Advances in Inflammatory Bowel Diseases. Regional Institute of Gastroenterology and Hepatology Octavian Fodor Cluj-Napoca, Romania

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1 Chapter 01 Inflammatory Bowel Diseases: Epidemiology and Natural History Roxana Zaharie 1,2 and Florin Zaharie 1,2 * 1 University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca, Romania 2 Regional Institute of Gastroenterology and Hepatology Octavian Fodor Cluj-Napoca, Romania * Corresponding Author: Zaharie Florin, University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca, Romania, florinzaharie@ yahoo.com First Published February 23, 2018 Copyright: 2018 Roxana Zaharie and Florin Zaharie. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source. 2

2 Nosology Ulcerative colitis (UC) and Crohn s disease (CD), chronic inflammatory diseases of the gastrointestinal tract, are identified and diagnosed by corroborating a set of clinical, endoscopic and histological features. The inflammatory response in the UC affects the mucosa and the submucosa, whereas in the CD all layers are affected, from the mucosa to serosis. UC only affects the colon, and colectomy is a curative procedure. Instead, CD can affect any segment of the gastrointestinal tract and the resectionof the affected segment does not cure the disease. There is a subgroup of patients- approximately 5-15% of all patientswith IBD with characteristics of both diseases and it is difficult to classify them, considering the diagnosis of indeterminate colitis (IC) [1]. Epidemiology The recent trend indicates a change in IBD epidemiology with a continuous increase in incidence in the previously reported low-incidence areas including some Eastern European countries [2]. The incidence of both diseases - UC and CD varies greatly between and / persons / year, with prevalence rates reaching up to 396 / 100,000 inhabitants [3]. Traditionally, IBDs were more common in developed, industrialized countries, involving urbanization as risk factor. Another aspect that changes is the predominance of the UC that seems to diminish, while CD is becoming more prevalent [2]. The geographical incidence of IBD also varies greatly; so the areas traditionally described as having the highest prevalence belonged to North and West Europe and North America, while lower prevalence rates were reported in Eastern Europe, South America and Asia [4,5]. The current trend is to stabilize the incidence in most Western European countries and North America, with declining rates previously reported for UC [4]. In addition, rising incidences are still re- 3

3 ported in some high-impact areas, such as northern Europe [6]. Differences in geographical distribution, changes that occur over time in a given area can provide extremely valuable information on the etiopathogenesis of the disease. Until recently, there were only few information about the epidemiology of IBD from other parts of the world, especially in Eastern European countries, mostly obtained from retrospective studies [7]. However, recent data from South and East Europe and Asia report an increase in incidence in these areas, which were initially low. In these countries, UC colitis appeared for the first time, and then, after a variable number of years CD, also [8,9]. But the incidence of IBD varies greatly across countries and populations and these variations may reflect differences in the distribution of environmental risk factors. However, the dilemma persists if it is a real increase in incidence or this increase is at least partly due to improved diagnosis methods or increased suspicion for this pathology [8]. IBD is an important health problem, particularly affecting young people, with an evolutionary course marked by rebounds that affect education, work capacity, social interactions, and last but not least, the quality of life. However, the question remains whether this new trend in IBD epidemiology is reflected in their natural history, and that further epidemiological information will be relevant to identifying predictors of the evolution of these diseases [10]. Natural History Ulcerative Colitis (UC) Classification Systems of UC The classification of the disease at the time of diagnosis is crucial because it can provide information on the subsequent course of the disease, information that is extremely useful to provide optimal therapy to each patient [11]. 4

4 The Montreal Working Party emphasized the relevance of a subclassification system for UC, and this is the most widely used [12]. This classification provides information on both the extent and severity of the disease, both of which have an important prognostic role. The extent of the disease is classified as being limited to the rectum (E1), distal to the right colic flexure (E2) or proximal to the splenic flexure (E3)- Table 1. The severity of the symptoms ranges from a lack of systemic manifestations (S0) to severe systemic manifestations (S3) - Table 2A. This sub-classification is of particular clinical relevance in responding to therapy in the desire to form a structure for better assessment of the natural history and prognosis of UC patients. There are also some serological and genetic markers associated with the presence of extensive colitis, so this subgroup is of remarkable importance [13]. Other classifications that provide informations about clinical activity (Table 2B) or about clinical and endoscopic activity (Table 2C) are also used in ulcerative colitis patients. Table 1: Montreal Classification for ulcerative colitis [12]. Extent Clinical entity Localization E1 Ulcerative proctitis Limited to the rectum E2 Left colitis Colorectal impairment distal to the splenic flexure E3 Extensive colitis Impairment proximal to the splenic flexure 5

5 Table 2A: Classification of ulcerative colitis according to disease activity- Montreal classification [14]. S0- Remission S1- Mild S 2 - S3- Severe Moderate Stools/day Asymptomatic 4 >4 6 and Blood May be Present Present present Pulse All Normal Minimal >90 b/min Temperature or no signs of or systemic disease >37.5 C or Hemoglobin <10.5 g/ ESR dl or >30mm/h Table 2B: Classification of ulcerative colitis according to disease activity-truelove and Witts [12,14]. Mild Moderate Severe Bloody stools/day <4 4 or more if 6 and Pulse <90 b/min 90 b/min >90 b/min or Temperature <37.5 C 37.8 C >37.8 C or Hemoglobin >11.5 g/dl 10.5 g/dl <10.5 g/dl or ESR <20 mm/h 30 mm/h >30 mm/h or CRP Normal 30 mg/l >30 mg/l 6

6 Table 2C: Classification of ulcerative colitis according to disease activity- MAYO [14,15]. Parameter Clinical evaluation (single choice) Score 1. Stool frequency normal number of stools 0 (per day) 1-2 more than normal more than normal 5 more than normal Rectal bleeding (indicate the most severe bleeding of the day) None streaks of blood with stool in in less than half of the cases 0 1 obvious blood with stools in most cases blood alone passes 3. Endoscopic findings normal mucosa or inactive disease mild activity (erythema, decreased vascular pattern, mild friability) moderate activity (marked erythema, lack of vascular pattern, friability, erosions) Physician s global assessment severe activity (spontaneous bleeding, large ulcerations) normal mild disease moderate disease severe disease Calculation formula: sum of the scores of the four parameters. Clinical response is defined as a decrease of at least 3 points and at least 30% versus baseline, which must include a decrease in the score for rectal bleeding of at least 1 point, or an absolute score for rectal bleeding not exceeding : Remission (provided that no sub score for each single parameter is greater than 1) 3 5: Mild activity 6 10: Moderate activity > 10: Severe activity 3 7

7 Extent of the Disease It has become obvious that UC, like CD, can be considered a progressive and dynamic disease. Many studies have shown that, in time, proctitis and left colitis can progress to extensive colitis [11]. In the Ibsen cohort, 14% of the patients with proctitis and 28% of those with left colitis progressed to extensive colitis within the first 10 years after diagnosis. The patients who are at increased risk of extensive disease are younger patients and those with primitive sclerosing cholangitis [16]. Disease Course The evolution of the disease in UC is marked by periods of activity alternating with remission periods; a minority of patients experience continuous activity. The severity of flares and the response to treatment vary from minor symptoms without systemic manifestations to potentially fatal fulminating colitis that does not respond to medical therapy and frequently requires colectomy [17]. One year after the onset of the disease, approximately 50% of the patients experience clinical and endoscopic remission; in their case the risk of colectomy is significantly lower compared to those without mucosal healing [18]. The activity of the disease tends to decrease over time. In a study carried out in Denmark on a cohort of patients who did not receive immunosuppressant medication, 40-50% of patients were in prolonged remission after several years, and the percentage of patients with active disease gradually decreased to 30%. One third of patients did not experience any recurrence 10 years after the onset of the disease. Patients with severe symptoms at the onset, but who did not require colectomy, had a more benign course of disease in the coming years [19]. 8

8 Colectomy in UC The indications for colectomy in UC may be divided into emergency and elective procedures. Emergency surgery is performed for life-threatening complications in non-responders to medical therapy, whereas refractory disease, medical intolerance and colon neoplasia are the most important indications of elective colectomy [11]. Even though fulminate colitis mortality decreased to less than 1% in the last decade [20], however, delaying surgery under such conditions may lead to an increase in the rate of complications and mortality [21]. However, there is concern that immunosuppressive and biological therapy administered prior to surgery could not compromise results with an increased risk of postoperative complications, but this is still in the assessment. Even though the rate of colectomy in emergency - about 50% of total colectomy in UC - remained stable over time [20,21], however, studies have shown that the total colectomy rate has declined over the last decade. Thus, Langholz et al. showed that, oneyear colectomy rate of UC patients between was 9% [22], and Vind et al, using the same methodology, found a lower colectomy rate at one year - only 6% for patients with UC in the period [23]. There are, however, large differences between studies of reported colectomy rates. Many studies have shown that the risk of colectomy is higher in the first year after diagnosis [24,25]. In the Ibsen cohort, nearly half of the colectomies reported for the first 10 years were performed within the first 2 years of diagnosis [16]. Colorectal Cancer in UC The association between the UC and the CRC has been a subject of study for many years. Consistent with literature data, CRC is responsible for 10-15% of deaths from IBD. CRC associated IBD affects patients at a younger age than sporadic CRC, but the prognosis is similar, with a 5-year survival of approximately 50% [26]. The risk of CRC 9

9 development appears to be the combined result of several factors: genetic, environmental, and acquired [27]. The association between inflammation and the development of neoplasia is well known, while the immunopathological, genetic and molecular biology substrate of the association between UC and CRC is not yet fully elucidated [26]. Crohn s Disease(CD) Classification Systems in CD The classification systems of CD are designed to address several aspects, the most important being to create patient subgroups as homogeneous as possibly, primarily for tracking patients in clinical trials. The formation of such subgroups will allow to establish more precise correlations between genotype and phenotype. An ideal classification system would involve the integration of genetic and environmental factors that produce and modulate the evolution of CD [28]. At present, these challenges are only partially met. Thus, the classifications based only on anatomical criteria, pattern and age of onset continue to be useful even if these are not perfect staging systems. The most commonly used is the Montreal classification (Table 3) [29]. Other classification systems use clinical and paraclinical parameters to include patients with Crohn s disease in varying degrees of severity (Table 4A, 4B). To determine the degree of activity in Crohn s disease, endoscopic classifications are also used (Table 5). Rutgeers score is an endoscopic score used in patients with Crohn who have undergone an ileo-colon resection. The presence of endoscopic recurrence predict with high probability the risk of symptomatic recurrence and identifies patients who may benefit from early postoperative aggressive therapy (Table 6). 10

10 Table 3: Montreal Classification for Crohn s Disease [29]. Age at diagnosis Localization Phenotype A1 below 16 years A years A3 over 40 years L1 ileum L2 colon L3 ileocolonic L4 isolated damage of the upper digestive tract B1 non-stenotic, non-fistulizing B2 stenotic B3 penetrating p perineal disease (modifier) 11

11 Table 4A: The Crohn s Disease Activity Index (CDAI) [14,30,31]. Assessment Weighting factor A. Number of liquid or soft stools each day for seven days Sum x 2 B. Abdominal pain: Sum x 5 none = 0; intermediate = 1 or 2; severe = 3 C. General well-being Sum x 7 Well = 0; intermediate = 1, 2 or 3; terrible = 4 D. Presence of extra-intestinal complications* Score x 20 arthritis/arthralgia, iritis/uveitis, skin/mouth lesions, peri-anal disease other fistula, fever >37.8 c (in the last week) E. Anti-diarrheal Taking medication for symptomatic relief from diarrhoea, eg bulking agents F. Presence of an abdominal mass Value x 30 Value x 10 *One point each is added for each set of complications. Remission cdai < 150 Response reduction in cdai >/= 100 Relapse increase in cdai by at least points, to a level >150 (0 as none, 2 as questionable, 5 as definite) G. Hematocrit of <0.47 in men and <0.42 in women Value x 6 H. Percentage deviation from standard weight 100 x (1 (current standard)) 12

12 Table 4B: The Harvey-Bradshaw index (Harvey-Bradshaw Index - HBI) [14,32]. Parameter Patient well-being (previous day) Abdominal pain (previous day) Number of liquid or soft stools (previous day) Abdominal mass Complications 0 = very well 1 = slightly below par 2 = poor 3 = very poor 4 = terrible 0 = none 1 = mild 2 = moderate 3 = severe blank field possibility to insert an integer, from 1 to 25 0 = none 1 = dubious 2 = definite 3 = definite and tender No (0 points) Yes (drop-down menu with multiple selection; each selected complication is counted with 1 point) arthralgia uveitis erythema nodosum aphthous ulcer pyoderma gangrenosum anal fissures appearance of a new fistula abscess Calculation formula: sum of the scores of all 5 parameters. A score below 5 is generally considered as clinical remission. A reduction of 3 points is considered as relevant to define clinical response. < 5: remission 5 7: mild activity 8 16: moderate activity > 16: severe activity 13

13 Table 5: Simple endoscopic score for Cohn s disease (SES-CD) calculation table [14,33]. Ulcers 0: no 1: aphthous ( cm) 2: large (0.5-2 cm) 3: very large (>2 cm) Surface involved by disease 0: 0% 1: <50% 2: 50-75% 3: >75% Surface involved by ulcerations 0: 0% 1: <10% 2: 10-30% 3: >30% Stenosis 0: No 1: Single, can be passed 2: Multiple, can be passed 3: Cannot be passed 0 2: remission Ileum Right Transverse L e f t Rectum Total colon colon colon and sigma = = = = + Grand Total = SES-CD score 3 6: mild endoscopic activity 7 15: moderate endoscopic activity > 15: severe endoscopic activity A decrease of 50% of the SES-CD score has recently been proposed as prognostically significant. 14

14 Table 6: Rutgeerts score [14]. Rutgeerts grade Endoscopic finding Risk of symptomatic recurrence at 5 years Probability of absence of symptoms at 5 years i0 No lesions in the distal ileum 6% 94% i1 Not more than 5 anastomotic aphthous 6% lesions in the distal ileum 94% i2 i3 More than 5 aphthous lesions with normal mucosa between the lesions, or skip areas of larger lesions or ulcers up to 1 cm confined to ileocolonic anastomosis Diffuse aphthous ileitis with diffusely inflamed mucosa between the multiple aphthae 27% 73% 63% 37% Localization of CD In the CD, any segment of the digestive tract can be affected, but there is a predilection for localization in the distal small intestine and the proximal colon [34]. Genetic factors seem to directly influence the localization of the disease in different parts of the intestine [35], but information is needed on the luminal and intestinal factors that influence this. Thus, at diagnosis, approximately 40% of patients have ileo-colon disease, 30% isolate ileal damage and 30% colon damage [36]. Approximately 5-15% have associated upper gastrointestinal damage [35]. The localization of lesions remains approximately stable over time; only 10-15% of patients show changes in localization 10 years after diagnosis [37]. Perianal Pathology: The cumulative incidence of perianal pathology varies between 22 and 45%. Most frequently, perianal pathology occurs after the onset of luminal disease symptomatology, but 15

15 in 24% of CD patients, it may precede this disease. The activity of perianal pathology is not always similar to luminal disease activity [38]. Perianal lesions can be divided into skin lesions (skin tag, hemorrhoids), anal canal (cracks, ulcers or anal strictures), fistulas and perianal abscesses. If the perianal fistula pathology was considered to belong to the penetrating pattern, with the Montreal classification, this manifestation was considered to be an entity distinct from the internal fistula [29]. CD Pattern Even though the localization of the disease remains relatively stable over time, the pattern of Crohn s Disease undergoes major changes along the way [39]. In the first years after the onset of the disease, the inflammatory pattern (non-stenotic, non-penetrating) predominates, so that later, with the onset of complications, the pattern becomes stenotic or penetrating. These two forms may even coexist, since internal fistulas can complicate intestinal stenosis over a longer period. The evolution of the disease is highly dependent on localization, the development of complications (stenosis, fistulas, abscesses) being more frequent and faster in the case of small intestine damage compared to colon location. There is no relationship between symptomatology and progression of intestinal lesions, most of the time, these complications showing mild or non-existent symptoms [17]. In addition, the progression rate to a more complicated pattern varies greatly from one patient to another, this being the result of different genetic and environmental influences [37]. Approximately 50% of the patients with CD show a mild disease progression of the disease, and in the case of these patients, overtreatment should be avoided. The rest of the patients with CD have a more aggressive disease with a high rate of relapse, complications, hospitalization and surgery, the early need for immunosuppressant drugs in disease progression [40]. 16

16 Surgery in CD The necessity of surgery in CD is practically the most objective measure of the complications of this disabling pathology. Nearly a decade ago, the likelihood of surgery was reported between 3% and 96% within 15 years of diagnosis, with relapse and reintervention rates between 50-60% and 28-45% over the next 15 years [41]. Surgical rates vary widely between studies, the first studies reporting very high surgery rates, of 30%, 50% and 60% at 5, 10, respectively 15 years in a cohort of CD patients, between [42] with rates of surgery unchanged, according to recent information about the same cohort [43]. Even higher rates of surgery have been reported in a cohort from Denmark up to 35% in the first year of diagnosis, with cumulative surgery rate of 61% and 82% after 10 and 20 years, respectively [44]. An association between the need for surgery and the disease phenotype has been reported in several studies. The localization at the terminal ileum, the stenotic or penetrating pattern and the young age at diagnosis (under 40 years of age) have been identified as risk factors for surgery. Instead, the sex of patients, corticosteroids need and smoking upon diagnostic have had no impact on the need for surgery [45]. Acknowledgment The current paper was supported by an internal grant of the Iuliu Hatieganu University, awarded to Assistant Professor Roxana Zaharie, MD, PhD (No. 4945/9/ ). References 1. Stenson WF. Inflammatory bowel disease. In: Yamada T, editor. Textbook of gastroenterology. 2nd edn. New Jersey: Blackwell Publishing Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases:up or down. World Journal of Gastroenterology. 2006; 12:

17 3. Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012; 142: Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004; 126: Loftus CG, Loftus EV Jr, Harmsen WS, Zinsmeister AR, Tremaine WJ, et al. Update on the incidence and prevalence of Crohn s disease and ulcerative colitis in Olmsted County, Minnesota, Inflammatory Bowel Diseases. 2007; 13: Ponder A, Long MD. A clinical review of recent findings in the epidemiology of inflammatory bowel disease. Clinical Epidemiology. 2013; 5: Ng SC, Bernstein CN, Vatn MH, Lakatos PL, Loftus EV Jr, et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut ; 62: Thia KT, Loftus EV Jr, Sandborn WJ, Yang SK.. An update on the epidemiology of inflammatory bowel disease in Asia. Am J Gastroenterol. 2008; 103: Lakatos L, Kiss LS, David G, Pandur T, Erdelyi Z, et al. Incidence, disease phenotype at diagnosis, and early disease course in inflammatory bowel diseases in Western Hungary, Inflamm Bowel Dis. 2011; 17: Lovasz BD, Golovics PA, Vegh Z, Lakatos PL. New trends in inflammatory bowel disease epidemiology and disease course in Eastern Europe. Dig Liv Dis. 2013; 45:

18 11. Monstad I, Hovde O, Solberg IC, A Moum B. Clinical course and prognosis in ulcerative colitis: results from populationbased and observational studies. Annals of Gastroenterology. 2014; 27: Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005; 19: Walsh AJ, Radford-Smith GL. Ulcerative Colitis and Ulcerative Proctitis: Clinical Course and Complications. In: SR Targan, F Shanahan, LC Karp, editors. Inflammatory bowel disease- translating basic science into clinical practice. 7th edn. New Jersey: Blackwell Publishing. 2010; The European Crohn s and colitis organization (ECCO) e- Guide Available at: Can Endoscopy Be Avoided in the Assessment of Ulcerative Colitis in Clinical Trials?. Inflamm Bowel Dis. Can Endoscopy Be Avoided in the Assessment of Ulcerative Colitis in Clinical Trials?. Inflamm Bowel Dis. 2012; 18: Solberg IC, Lygren I, Jahnsen J, Aadland E, Høie O, et al. Clinical course during the first 10 years of ulcerative colitis: results from a populationbased inception cohort (IBSEN Study). Scand J Gastroenterol. 2009; 44: Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and Natural History of Inflammatory Bowel Diseases. Gastroenterology. 2011; 140: Frøslie KF, Jahnsen J, Moum BA, Vatn MH; IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwegian population- based cohort. Gastroenterology. 2007; 133:

19 19. Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology. 1994; 107: Turner D, Walsh CM, Steinhart AH, Griffiths AM. Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression. Clin Gastroenterol Hepatol. 2007; 5: Kaplan GG, Seow CH, Ghosh S, Molodecky N, Rezaie A, et al. Decreasing colectomy rates for ulcerative colitis: a population-based time trend study.. Am J Gastroenterol. 2012; 107: Langholz E. Ulcerative colitis. An epidemiological study based on a regional inception cohort, with special reference to disease course and prognosis. Dan Med Bull. 1999; 46: Vind I, Riis L, Jess T, Knudsen E, Pedersen N, 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: Langholz E, Munkholm P, Davidsen M, Binder V.. Colorectal cancer risk and mortality in patients with ulcerative colitis. Gastroenterology. 1992; 103: CE Leijonmarck, PG Persson, G Hellers. Factors affecting colectomy rate in ulcerative colitis: an epidemiologic study. Gut. 1990; 31: Dyson JK, Rutter MD. Colorectal cancer in inflammatory bowel disease: what is the real magnitude of the risk? World J Gastroenterol. 2012; 18: Askling J, Dickman PW, Karlén P, Broström O, Lapidus A, et al. Family history as a risk factor for colorectal cancer in 20

20 inflammatory bowel disease. Gastroenterology. 2001; 120: Sands BE. Crohn s Disease: Clinical Course and Complications. In: SR Targan, F Shanahan, LC Karp, editors. Inflammatory bowel disease- translating basic science into clinical practice. New Jersey: Blackwell. 2010; Satsangi J, Silverberg MS, Vermeire S, Colombel JF. The Montreal classification of inflammatory bowel disease: controversies, consensus and implications. Gut. 2006; 55: Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn s disease activity index. National Cooperative Crohn s Disease Study. Gastroenterology. 1976; 70: Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, et al. Infliximab maintenance therapy for fistulizing Crohn s disease. N Engl J Med. 2004; 350: Sandborn WJ, Feagan BG, Hanauer SB, Lochs H, Löfberg R, et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn s disease. Gastroenterology. 2002; 122: Moskovitz DN, Marco Daperno, GA Van Assche. Defining and validating cut-offs for the Simple Endocopic Score for Crohn s Disease. Gastroenterology. 2007; 132: S Hugh J Freeman. Application of the Montreal classification for Crohn s disease to a single clinician database of 1015 patients. Can J Gastroenterol. 2007; 21: Newman B, Silverberg MS, Gu X, Zhang Q, Lazaro A, et al. CARD15 and HLA DRB1 alleles influence susceptibility and disease localization in Crohn s disease. Am J Gastroenterol. 2004; 99:

21 36. Vatn MH. Natural history and complications of IBD. Curr Gastroenterol Rep. 2009; 11: Papi C, Festa V, Fagnani C, Stazi A, Antonelli G, et al. Evolution of clinical behaviour in Crohn s disease: predictive factors of penetrating complications. Dig Liver Dis. 2005; 37: Tang LY, Rawsthorne P, Bernstein CN. Are perineal and luminal fistulas associated in Crohn s disease? A populationbased study. Clin Gastroenterol Hepatol. 2006; 4: E Louis, A Collard, A Oger, E Degroote, FANEl Yafi, et al. Behaviour of Crohn s disease according to the Vienna classification: changing pattern over the course of the disease. Gut. 2001; 49: Peter Laszlo Lakatos. Prediction of disease course in inflammatory bowel diseases. World J Gastroenterol. 2010; 16: Wolters FL, Russel MG, Stockbrügger RW. Systematic review: has disease outcome in Crohn s disease changed during the last four decades? Aliment Pharmacol Ther. 2004; 20: Hellers G. Crohn s disease in Stockholm county A study of epidemiology, results of surgical treatment and long-term prognosis. Acta Chir Scand Suppl. 1979; 490: Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn s disease. Ann Surg. 2000; 231:

22 44. Munkholm P, Langholz E, Davidsen M, Binder V. Intestinal cancer risk and mortality in patients with Crohn s disease. Gastroenterology. 1993; 105: Solberg IC, Vatn MH, Høie O, Stray N, Sauar J, et al. Clinical course in Crohn s disease results of a Norwegian population-based ten-year follow up study.. Clin Gastroenterol Hepatol. 2007; 5: