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Available online at www.sciencedirect.com Digestive and Liver Disease 40 (2008) 12–15 Mini-Symposium Early onset IBD: What’s the difference? E.E.S. Nieuwenhuis 1 , J.C. Escher ,1 Department of Pediatric Gastroenterology, Sophia Children’s Hospital-Erasmus Medical Center, Rotterdam, The Netherlands Received 23 July 2007; accepted 26 July 2007 Available online 7 November 2007 Abstract In this paper we describe an array of differences between paediatric and adult inflammatory bowel diseases. Specifically, patient specifics such as genetics, disease location, immune responses and drug responsiveness are addressed. Given the distinct disease phenotype in children, it seems warranted that early onset inflammatory bowel diseases will be denoted as a specific disease entity. © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Children; Disease phenotype; Epidemiology; Genetics; IBD; Immunology 1. Introduction Inflammatory bowel diseases (IBD) result from aberrant mucosal immune responses to intestinal bacteria. Environ- mental triggers and genetic susceptibility are regarded as crucial contributors to the IBD pathogenesis. In children both the mucosal immune system and the intestinal microflora are still developing. Taken together it seems likely that paediatric IBD represents a specific group of patients with particular gene defects, phenotypic appearance, drug responsiveness and immune pathology. In this paper, we will focus on the differences between paediatric and adult IBD. 2. Epidemiology About 10–15% of IBD patients are diagnosed before the age of 18 years [1]. Consistent with a peak around the age of 30 years, the incidence is 7 per 100,000 per year dur- ing puberty, and increases further during adolescence to 12 Corresponding author at: Department of Paediatric Gastroenterology, Erasmus Medical Center-Sophia Children’s Hospital, POB 2060, 3000 CB Rotterdam, The Netherlands. Tel.: +31 10 4637093/6049; fax: +31 10 4636811. E-mail address: [email protected] (J.C. Escher). 1 Both authors contributed equally to this work. per 100,000 years in 20–29 year olds [2]. In children, most cohort studies show a predominance of incident cases of Crohn’s disease (CD) over ulcerative colitis (UC) [3], with CD incidence clearly increasing over the past decade. By contrast, UC incidence is found to be stable in some studies [4–6] but increasing in other cohorts [7–9]. In most paedi- atric studies, the median age of onset of symptoms in UC is 12 years [2,10,11], and the diagnostic delay is considerably shorter compared to CD. The clinical presentation of UC is often more severe in children compared to adults, which may be explained by the predominant finding of pancolitis (in 70–80% of children) already at the time of diagnosis [11,12]. In addition to the lower incidence number in children as compared to adults, and the predominance of CD over UC in children, another interesting difference exists between early onset and late onset IBD: a male preponderance is reported in paediatric CD [1,11,13], while female preponderance is only seen among patients diagnosed in adolescence (13–19 years) [14], in accordance with the overall higher incidence of CD in females. 3. Genetics IBD results from aberrant mucosal immune responses to environmental factors such as commensal bacteria. Based on the relatively short exposure time to environmental factors 1590-8658/$30 © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2007.07.166

Early onset IBD: What's the difference?

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Available online at www.sciencedirect.com

Digestive and Liver Disease 40 (2008) 12–15

Mini-Symposium

Early onset IBD: What’s the difference?

E.E.S. Nieuwenhuis 1, J.C. Escher ∗,1

Department of Pediatric Gastroenterology, Sophia Children’s Hospital-Erasmus Medical Center,Rotterdam, The Netherlands

Received 23 July 2007; accepted 26 July 2007Available online 7 November 2007

bstract

In this paper we describe an array of differences between paediatric and adult inflammatory bowel diseases. Specifically, patient specificsuch as genetics, disease location, immune responses and drug responsiveness are addressed. Given the distinct disease phenotype in children,t seems warranted that early onset inflammatory bowel diseases will be denoted as a specific disease entity.

2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

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eywords: Children; Disease phenotype; Epidemiology; Genetics; IBD; Im

. Introduction

Inflammatory bowel diseases (IBD) result from aberrantucosal immune responses to intestinal bacteria. Environ-ental triggers and genetic susceptibility are regarded as

rucial contributors to the IBD pathogenesis. In children bothhe mucosal immune system and the intestinal microflora aretill developing. Taken together it seems likely that paediatricBD represents a specific group of patients with particularene defects, phenotypic appearance, drug responsivenessnd immune pathology. In this paper, we will focus on theifferences between paediatric and adult IBD.

. Epidemiology

About 10–15% of IBD patients are diagnosed before thege of 18 years [1]. Consistent with a peak around the age

f 30 years, the incidence is 7 per 100,000 per year dur-ng puberty, and increases further during adolescence to 12

∗ Corresponding author at: Department of Paediatric Gastroenterology,rasmus Medical Center-Sophia Children’s Hospital, POB 2060, 3000 CBotterdam, The Netherlands. Tel.: +31 10 4637093/6049;

ax: +31 10 4636811.E-mail address: [email protected] (J.C. Escher).

1 Both authors contributed equally to this work.

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590-8658/$30 © 2007 Editrice Gastroenterologica Italiana S.r.l. Published by Elseoi:10.1016/j.dld.2007.07.166

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er 100,000 years in 20–29 year olds [2]. In children, mostohort studies show a predominance of incident cases ofrohn’s disease (CD) over ulcerative colitis (UC) [3], withD incidence clearly increasing over the past decade. Byontrast, UC incidence is found to be stable in some studies4–6] but increasing in other cohorts [7–9]. In most paedi-tric studies, the median age of onset of symptoms in UC is2 years [2,10,11], and the diagnostic delay is considerablyhorter compared to CD. The clinical presentation of UC isften more severe in children compared to adults, which maye explained by the predominant finding of pancolitis (in0–80% of children) already at the time of diagnosis [11,12].

In addition to the lower incidence number in children asompared to adults, and the predominance of CD over UC inhildren, another interesting difference exists between earlynset and late onset IBD: a male preponderance is reported inaediatric CD [1,11,13], while female preponderance is onlyeen among patients diagnosed in adolescence (13–19 years)14], in accordance with the overall higher incidence of CDn females.

. Genetics

IBD results from aberrant mucosal immune responses tonvironmental factors such as commensal bacteria. Based onhe relatively short exposure time to environmental factors

vier Ltd. All rights reserved.

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n children, genetic mutations that either enhance the sus-eptibility for or protect from these pathogenic responses arehought to play an increasing role in early onset disease. Ateast two reports support this hypothesis [15,16]. As such, itas recently shown that in comparison with adults, paediatricD is associated with a higher frequency of mutation in theOD2/CARD 15 gene in comparison to adult IBD patients.

. Early immune responses

Traditionally, aberrant adaptive mucosal immuneesponses by (NK)T and B cells have been regarded ashe main contributors to the pathogenesis of IBD [17].ecent discoveries of defects in genes that mainly regulate

nteractions with the innate immune system have (re)focusedhe attention on the earliest phases of the immune response18,19]. As such, both hypo- as well as hyper-responsivenessf these innate immune-cells have been put forward.or example, a loss of innate function in IBD has beenstablished by showing a diminished expression of thentimicrobial defensins in Paneth cells (PC) of adult CDatients. Loss of function has also been described innother innate cell, the macrophage. Macrophages derivedrom CD patients with a mutation in NOD2/CARD-15roduced less of the pro-inflammatory chemo-attractantnterleukine-8 on stimulation. These defects could thereforeead to suboptimal clearance and colonization control ofntestinal bacteria resulting in chronic inflammation [20,21].s loss of function mechanisms have not been identifiedet in paediatric IBD patients, it is quite surprising thatecent papers describe the opposite phenomenon, i.e. innateyper-responsiveness. A group of paediatric CD patientshowed enhanced epithelial chemokine production andesponsiveness in comparison to adult CD patients. Whetherhis state of hyper-responsiveness will sustain into adulthoodnd would therefore represent a specific feature of earlynset CD remains to be elucidated [22]. Of particular interests the subset of patients with a very early onset IBD (onsetefore the age of 1 year). These patients presented withectal bleeding and all seem to have colonic involvement.ntriguingly, there is evidence of an association with neonatalr early onset bacterial infections and use of antibiotics prioro the onset of IBD [23]. Taken together with the notionhat both the intestinal microbiota as well as the mucosalmmune system are still under development in children wepeculate that the contributions of innate immune defects tohe pathogenesis of IBD are inversely related to the age ofisease onset.

. Disease phenotype: location of disease

In the patients diagnosed with IBD at young age (before 5ears), anatomic distribution is clearly different with less iso-ated ileal disease in CD and more large bowel involvement

iama

and Liver Disease 40 (2008) 12–15 13

n all types of IBD [24–26]. The most commonly affectedites in CD are the terminal ileum (in 71% of patients atiagnosis) and right colon (71%) [11]. Upper gastrointestinalnvolvement is commonly seen in paediatric CD [22,27,28],ut this finding may be due to routine upper gastrointestinalndoscopy with biopsies at diagnosis (in addition to ileo-olonoscopy) as dictated by consensus guidelines [29].

In ulcerative colitis, the disease is more widespread inhildren compared to adults at diagnosis: pancolitis in up to0% [1,11,12], and proctitis in only a minority of 4–13%.he more extensive localisation and the occurrence of rectalparing in up to 30% of paediatric patients with UC [30] war-ant a thorough complete diagnostic work-up in children withloody diarrhoea. Evidence from the literature supporting theolonoscopy with ileal intubation (and multiple biopsies) isrovided by retrospective cohort studies [30–32]. In conclu-ion, sigmoidoscopy may be sufficient in adults, but certainlyot in children or adolescents with suspected UC.

Follow-up studies in paediatric IBD have shown that thextent of disease may change over time. As Crohn’s diseaserogresses, anatomic distribution of macroscopic disease isrobably similar in early and late onset disease [12,14,33]. Inlcerative colitis, proximal extension of proctosigmoiditis isstimated to occur in 25% of young patients within 3 years ofnitial diagnosis and in 29–70% over the course of follow-up33–35].

. Disease phenotype: disease behaviour

In paediatric CD, simple inflammatory disease isescribed to be predominant (90%) at diagnosis [1]. However,omplex stricturing and penetrating behaviour become moreommon over time. In a retrospective cohort of 224 patientsith early onset CD with a mean follow-up of 12.2 years,

he incidence of strictures (29%) and penetrating behaviour46%) were similar to adults followed for the same period ofime [14].

In paediatric CD, only 25% of patients present with theclassic triad” of abdominal pain, weight loss and diarrhoea11]. Non-classical features such as lethargy or anorexiaay be present, and abdominal pain is present in 72%

ut may be mild. A family history of IBD, growth failurepresent in up to 65% of CD patients at diagnosis depend-ng on its definition), pubertal delay or abnormalities oneri-anal examination should prompt further investigationeading to a diagnosis of CD. Extra intestinal manifestationsin 8.4%) and growth failure (in 3.3%) may predominateuring years in absence of gastrointestinal symptoms [12].rowth failure is three times less common in UC, compared

o CD. Symptoms of blood loss (84%), diarrhoea (74%)nd abdominal pain (62%) are often present at diagnosis

n paediatric UC [11]. The above-mentioned difference innatomic distribution is the most probable reason for theore severe clinical presentation in children, as compared to

dults.

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Osteopenia may be present in children or adolescents atiagnosis [36,37] and although no long-term data are presentnd no proven treatment strategy has been published, screen-ng and careful follow-up of bone health is warranted inhildren and adolescents with IBD [38].

Follow-up studies in paediatric IBD are now emerging andill yield important data on the clinical course of early onsetisease. Whether the course of disease is different in children,dolescents and adults is unknown at present. Only a fewtudies however have compared patients with early onset andate-onset disease [14,33]. Langholz and co-workers reportedn the course of clinical disease activity in patients with dis-ase onset below and above age 14 [33]. In this retrospectivetudy, no significant differences in disease activity at the timef diagnosis were found between young (≤14 years) patientsnd older (>14 years) patients. Disease activity was mod-rate to high in 74% of younger patients with UC, and in3% of the young CD patients at diagnosis. After a year andontinuing over a 10-year follow-up, about 50% of youngD patients were in clinical remission, none of the patientseing treated with azathioprine at the time. Clinical remis-ion was seen in 60–70% of young UC patients after a fewears.

A more recent study on the clinical course of CD in chil-ren and adolescents shows that the spectrum of diseaseeverity during 5-years of follow-up has remained constanturing the decades 1980–1988 and 1990–1999: one thirdas mild symptoms only, one third has occasional exacer-ations returning to remission, while one third is chronicallyteroid-dependent or steroid-refractory [39].

The frequency of surgery in children with CD was reportedo be 31.5% at 5-year follow-up, which is similar to therequency in adults [3]. In this prospective study, the chil-ren who underwent surgery (mainly for ileal stenosis) wereignificantly younger (mean age 11 years) than those whoid not (mean age 14.2 years). Retrospective data from theSA paediatric IBD consortium show a lower cumulative

isk for surgery of 17% at 5 years and 28% at 10 years40]. Recent data from the EPIMAD cohort, a populationased cohort of IBD patients diagnosed from 1988 to 2002n North-West France, show a cumulative risk of surgeryn 10%, 22% and 36% of young (<17 years at diagnosis,= 472) CD patients at 1 year, 3 years and 5 years after diag-osis [41]. The cumulative incidence of surgery ranges from0% to 70% at 10 years from the time of diagnosis of CD indults.

In paediatric UC, 70% of patients enter remission withinmonths of initial diagnosis, irrespective of the severity at

resentation (mild, moderate or severe) [42]. The severity ofnitial presentation correlated with long-term likelihood ofolectomy: by 1 year, 9% and by 5 years, 26% of those pre-enting with moderate to severe disease required colectomy.

ata from the EPIMAD cohort demonstrate a cumulative

isk of surgery in 9%, 15% and 20% of UC patients (aged17 years) at 1 year, 3 years and 5 years after diagnosis43].

and Liver Disease 40 (2008) 12–15

. Conclusion

In this paper we have described an array of differencesetween paediatric and adult IBD. Initiatives need to be takenn order to revise the nomenclature of IBD based on patientpecifics such as genetics, disease location and drug respon-iveness. In the light of these plans it seems warranted thatarly onset IBD will be denoted as a specific disease entity.

Practice points

• Genetic mutations are thought to play anincreasing role in early onset IBD.

• Contributions of innate immune defects tothe pathogenesis of IBD seem to be inverselyrelated to the age of disease onset.

• Disease location is different in early onset IBDcompared to adult IBD:- more upper GI involvement and less iso-

lated terminal ileum involvement in CD.- more pancolitis and less proctitis in UC.

• Early onset IBD may have a more severe clin-ical presentation as compared to adults.

• Sigmoidoscopy may be sufficient in adults,but certainly not in children or adolescentswith suspected UC.

Research agenda

• Further geno-, immuno- and pheno-typing ofearly onset IBD.

• Denotation of early onset IBD as a specificdisease entity.

onflict of interest statementone declared.

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