RESULTS
Demographic data
A total of 1147 pediatric-‐IBD cases were identified over the period 1988-‐2008 (8% of all IBD patients – pediatric and adults). Among them, 846 had a diagnosis of CD (73,8%), 271 had a diagnosis of UC (23,6%) and 30 of IBDU (2,6%) (Figure 5). A global incidence, (i.e. over the entire study period) of 4.0 per 100,000 person-‐years [95% CI: 3.7-‐4.2] was found for the whole IBD group. In particular an incidence of 2.9 per 100,000 person-‐years [95% CI: 2.7-‐3.1] was observed for CD, of 0.9 per 100,000 person-‐years [95% CI: 2.7-‐3.1] for UC and of 0.1 per 100,000 person-‐ years [95% CI: 0.07-‐0.14] for IBDU.
Over the study period, a significant incidence increase was observed for both CD and UC (Fig.6). Between the years 1988-‐90 and 2006-‐08 this incidence increased for CD from 2.1 [95% CI: 1.6-‐2.5] to 4.8 [95% CI: 2.7-‐3.1] per 100,000 person-‐years (+128.5%; p<0,0001). For UC the incidence rate increased from 0.8 [95% CI: 0.5-‐1.1] to 1.5 [95% CI: 1.1-‐5.5] per 100,000 person-‐years (+87.5%; p<0,0001). The IBDU trend remained stable.
Figure 5. Percentage distribution of pediatric IBD cases among the different phenotypes (Crohn’s disease, Ulcerative Colitis, Inflammatory Bowel Disease Unclassified)
0 10 20 30 40 50 60 70 80 CD UC U-‐IBD
Fig. 6 Time course of incidence rates, expressed as new cases per 100,000 person-‐years, for Crohn’s Disease (CD), Ulcerative Colitis (UC) and Inflammatory Bowel Disease Unclassified (U-‐IBD). Every data point is expressed as the mean value over a three-‐years period.
Observing the patient distribution in the age-‐specific classes, the teenager class (10-‐16 years) always resulted to be the most represented, both for CD and for UC (Fig. 7 A and B).
2,1 4,8 0,8 1,5 0,2 0,1 0 1 2 3 4 5 6 1988-‐1990 1991-‐1993 1994-‐1996 1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008 Incid ence r at es (e vents /1 00 0 00 ) CD UC U-‐IBD
Fig. 7 A Time course of incidence rates of CD according to age
Fig. 7 B Time course of incidence rates of UC according to age
0,2 0,7 0,9 2,2 4,3 9,6 0 2 4 6 8 10 12 1988-‐1990 1991-‐1993 1994-‐1996 1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008 In ci de nc e ra te s (e ve nts /1 00 0 00 )
Crohn's disease
0-‐4 years 5-‐9 years 10-‐16 years 0,2 0,3 0,3 0,7 1,6 2,9 0 0,5 1 1,5 2 2,5 3 3,5 1988-‐1990 1991-‐1993 1994-‐1996 1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008 In ci de nc e ra te s (e ve nts /1 00 0 00 )UlceraCve ColiCs
0-‐4 years 5-‐9 years 10-‐16 years
As regards the age-‐specific incidence rates, a significant increase was observed among the teenagers (10-‐16 years of age), both for CD and UC. Moreover, in CD a significant increase was also observed in the 5-‐9 year class (0.9 to 2.2 per 100,000, p<0.001).
The increase was particularly striking in the teenage class, in particular in CD patients since it passed from 4.3 per 100,000 person-‐years in 1988-‐1990 to 9.6 in 2006-‐2008 (p<0.001). In the UC patients, on the other hand, the incidence increased of a lesser degree and passed from 1.6 per 100,000 person-‐years to 2.9 (p<0.001). In the IBDU patients there was no significant evolution for all age classes.
Over the period, no sex-‐related difference was noted both in the CD and in the UC patients group (Fig 8 A and B).
Fig 8 A. Time course of incidence rates of CD according to sex 0 1 2 3 4 5 6 1988-‐1990 1994-‐1996 2000-‐2002 2006-‐2008 In ci de nc e ra te s (e ve nts /1 00 0 00 )
Crohn's disease
Girls Boys
Fig 8 B. Time course of incidence rates of UC according to sex
Also considering the teenagers class, no differences were found in sex distribution for both diseases (Fig. 9 A and B).
Fig 9 A. Time course of incidence rates of CD according to sex in the teenagers class
0 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8 1988-‐1990 1994-‐1996 2000-‐2002 2006-‐2008 In ci de nc e ra te s (e ve nts /1 00 0 00 )
UlceraCve coliCs
Girls Boys 0 2 4 6 8 10 12 1988-‐1990 1991-‐1993 1994-‐1996 1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008 In ci de nc e ra te s (e ve nts /1 00 0 00 ) Girls 10-‐16 years Boys 10-‐16 years
Fig 9 B. Time course of incidence rates of UC according to sex in the teenagers class
The median age of diagnosis of pediatric-‐IBD was 14.4 [IQ: 11.7-‐16.0] years and it was similar for CD (14,5 [IQ: 11.9-‐16.1] years) and UC (14,1 [IQ: 11.0-‐16.0] years) (p=0.11). Over the period, the age of diagnosis remained stable both for the entire group (p=0.5) of pediatric-‐IBD and for the two diseases, CD and UC (p=0.24 and p=0.7).
0 0,5 1 1,5 2 2,5 3 3,5 1988-‐1990 1991-‐1993 1994-‐1996 1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008 In ci de nc e ra te s (e ve nts /1 00 0 00 ) Girls 10-‐16 years Boys 10-‐16 years 0 0,5 1 1,5 2 2,5 3 3,5 1988-‐1990 1991-‐1993 1994-‐1996 1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008 CD UC
Fig. 10 Time course of the median diagnostic delay (in months) for Crohn’s disease (CD) and Ulcerative Colitis (UC).
Family history
A total of 169 patients (14.7%) were reported to have a positive family history for IBD, with no difference between CD and UC (15.3 % and 13.3% for CD and UC, respectively, p=0.4). Over the period, the percentage of a positive family history for IBD did not change significantly in the entire IBD group (test for trend, p=0.5), nor in CD patients (p=0.87) or in UC patients (p=0.3).
Instrumental examinations
Marked changes were observed, as one would expect, in the diagnostic work-‐up for pediatric CD and UC over the two decades examined (Fig. 11 and Fig.12).
As regards CD (Fig. 11), the percentage of patients who underwent a complete digestive examination (coloscopy with abdominal X-‐ray (radiograph) or coloscopy with abdominal MRI scan) was stable between 1988 and 2008 and was around 41%. As easily predictable, the percentage of abdominal RMI scans rapidly increased: from 0% in the year 1988-‐1990 to 20.2% in the year 2006-‐ 2008 (p<0.0001) with a consensual decrease of abdominal X-‐ray (from 85.2% to 32.4%, p=<0.0001). A consistent increase was also observed for upper endoscopy that was done in about half of the patients in 1988-‐1990 and in 81% in the 2006-‐2008 (p<0.0001).
Fig 11. Time course of the various diagnostic techniques employed in CD work-‐up (see text).
Considering UC (Fig. 12), during the study period, the number of total coloscopy doubled from 35.5% in the year 1988-‐1990 to 77.6% in the year 2006-‐2008 (p<0.0001). As shown in fig. 8, this increase occurred mainly in the first decade and was followed by a plateau in the second decade. 2,5% 58,0% 50,6% 80,9% 0,0% 20,2% 42,0% 42,0% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90%
Total coloscopy and ileoscopy upper endoscopy Enterosocanner/ RMI/EnteroRMI Complete examinadon
Fig. 12 Time course of total coloscopy employed in UC work-‐up (see text).
Disease location, clinical presentation and behaviour
The anatomic location of CD and UC involvement at the time of diagnosis was categorized by using the Paris classification and is shown in fig. 13 and fig. 15.
As regards CD (Fig 13), the most common location was L3 (73,3%), with no significant change over the time. From 1988 to 2008, L1, L2 and L3 remained stable with a mean of 12.2%, 14.5% and 73.3%, respectively (p=0.52). A perianal location was present in 6.5% of pediatric patients and did also not change over the study period (p=0.37). The extra-‐intestinal manifestations (eyes, skin, mouth, articulations…) concerned 20.4% of patients over the study period and did also not show significant changes (p=0.24). 35,5% 58,6% 65,8% 77,5% 67,7% 75,0% 77,6% 30,0% 40,0% 50,0% 60,0% 70,0% 80,0% 90,0% 1988-‐1990 1991-‐1993 1994-‐1996 1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008
Total coloscopy
Fig 13. Time course of CD anatomic locations: L1 (ileal localization), L2 (colonic localization) and L3 (ileo-‐colonic localization).
The time course of CD behaviour is shown in fig. 14. During the 21 year-‐study period, there was a significant change of the distribution of the three phenotypes: B1 (inflammatory), B2 (stricturing) and B3 (penetrating) (p=0.004). Overall, the most common behaviour found was the inflammatory phenotype (76.5% of patients over the entire study period), that slightly but significantly increased from 63.6% in 1988-‐1990 to 82.3% 2006-‐2008 (p=0.002). The other two, more aggressive phenotypes, showed a different behaviour: B2 (stricturing type) showed a progressive and significant decrease (from 33.8% to 10.1%, p<0.0001), whereas B3 (penetrating type) showed non-‐ significant fluctuating variations.
18% 14% 14% 12% 8% 13% 10% 13% 9% 13% 17% 16% 12% 18% 68% 78% 72% 71% 76% 75% 72% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 1988-‐1990 1991-‐1993 1994-‐1996 1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008 L3 L2 L1
Fig 14. The time course of CD phenotypes behaviour: B1 (inflammatory), B2 (stricturing) and B3 (penetrating).
Regarding UC (fig.15), there were no significant changes in location during the study period (p=0.37). Overall, the relative percentages of the various locations (E1, E2, E3, E4) were 31.1%, 25.4%, 10.5% and 32.9%. We can notice however, that the group of patients with pancolitis (E4) was the only one in which the percentage constantly, albeit not significantly, increased over time possibly also because of the increased number of pancoloscopy performed.
64% 76% 73% 74% 79% 80% 82% 34% 23% 22% 22% 16% 18% 10% 3% 1% 5% 4% 5% 3% 8% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 1988-‐1990 1991-‐1993 1994-‐1996 1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008 B3 B2 B1
Fig 15. Time course of UC anatomic locations: E1 (involvement limited to the rectum, i.e. distal to the rectosigmoid junction), E2 (involvement of the colorectum, distal to the splenic flexure), E3 (involvement distally to hepatic flexure), E4 (involvement proximal to hepatic flexure).
Delay in diagnosis and related factors
The diagnostic delay was defined as the time between the onset of symptoms and the formulation of a diagnosis. Among the whole group of pediatric-‐IBD patients the median diagnostic delay was 3 months [IQ: 1.0-‐6.0] over the entire study period. This delay showed no statistical change over time (p=0.55).
Considering the two diseases, there was a significantly longer delay for CD compared to UC (median 3.0 months [IQ: 1.0-‐6.0] vs 2.0 months [1.0-‐4.0], p<0.001). There was no significant evolution over time for both CD and UC (p=0.85 and 0.10 respectively). Univariate analysis of potential factors related to the diagnostic delay showed that a shorter delay was associated with the presence of weight loss (p=0.04), of hyperthermia (more than 38.0°C) (p=0.004) and of rectal
36% 46% 29% 26% 22% 28% 32% 24% 14% 19% 26% 41% 36% 19% 20% 11% 16% 15% 4% 0% 11% 20% 29% 35% 32% 33% 36% 38% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 1988-‐1990 1991-‐1993 1994-‐1996 1997-‐1999 2000-‐2002 2003-‐2005 2006-‐2008 E4 E3 E2 E1
growth (p=0.09). No effect was found for the presence/absence of symptoms such as abdominal pain, mucus stools or diarrhoeas.
