Twelve of 65 (18.5%) patients with CD, 4 of 39 (10.3%) patients with UC, and 1 patient with IBD-U had a positive family (a first-degree or a second-degree relative) history. There was no statistically significant difference between the patients with CD and UC regarding the positive family history (P > 0.05). We found no statistically significant association between the age at diagnosis and the presence of a positive family history (P > 0.05).
Delay in Diagnosis
The median delay from the onset of symptoms to diagnosis for all of the cases of IBD was 6.2 months, ranging from <1 month to 4 years. The median delay for CD was 8.1 months and for UC 3.1 months. There was a statistically significant difference between CD and UC (P < 0.001) regarding the length of delay; however, there was no association between length of delay and sex (P > 0.05).
Presenting Symptoms and Signs
The majority of patients with IBD presented with abdominal pain (92.5%), diarrhea (78.5%), and weight loss (69.2%). A substantial proportion of CD cases did not present with diarrhea (32.3%), and only 47.7% of them had the classic triad of symptoms (abdominal pain, diarrhea, and weight loss). Nine children (13.8%) with CD had perianal disease at presentation. Growth impairment (G1) was found in 24.3% of all of the IBD cases, in 30.7% of patients with CD, and 12.8% of patients with UC.
Diagnostic procedures performed at diagnosis are presented in Table 3. In total, in 43 of 65 patients with CD the Porto diagnostic criteria for complete diagnostic workup (upper GI endoscopy, colonoscopy including terminal ileoscopy, and reliable small bowel investigation) were reached.
The median follow-up was 34.8 months for IBD (range 2–107), 35.9 months for CD (range 2–107), and 32.8 months (range 6–96) for UC. The minimum follow-up was 2 months. Seventy-seven percent (30/39) of patients with UC and 81.5% (53/65) of patients with CD had a follow-up period of >2 years.
During the follow-up, repeated colonoscopies were performed in 73.8% (48/65) patients with CD, capsule endoscopy in 41.5% (27/65), and SBFT in 29.2% (19/65) of patients with CD. Of the 48 patients with CD with repeated endoscopic examinations, in 43 (89.4%) ileocolonoscopy was performed. In patients with UC, colonoscopy was repeated in 48.6% (19/39).
EIMs were observed in 32.6% (35/107) of all of the patients with IBD at diagnosis or at follow-up. Of the 3 patients with IBD-U, none had EIM. Joint problems (arthralgia and/or arthritis) were reported in 30.8% (20/65) of patients with CD and 7.7% (3/39) patients with UC (P < 0.01). Oral aphthous lesions were present in 16.9% (11/65) of patients with CD and in 2.6% of patients with UC (P < 0.05). One patient with CD experienced severe orofacial granulomatosis. Only 1 patient had ocular EIM (an 11-year-old girl with UC and episcleritis). Skin manifestations were observed in 3.7% (4/107), in 3 patients with CD and 1 with UC. Only 1 patient presented with pyoderma gangrenosum; the others had erythema nodosum. The patient with CD with pyoderma gangrenosum was receiving infliximab therapy at the time of the occurrence of skin lesions. Hepatobiliary EIMs were documented in 5 (4.7%) patients. Among patients with UC, hepatobiliary disease was observed in 3 (7.7%) cases; 1 of the patients had primary sclerosing cholangitis, and 2 had the autoimmune hepatitis/sclerosing cholangitis (AIH/SC) overlap syndrome. Both patients with CD who had hepatobiliary EIM were diagnosed as having the AIH/SC overlap syndrome. Rare EIMs were found in 2 patients, both with CD. The first patient experienced acute pancreatitis 1 month before the diagnosis of CD, and the other had pericarditis at the time of diagnosis.
Disease Activity at the Time of Diagnosis
Moderate and severe disease activities (PCDAI > 30) were found in 37 (56.9%) patients with CD at presentation. Because of the retrospective nature of the study, we were able to determine PUCAI only in 82.0% (32/39) of patients with UC. Severe disease activity at the time of diagnosis (PUCAI ≥ 65) was seen in 25% (8/32) of these patients with UC.
Disease Location in Patients With CD
Disease location could be determined according to the Paris classification in 66.2% (43/65) patients with CD at presentation. Terminal ileal disease (±limited cecal disease, L1) was seen at diagnosis in 20.9% (9/43), isolated colonic disease (L2) in 4.6% (2/43), and ileocolonic disease (L3) in 74.5% (32/43) of patients with CD. Upper GI inflammation proximal to the ligament of Treitz (L4a) was present in 48.9% (21/43), and small bowel inflammation (L4b) in 34.9% (15/43) of patients with CD. The inflammation of the entire GI tract (L3L4ab) was observed in 16.3% (7/43) of patients with CD. There were no cases of isolated upper GI involvement proximal to the ligament of Treitz (L4a) without associated inflammation elsewhere in the GI tract.
In the group of 53 patients with CD who had a follow-up period of >2 years, there were 69.8% (37/53) patients with a complete diagnostic follow-up. In this group of patients with CD, terminal ileal disease (±limited cecal disease, L1) was observed in 21.6% (8/37), isolated colonic disease (L2) in 2.7% (1/37), and ileocolonic disease (L3) in 75.6% (28/37). Upper GI inflammation proximal to the ligament of Treitz (L4a) was found in 54% (20/37), and small bowel inflammation (L4b) in 43.2% (16/37). Inflammation of the entire GI tract (L3L4ab) was found in 21.6% (8/37) in patients with CD with a follow-up >2 years. The CD location at diagnosis and at follow-up reexamination is presented in Figure 2.
Disease Extent in Patients With UC
At presentation, 61.4% (24/39) of patients with UC had pancolitis (E4), 7.7% (3/39) extensive colitis distal to hepatic flexure (E3), 25.6% (10/39) left-sided colitis (E2), and 5.2% (2/39) ulcerative proctitis (E1). In a group of patients with UC who were followed up >2 years (30/39), 17 patients with UC had repeated colonoscopy. In this group of patients, pancolitis was observed in 76.5% (13/17), extensive colitis in 5.9% (1/17), and left-sided colitis in 17.6% (3/17). There were no cases of ulcerative proctitis in this group. The extent of UC at diagnosis and at follow-up reexamination is presented in Figure 3.
Disease Behavior in Patients With CD and UC
At presentation, 86% (56/65) of patients with CD had the inflammatory type (nonstricturing and nonpenetrating) of the disease (B1). Stricturing (B2) and fistulizing (B3) phenotypes were seen in 6% (4/65) and 8% (5/65) at diagnosis, respectively. During the follow-up, B1 phenotype decreased to 71% (46/65), and B2 and B3 phenotypes increased to 14% (9/65) and 15% (10/65), respectively.
Of the 39 patients with UC, PUCAI could be determined in 32 patients with UC at diagnosis and later during the follow-up. In this group of patients of UC, 31.2% (10/32) had severe disease with PUCAI ≥ 65 at least once during the follow-up (classified as S1).
Therapy and Surgery
The type of medication at presentation (within 30 days of the initial diagnosis) and during the follow-up period (until the last follow-up visit) is presented in Table 4.
At diagnosis, 46.2% (30/65) and 41.6% (27/65) patients with CD were treated with corticosteroids and exclusive enteral nutrition, respectively. Thiopurines (azathioprine/6-mercaptopurine) were introduced in 47.7% (31/65) of patients with CD within 30 days of initial diagnosis. Until the end of the follow-up, the frequency rate of administration of corticosteroids, exclusive enteral nutrition, and thiopurines in patients with CD increased to 75.5%, 64.7%, and 80.1%, respectively.
In patients with UC, corticosteroids were administered in 41% and thiopurines in 10.2% of patients within 30 days of presentation. Until the end of the follow-up period, corticosteroids and thiopurines were used in 87% and 53.7%, respectively, of patients with UC.
Within 30 days of initial diagnosis, 2 patients with severe fulminant UC received infliximab. Until the end of the follow-up period, infliximab was used in 36.9% (24/65) of all of the patients with CD, and in 10.3% (4/39) of patients with UC, whereas adalimumab was used in 9 patients (13.9%) with CD and 1 patient (2.6%) with UC.
During the study period, 29% (19/65) of all of the patients with CD underwent CD-related surgery. Major surgery (resections of small and large bowels) was required in 18.5% (12/65) of all of the patients with CD. Of all the 19 patients with CD who underwent surgery, 10 had bowel surgery (bowel resection), 7 underwent nonbowel surgery (abscess drainage and/or fistulotomy), and 2 required both types of surgery during the follow-up (fistulotomy and abscess drainage, and bowel resection).
Among all of the patients with UC, only 1 patient had a disease refractory to all conventional medical therapy, including infliximab and adalimumab, and required a total colectomy with J-pouch formation.
This study describes the incidence and phenotypic characteristics of pediatric IBD in NE Slovenia during the period from 2002 to 2010. It is the first epidemiological survey of IBD in this region of Slovenia, and it covered approximately one-third of the pediatric population in Slovenia.
The mean annual incidence rates of total IBD, CD, and UC for the total study period were 7.6, 4.6, and 2.8, respectively, per 100,000 children ages 0 to 18 years. These incidence rates are comparable with those in western European countries (21–23), and are the highest reported from the central-eastern European region (24,25). Significantly higher incidence rates have only been observed in some parts of North America (16,17) and Scandinavian countries (15,18,19).
It seems that the incidence rate of pediatric IBD in Slovenia is growing. A substantial increase, although not statistically significant, was observed comparing the early and late periods of our study. We found a 2.3-fold increase in the CD and a 1.4-fold increase in the UC incidence from 2002 to 2010. The same has been documented in most other European countries (15,18,19,21–23).
In our study from the central and western Slovenia for the period 1994–2005, we reported mean annual incidence rates of total IBD, CD, and UC of 4.03, 2.42, and 1.14, respectively (26). Although the incidence of IBD increased from 3.04 in the period 1994–1999 to 5.14 in the period 2000–2005, it was still significantly lower compared with 8.9 in the last 3-year interval of our present study. This increase in incidence could not be attributed to different study designs, because we used similar methodology in both. It can be speculated that the differences are the consequence of 2 different study populations, residents of the western and central parts of Slovenia in the first study, and northeastern in the second study. In future, it would seem reasonable to conduct an epidemiological study covering total Slovenian childhood population during the same time period to be able to answer this question.
The genetic background of the total Slovenian population seems to be homogeneous, given that in the last century, the migration of people from one part of the country to another has been substantial, whereas the number of immigrants from other countries was relatively low. Moreover, central and western parts of Slovenia are economically more developed, and the standard of living is higher when compared with the northeastern part. Because the economic development is regarded as a potential risk factor for IBD, we could expect an even higher and not lower incidence rate in the central and western parts of the country when compared with the northeastern part.
In our study, the evaluation of the disease extent was based on the Paris classification and showed that one-fifth of patients with CD presented with terminal ileal disease (±limited cecal disease, L1), three-fourths of patients with CD with ileocolonic disease (L3), and only 5% with isolated colonic disease (L2). In comparison with the recent EUROKIDS data (33), the distribution of inflammation in our patients with CD is similar, but with 1 major and some minor differences. The proportion of isolated colonic disease in our study is lower (5% vs 27%). The involvement of upper GI tract proximal to the ligament of Treitz (L4a) was present in 48.9% of our patients with CD with complete diagnostic workup at diagnosis. This observation is in line with the data reported by some other authors (34,35); however, in the recent EUROKIDS report, a slightly lower percentage of upper GI involvement has been reported (33). Small bowel (jejunal/proximal ileal) involvement (L4b) was detected in one-third of our patients with CD compared with one-fourth of patients with CD from the EUROKIDS cohort.
At diagnosis, pancolitis was present in 61.4% of our children with UC. This may seem lower than usually reported in the pediatric literature. There are 2 possible explanations for the observed difference. The first is methodological. Earlier studies performed before introduction of the Paris classification were based on the Montreal classification, in which patients with UC classified as having the disease extent E3 (extensive disease proximal to splenic flexure) were regarded as having pancolitis. In Paris classification, this category has been split into 2 distinctive categories: E3 (extensive colitis distal to hepatic flexure) and E4 (extensive colitis proximal to hepatic flexure). Therefore, both patients classified as E3 and E4 fulfilled the criteria for being classified as extensive colitis according to the older Montreal classification. These 2 groups together represented 70% of all of the patients with UC in our population. This proportion is comparable with some of the other pediatric reports on the UC extent, such as the EUROKIDS, which reported pancolitis or extensive colitis in 77% (36), and the Scottish study by Van Limbergen et al (37) with 74.7% of UC children with extensive colitis at diagnosis.
There are, however, several studies reporting significantly larger or smaller proportions of pediatric patients with UC with extensive colonic involvement. Kugathasan et al (38) reported that 90% of patients with UC had pancolitis at presentation. In contrast, only 32% of pediatric patients with UC had pancolitis in a population-based study from France (12), showing that the prevalence of the extensive colitis/pancolitis needs to be further studied in future.
We found that the disease extent progressed in patients with both CD and UC during the follow-up period. At diagnosis, 16.3% had inflammation of the entire GI tract (L3L4ab), whereas during the follow-up period, such extensive involvement was observed in 21.6% of patients. Similarly, the proportion of patients with UC with pancolitis (E4) increased from 61.4% to 76.5%. Although we can argue that these observations could also be the consequence of more aggressive diagnostic approach with repeated endoscopies and imaging procedures in patients with more severe disease during the follow-up period, this could not explain the progression of the disease behavior. At presentation, only 6% of patients with CD had stricturing and 8% had penetrating phenotype, and these complicated phenotypes were present in 14% and 15%, respectively, during a relatively short mean follow-up period. Similarly, in a large population-based study, Vernier-Massouille et al (39) observed a 2-fold rise in the prevalence of complicated CD behavior during the follow-up. The results are important if we take into consideration a relatively aggressive treatment used in our study cohort, with corticosteroids used at least once in >75%, thiopurines in 80%, infliximab in 37%, and adalimumab in 14% of patients with CD. One of the most intriguing challenges for the future is to answer the question whether the use of the most efficient therapeutics such as biologics as the first-line therapy in newly recognized patients, advocated by some experts, could alter the detrimental course of the disease.
Even more intriguing is which factor or factors can be blamed for the continuous increase in IBD incidence rate observed in our and many other studies. Do we have the potential to prevent this disease? Such a rapid increase in childhood IBD cannot be explained by the genetic background only; thus, strong environmental factors must influence this increase. The level of hygiene and the usage of detergents have undoubtedly increased in Slovenia in recent years; however, recent studies could not confirm the influence of environmental factors of the hygiene hypothesis (40). In the last 20 years, the lifestyle in Slovenia has westernized, and fast food restaurants have spread all across the country. Several studies pointed out the role of a diet with low fiber, high fat, and refined sugar content, as well as fried food using “recycled” oil rich in transfatty acids, as a possible risk factor for IBD development (41). It has been postulated that in IBD abnormal immune response to the gut microorganisms is a crucial trigger and promotor of intestinal inflammation. Many differences in the composition of intestinal microbiota, both fecal (luminal) and mucosa associated, have been observed between patients with IBD and healthy individuals (42–45). It has been postulated that diet is probably the most important factor influencing the composition and function of the intestinal microbiota (46–48). Therefore, we can hypothesize that changes in dietary habits leading to disturbance of the intestinal microbiota composition and function may be responsible for the increasing incidence of pediatric IBD in Slovenia and worldwide. Hence there is hope that growing knowledge about the role of food and microbes in the development of IBD will lead to new strategies to prevent the disease development and decrease its incidence.
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Keywords:© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
epidemiology; inflammatory bowel disease; Paris classification; pediatrics