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Original Articles: Gastroenterology: Inflammatory Bowel Disease

Extraintestinal Manifestations Are Associated With Disease Severity in Pediatric Onset Inflammatory Bowel Disease

Jansson, Sabine; Malham, Mikkel; Paerregaard, Anders; Jakobsen, Christian∗,†; Wewer, Vibeke

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Journal of Pediatric Gastroenterology and Nutrition: July 2020 - Volume 71 - Issue 1 - p 40-45
doi: 10.1097/MPG.0000000000002707
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What Is Known/What Is New

What Is Known

  • Extraintestinal manifestations are common in pediatric onset inflammatory bowel disease.
  • Pediatric onset inflammatory bowel disease is characterized by a more aggressive disease course compared with adult onset inflammatory bowel disease.

What Is New

  • The presence of extraintestinal manifestations is associated with a more severe disease course in pediatric onset inflammatory bowel disease.
  • Activity of extraintestinal manifestation is often in a positive temporal relationship with relapse of inflammatory bowel disease.

Inflammatory bowel disease (IBD) includes Crohn disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBDU) and is characterized by a chronic inflammation in various parts of the gastrointestinal tract. Although IBD primarily affects the intestines, it can also cause debilitating conditions outside the gastrointestinal (GI) tract. These extraintestinal manifestations (EIM) are often seen in joints and liver while eye and skin involvement are less frequently recorded in pediatric onset IBD (pIBD). In population-based studies, the reported frequency of EIM in pIBD ranges between 9 and 26% at the time of IBD diagnosis (1–8).

The clinical course of IBD can vary; while some patients achieve long-lasting clinical remission, others experience a more severe disease course with frequent flair-ups, aggressive medical treatment, hospitalization, and GI surgery. The few population-based studies that report on the disease course in IBD have consistently found pIBD to be a more aggressive phenotype compared with adult-onset IBD, irrespectively of the occurrence of EIM (2,8–11). In these studies, the disease course in pIBD was characterized by extensive intestinal involvement, rapid early progression, and a higher risk of treatment with immunosuppressive therapy and biological agents (2,8–12).

Little is known whether patients diagnosed with an EIM experience a more severe disease course. A few population-based studies, however, found decreased growth and nutritional status in pIBD patients with EIM at diagnosis of IBD (13). These patients also had an increased need for corticosteroids and immunosuppressives, as well as higher surgery rates (4–6,14). It remains to be seen whether EIMs have an aggravating effect on pIBD.

In this study, we aim to describe the disease course in pIBD patients with and without EIM and investigate the possible impact of EIM on the disease course in a large population-based pIBD cohort from Denmark.


Study Design and Patient Inclusion

Patients included in this study were diagnosed with pIBD (defined as Classification of Diseases tenth revision [ICD-10], code group K50, K51, or K52.3) between January 1, 1998 and December 31, 2008 in the Capital Region and Zealand Region of Denmark. In this study, pIBD was defined as patients having a diagnosis of IBD before 15 years of age. This cohort was established in 2009 when pediatric patients in Denmark were followed at pediatric departments from 0 to 15 years of age. Patients were followed from diagnosis until December 31, 2014 (or until death or emigration). All patients were included through pediatric departments in the 2 regions (in Denmark, all pIBD patients are followed at government hospitals). To ensure complete enrollment, the local databases of all hospitals in the specified regions were searched for the previously mentioned ICD-10 codes. Only EIMs that were reliably registered in the files were included (defined below). Data on incidence and disease behavior including parts of this pIBD cohort have previously been published (12,15–20).

Data Collection and Definitions

All variables were recorded from patient charts. These were retrieved from the treating hospitals and manually scrutinized at end of follow-up (also if patients had transitioned into adult care). Patients not meeting the previously well-defined criteria (21,22) for IBD diagnosis were excluded.


The Paris classification was used to define phenotype in both CD and UC (23). In CD, disease localization was subsequently divided into L1 (terminal ileum), L2 (colon), L3 (ileocolonic), and L4 (upper GI disease with or without involvement of L1--L3) for comparisons. Behavior was classified as inflammatory (nonstricturing, nonpenetrating) (B1), stricturing (B2), penetrating (B3), or both stricturing and penetrating (B2B3). In UC, disease extent was classified as E1 (proctitis), E2 (distal to splenic flexure), E3 (proximal to splenic flexure), and E4 (proximal to hepatic flexure). Diagnosis and phenotype were documented both at diagnosis and at end of follow-up. In both CD and UC, the phenotype at end of follow-up was defined as the most severe phenotype found in the observation period and the phenotype at end of follow-up was used for comparisons, unless noted otherwise. As only a few IBDU patients (n = 14) were included and IBDU previously was found to have a different disease course than CD and possibly also UC, IBDU patients were only included in the prevalence of EIM, but were excluded from further analysis (24).

Extraintestinal Manifestations

All EIM were recorded at time of diagnosis and during follow-up. We included and defined EIM as follows: Liver (primary sclerosing cholangitis (PSC), autoimmune hepatitis or overlap syndrome), joints (arthritis including objective signs of inflammation), eyes (uveitis or scleritis), and skin (erythema nodosum or pyoderma gangrenosum). All patients with EIM of the liver, joint, and eyes were diagnosed and subsequently followed by a specialist (pediatric hepatologist, pediatric rheumatologist, or an ophthalmologist). For each consecutive 3-month period from diagnosis until end of follow-up, data on activity of the joints, eyes, and skin were recorded as being active or inactive based on patients’ complaints and the relevant specialist's judgement. EIM manifestations that presented before the IBD diagnosis were termed EIM in this study. For EIM of the liver, only data on the first presentation of liver disease was recorded as the relevant blood tests to evaluate activity were not available throughout the study period.


Medical treatments included oral 5-aminosalicylic acid (5-ASA), systemic steroid treatment (SST), immunosuppressives (azathioprine or 6-mercaptopurine), biologics (infliximab or adalimumab), local administration of steroids or 5-ASA, and exclusive enteral nutrition. Bowel resections (including colectomy) were the only surgical treatments included. The type of treatment (including drug dose increases) and the date of administration were documented by manual revision of patient charts.


Similar to Romberg-Camps et al (25), we defined an IBD relapse as gastrointestinal symptoms leading to a change in medical treatment (a higher dose or frequency of already prescribed medication, introduction of a more potent drug, or the need of bowel resection). Following this definition, increased medication because of EIM was not defined as an IBD relapse. An increased dose of a drug because of increase in body weight, which is a common event in pediatric patients, was not considered a relapse and neither was a change in treatment occurring within 2 weeks of diagnosis or a previous relapse.


Descriptive data are shown as numbers, percentages, or median and range whenever appropriate. Descriptive data were compared using the χ2-test. Medians were compared using the Wilcoxon rank-sum test. For all analyses on disease course (medical treatment, surgery, and relapses), EIM was treated as a time-dependent variable. Thus, for patients developing EIM during the study period, follow-up time before first EIM diagnosis was allocated to the non-EIM group and follow-up time after the first EIM diagnosis was allocated to the EIM group. Survival analyses (Kaplan-Meier and Cox regression) were used to analyze differences in time to first treatments with drugs and surgery. Differences in relapse rates during the first 7 years after diagnoses were calculated by comparing the standardized relapse rates for each year and are presented as standardized rate ratios between patients with and without EIM. A 1-sided 1 sample t-test was used to calculate if the time proportions with concordance of IBD and EIM activity was >50%. A P-value <0.05 was considered statistically significant. The statistical analysis was performed with SAS Enterprise (version 7.11) statistical software (SAS Institute, Cary, NC).

Ethical Considerations

The Regional Ethics Committee approved this study cohort (KF-01-327756).


A total of 333 pIBD patients were included in this study resulting in 3100 patient-years of follow-up. Demographic characteristics are presented in Table 1. Sixty-one (18.3%) patients were diagnosed with 1 or more EIM during the study period. Of these, 14 patients (4.2%) had been diagnosed with an EIM before the IBD diagnosis, and an additional 47 patients (14.1%) developed EIM during follow-up. Median time from IBD diagnosis to diagnosis of EIM was 1.1 years (interquartile range [IQR]: 100--1200 days). Further details are presented in Figure 1 and Table 2. Median follow-up time was 9.6 years for patients with EIM and 8.8 years for patients without. Overall, no difference was seen in the frequency of EIM between CD and UC. When looking at the type of EIM, UC patients more often developed EIM of the liver compared with CD patients (9 [6% of UC patients] vs 3 [1.8% of CD patients] in UC/CD, respectively, P = 0.046).

The demographic characteristics of included patients
The proportion of patients with Crohn disease (A) and ulcerative colitis (B) not diagnosed with an extraintestinal manifestation.
Extraintestinal manifestations diagnosed in the pediatric inflammatory bowel disease cohort at diagnosis and during follow-up


In CD, neither the disease localization nor behavior at diagnosis impacted on the risk of developing EIM (P = 0.4/P = 0.7, respectively). In UC, the extent of disease had no impact on the risk of developing EIM (P = 0.8).

Medical Treatment

Systemic Steroid Treatment

To minimize confounding factors, we excluded patients with liver manifestations as many of these conditions in themselves are treated with SSTs (n = 9). Forty-six patients with EIM (98% of patients with EIM) and 223 patients without EIM (86% of patients without EIM) were treated with SST during follow-up. Overtime, the hazard ratio (HR) of receiving SST was 2.0 (95% confidence interval [CI]: 0.9--4.3), P = 0.07, in CD patients and 2.1 (95% CI: 0.9--4.9), P = 0.07, in UC patients with EIM compared with patients without EIM.

Immunosuppressive Treatment

Only thiopurine and 6-mercaptopurine were included. In Denmark, methotrexate is mainly used because of concomitant EIM of the joints. Hence, this treatment modality was not included. During follow-up, 47 (80%) patients with EIM and 194 (75%) patients without EIM were treated with immunosuppressives (P = 0.4). The HR of receiving immunosuppressives was 1.2 (95% CI 0.6--2.3), P = 0.5, in CD patients and 1.4 (95% CI: 0.8--2.4), P = 0.3, in UC patients with EIM compared with patients without EIM.

Biological Treatment

In only 3 patients, the decision to start biological treatment was either partly or entirely because of EIM involving the joints. These patients were excluded from this analysis. In all patients receiving biological treatment, the first line medication was an anti-TNF-α agent (infliximab or adalimumab). During follow-up, 34 (60%) patients with EIM and 100 (38%) patients without EIM were treated with biologics (P = 0.003). The HR of requiring biologics in patients with EIM compared with patients without EIM was 1.5 (95% CI: 0.8--2.8), P = 0.19, in CD and 2.6 (95% CI: 1.3–5.5), P = 0.008, in UC.

Surgical Intervention

In total, 76 CD patients (45%) and 21 UC patients (14%) had a bowel resection performed during follow-up. Of patients with an EIM, 25 (42%) had a bowel resection performed during follow-up compared with 72 (27%) of the patients without an EIM (P = 0.03). During follow-up, the HR of requiring a bowel resection in patients with EIM compared with patients without EIM was 1.3 (95% CI: 0.6–2.5), P = 0.5 in CD and 2.9 (95% CI: 1.1–7.7), P = 0.03 in UC.

Gastrointestinal Relapse

During the first 7 years of follow-up after IBD diagnosis, the standardized rate ratio of relapses in patients with EIM compared with those without was 1.3 (95% CI: 1.1–1.5), P = 0.001, in CD and 1.0 (95% CI: 0.8–1.2), P = 0.86, in UC.

Temporal Relationship Between Relapse of Inflammatory Bowel Disease and Activity in Extraintestinal Manifestations

In the following analyses, we only included IBD patients who developed EIM and only follow-up time after the EIM diagnosis: patients had a relapse of IBD during 20% of the follow-up time, corresponding to a median of 18 months (IQR: 9.0–30.0). Patients had activity of the EIM during 7% of the follow-up time, corresponding to a median of 6 months (IQR: 3.0–9.0). When looking at the relationship between IBD and EIM (during the length of follow-up time): patients had activity in both IBD and EIM during 4% of follow-up time, corresponding to a median of 3 months (IQR: 3.0–6.0); patients had activity in either IBD or EIM during 21% of follow-up time, corresponding to a median of 18 months (IQR: 9.0–30.0); and patients had no activity in neither IBD nor EIM during 73% of follow-up time, corresponding to a median of 63 months (IQR: 33.0--93.0). Thus, during follow-up, there was a consistency between relapse of IBD and activity/nonactivity of EIM (P < 0.0001).


In this population-based study, we aimed to describe the disease course in pIBD patients with and without EIM. We found an increased risk of requiring biologics and need of surgery in UC patients with EIMs and an increased risk of requiring escalation of treatment because of uncontrolled disease activity in CD patients with EIM compared with those without. We also observed a positive temporal relationship between the GI relapses and the activity of the EIM.

Only 4.2% of the patients in our study presented with an EIM at the time of IBD diagnosis. This is lower than in previously published pediatric data (1–8,26) and most likely because of our strict definition of EIM of the joints, including only arthritis with classic signs of inflammation. Further, in contrast to the other studies, we did not include aphthous stomatitis. At the end of follow-up, however, 18.3% of patients had been diagnosed with an EIM, which is in accordance with other studies (4,7).

In our study the phenotype at diagnosis (disease localization and behavior in CD and the extent in UC) did not impact on the risk of developing EIM. A population-based study by Duricova et al (5,6) found no association between disease extent and EIM in patients with pediatric onset ulcerative colitis (pUC), however, CD patients with upper GI involvement at time of diagnosis had an increased risk of EIM. Without stratifying for upper GI involvement, a multicenter study by Dotson et al (27) did not find an association between disease distribution and EIM in pediatric onset Crohn disease (pCD). Further, they observed that pUC patients with pancolitis were more likely to experience EIM than patients with isolated rectosigmoid disease (27).

In several studies, EIM at diagnosis has been found to increase the risk of SST and immunosuppressive treatment in both pediatric and adult patients (5,6,28). In our study, however, we did not find an increased risk, which might be because of the exclusion of liver disease and the low fraction of patients with EIM at diagnosis. As thiopurine treatment is standard treatment protocol for most CD patients in Denmark, regardless of disease severity, it would explain the frequent use of immunosuppressives in our study population compared with the studies mentioned above.

We observed an increased risk in use of biologics (infliximab and adalimumab) in UC patients with EIM. These findings are consistent with previous results from French and Swiss population-based pUC cohorts (4,5). The risk of anti-TNF-alfa treatment in a corresponding French pCD cohort was higher in patients with EIM, but not statistically significant (6). Likewise, we could not detect an increased risk of requiring biologics in CD patients with EIM.

The prevalence of surgery in both CD and UC are in line with previous pediatric studies from the French EPIMAD registery (2,5,6,14,29) and results from a population-based pUC cohort (7). In our study, the risk of surgery in pUC patients with EIM was increased 3-fold compared to pUC patients without EIM. This finding is in contrast with population-based pIBD studies from France and the United States where they found that EIM at diagnosis did not increase the risk of surgery (5–7).

CD patients with EIM had a significantly increased risk of uncontrolled inflammation leading to an escalation in medication or surgery (not including treatment administered because of EIM) during the first 7 years after diagnosis of IBD. This has not previously been reported in the literature.

Chronic IBD activity has been found to be a risk factor for developing EIM in both pediatric and adult studies (27,30,31); however, the pathogenesis of EIM is not fully understood. While 1 theory suggests that EIM is an independent inflammatory event, another proposes EIM to be triggered by immune responses from underlying IBD activity (32). In support of the latter theory, we found that GI relapses seem to be in a positive temporal relationship with the activity of EIM. Our results are consistent with results from previous adult studies, where activity in certain EIMs (such as erythema nodosum and arthritis) are described to be contemporaneous with IBD activity (33–36). Pediatric data describing simultaneous activity of EIM and pIBD are scarce, although a couple of studies have found arthritis to be most prominent during IBD activity (37,38).

A major strength of this study is the population-based design, avoiding selection bias of the patient cohort included. The large study population and the systematic scrutinization of patient charts resulted in reliable data. The retrospective data collection, including data on EIM, could lead to an underestimation of EIM and explain a relatively low prevalence. Even though the definition of joint EIM is precise and ensures that noninflammatory arthralgia is not included, it challenges the comparison with other studies, especially as joint manifestations are one of the most common EIM. Furthermore, differences in other definitions, design, study population, and time periods need to be taken into consideration when comparing results.

In conclusion, pIBD patients that presented with EIM or developed EIM during follow-up had an increased risk of requiring biological treatment (UC), surgical intervention (UC), and escalation of medical therapy because of uncontrolled disease activity (CD). On the basis of these findings, we hypothesize that presence of/or development of EIM is an independent risk factor of a more aggressive disease course in pIBD. Prospective studies are, however, needed to prove this hypothesis.


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children; Crohn disease; disease activity; disease course; ulcerative colitis

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