Bent Ascanius Jacobsen

Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial

Objective Although the reasons for secondary loss of response to infliximab (IFX) maintenance therapy in Crohn’s disease vary, dose intensification is usually recommended. This study investigated the cost-effectiveness of interventions defined by an algorithm designed to identify specific reasons for therapeutic failure. Design Randomised, controlled, single-blind, multicentre study. 69 patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) (n=36) or interventions based on serum IFX and IFX antibody levels using the proposed algorithm (n=33). Predefined co-primary end points at week 12 were proportion of patients responding (Crohns Disease Activity Index (CDAI) decrease ≥70, or ≥50% reduction in active fistulas) and accumulated costs related to treatment of Crohn’s disease, expressed as mean cost per patient, based on the Danish National Patient Registry for all hospitalisation and outpatient costs in the Danish healthcare sector. Results Costs for intention-to-treat patients were substantially lower (34%) for those treated in accordance with the algorithm than by IFX dose intensification: €6038 vs €9178, p<0.001. However, disease control, as judged by response rates, was similar: 58% and 53%, respectively, p=0.81; difference 5% (−19% to 28%). For per-protocol patients, treatment costs were even lower (56%) in the algorithm-treated group (€4062 vs €9178, p<0.001) and with similar response rates (47% vs 53%, p=0.78; difference −5% (−33% to 22%)). Conclusions Treatment of secondary IFX failure using an algorithm based on combined IFX and IFX antibody measurements significantly reduces average treatment costs per patient compared with routine IFX dose escalation and without any apparent negative effect on clinical efficacy. Trial Registration No NCT00851565.

pH-Profile and regional transit times of the normal gut measured by a radiotelemetry device

The pH of the gut lumen was measured in 39 healthy persons using a pH‐sensitive, radiotransmitting capsule. Thirteen persons were studied twice. The location of the capsule was determined by X‐ray. The pH rose from 6.4 in the duodenum to 7.3 in the distal part of the small intestine. In 17 persons the pH dropped by 0.1–0.8 pH units during the last hours of the small intestinal transit. The pH was 5.7 in the caecum, but rose to 6.6 in the rectum. Gastric residence time was 1.1 h, small intestinal transit was 8 h, and colonic transit time was 17.5 h (median values). The results provide a firmer basis for prediction of the level, and the rate of release of active substance from pH‐dependent sustained‐release oral preparations.

Disease Activity in Pregnant Women With Crohn's Disease and Birth Outcomes: A Regional Danish Cohort Study

OBJECTIVES: CD is associated with increased risk of adverse birth outcomes, but existing studies have not assessed the impact of disease activity during pregnancy. We examined the impact of disease activity on birth outcomes: LBW, preterm birth, LBW at term, and CAs.METHODS: All births by CD women in North Jutland County, Denmark, from January 1, 1977 to December 31, 2005, were evaluated in a cohort study based on linkage between the Danish National Registry of Patients and the Medical Birth Registry. After identification of all births by CD women, review of medical records allowed collection of clinical details (including disease activity and drug therapy during pregnancy). The exposed cohort (N = 71) constituted pregnancies with low/moderate-high disease activity during pregnancy, and the unexposed cohort (N = 86) those with inactive disease. Logistic regression analyses were used to estimate the adjusted relative risks (with 95% confidence intervals) for adverse birth outcomes associated with disease activity in CD pregnancies. In subanalysis, we examined the impact of moderate-high activity.RESULTS: In women with disease activity, the adjusted risks of LBW, LBW at term, preterm birth, and CAs were 0.2 (0.0–2.6), 0.4 (0.0–3.7), 2.4 (0.6–9.5), and 0.8 (0.2–3.8), respectively. The crude risk of preterm birth was 3.4 (1.1–10.6) in those with moderate-high disease activity.CONCLUSIONS: Disease activity during pregnancy only increased the risk of preterm birth (especially in those with high disease activity). Further research is needed to assess the critical impact of disease activity in larger cohorts of CD women.

Increase in incidence and prevalence of inflammatory bowel disease in northern Denmark: A population-based study, 1978-2002

Objectives Although incidence rates of inflammatory bowel disease have been reported worldwide, few long-term population-based studies with current time-trend analyses exist. We therefore examined time trends in the incidence rate of inflammatory bowel disease in a 25-year study period, and estimated the prevalence in 2002. All patients diagnosed between 1978 and 2002 were included as incident cases (n=2326) and all patients living in North Jutland County on 31 December 2002 were used to estimate prevalent cases (n=2205). Methods Medical records of all patients diagnosed with ulcerative colitis and Crohns disease in the North Jutland County Hospital Discharge Registry were reviewed to examine if the diagnostic criteria were fulfilled. Age-specific and gender-specific standardized incidence rates were calculated. Results For ulcerative colitis, incidence rates in women increased from 8.3 (95% confidence interval (CI): 6.7–9.9) in 1978–1982 to 17.0 (95% CI: 14.7–19.3) per 100 000 person-years in 1998–2002. The corresponding figures for men were 7.7 (95% CI: 6.1–9.3) and 16.7 (95% CI: 14.4–18.8) per 100 000 person-years. For Crohns disease, the incidence rates in women increased from 4.1 (95% CI: 3.0–5.2) in 1978–1982 to 10.7 (95% CI: 8.8–12.5) per 100 000 person-years in 1998–2002. The corresponding figures for men were 3.2 (95% CI: 2.1–4.2) and 8.5 (95% CI: 6.9–10.2) per 100 000 person-years. The prevalence of ulcerative colitis and Crohns disease was 294 and 151 per 100 000 inhabitants, respectively. Conclusions A marked and parallel increase was seen in both ulcerative colitis and Crohns disease in both genders during the last 25 years, with a corresponding high prevalence of both diseases.

Very low intraluminal colonic pH in patients with active ulcerative colitis

Intraluminal gastrointestinal pH was measured in seven patients with active ulcerative colitis (four male, three female). A radiotelemetry capsule was used, and its location was determined by fluoroscopy. Satisfactory measurements were obtained from six, in all of whom pH levels were normal in the stomach and small intestine. Three patients also had normal pH values in the colon. However, in the remaining three patients very low pH levels (lowest values 2.3, 2.9, and 3.4) were found in the proximal parts of the colon. Five of the seven patients, including the three with low pH in the colon, underwent colectomy. The mechanism behind the low intraluminal pH in some patients with ulcerative colitis is speculative. Increased fecal concentrations of lactate occur in active disease, but some of the pH values measured in our study were below the pKa value of lactate. The study demonstrates that very low intraluminal pH levels in the colon occur in some patients with active ulcerative colitis. This might be an indicator of severe activity of the disease.

Birth outcome in women exposed to 5-aminosalicylic acid during pregnancy: a Danish cohort study

Background: 5-Aminosalicylic acid (5-ASA) preparations are the firstline drugs in the treatment of inflammatory bowel disease. Data on the safety of these drugs in pregnancy are sparse. Aims: To examine the risk of adverse birth outcome in women who were prescribed 5-ASA drugs during pregnancy. Patients: Women were included in the study if they were prescribed 5-ASA drugs immediately before or during pregnancy. To examine the risk of malformations, we included 60 pregnancies exposed to 5-ASA drugs 30 days before pregnancy or in the first trimester. To examine stillbirths, preterm births, and low birth weight, we included 88 pregnancies exposed during the entire pregnancy. Outcomes were compared with those of 19 418 pregnancies in which no drugs were prescribed for mothers during the study period. Methods: We conducted a Danish cohort study based on data from a population based prescription registry, the Danish Birth Registry, and the Hospital Discharge Registry in North Jutland County. Results: Odds ratios for malformations, stillbirth, preterm birth, and low birth weight in women who received prescriptions for 5-ASA drugs were 1.9 (95% confidence interval 0.7–5.4), 6.4 (1.7–24.9), 1.9 (0.9–3.9), and 1.2 (0.4–3.3), respectively. The increased risk of stillbirth and preterm birth were found only in patients with ulcerative colitis. Conclusions: We found an increased risk of stillbirth and preterm birth in women who had been prescribed 5-ASA drugs during pregnancy but no substantial increased risk of malformations. It was difficult to distinguish the specific effects of disease activity and 5-ASA drugs.

Cancer risk in inflammatory bowel disease according to patient phenotype and treatment: A danish population-based cohort study

OBJECTIVES:Population-based studies of site-specific cancer risk in patients with inflammatory bowel disease (IBD) according to IBD phenotype and treatment are lacking. We studied cancer risk in a well-characterized population-based IBD cohort from North Jutland County, Denmark.METHODS:A total of 1,515 patients were diagnosed with ulcerative colitis (UC) and 810 with Crohn’s disease (CD) during 1978–2002. Patients were followed until 31 December 2010 for occurrence of incident cancer, identified in the Danish Cancer Registry. Observed numbers of cancer were compared with expected numbers (based on age- and sex-specific background rates) and presented as standardized incidence ratios (SIRs) with 95% confidence intervals (CIs).RESULTS:Patients with UC were not at increased risk of cancer overall (SIR, 1.12; 95% CI, 0.97–1.28) despite increased risk of prostate cancer (SIR, 1.82; 95% CI, 1.17–2.71). Patients with CD had a 55% increased risk of cancer overall (SIR, 1.55; 95% CI, 1.29–1.84) related to young age, colonic disease, smoking, and thiopurine exposure. Patients were at increased risk of small bowel cancer (SIR, 15.18; 95% CI, 1.84–54.78), lung cancer (SIR, 2.13; 95% CI, 1.19–3.52 (associated with female gender and smoking)), colorectal cancer in males (SIR, 2.43; 95% CI, 1.05–4.78), cervical dysplasia (SIR, 1.65; 95% CI, 1.10–2.37 (associated with young age at diagnosis, smoking, 5-aminosalicylic acid, and thiopurine exposure)), and non-Hodgkin lymphoma (SIR, 3.43; 95% CI, 1.38–7.07 (unrelated to thiopurine exposure)).CONCLUSIONS:Patients with CD, but not UC, have an overall excess risk of cancer. Clinical characteristics of IBD patients at excess risk differ by cancer subtype.

Measurement of gastrointestinal pH and regional transit times in normal children

Summary: Gastrointestinal pH and regional intestinal transit times of a capsule were measured in twelve healthy children aged 8–14 years using a radiotransmitting pH-sensitive capsule. The location of the capsule was determined by fluoroscopy. pH in the stomach was 1.5, but rose to 6.4 in the duodenum (mean values). pH gradually rose in the small intestine and reached an alkaline peak value of 7.4 in the distal part. pH dropped to 5.9 in the cecum but rose to 6.5 in the rectum. Median gastric residence time of the capsule was 1.1 h. Small intestinal transit time was 7.5 h, and colonic transit time was 17.2 h. pH profile and intestinal transit times found in the present study are almost identical to values found in studies on healthy adults. It is therefore concluded that the release pattern of pH-dependent sustained-release tablets in children is likely to be equal to that of adults.

Small intestinal transit time and intraluminal pH in ileocecal resected patients with Crohn's disease

The pH and transit times of the gut areimportant for the delivery of active drug from severaltablets used in the treatment of Crohns disease (CD).Many patients with CD undergo an ileocecal resection, which might influence small intestinal pH andtransit time. The effect of ileocecal resection on thesevariables has not previously been studied. IntraluminalpH and transit time were measured in nineileocecal-resected CD patients and 13 healthy volunteers usingpH-sensitive radiocapsules. Small intestinal transittime (SITT) was significantly shorter inileocecal-resected patients (5.2 hr, controls 8.0 hr).The pH levels of the small intestine were identical inpatients and controls, whereas cecal pH was 0.9 pH unitshigher in resected CD patients. The time spent with pHhigher than 5.5, 6.0, 6.5, and 7.0 was significantly shorter in patients than in controls. There wasno correlation between the SITT and the length ofresected ileum or between the SITT and the time elapsedsince the resection. We conclude that ileocecal resection decreases the SITT and the time withpH higher than 5.5-7.0. The study indicates that thisreduction of the SITT is mainly due to the resection ofthe ileocecal valve and is, to a certain extent, independent of the length of resected ileum. Anileocecal resection might therefore affect the deliveryof active drug from tablets with pH-dependentdelivery.

Topical and systemic availability of 5‐amino‐salicylate: comparisons of three controlled release preparations in man

The bioavailability of three pure 5‐aminosalicylic (5‐ASA) preparations (Asacol, Claversal, and Pentasa) was studied in 8 ileostomy patients and 12 normal subjects after 6 days of treatment with 2000 mg 5‐ASA. The local bioavailability, reflected by the 5‐ASA concentration was thereby measured at two clinically relevant areas of the gut: at the entrance to, and the exit from the colon. Estimates of the systemic bioavailability were obtained from the urinary excretions and the plasma values of 5‐ASA and Acetyl‐5‐ASA (Ac‐5‐ASA) during the three regimens. The three preparations studied are designed to release 5‐ASA at different levels in the intestine, but there was no significant difference in the 5‐ASA concentrations in the ileostomy effluents (Asacol 1.8 mmol/L, Claversal 3.4 mmol/L, Pentasa 2.0 mmol/L, median values). However, we found a smaller urinary excretion of 5‐ASA and Ac‐5‐ASA (5.2%vs Claversal 27.9% and Pentasa 23.0%, median values of ingested daily dose) and a lower concentration of Ac‐5‐ASA in the ileostomy effluents after Asacol treatment (0.8 mmol/L, median value) which indicates a more distal release from this preparation compared with Claversal (2.4 mmol/L, median value) and Pentasa (5.5 mmol/L, median value). In normal subjects a higher faecal water concentration of 5‐ASA was found after Asacol (9.8 mmol/L, median value) compared with Claversal (5.0 mmol/L, median value), whereas no difference between the faecal water concentrations of Ac‐5‐ASA was found (Asacol 21.5 mmol/L, Claversal 21.6 mmol/L, median values). This can be explained by a larger systemic absorption of 5‐ASA from Claversal, and accordingly Claversal treatment resulted in the largest urinary excretion of 5‐ASA and Ac‐5‐ ASA (43.7% us Asacol 35.6% and Pentasa 31.6 %, median values of ingested daily dose). The high Ac‐5‐ASA concentration in the ileostomy effluents and in the faeces after Pentasa, and the low plasma values, indicate a slow 5‐ASA release from this preparation throughout the small and large intestine. The results of the study indicate that Asacol is released in the distal part of the small intestine, that Pentasa is gradually released in the small and large intestine, and that Claversal shows an intermediate release pattern.