) Anti-tumor necrosis factor agents.
Gut and Liver 2022; 16: 236-245https://doi.org/10.5009/gnl20337

Fig 4.

Figure 4.Cumulative probability of disease extension in 109 patients with E1/E2 ulcerative colitis and three subcohorts classified according to the date of diagnosis. (A) Cumulative probability of extension in E1, E2 groups. (B) Cumulative extension rate in three subcohorts based on the date of diagnosis.
NS, not significant.
Gut and Liver 2022; 16: 236-245https://doi.org/10.5009/gnl20337

Fig 5.

Figure 5.Cumulative risk of colectomy in 208 pediatric patients with ulcerative colitis.
Gut and Liver 2022; 16: 236-245https://doi.org/10.5009/gnl20337

Fig 6.

Figure 6.Cumulative probability of colorectal cancer in 208 pediatric patients with ulcerative colitis.
Gut and Liver 2022; 16: 236-245https://doi.org/10.5009/gnl20337

Table 1 Baseline and Clinical Characteristics of the 208 Pediatric Patients with Ulcerative Colitis According to the Year of Diagnosis

VariableTotal
(1986–2013)
Subcohort 1
(1986–2000)
Subcohort 2
(2001–2005)
Subcohort 3
(2006–2013)
p-value
No. of patients208 (100)51 (24.5)44 (21.2)113 (54.3)
Male sex119 (57.2)30 (58.8)25 (56.8)64 (56.6)0.982
Age at diagnosis, yr15.5 (1.3–17.9)15.1 (11.0–17.9)15.4 (4.0–17.9)15.1 (1.3–17.9)0.985
Time between onset of symptoms and UC diagnosis, mo2.3 (0–91.0)3.0 (0–40.0)2 (0–70.0)2.1 (0–91.0)0.543
Follow-up period, yr6.5 (0.3–29.3)18.1 (1.3–29.3)9.5 (0.3–15.0)4.0 (0.4–8.4)
Age at diagnosis0.723
A1a (0–9 yr)5 (2.4)01 (2.3)4 (3.5)
A1b (10–16 yr)158 (76.0)41 (78.4)32 (72.7)86 (76.1)
A2 (≥17 yr)45 (21.6)11 (21.6)11 (25.0)23 (20.4)
Family history of IBD23 (11.1)7 (13.7)5 (11.4)11 (25.0)0.731
PUCAI score at diagnosis0.344
Remission5 (2.6)01 (2.4)4 (3.6)
Mild75 (38.5)21 (50.0)12 (28.6)42 (37.8)
Moderate87 (44.6)18 (42.9)22 (52.4)47 (42.3)
Severe28 (14.3)3 (7.1)7 (16.7)18 (16.2)
Extent at diagnosis (n=191)0.931
Ulcerative proctitis (E1)55 (28.8)13 (31.0)10 (25.0)32 (29.4)
Left-sided colitis (E2)53 (27.8)13 (31.0)10 (25.0)30 (27.5)
Extensive colitis (E3)10 (5.2)1 (2.4)3 (7.5)6 (5.5)
Pancolitis (E4)73 (38.2)15 (35.7)17 (42.5)41 (37.6)
Maximum extent during follow-up (n=191)0.625
Ulcerative proctitis (E1)32 (16.8)5 (11.9)5 (12.5)22 (20.2)
Left-sided colitis (E2)41 (21.5)11 (26.2)6 (15.0)24 (22.0)
Extensive colitis (E3)15 (7.8)4 (9.5)4 (10.0)7 (6.4)
Pancolitis (E4)103 (53.9)22 (52.4)25 (62.5)56 (51.4)
Appendiceal orifice inflammation36 (17.3)6 (11.8)12 (27.3)18 (15.7)0.127
Backwash ileitis14 (6.8)3 (5.9)3 (6.8)9 (8.0)0.955
Extraintestinal manifestations31 (14.9)13 (25.5)6 (13.6)12 (10.6)0.045
Systemic corticosteroid144 (69.2)36 (70.6)35 (79.5)73 (64.6)0.185
Colectomy18 (8.7)7 (13.7)5 (11.4)6 (5.3)0.179
Colorectal cancer3 (1.4)3 (5.9)000.023

Data are presented as number (%) or median (range).

UC, ulcerative colitis; IBD, inflammatory bowel disease; PUCAI, Pediatric Ulcerative Colitis Activity Index.


Table 2 Risk of Colectomy in 208 Pediatric Patients with Ulcerative Colitis Analyzed by the Log-Rank Test

VariableNo. of patientsColectomyp-value
Age group0.385
A1a (0–9 yr)51
A1b (10–16 yr)15815
A2 (≥17 yr)452
Sex0.794
Male11911
Female897
Family history of IBD0.352
No18517
Yes231
Extent at diagnosis0.007
Ulcerative proctitis (E1)552
Left-sided colitis (E2)532
Extensive colitis (E3) 100
Pancolitis (E4)7312
Maximum extent during follow-up0.002
Ulcerative proctitis (E1)320
Left-sided colitis (E2)410
Extensive colitis (E3)150
Pancolitis (E4)10316
ANCA0.268
Negative928
Positive1015
PSC0.549
Negative19616
Positive122
EIM0.835
Negative17415
Positive313
PUCAI at diagnosis<0.001
Remission50
Mild751
Moderate878
Severe288
AOI0.336
Negative17217
Positive361
Systemic corticosteroid0.028
Negative641
Positive14417
Immunosuppressant0.273
Negative13210
Positive728
Anti-TNF-α0.155
Negative18815
Positive203

IBD, inflammatory bowel disease; ANCA, antineutrophil cytoplasmic antibody; PSC, primary sclerosing cholangitis; EIM, extraintestinal manifestation; PUCAI, Pediatric Ulcerative Colitis Activity Index; AOI, appendiceal orifice inflammation; TNF, tumor necrosis factor.


Table 3 Risk of Colorectal Cancer in 208 Pediatric Patients with Ulcerative Colitis Analyzed by the Log-Rank Test

VariableNo. of patientsColorectal
cancer
p-value
Age groupNC
A1a (0–9 yr)50
A1b (10–16 yr)1583
A2 (17 yr)450
Sex0.759
Male1192
Female891
Family history of IBD0.410
No1853
Yes230
Extent at diagnosisNC
Ulcerative proctitis (E1)550
Left-sided colitis (E2)530
Extensive colitis (E3)100
Pancolitis (E4)733
Maximum extent during follow-up0.302
Ulcerative proctitis (E1)320
Left-sided colitis (E2)410
Extensive colitis (E3)150
Pancolitis (E4)1033
ANCA0.642
Negative922
Positive1011
PSC0.002
Negative1961
Positive122
EIM0.113
Negative1742
Positive311
PUCAI at diagnosisNC
Remission50
Mild751
Moderate878
Severe288
AOI0.579
Negative1723
Positive360
Systemic corticosteroid0.359
Negative640
Positive1443
Immunosuppressant0.594
Negative1322
Positive721
Anti-TNF-α NC
Negative1883
Positive200

IBD, inflammatory bowel disease; ANCA, antineutrophil cytoplasmic antibody; PSC, primary sclerosing cholangitis; EIM, extraintestinal manifestation; PUCAI, Pediatric Ulcerative Colitis Activity Index; AOI, appendiceal orifice inflammation; TNF, tumor necrosis factor; NC, not calculable.


References

  1. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46-54.
    Pubmed CrossRef
  2. Benchimol EI, Fortinsky KJ, Gozdyra P, Van den Heuvel M, Van Limbergen J, Griffiths AM. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis 2011;17:423-439.
    Pubmed CrossRef
  3. Yang SK, Yun S, Kim JH, et al. Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, 1986-2005: a KASID study. Inflamm Bowel Dis 2008;14:542-549.
    Pubmed CrossRef
  4. Ishige T, Tomomasa T, Hatori R, et al. Temporal trend of pediatric inflammatory bowel disease: analysis of national registry data 2004 to 2013 in Japan. J Pediatr Gastroenterol Nutr 2017;65:e80-e82.
    Pubmed CrossRef
  5. Wang XQ, Zhang Y, Xu CD, et al. Inflammatory bowel disease in Chinese children: a multicenter analysis over a decade from Shanghai. Inflamm Bowel Dis 2013;19:423-428.
    Pubmed CrossRef
  6. Ong C, Aw MM, Liwanag MJ, Quak SH, Phua KB. Rapid rise in the incidence and clinical characteristics of pediatric inflammatory bowel disease in a South-East Asian cohort in Singapore, 1994-2015. J Dig Dis 2018;19:395-403.
    Pubmed CrossRef
  7. Kim S, Lee J, Kwak G, et al. P804 Temporal trends and the influence of regional and socioeconomic status on the incidence of inflammatory bowel disease: using National Health Insurance Service Database in Korea, 2005-2017. J Crohns Colitis 2020;14(Suppl_1):S629-S630.
    CrossRef
  8. Wanderås MH, Moum BA, Høivik ML, Hovde Ø. Predictive factors for a severe clinical course in ulcerative colitis: results from population-based studies. World J Gastrointest Pharmacol Ther 2016;7:235-241.
    Pubmed KoreaMed CrossRef
  9. Aloi M, D'Arcangelo G, Pofi F, et al. Presenting features and disease course of pediatric ulcerative colitis. J Crohns Colitis 2013;7:e509-e515.
    Pubmed CrossRef
  10. Moon JS. Clinical aspects and treatments for pediatric inflammatory bowel disease. Intest Res 2019;17:17-23.
    Pubmed KoreaMed CrossRef
  11. Gower-Rousseau C, Dauchet L, Vernier-Massouille G, et al. The natural history of pediatric ulcerative colitis: a population-based cohort study. Am J Gastroenterol 2009;104:2080-2088.
    Pubmed CrossRef
  12. Markowitz J, Hyams J, Mack D, et al. Corticosteroid therapy in the age of infliximab: acute and 1-year outcomes in newly diagnosed children with Crohn's disease. Clin Gastroenterol Hepatol 2006;4:1124-1129.
    Pubmed CrossRef
  13. Moore JC, Thompson K, Lafleur B, et al. Clinical variables as prognostic tools in pediatric-onset ulcerative colitis: a retrospective cohort study. Inflamm Bowel Dis 2011;17:15-21.
    Pubmed CrossRef
  14. Hyams JS, Davis P, Grancher K, Lerer T, Justinich CJ, Markowitz J. Clinical outcome of ulcerative colitis in children. J Pediatr 1996;129:81-88.
    Pubmed CrossRef
  15. Levine A, Koletzko S, Turner D, et al. ESPGHAN revised porto criteria for the diagnosis of inflammatory bowel disease in children and adolescents. J Pediatr Gastroenterol Nutr 2014;58:795-806.
    Pubmed CrossRef
  16. Turner D, Ruemmele FM, Orlanski-Meyer E, et al. Management of paediatric ulcerative colitis, part 1: ambulatory care-an evidence-based guideline from European Crohn's and Colitis Organization and European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2018;67:257-291.
    Pubmed CrossRef
  17. Kim HJ, Oh SH, Kim DY, et al. Clinical characteristics and long-term outcomes of paediatric Crohn's disease: a single-centre experience. J Crohns Colitis 2017;11:157-164.
    Pubmed CrossRef
  18. Levine A, Griffiths A, Markowitz J, et al. Pediatric modification of the Montreal classification for inflammatory bowel disease: the Paris classification. Inflamm Bowel Dis 2011;17:1314-1321.
    Pubmed CrossRef
  19. Turner D, Otley AR, Mack D, et al. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology 2007;133:423-432.
    Pubmed CrossRef
  20. Hochart A, Gower-Rousseau C, Sarter H, et al. Ulcerative proctitis is a frequent location of paediatric-onset UC and not a minor disease: a population-based study. Gut 2017;66:1912-1917.
    Pubmed CrossRef
  21. Lovasz BD, Lakatos L, Horvath A, et al. Incidence rates and disease course of paediatric inflammatory bowel diseases in Western Hungary between 1977 and 2011. Dig Liver Dis 2014;46:405-411.
    Pubmed CrossRef
  22. Fumery M, Duricova D, Gower-Rousseau C, Annese V, Peyrin-Biroulet L, Lakatos PL. Review article: the natural history of paediatric-onset ulcerative colitis in population-based studies. Aliment Pharmacol Ther 2016;43:346-355.
    Pubmed CrossRef
  23. Jakobsen C, Bartek J Jr, Wewer V, et al. Differences in phenotype and disease course in adult and paediatric inflammatory bowel disease: a population-based study. Aliment Pharmacol Ther 2011;34:1217-1224.
    Pubmed CrossRef
  24. Rinawi F, Assa A, Hartman C, et al. Long-term extent change of pediatric-onset ulcerative colitis. J Clin Gastroenterol 2018;52:326-332.
    Pubmed CrossRef
  25. Peneau A, Savoye G, Turck D, et al. Mortality and cancer in pediatric-onset inflammatory bowel disease: a population-based study. Am J Gastroenterol 2013;108:1647-1653.
    Pubmed CrossRef
  26. Ditisheim S, Fournier N, Juillerat P, et al. Inflammatory articular disease in patients with inflammatory bowel disease: result of the Swiss IBD cohort study. Inflamm Bowel Dis 2015;21:2598-2604.
    Pubmed CrossRef
  27. Isene R, Bernklev T, Høie O, et al. Extraintestinal manifestations in Crohn's disease and ulcerative colitis: results from a prospective, population-based European inception cohort. Scand J Gastroenterol 2015;50:300-305.
    Pubmed CrossRef
  28. Ye BD, Yang SK, Boo SJ, et al. Clinical characteristics of ulcerative colitis associated with primary sclerosing cholangitis in Korea. Inflamm Bowel Dis 2011;17:1901-1906.
    Pubmed CrossRef
  29. Rinawi F, Assa A, Eliakim R, et al. Risk of colectomy in patients with pediatric-onset ulcerative colitis. J Pediatr Gastroenterol Nutr 2017;65:410-415.
    Pubmed CrossRef
  30. Lee HS, Park SH, Yang SK, et al. Long-term prognosis of ulcerative colitis and its temporal change between 1977 and 2013: a hospital-based cohort study from Korea. J Crohns Colitis 2015;9:147-155.
    Pubmed CrossRef
  31. Lee HS, Park SH, Yang SK, et al. The risk of colorectal cancer in inflammatory bowel disease: a hospital-based cohort study from Korea. Scand J Gastroenterol 2015;50:188-196.
    Pubmed CrossRef
  32. Fraga M, Fournier N, Safroneeva E, et al. Primary sclerosing cholangitis in the Swiss Inflammatory Bowel Disease Cohort Study: prevalence, risk factors, and long-term follow-up. Eur J Gastroenterol Hepatol 2017;29:91-97.
    Pubmed CrossRef
Gut and Liver

Vol.16 No.5
September, 2022

pISSN 1976-2283
eISSN 2005-1212

qrcode
qrcode

Supplementary

Share this article on :

  • line

Popular Keywords

Gut and LiverQR code Download
qr-code

Editorial Office