Christian Jakobsen

Pediatric inflammatory bowel disease: increasing incidence, decreasing surgery rate, and compromised nutritional status: A prospective population-based cohort study 2007-2009.

Background: The aim was to evaluate the incidence, treatment, surgery rate, and anthropometry at diagnosis of children with inflammatory bowel disease (IBD). Methods: Patients diagnosed between January 1, 2007 to December 31, 2009 in Eastern Denmark, Funen, and Aarhus were included from a background population of 668,056 children <15 years of age. For evaluation of incidence, treatment, and surgery rate, a subcohort from Eastern Denmark was extracted for comparison with a previously published population‐based cohort from the same geographical area (1998–2006). Results: In all, 130 children with IBD: 65 with Crohns disease (CD), 62 with ulcerative colitis (UC), and three with IBD unclassified (IBDU) were included. The mean incidence rates per 106 in 2007–2009 were: IBD: 6.4 (95% confidence interval [CI]: 5.4–7.7), CD: 3.2 (2.5–4.1), UC: 3.1 (2.4–4.0) and IBDU: 0.2 (0.05–0.5). Comparing the two cohorts from Eastern Denmark we found higher incidence rates for IBD (5.0 and 7.2 in 1998–2000 and 2007–2009, respectively, P = 0.02) and CD (2.3 versus 3.3, P = 0.04). Furthermore, we found a significant decrease in surgery rates (15.8/100 person‐years versus 4.2, P = 0.02) and an increase in the rate of initiating immunomodulators (IM) within the first year (29.0/100 person‐years versus 69.2, P < 0.001). IM use was associated with a trend towards a decreased surgery risk (relative risk [RR] 0.38; 0.15–1.0). Children with CD had poor nutritional status at diagnosis compared with the general pediatric population. Conclusions: Over the past 12 years we found an increase in the incidence of IBD in children, an increasing use of IM, and decreasing 1‐year surgery rates. CD patients had poor nutritional status.

Paediatric inflammatory bowel disease during a 44-year period in Copenhagen County: occurrence, course and prognosis--a population-based study from the Danish Crohn Colitis Database.

Aim To describe the development in incidence, disease localization, activity, surgery and prognosis in two Danish paediatric population-based inflammatory bowel disease (IBD) cohorts comparing the time periods 1962–1987 (period I) and 1998–2006 (period II). Materials and methods Incident IBD patients below 15 years of age were included. Disease localization was classified according to the Montreal classification for ulcerative colitis (UC) patients and into small bowel, large bowel and small and large bowel combined for Crohns disease (CD) patients. Disease activity and surgery in the first 2 years after diagnosis were assessed. Standardized cancer incidence rates and standardized mortality rates were calculated. Results One hundred and nineteen IBD patients (77 UC and 42 CD) were included. Comparing periods II and I, the incidence rate ratios were 0.81 [95% confidence interval (CI): 0.5–1.4] and 15.6 (95% CI: 7.5–32.7) in UC and CD, respectively. The number of UC patients with extensive disease (E3) increased from period I to II (46.7 vs. 94.1%, P<0.001). No colectomies were performed in UC patients in period II compared with nine in period I (P = 0.13) within the first 2 years after diagnosis. For patients diagnosed in period I, the standardized cancer incidence rate for UC was 37.9 (95% CI: 4.6–136.7) after a median follow-up period of 26 years. Conclusion We found a significant 15-fold increase in the incidence of CD and a significant increase in the number of UC patients with extensive disease in period II compared with period I. After a median follow-up time of 26 years, a possible increased risk of colorectal cancer in UC patients was detected.

Steroid dependency and pediatric inflammatory bowel disease in the era of immunomodulators—A population‐based study

Background: The aim was to investigate the impact of systemic steroid treatment (SST) and immunomodulators (IM) on disease course in children with inflammatory bowel disease (IBD). Methods: All IBD patients in eastern Denmark <15 years of age diagnosed in the period 1998–2006 starting their first SST within 2 years of diagnosis were included. Results: In all, 205 IBD patients were included (105 Crohns disease [CD], 100 ulcerative colitis [UC]). Eighty‐seven CD (83%) and 77 (77%) UC patients started SST. In CD, 55 (63%), 25 (29%), and 7 (8%) had a complete response (CR), partial response (PR), or no response (NR), respectively, 30 days after initiation of SST. Fifty (58%) had a prolonged response (PRO) and 32 (37%) were steroid‐dependent (SD). In UC, 49 (64%), 22 (28%), and 6 (8%) had CR, PR, and NR, respectively, and 38 (49%) and 38 (49%) were PRO and SD. The cumulative risk of surgery 1 year after starting SST was 11.5% and 7.8% for CD and UC patients, respectively. After a median follow‐up period of 5.1 years, no difference in the risk of surgery or periods of activity and remission was found between PRO and SD in CD or UC. IM use was associated with a milder disease course in UC patients. Conclusions: No difference in surgery rates or disease course was found between SD and PRO. Surgery rates were lower than rates from studies predating the era of IM, indicating a putative effect of IM on disease course. (Inflamm Bowel Dis 2010;)

Surgery and postoperative recurrence in children with Crohn disease.

Objectives: The aim of this study was to describe surgery rates, complications, and risk of disease recurrence after surgery in paediatric Crohn disease (CD). Methods: Children <18 years with a diagnosis of CD and a least 1 intestinal resection from the period January 1, 1978 to December 31, 2007 were identified using the Danish National Patient Registry. Patient charts were used to extract data. Results: A total of 115 of 422 children with CD, who had surgery in 2 referral centres, were further studied. Disease extension according to the Montreal classification at the time of operation was available in 106/115 patients: B1, 39/106 (37%); B2, 59/106 (56%); and B3, 8/106 (7%). Before/after surgery 89%/36% of the patients received corticosteroids, 26%/61% azathioprine, and 15%/34% infliximab. Ileocoecal resection was performed in 54 (47%); 17 (15%) underwent ileal resection, 21 (18%) colectomy, 13 (11%) hemicolectomy, and 10 (9%) a combined colonic and ileal resection. Median time from diagnosis to surgery was 23 months (range 0–147). The median follow-up time after surgery was 121 months (16–226), and median time to disease recurrence was 12 months (3–160). The cumulative clinical recurrence rates at 1, 5, and 10 years were 50%, 73%, and 77%, respectively. More than 1 bowel resection was needed in 39%. Postoperative azathioprine treatment did not affect rate of recurrence after surgery. Conclusions: In this large cohort of children with CD studied for >10 years postoperatively, we found a high postoperative recurrence rate of disease and a frequent need for >1 intestinal resection.

Genetic susceptibility and genotype–phenotype association in 588 Danish children with inflammatory bowel disease

AIM To investigate the association between known inflammatory bowel disease (IBD)-associated genetic variants and development of paediatric IBD, and specific clinical sub-phenotypes. MATERIAL AND METHODS In this case-control study we included IBD patients <18 years of age at diagnosis from the Danish National Patient Registry and healthy children <18 years of age were randomly selected from the Danish Central Office of Civil Registration. The latter had filled out a questionnaire regarding health status, and DNA was obtained from blood samples and the buccal mucosa. Patient files were retrieved and clinical information was extracted. DNA was obtained from Guthrie cards from the Danish National Neonatal Screening Biobank (PKU-biobanken) at Statens Serum Institut and from blood samples. RESULTS A total of 588 IBD patients (244 Crohns disease (CD), 318 ulcerative colitis (UC) and 26 IBD-unclassified (IBDU)) and 543 healthy controls were included. We found an association between CD and rs22411880 (ATG16L1, odds ratio (OR)=1.7 [1.1-1.7], p=0.003), rs5743289 (NOD2, OR=1.4 [1.1-1.9], p=0.009) and the paediatric specific rs1250550 (ZMIZ1, OR=0.7 [0.5-0.9], p=0.01). None of the investigated 41 SNPs were associated with disease localisation, medical treatment or surgery after correcting for multiple analyses. CONCLUSION We found an association between CD and three previously published genetic variants and replicated the association with the paediatric specific ZMIZ1 gene. No Bonferroni corrected significant genotype-phenotype associations were found. For future studies aimed at finding predictors for disease course in (paediatric) IBD, it will be worthwhile to include a combination of genetic, clinical and serological markers.

Vedolizumab in Paediatric Inflammatory Bowel Disease: A Retrospective Multi-Centre Experience From the Paediatric IBD Porto Group of ESPGHAN.

Background Vedolizumab, an anti-integrin antibody, has proven to be effective in adults with inflammatory bowel disease [IBD], but the data in paediatrics are limited. We describe the short-term effectiveness and safety of vedolizumab in a European multi-centre paediatric IBD cohort. Method Retrospective review of children [aged 2-18 years] treated with vedolizumab from 19 centres affiliated with the Paediatric IBD Porto group of ESPGHAN. Primary outcome was Week 14 corticosteroid-free remission [CFR]. Results In all, 64 children were included (32 [50%] male, mean age 14.5 ± 2.8 years, with a median follow-up 24 weeks [interquartile range 14-38; range 6-116]); 41 [64%] cases of ulcerative colitis/inflammatory bowel disease unclassified [UC/IBD-U] and 23 [36%] Crohns disease [CD]. All were previously treated with anti-tumour necrosis factor [TNF] [28% primary failure, 53% secondary failure]. Week 14 CFR was 37% in UC, and 14% in CD [P = 0.06]. CFR by last follow-up was 39% in UC and 24% in CD [p = 0.24]. Ten [17%] children required surgery, six of whom had colectomy for UC. Concomitant immunomodulatory drugs did not affect remission rate [42% vs 35%; p = 0.35 at Week 22]. There were three minor drug-related adverse events. Only 3 of 16 children who underwent endoscopic evaluation had mucosal healing after treatment (19%). Conclusions Vedolizumab was safe and effective in this cohort of paediatric refractory IBD. These data support previous findings of slow induction rate of vedolizumab in CD and a trend to be less effective compared with patients with UC.

Self-managed ehealth Disease Monitoring in Children and Adolescents with Inflammatory Bowel Disease: A Randomized Controlled Trial.

Background: To evaluate the impact of eHealth on disease activity, the need for hospital contacts, and medical adherence in children and adolescents with inflammatory bowel disease (IBD). Furthermore, to assess eHealths influence on school attendance and quality of life (QoL). Methods: Patients with IBD, 10 to 17 years attending a public university hospital, were prospectively randomized to a 2-year open label case-controlled eHealth intervention. The eHealth-group used the web-application young.constant-care.com (YCC) on a monthly basis and in case of flare-ups, and were seen at one annual preplanned outpatient visit. The control-group continued standard visits every third month. Every 3 months, both groups had blood and fecal calprotectin tested and the following were assessed: escalation in medication, disease activity, hospital contacts, medical adherence, school absence, and QoL. Results: Fifty-three patients in nonbiological treatment were included (27 eHealth/26 control). We found no differences between the groups regarding escalation in treatment and disease activity (symptoms, fecal calprotectin, and blood). The number of total outpatient visits (mean: eHealth 3.26, SEM 0.51; control 7.31, SEM 0.69; P < 0.0001) and IBD-related school absence (mean days: eHealth 1.6, SEM 0.5; control 16.5, SEM 4.4; P < 0.002) was significantly lower in the eHealth-group. No differences in medical adherence and QoL were found. Adherence to YCC was 81% (384 of the 475 expected entries). None of the patients or parents felt unsafe using the eHealth system. Conclusions: The use of eHealth in children and adolescents with IBD is feasible, does not lead to impaired disease control, and can be managed by the patients without risk of increased disease activity.

Individualized Infliximab Treatment Guided by Patient-managed ehealth in Children and Adolescents with Inflammatory Bowel Disease

Background: To individualize timing of infliximab (IFX) treatment in children and adolescents with inflammatory bowel disease (IBD) using a patient-managed eHealth program. Methods: Patients with IBD, 10 to 17 years old, treated with IFX were prospectively included. Starting 4 weeks after their last infusion, patients reported a weekly symptom score and provided a stool sample for fecal calprotectin analysis. Based on symptom scores and fecal calprotectin results, the eHealth program calculated a total inflammation burden score that determined the timing of the next IFX infusion (4–12 wk after the previous infusion). Quality of Life was scored by IMPACT III. A control group was included to compare trough levels of IFX antibodies and concentrations and treatment intervals. Patients and their parents evaluated the eHealth program. Results: There were 29 patients with IBD in the eHealth group and 21 patients with IBD in the control group. During the control period, 94 infusions were provided in the eHealth group (mean interval 9.5 wk; SD 2.3) versus 105 infusions in the control group (mean interval 6.9 wk; SD 1.4). Treatment intervals were longer in the eHealth group (P < 0.001). Quality of Life did not change during the study. Appearance of IFX antibodies did not differ between the 2 groups. Eighty percent of patients reported increased disease control and 63% (86% of parents) reported an improved knowledge of the disease. Conclusions: Self-managed, eHealth-individualized timing of IFX treatments, with treatment intervals of 4 to 12 weeks, was accompanied by no significant development of IFX antibodies. Patients reported better control and improved knowledge of their IBD.

Does infliximab prevent colectomy in acute and chronic active ulcerative colitis

Objectives: The aim of the study was to evaluate clinical response, use of colectomy, and adverse events related to infliximab (IFX) treatment in acute and chronic active ulcerative colitis (UC) in children. Methods: Children from 3 centers, who had received IFX for UC, were identified, and patient charts were reviewed retrospectively. Data concerning symptoms, biochemistry, concomitant medical treatment, colectomy, and adverse events were registered. Results: A total of 45 patients with UC (median age at diagnosis 12 years, interquartile range 10–14) were included, and studied for a median of 15 months (interquartile range 4.5–29) after first IFX infusion. The cumulative 1- and 2-year risks of colectomy were 21% and 26%, respectively. The cumulative 1- and 2-year risks of receiving a new course of systemic corticosteroids were 32% and 48%, respectively. Twenty-one patients (46%) experienced adverse events. Most common were mild infusion reactions, but 3 (7%) had serious adverse events. Conclusions: IFX was efficient in preventing colectomy in children with UC. The risk of receiving systemic corticosteroids was lower than that reported in other studies. Most adverse events were mild to moderate and self-limiting.

F-calprotectin and blood markers correlate to Quality of Life in Pediatric Inflammatory Bowel Disease.

Objectives: Our aim was to investigate predictors of health-related quality of life (HRQoL) with respect to changes in disease parameters over time in children with inflammatory bowel disease. Methods: This was a prospective longitudinal study examining the association between HRQoL (IMPACT III) and symptom scores (Pediatric Crohn Disease Activity Index, abbreviated Pediatric Ulcerative Colitis Activity Index), fecal calprotectin measures and blood analyses (C-reactive protein, erythrocyte sedimentation rate, orosomucoid, albumin, hemoglobin, and vitamin-D) in a cohort of 10- to 17-year-old patients with inflammatory bowel disease. Data were collected prospectively at 3-month intervals during a 2-year period. Associations were analyzed using linear mixed-effect models. Patients were divided into 2 groups, which received nonbiological oral treatment or biological parenteral treatment. Results: From 79 patients (39 Crohn disease/40 ulcerative colitis), representing a total of 43,132 days of observation, 572 IMPACT measurements were paired with variables. A decrease in the IMPACT III score was significantly associated with increased ulcerative colitis-symptom score in the biological group (P = 0.005), and a similar inverse tendency was found in the nonbiological group and for Crohn disease symptoms in both groups. We found in both treatment groups overall a significant (P < 0.05) inverse association between the IMPACT III and the levels of fecal calprotectin, erythrocyte sedimentation rate, and orosomucoid, whereas albumin, hemoglobin, and vitamin-D were directly significantly associated. Conclusions: The IMPACT score, already known to correlate with disease activity, has now been shown to be associated with disease markers in feces and blood. This emphasizes that objective markers of disease activity indirectly can predict the patients HRQoL.