The incidence of ulcerative colitis ( ) and Crohn's disease ( ) Based on nationwide Danish registry data

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1 Journal of Crohn's and Colitis (2014) 8, Available online at ScienceDirect The incidence of ulcerative colitis ( ) and Crohn's disease ( ) Based on nationwide Danish registry data Bente Mertz Nørgård a,b,, Jan Nielsen a,b, Kirsten Fonager c,d, Jens Kjeldsen e,f, Bent Ascanius Jacobsen g, Niels Qvist h,i a Center for Clinical Epidemiology, Odense University Hospital, DK-5000 Odense C, Denmark b Research Unit of Clinical Epidemiology, Institute of Clinical Research, University of Southern Denmark, DK-5000 Odense C, Denmark c Department of Social Medicine, Aalborg University Hospital, DK-9000 Aalborg, Denmark d Department of Health Science and Technology, Faculty of Medicine, Aalborg University, DK-9000 Aalborg, Denmark e Department of Medical Gastroenterology S, Odense University Hospital, DK-5000 Odense C, Denmark f Research Unit of Medical Gastroenterology, Institute of Clinical Research, University of Southern Denmark, DK-5000 Odense C, Denmark g Department of Medical Gastroenterology, Aalborg University Hospital, DK-9000 Aalborg, Denmark h Department of Surgical Gastroenterology A, Odense University Hospital, DK-5000 Odense C, Denmark i Research Unit of Surgery, Institute of Clinical Research, University of Southern Denmark, DK-5000 Odense C, Denmark Received 15 December 2013; received in revised form 29 January 2014; accepted 6 March 2014 KEYWORDS Incidence; Ulcerative colitis; Crohn's disease; Epidemiology Abstract Background and aims: The incidence of ulcerative colitis (UC) and Crohn's disease (CD) has increased during the 20th century in North America and Western Europe. However, there are conflicting reports whether the incidence has declined, stabilized or even continued to increase. No nationwide Danish data on the incidence of UC and CD exist after 1992, and therefore we studied the incidence of UC (1995 through 2011) and CD (1995 through 2012). Methods: Based on data from the Danish National Patient Registry we identified patients recorded with a first time diagnosis of UC or CD in the study periods. Among these patients Abbreviations: UC, ulcerative colitis; CD, Crohn's disease; NPR, Danish National Patient Registry; ICD, International Classification of Diseases; IRR, incidence rate ratio. Corresponding author at: Center for Clinical Epidemiology, Odense University Hospital, Sdr. Boulevard 29, entrance 1014th, DK-5000 Odense C, Denmark. Tel.: addresses: bente.noergaard@rsyd.dk (B.M. Nørgård), jan.nielsen2@rsyd.dk (J. Nielsen), k.fonager@rn.dk (K. Fonager), jens.kjeldsen@rsyd.dk (J. Kjeldsen), beaj@rn.dk (B.A. Jacobsen), niels.qvist@rsyd.dk (N. Qvist) / 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

2 Incidence of inflammatory bowel disease 1275 were only included in the study as incident cases if they had at least one more discharge diagnosis of UC/CD or at least three subsequent outpatient visits. Results: We identified 17,500 patients with UC and 7863 patients with CD. The mean incidence rate for UC in was 14.4 per 100,000 per year for women and 13.8 for men, increasing to 23.2 per 100,000 per year for women and 23.4 for men in the period of The mean incidence rate for CD in was 7.8 per 100,000 per year for women and 5.6 for men, increasing to 10.3 per 100,000 per year for women and 8.9 for men in the period of Conclusions: Based on nationwide Danish data from the last two decades, the incidence rates of UC and CD have continued to increase European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved. 1. Introduction The incidence of ulcerative colitis (UC) and Crohn's disease (CD) is subject to considerable variation between geographic regions and time, and the incidence has increased during the past half century in the populations of Western Europe and North America. The highest occurrence of UC and CD is found in Canada 1 3 and Europe 3,4, and within Europe the highest incidence rates are found in Scandinavia 5 18 and the United Kingdom During the last decades it has been discussed whether the incidence has continued to increase, has stabilized or has even declined There are, however, some indications of a continuing increase of the incidence of UC and CD, 3,23,27,28 and a recent Swedish study showed one of the highest incidences of UC in the world. 23 No nationwide Danish data on the incidence of UC and CD have been reported since 1992 (with reported mean incidence for UC of 13.2 per 100,000 person-years and for CD 4.6 per 100,000 personyears). 12 Later reported local data from the Northern Jutland and Copenhagen County in Denmark have indicated a continuous increase in the incidence rates of UC and CD. 7,8 UC and CD are relatively rare diseases and it is both extremely time consuming and expensive to estimate incidence rates based on prospective registration. Furthermore, surveillance bias may be a problem if disease registration varies between regions and over time. For these reasons it is valuable if existing public health registers can provide valid surveillance data according to incidence rates over longer time periods. Based on nationwide data from the Danish National Patient Registry (NPR), we aimed to examine the incidence rates of UC and CD from Materials and methods 2.1. Study population and setting In Denmark, all citizens have free access to a tax supported health care system throughout the study period. Its uniform organization allowed us to use a population-based setting using nationwide data. Since 1977, all patients are registered in the NPR when they are discharged from Danish hospitals, and the NPR also includes all outpatient visits since ,30 The population of Denmark was approximately 5.2 million (in 1995) increasing to 5.6 million (in 2012). The start of the period, 1 January 1995, was chosen since this was the time for inclusion of also outpatient visits in the NPR. The study population included new diagnosed patients with CD in the study period of 1995 through 2012, while the study population of UC patients included new diagnosed patients from 1995 through Thus, data from 2012 on UC patients were excluded because of a reclassification from the World Health Organization of the International Classification of Diseases (ICD) 10 diagnostic codes for UC (implemented in Denmark by 1, January 2012) Identification of UC and CD patients Information in the NPR includes patients' unique civil registration numbers, hospital, departments, dates of admission and discharge, procedures performed and up to 20 discharge diagnoses based on the ICD, 8th revision before 1994 and ICD, 10th revision from 1994 onward (ICD-9 has never been used in Denmark). All patients with a valid civil registration number, who were discharged with affirmative UC (ICD-8 codes: , ; ICD-10 codes: DK51.0, DK51.1, DK51.2, DK51.3) or affirmative CD (ICD-8 codes: ; ICD-10 codes: DK50.0, DK50.1, DK50.8) from any hospital in Denmark were identified in the NPR from 1 January 1977, and all patients diagnosed for the first time with UC from 1995 through 2011 and CD from 1995 through 2012 were identified. Among these patients were only included in the study as incident cases if they also had at least one subsequent discharge diagnosis of UC/CD or at least three subsequent outpatient visits Statistical analysis The annual incidence rates for UC and CD and for each gender were estimated as the number of incident patients, divided by the number of inhabitants in the middle of the same calendar year. Information on the size of population for each year was obtained from the National Central Statistical Register. 31 Some patients were registered with both UC and CD in the NPR and in order to compare changes in the incidence rate over time, patients with both diagnoses were included under the first disease registration. The incidence rates for UC were directly standardized to the 2011 Danish population using 15-year age groups, and similarly the incidence rates for CD were standardized to the 2012 population. Age-adjusted incidence rates were also summarized within four calendar periods of time (1995

3 1276 B.M. Nørgård et al. 1998, , , and /2012). The 95% confidence intervals (CI) of the estimated incidence rates were based on the assumption of Gamma distribution. 32 Furthermore, the mean incidence rates for UC and CD were given within different age groups (b 15, 15 29, 30 44, 45 59, 60 74, N75) and according to gender. Poisson regression models were used to estimate the incidence rate ratio (IRR) for the annual change in the incidence, adjusted for gender and age (using the abovementioned age categories). All analyses were conducted using Stata 13 software (StataCorp LP, College Station, TX, USA) Ethical approvals and permissions According to Danish law there are no ethical approvals of register-based studies. The study was approved by the Danish Data Protection Agency (J.nr ). 3. Results There were 17,500 patients fulfilling our criteria for incident cases of UC from 1995 through 2011, and 7863 patients of CD from 1995 through Incidence rate of UC Fig. 1 shows the age-standardized incidence rates for UC according to gender and each calendar year in the study period. In 1995 the estimated rate was 13.6 (95% CI: ) per 100,000 person years for men and 13.9 (95% CI: ) per 100,000 person years for women. In the period from 1995 throughout 2011 the rate for both men and women increased, and in 2011 reaching 23.5 (95% CI: ) for men and 22.4 (95% CI ) for women. The mean age-adjusted incidence rate for UC in four time periods is summarized in Table 1 and shows the increasing incidence, reaching a mean incidence in the period of 23.2 per 100,000 per year for women and 23.4 per Incidence rate per person years Female Male Year Figure 1 The incidence rate of ulcerative colitis, Incidence rates were standardized to the 2011 Danish population by 15 year age groups. Vertical lines: 95% confidence intervals. Dotted line: men. Solid line: women. 100,000 per year for men. Table 2 shows the mean incidence rates per year for UC within different age groups and according to gender. In women the highest incidence rates were found in age groups years and years, and in men the highest incidence rates were found in the same age groups. The result from the Poisson regression model showed an IRR of (95% CI: ), corresponding to an annual increase of the incidence rate of 3.5% adjusted for age and gender. The IRR also corresponds to a doubling in the incidence rate of UC during a period of 20.4 years (95% CI: ) Incidence rate of CD Fig. 2 shows the age-standardized incidence rates for CD according to gender and each calendar year in the study period. In 1995 the estimated rate was 6.8 (95% CI: ) per 100,000 person years for women and 4.6 (95% CI: ) per 100,000 person years for men. In the period of 1995 through 2012 the incidence rates increased, and in 2012 reaching 9.5 (95% CI: ) per 100,000 person years for women and 8.8 (95% CI: ) per 100,000 person years for men. The mean age-adjusted incidence rate for CD in four time periods is summarized in Table 3 and shows the increasing incidence, reaching a mean incidence from 2009 through 2012 of 10.3 per 100,000 per year for women and 8.9 per 100,000 per year for men. Table 4 shows the mean incidence rates per year for CD within different age groups and according to gender. For both men and women the highest incidence rate was found in the age group years. The Poisson regression model estimated an IRR of (95% CI: ), corresponding to an annual increase of the incidence rate of 2.4% adjusted for age and gender and to a doubling in the incidence rate of CD during a period of 28.7 years (95% CI: ). 4. Discussion In this population based study, using nationwide Danish data from the last two decades, we found increasing trends in the incidence rates of UC and CD. In the study periods, the mean incidence rate for UC increased from approximately 14 to 23 per 100,000 per year for both men and women; and the mean incidence rate for CD increased from 7.8 to 10.3 per 100,000 per year for women and from 5.6 to 8.9 per 100,000 per year for men. Our study has several strengths. Data were obtained independently of the study question, and a population-based approach is possible in Denmark due to a unique availability of nationwide registries. Internationally, the NPR is considered to be the most comprehensive of its kind, 29 and the NPR records more than 99% of all hospital discharges for somatic diseases. 30 We thus had access to the obligatory registration from Danish hospitals since 1977 and all outpatient visits since We used the NPR to identify patients with diagnoses of UC and CD, and the completeness and the validity of UC and CD diagnoses in the NPR are of high quality. The completeness of diagnoses of UC and CD has been examined in a Danish study using the pathology system

4 Incidence of inflammatory bowel disease 1277 Table 1 Mean incidence rate for ulcerative colitis (UC) in four time periods, covering 1995 through Number of UC patients (n = 17,500) as a reference standard showing that of all patients with a confirmed diagnosis of UC or CD, 94% were included in the NPR. 33 The completeness of UC and CD registration in the NPR is most probably even higher in our study period as UC and CD diagnoses given in outpatient visits are now also registered. Furthermore, the overall positive predictive values (i.e. the percentage of patients registered under the disease code fulfilling the criteria of CD and UC) were 97% and 90% for CD and UC, respectively. 33 The positive predictive value of UC diagnoses increased further (to 94%) when the diagnosis was given at a specialized department of gastroenterology. 33 The validity of diagnostic coding for UC and CD in the NPR is essential. Based on the results of the validity study of UC and CD 33, and because we have been very restrictive according to our definition of incident cases we believe that our results are valid. First of all we have included only affirmative codes for UC and CD, and thus not included unspecified UC and CD codes in our study. Furthermore, we have been very strict in our criteria of incident cases, i.e., included patients had at least two discharge diagnoses of UC/CD or one discharge diagnosis with at least three subsequent outpatient visits. Therefore, we might in fact have underestimated the true incidence rates of UC and CD. The figures showing the incidence trends for UC and CD indicate a decrease in the rates at the end of the study periods. This is most probably due to our methodological approach. Thus, it is not surprising that the incidence curves for UC and CD flatten out/even decrease at the end of the Mean incidence rates per 100,000 person years (95% confidence interval) a Time period Female Male Female Male b ( ) 13.8 ( ) ( ) 19.7 ( ) ( ) 23.0 ( ) c ( ) 23.4 ( ) a Incidence rates were directly standardized to the 2011 population by 15 year age group. The 95% confidence intervals were based on assumption of the Gamma distribution. b Includes only four calendar years. c Includes only three calendar years. Table 2 Mean incidence rates per 100,000 person years for ulcerative colitis (UC) in different age groups. Age group a (years) Total number of UC patients (n = 17,500) Mean incidence rates per 100,000 person years (95% confidence internal) Female Male Female Male b ( ) 2.4 ( ) ( ) 26.9 ( ) ( ) 26.5 ( ) ( ) 20.7 ( ) ( ) 23.4 ( ) N ( ) 19.1 ( ) a Age at first admission. study periods since a patient with first time diagnosis at the end of the study period has a lesser chance of fulfilling the criteria for being included as incident case (i.e., having a second UC/CD diagnosis in the NPR/at least three visits as outpatients) compared to a patient with a first UC/CD diagnosis several years ago. Thus, for 25% of UC patients, the distance between the first and the second diagnoses in the NPR was more than 2.3 years and the corresponding figure for CD patients was 1.2 year. The advantage of our methodological approach and our strict criteria for counting a patient as an incident case is, however, that it provides insurance on the validity of our results. Our study also has limitations. The continuous increasing incidence rates found in our study might be influenced by an improved classification system and improved diagnostic tools (e.g. capsule endoscopies). Furthermore, it is also possible that greater awareness, either by physicians or by patients, may result in the diagnosis of mild cases which might have been previously unnoticed. However, the increasing incidence of UC and CD found in this study is a continuation of the incidence trend reported in the former Danish study using nationwide registry data based on ICD-8 codes, 12 and we do not see sudden dramatic peeks in the incidence during the recent years reflecting a sudden greater awareness of the disease, introduction of new diagnostic tools, or sudden peaks according to the shift to ICD-10 codes. One might speculate whether the increasing incidence of UC and CD reflects an increasing tendency to refer patients from the general practitioner to hospitals, but it is our experience that only very few UC and CD patients are handled in the primary health care or the very small private sector, and for decades it has been a common practice in Denmark to refer these patients to public hospital units for diagnosis and treatment. A recent study from our neighbor country, Sweden, also reported an increasing incidence and showed that the proportion of severe cases was similar to historical data indicating a true increase and not attributing to better diagnostics. 23 Despite a theoretical influence of the abovementioned factors, such as change in classification system and greater awareness, we thus believe that our study indicates a real increase in the incidence rates of UC and CD during the last two decades. Former Danish studies from two specific counties have reported incidence rates for early periods also included in this study. In the study by Jacobsen et al. 8 the incidence rates for CD and UC at the end of their study period (2002) are in accordance with our results. In the period of , our results on CD

5 1278 B.M. Nørgård et al. Incidence rate per person years Female Male Year Figure 2 The incidence rate of Crohn's disease, Incidence rates were standardized to the 2012 Danish population by 15 year age groups. Vertical lines: 95% confidence intervals. Dotted line: men. Solid line: women. are also in line with the study by Vind et al. 7,whereaswefind higher incidence rate for UC. The study from Vind et al. was not based on the NPR but on specific county hospital departments/ private gastroenterological surgeons where not all were participating, and thus the results of Vind et al. might have been underestimated. An alternative explanation is that county specific results are not in all aspects easily compared to nationwide data due to possible interregional differences in the incidence of UC and CD across Denmark. The existence of such differences in the incidence rates is recently underlined in the paper from the ECCO-EpiCom cohort showing that the incidence rates in 2010 varied considerably across Danish participating centers (for UC between 7.4 and 20.1 per 100,000 and for CD between 4.8 and 11.4 per 100,000). 34 There have been reports of a stabilization of the incidence rates in Western Europe countries and North America. 25,26 However, continuously increasing incidence rates have also been reported 7,16,28 and a comprehensive review from 2012 concludes that the incidence of UC and CD is increasing with time and in different regions around the world, indicating its emergence as a global disease. 3 Our estimated incidence rates of UC and CD correspond with recent results from two Swedish studies from Uppsala Table 3 Mean incidence rate for Crohn's disease (CD) in four time periods, covering 1995 through Number of CD patients (N = 7863) Mean incidence rates per 100,000 person years (95% confidence interval) a Time period Female Male Female Male b ( ) 5.6 ( ) ( ) 7.0 ( ) ( ) 8.3 ( ) b ( ) 8.9 ( ) a Incidence rates were directly standardized to the 2012 population by 15 year age group. The 95% confidence intervals were based on assumption of the Gamma distribution. b Includes only four calendar years. Table 4 Mean incidence rates per 100,000 person years for Crohn's disease (CD) in different age groups. Age group a (years) Total number of CD patients (N = 7863) Female Male Female County. 23,35 Our study indicates that the incidence rate of UC in Denmark is among the highest in the world and in the same level as reported rates from Canada (19.2 per 100,000 per year), Iceland (24.3 per 100,000 per year), and Sweden (20.0 per 100,000 per year). 1,3,23,36 Also, our estimated incidence rate of CD is among the highest in Northern Europe and in line with reported rates from the United Kingdom (10.6 per 100,000 per year) and Sweden (9.9 per 100,000 per year). 3,22,35 Studies of variations of the incidence of UC and CD across demographic factors, such as age and gender, are important because they yield clues to the etiology of disease. Furthermore, studies of incidence provide valuable information about the burden of illness for policy makers and resource planners in the health care system. As UC and CD affect individuals in the most formidable and productive years of life the diseases result in long-term cost to the patient, heath care system, and society. 37 Many studies have been published to understand the underlying reasons for the increased incidence of UC and CD, but so far without great success. 3,38 The emergence of UC and CD in traditionally low prevalent regions suggests that the development of diseases may be influenced by environmental risk factors and studies have indicated that environmental factors, not genetics (with ethnicity a proxy), are the major driving force for the increase in incidence over time. 3,38 It is, however, still unclear what the main component of environmental factors is. 3,27 In conclusion, based on nationwide Danish data from the last two decades, the incidence rates of UC and CD have continued to increase. Conflict of interest The authors have no conflict of interest. Acknowledgment Mean incidence rates per 100,000 person years (95% confidence internal) Male b ( ) 3.3 ( ) ( ) 13.7 ( ) ( ) 8.2 ( ) ( ) 6.8 ( ) ( ) 6.1 ( ) N ( ) 4.9 ( ) a Age at first admission. The study was not supported by grants. The specific author contributions: BMN and KF have contributed to the conception and design, the analysis and interpretation of data, drafting the article for intellectual content, and finally approved the version to be published. JN has contributed to the design, carried out the data

6 Incidence of inflammatory bowel disease 1279 analyses, contributed to the interpretation of data, reviewed the article critically for intellectual content, and finally approved the version to be published. JK, BAJ, and NQ have contributed to the design, the interpretation of data, revised the article critically for intellectual content, and finally approved the version to be published. References 1. Bernstein CN, Wajda A, Svenson LW, MacKenzie A, Koehoorn M, Jackson M, et al. The epidemiology of inflammatory bowel disease in Canada: a population-based study. Am J Gastroenterol 2006;101: Rocchi A, Benchimol EI, Bernstein CN, Bitton A, Feagan B, Panaccione R, et al. Inflammatory bowel disease: a Canadian burden of illness review. Can J Gastroenterol 2012;26: Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142: Burisch J, Jess T, Martinato M, Lakatos PL. The burden of inflammatory bowel disease in Europe. J Crohns Colitis 2013;7: Munkholm P, Langholz E, Nielsen OH, Kreiner S, Binder V. Incidence and prevalence of Crohn's disease in the county of Copenhagen, : a sixfold increase in incidence. Scand J Gastroenterol 1992;27: Langholz E, Munkholm P, Nielsen OH, Kreiner S, Binder V. Incidence and prevalence of ulcerative colitis in Copenhagen County from 1962 to Scand J Gastroenterol 1991;26: Vind I, Riis L, Jess T, Knudsen E, Pedersen N, Elkjaer M, et al. Increasing incidences of inflammatory bowel disease and decreasing surgery rates in Copenhagen City and County, : a population-based study from the Danish Crohn colitis database. Am J Gastroenterol 2006;101: Jacobsen BA, Fallingborg J, Rasmussen HH, Nielsen KR, Drewes AM, Puho E, et al. Increase in incidence and prevalence of inflammatory bowel disease in northern Denmark: a populationbased study, Eur J Gastroenterol Hepatol 2006;18: Moum B, Vatn MH, Ekbom A, Aadland E, Fausa O, Lygren I, et al. Incidence of ulcerative colitis and indeterminate colitis in four counties of southeastern Norway, A prospective population-based study. The Inflammatory Bowel South-Eastern Norway (IBSEN) Study Group of Gastroenterologists. Scand J Gastroenterol 1996;31: Moum B, Vatn MH, Ekbom A, Aadland E, Fausa O, Lygren I, et al. Incidence of Crohn's disease in four counties in southeastern Norway, A prospective population-based study. The Inflammatory Bowel South-Eastern Norway (IBSEN) Study Group of Gastroenterologists. Scand J Gastroenterol 1996;31: Lindberg E, Jornerot G. The incidence of Crohn's disease is not decreasing in Sweden. Scand J Gastroenterol 1991;26: Fonager K, Sorensen HT, Olsen J. Change in incidence of Crohn's disease and ulcerative colitis in Denmark. A study based on the National Registry of Patients, Int J Epidemiol 1997;26: Manninen P, Karvonen AL, Huhtala H, Rasmussen M, Collin P. The epidemiology of inflammatory bowel diseases in Finland. Scand J Gastroenterol 2010;45: Tysk C, Jarnerot G. Ulcerative proctocolitis in Orebro, Sweden. A retrospective epidemiologic study, Scand J Gastroenterol 1992;27: Ronnblom A, Samuelsson SM, Ekbom A. Ulcerative colitis in the county of Uppsala : incidence and clinical characteristics. J Crohns Colitis 2010;4: Lapidus A. Crohn's disease in Stockholm County during : an epidemiological update. World J Gastroenterol 2006;12: Roin F, Roin J. Inflammatory bowel disease of the Faroe Islands, A prospective epidemiologic study: primary report. Scand J Gastroenterol Suppl 1989;170: Bjornsson S, Johannsson JH. Inflammatory bowel disease in Iceland, : a prospective, nationwide, epidemiological study. Eur J Gastroenterol Hepatol 2000;12: Gunesh S, Thomas GA, Williams GT, Roberts A, Hawthorne AB. The incidence of Crohn's disease in Cardiff over the last 75 years: an update for Aliment Pharmacol Ther 2008;27: Fellows IW, Freeman JG, Holmes GK. Crohn's disease in the city of Derby, Gut 1990;31: Rubin GP, Hungin AP, Kelly PJ, Ling J. Inflammatory bowel disease: epidemiology and management in an English general practice population. Aliment Pharmacol Ther 2000;14: Thompson NP, Fleming DM, Charlton J, Pounder RE, Wakefield AJ. Patients consulting with Crohn's disease in primary care in England and Wales. Eur J Gastroenterol Hepatol 1998;10: Sjoberg D, Holmstrom T, Larsson M, Nielsen AL, Holmquist L, Ekbom A, et al. Incidence and natural history of ulcerative colitis in the Uppsala Region of Sweden results from the IBD Cohort of the Uppsala Region (ICURE). J Crohns Colitis 2013;7(9):e Binder V. Epidemiology of IBD during the twentieth century: an integrated view. Best Pract Res Clin Gastroenterol 2004;18: Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases: up or down? World J Gastroenterol 2006;12: Loftus Jr EV. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology 2004;126: Economou M, Pappas G. New global map of Crohn's disease: genetic, environmental, and socioeconomic correlations. Inflamm Bowel Dis 2008;14: Malmborg P, Grahnquist L, Lindholm J, Montgomery S, Hildebrand H. Increasing incidence of paediatric inflammatory bowel disease in northern stockholm county, J Pediatr Gastroenterol Nutr 2013;57: Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health 2011;39: Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull 1999;46: Statistics Denmark. Key information on the Danish population for each relevant calendar year. Accessed July 16, 2013, at, Tiwari RC, Clegg LX, Zou Z. Efficient interval estimation for age-adjusted cancer rates. Stat Methods Med Res 2006;15: Fonager K, Sorensen HT, Rasmussen SN, Moller Petersen J, Vyberg M. Assessment of the diagnoses of Crohn's disease and ulcerative colitis in a Danish hospital information system. Scand J Gastroenterol 1996;31: Burisch J, Pedersen N, Čuković-Čavka S, Brinar M, Kaimakliotis I, et al. East West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort. Apr ;GUT [published online]. 35. Sjoberg D, Holmstrom T, Larsson M, Nielsen AL, Holmquist L, Ekbom A, et al. Incidence and clinical course of Crohn's disease during the first year results from the IBD Cohort of the Uppsala Region (ICURE). J Crohns Colitis 2014;8: Shivananda S, Lennard-Jones J, Logan R, Fear N, Price A, Carpenter L, et al. Incidence of inflammatory bowel disease

7 1280 B.M. Nørgård et al. across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut 1996;39: Yu AP, Cabanilla LA, Wu EQ, Mulani PM, Chao J. The costs of Crohn's disease in the United States and other Western countries: a systematic review. Curr Med Res Opin 2008;24: Ekbom A. The epidemiology of IBD: a lot of data but little knowledge. How shall we proceed? Inflamm Bowel Dis 2004; 10(Suppl 1):S32 4.