Incidence of ulcerative colitis and Crohn's disease in Danish children: Still rising or levelling out?

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1 Journal of Crohn's and Colitis (2008) 2, available at Incidence of ulcerative colitis and Crohn's disease in Danish children: Still rising or levelling out? Christian Jakobsen a,, Vibeke Wewer a, Frederikke Urne a, Jesper Andersen b, Jan Faerk c, Iza Kramer d, Bent Stagegaard e, Bente Pilgaard f, Birgitte Weile g, Anders Paerregaard a a Department of Pediatrics, Hvidovre Hospital, Denmark b Department of Pediatrics, Hilleroed Hospital, Denmark c Department of Pediatrics, Holbaek Hospital, Denmark d Department of Pediatrics, Nykoebing Falster Hospital, Denmark e Department of Pediatrics, Naestved Hospital, Denmark f Department of Pediatrics, Roskilde Hospital, Denmark g Department of Pediatrics, Gentofte Hospital, Denmark Received 23 November 2007; accepted 5 January 2008 KEYWORDS Inflammatory bowel disease; Genetics; Environmental factors; Epidemiology Abstract Aim: To describe the development in incidence and prevalence of paediatric inflammatory bowel disease (IBD) in Eastern Denmark during a six-year period. Methods: All patients b15 years with IBD in Eastern Denmark in the two following periods were included: 1) and 2) The mean background population (children b15 years) in Eastern Denmark was 421,898 persons in period 1 and 439,443 persons in period 2. Patients were identified using the ICD-10 classification (DK ). The following data were extracted from the files: diagnosis, change in diagnosis, age at diagnosis, localisation, extra-intestinal symptoms, surgery and county of residence. Incidence and prevalence for ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC) were calculated per 100,000 children b15 years. Results: 98 patients (50 UC, 44 CD, 4 IC), median age 9.8 years (range 2 14) and 12.8 (range ) for UC and CD, respectively, were identified in period 1. In the second period 145 patients (70 UC, 64 CD, 11 IC) were included with a median age of 11 years (range 1 14) and 12.5 (range ) for UC and CD, respectively. The prevalence of IBD was 15.8 and 20.3 in and , respectively. The incidence of IBD was 4.3 (UC: 1.8; CD: 2.3; IC: 0.2) and 6.1 (UC: 2.6; CD: 3.1; IC: 0.3), respectively, for the two periods (pn0.05). This work was presented at the 40th. Annual ESPGHAN meeting in Barcelona Corresponding author. University Hospital of Hvidovre, Kettegaard Alle 30, 2650 Hvidovre., Denmark. Tel.: ; fax: addresses: Christian.jakobsen@hvh.regionh.dk (C. Jakobsen), vibeke.wewer@hvh.regionh.dk (V. Wewer), fuurne@hotmail.com (F. Urne), jesan@noh.regionh.dk (J. Andersen), janfae@vestamt.dk (J. Faerk), suikra@stam.dk (I. Kramer), bent.stagegaard@dadlnet.dk (B. Stagegaard), b.pilgaard@dadlnet.dk (B. Pilgaard), weile@dadlnet.dk (B. Weile), anders.paerregaard@hvh.regionh.dk (A. Paerregaard) /$ - see front matter 2008 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi: /j.crohns

2 Incidence of ulcerative colitis and Crohn's disease in Danish children 153 Conclusions: In our study we found an insignificant increase in the incidence of both CD and UC, indicating that the previously reported rising incidence might be levelling out European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. 1. Introduction Inflammatory bowel disease (IBD), including ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC) have the highest incidence rates in patients aged years, but at least 6 7% will present during childhood. 1 The epidemiology of the adult IBD population has been extensively studied, but similar studies in children are sparse. Studies from other industrialized countries, 1 21 have shown incidences of UC ranging from per 100,000 children, but without a rising tendency. The incidences of CD have been ranging from per 100,000 children, with a high and increasing incidence in North-Western Europe 7 and the United States. 2 The total incidence of IBD ranges from per 100,000 children. In general these studies have shown an incidence of CD exceeding that of UC (generally by a factor 2) 2,7,15 and/or an incidence of CD that has recently risen considerably when compared to previous observations. 4,10 The incidence of UC has been stable in most studies, which is in contrast to new reports from Bristol in the UK, 19 which showed an increase in the incidence of UC ( ) in the period but unchanged incidence of CD ( ), and a recent study from Finland, 20 covering the period , showing an increasing incidence of both CD and UC. In this study we have investigated the development of incidence, prevalence and age at diagnosis of IBD in unselected children below the age of 15 years in Eastern Denmark. 2. Materials and methods Data were obtained separately from two three-year periods, and (January 1 to December 31). The background population included all 439,443 and 421,898 ( and , respectively) individuals b15 years living in the Eastern part of Denmark (43% of inhabitants b15 years living in Denmark.) (Fig. 1). 23 Since 1997 the treatment of IBD patients has been organised in collaboration between the local paediatric units in Eastern Denmark and the paediatric unit at Hvidovre Hospital, which has specialised in paediatric gastroenterology. The patients were prospectively registered in the hospital electronic register at Hvidovre Hospital. This makes population based epidemiological studies in this area ideal since no patients with IBD below the age of 15 years are diagnosed or treated outside this setting. Patients from the hospital register were included if they had an electronically registered ICD-10 diagnosis of DK and fulfilled the diagnostic criteria described below. To make sure all patients were included all paediatric departments in Eastern Denmark were asked to search their local databases for ICD-10 diagnoses of DK in patients b15 years, which resulted in 20 more patients not primarily included. Additionally, in the first period, we sent out a letter to all the adult gastroenterology departments in Eastern Denmark asking about paediatric patients. None of these departments treated IBD patients below the age if 15 years. In this study we only included data that Figure 1 The geographical area of Eastern Denmark and Copenhagen County.

3 154 C. Jakobsen et al. Table 1 Incidence and prevalence figures per 100,000 under 15 years Incidence/prevalence Incidence/prevalence IBD 4.8/ / / / / /24.2 UC 1.9/ / / / / /12.3 CD 2.4/ / / / / /10.3 IC 0.5/ /0.9 0/ / / /1.6 wouldbereliableinaretrospectivestudy:diagnosis,ageat diagnosis, change in diagnosis, localisation (CD and UC), extraintestinal symptoms, surgery, incidence and prevalence. For the period only diagnosis, age at diagnosis, localisation (CD only), incidence and prevalence were recorded Diagnostic criteria The diagnoses were based on clinical symptoms, colonoscopy, histology of biopsy specimens or resected bowel segments, and small-bowel follow-through. The diagnostic criteria of Lennard-Jones 24 for UC and CD were used. Patients were classified as having IC when endoscopy was equivocal and microscopy showed features of IBD but absence of diagnostic features for either CD or UC in mucosal biopsies from different segments of the colon. Patients with infectious or other specific underlying enteritis or colitis were excluded Localisation Localization was based on macroscopic findings at endoscopy or radiological abnormalities. Upper endoscopy was not carried out routinely during work-up. In CD we divided localisation into: 1) oral 2) gastric and duodenal 3) jejunal and ileal (not including the terminal ileum) 4) ileocoecal, including the terminal ileum 5) colonic 6) perianal disease. The localisation for UC was only systematically registered in and was divided into: 1) proctitis (disease localized to the rectum) 2) left-sided disease (distal to the splenic flexure) 3) extensive disease (proximal to the splenic flexure) Extra-intestinal symptoms Extra-intestinal symptoms were divided as originating from eye (uveitis), skin (erythema nodosum, pyoderma gangraenosum) and liver (primary sclerosing cholangitis, autoimmune hepatitis). Data for joint symptoms were not included as these were regarded as unreliable when registered in a retrospective fashion Follow-up All patients were followed up for at least 1 year in both time periods before inclusion to observe any change in diagnosis Incidence and prevalence The incidence was calculated as the number of new patients with IBD per 100,000 children b15 years of age per year. The prevalence was the total number of patients with IBD per 100,000 children b15 years Statistics Trends or differences in incidences were evaluated using Poisson regression analysis with time as the explaining variable. Significance level was set as pb Results In the total number of patients was 98; 50 patients with UC (51%), 44 patients with CD (45%) and 4 patients with IC (4%). The total number of patients fulfilling the diagnostic criteria in was 145. Seventy patients had UC (48%), 64 patients had CD (44%) and 11 patients had IC (8%). Combining the two time periods we found male:female ratios of IBD, CD, UC and IC of 1.08:1, 1.16:1, 0.96:1 and 1.75:1, respectively. In the mean annual incidence of IBD was 4.3 per 100,000 children b15 years (UC: 1.8; CD: 2.3; IC: 0.2). Figure 2 Incidence figures over time in Eastern Denmark. Figure 3 Age at diagnosis in the two time periods and

4 Incidence of ulcerative colitis and Crohn's disease in Danish children 155 Table 2 Extraintestinal manifestations in CD and UC patients Crohn's disease Ulcerative colitis Skin 2 (3.1%) 0 Eyes 0 2 (2.9%) Liver 1 (1.6%) 5 (7.1%) a a None of the IC patients had extra intestinal symptoms. The mean prevalence of IBD was 15.8 per 100,000 children b15 years (UC: 8.3; CD 6.7; IC: 0.8). In the period the mean annual IBD incidence was 6.1 (UC: 2.7; CD: 3.1; IC: 0.3). The mean annual IBD prevalence was 20.3 (UC: 10.5; CD: 8.2; IC: 1.5) Fig. 2. Point estimates of incidence and prevalence rates for each year are shown in Table 1. Between and the increase in incidence was 42%, 35% and 44% for IBD (p=0.06),cd(p=0.13) and UC (p=0.22), respectively. The age distribution at diagnosis for the two periods combined is shown in Fig. 3. Median age at diagnosis for IBD was 11.3 years (range ): 10.5 years (1 14) for UC, 12.0 (0.5 14) for CD and 11.3 (7 14) for IC. In and two (2%) and 7 patients (5%) changed diagnosis, respectively. In the latter time period three patients changed from IC to UC, two patients from IC to CD and another two patients from UC to CD. In the first time period data was not available. Many of the CD patients had more than one affected bowel segment. In : 28/44 CD patients (64%) had colonic involvement, 19/44 (43%) had ileocoecal involvement and 6/44 (14%) had perianal disease. In : 8/64 (13%) CD patients had oral localization, 3/64 (5%) had disease in the stomach and/or duodenum, 9/64 (14%) had disease in the jejunum and/or ileum, 34/64 (53%) had ileocoecal involvement, 47/64 (73%) had colonic involvement, and 12/64 (19%) had perianal disease. Localisation for UC patients was not systematically registered in the first time period but most patients had extensive disease. In ; 54/70 (77%) of the UC patients had extensive disease, 13/70 (19%) left sided disease and 3/70 (4%) had proctitis. Extraintestinal symptoms in the period are shown in Table 2. In surgical treatment was performed in 19 patients (13%) of which 14 had CD (22% of CD patients) (Fig. 4) and 5 had UC (7% of UC patients). All the UC patients underwent subtotal colectomy. None of the IC patients underwent surgery. 4. Discussion This study showed a non-significant increase in the incidences of CD and UC, indicating that the previously reported rising incidence might be levelling out. An earlier study 1 from in Copenhagen County (background population of 136,436 b 15 years) found incidences of 2.0 and 0.2 per 100,000 Danish children b15 years for UC and CD, respectively. A recent study 3 from from Copenhagen County and city (background population 203,205 b15 years), showed an increasing incidence of not only CD (13 fold increase) but also of UC (incidence of 2.4/ b 15 years). Colonoscopy was introduced in Denmark in Therefore, the study including patients diagnosed during the period carries a risk of underestimation of IBD and lower power to discriminate between CD and UC. However, the incidence rates before and immediately after 1977 did not differ. The geographical area in our study covers a larger area than the two previous studies. In contrast to a recent study from Sweden 15 we found a small preponderance of prevalent UC patients compared to CD patients in the two time periods, in accordance with other studies from Scandinavia. 16,21 The preponderance of UC was most evident in the younger age groups (b10 years) as CD was Figure 4 Surgical procedures performed in CD patients.

5 156 C. Jakobsen et al. more prevalent among the older children (N10 years). The reason for this difference between these geographically adjacent countries is not known. Both our studies had a well defined background populations and the paediatric units were referral centres for all suspected cases of IBD from the background population. The upper age limit of the included patients differed slightly ( 14 years of age and 15 in our study and the Swedish study, respectively). Different application in the use of diagnostic criteria might also be of importance, but both studies have used strict criteria and IC patients were included. In this study age distribution at diagnosis (Fig. 2) showed that the majority of patients were more than 10 years at diagnosis. Thirty-one percent and 24% of the patients were under the age of 10 years at diagnosis in and , respectively and the majority of these patients had a diagnosis of UC in both time periods. This distribution is in accordance with some studies, 26 but not others 25,15 where CD and IC were found to be more prevalent in the young age groups. One reason for this inconsistency is that UC was more prevalent in our study. We would therefore expect to identify more UC than CD patients in all age groups, but it is striking that only one CD patient was under the age of 7 years. Alternatively, the incidence of CD could have been underestimated, because during the study period not all patients with an apparent UC diagnosis had an upper GI endoscopy carried out as recommended in the Porto criteria. 27 However, the same diagnostic strategy was applied to all patients and should therefore affect all age groups in a similar fashion. The time period from which the patients were included might also influence the observed age distribution. In the study by Mamula et al. 25 some of the patients were diagnosed in the 1970s and early 1990s, where the diagnostic tools were not as exact as they are at present. This could explain the large amount of IC patients, but not the CD patients in that study. In the study by Hildebrand et al. 15 the patients were collected from and all had colonoscopy and most also upper GI endoscopy performed. The reason for the discrepancies in the age related distribution of diagnosis is therefore unknown. IBD is believed to arise as a consequence of the interaction between genetic and environmental factors. New genetic mutations are unlikely to occur within a short time span. This makes environmental factors the most likely explanation for the observed changes in the incidence patterns in Eastern Denmark over the last years. Differences in dietary habits in populations, closely related with respect to geography and genetics, have previously had significant influence on the prevalence of other intestinal diseases such as celiac disease. 28 Further epidemiological studies and studies on the putative importance of environmental factors in this region are needed in order to clarify this hypothesis. Acknowledgments The authors would like to thank Karsten Hjelt, M.D, D. Med. Sci., Department of Paediatrics, Glostrup Hospital Copenhagen for his contribution in collecting data for this study. AP designed the study. CJ carried out the study, data analyses and drafted the manuscript. VW, FU, JA, JF, IZ, BS, BP, BW and AP contributed in collecting data and helped in drafting the manuscript. All authors read and approved the final manuscript. References 1. Langholz E, Munkholm P, Krasilnikoff A, Binder V. Inflammatory bowel diseases with onset in childhood. 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