Jan Fallingborg

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.

Budesonide treatment of collagenous colitis: a randomised, double blind, placebo controlled trial with morphometric analysis

Background: Collagenous colitis is characterised by diarrhoea, lymphocytic inflammation, and a thickened subepithelial collagen layer in the colorectal mucosa. No standard treatment of the disease is established. Aims: To investigate the clinical and histological effect of oral budesonide (Entocort, AstraZeneca) in the treatment of collagenous colitis. Patients: Twenty patients with collagenous colitis (collagen layer >10 μm) and diarrhoea (>4 stools/day and/or stool weight >200 g/day). Methods: A randomised, double blind, placebo controlled trial of budesonide treatment. Patients were randomised to placebo or budesonide for eight weeks. Stool frequency and stool weight were registered before and after treatment. Sigmoidoscopy was performed before and after treatment, and biopsies at fixed locations were obtained for morphometric analysis. Results: Ten patients were randomised to budesonide and 10 to placebo. All 10 patients receiving budesonide had a clinical response compared with two in the placebo group (p<0.001). In the budesonide group, stool weight was reduced from 574 g/day to 200 g/day and stool frequency was reduced from 6.2/day to 1.9/day (p<0.01). The histological inflammation grade in the sigmoid mucosa and the thickness of the collagen layer were significantly reduced. A correlation between the grade of inflammation as well as collagen layer thickness and stool weight was found. No side effects were reported. Eight of 10 patients had relapse of symptoms within eight weeks after stopping treatment. Conclusions: Budesonide is a highly effective and well tolerated treatment of collagenous colitis. There is a high risk of relapse after stopping eight weeks of treatment.

Hepatobiliary Dysfunction and Primary Sclerosing Cholangitis in Patients with Crohn's Disease

BACKGROUND Only a few studies have attempted to determined the prevalence of long-standing abnormal liver function and primary sclerosing cholangitis (PSC) in patients with Crohns disease (CD). The aim of the study was to determine the prevalence of long-standing abnormal liver function test results and to describe the clinical, biochemical, and histologic findings in patients with large-duct classic PSC and small-duct PSC (that is, normal cholangiogram) in patients with CD during a 15-year period. METHODS Patients with CD and long-standing abnormal liver function results were investigated individually with endoscopic retrograde cholangiography and liver biopsy. RESULTS Of 262 consecutive patients with CD, 38 (15%) had long-standing increased alkaline phosphatase (ALP) values (mean, 1065 U/l; range, 321-4165 U/l). Of these, 10 patients were classified as having hepatic disease (4%), of which 9 had PSC and 1 had a non-specific reactive hepatitis. Of nine patients with PSC (3.4%), three were classified as having large-duct PSC; five, small-duct PSC; and one, unclassified. In patients with large-bowel CD (n = 102) the prevalence of PSC was 9%. Mean age at diagnosis of PSC was 35 years (22-46 years), and the female to male ratio, 7:2. All PSC patients had large-bowel involvement (P < 0.00015), and two of them developed colonic carcinoma of the large bowel (P < 0.01). All cases of small-duct PSC were stage 1, whereas large-duct PSC were stage 2-3. During the observation period (mean, 5.4 years) no PSC patients died. CONCLUSIONS The results of our study indicate that PSC is the major hepatic disease in patients with CD and long-standing abnormal liver function tests and is approximately as prevalent as in ulcerative colitis. Patients with PSC and CD may have a milder liver disease than patients with PSC and ulcerative colitis, perhaps because large-duct PSC is less common in patients with CD. Cholangiograms and liver biopsies are both needed to evaluate the extent of the disease.

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.

Azathioprine treatment during lactation

Background  Thiopurines are widely used to maintain remission in inflammatory bowel disease. Treatment during pregnancy is generally recommended to improve the chance of a normal birth outcome, but advice concerning breastfeeding is conflicting.

Microscopic Appearance of the Esophageal Mucosa in a Consecutive Series of Patients Submitted to Upper Endoscopy: Correlation with Gastroesophageal Reflux Symptoms and Macroscopic Findings

The histologic finding of basal-layer hyperplasia and papillosis as consequences of gastroesophageal reflux still constitute an area of controversy. Consequently, a prospective study of symptoms and endoscopy and biopsy interpretation was undertaken in 200 patients consecutively submitted to upper endoscopy, whereof 12 were excluded. Complete agreement among all three variables was found in half of the patients and harmony between two of the variables in one fourth. In the last fourth the outcome was positive in one variable only, equally distributed among the symptoms, endoscopy, and histology. It is concluded that histology is of considerable value in gastroesophageal reflux disease.

Long-term budesonide treatment of collagenous colitis: a randomised, double-blind, placebo-controlled trial

Objective: To evaluate the efficacy and safety of long-term budesonide therapy for the maintenance of clinical remission in patients with collagenous colitis. Design: Randomised, placebo-controlled study with a 24-week, blinded follow-up period without any treatment. Setting: Three gastroenterology clinics in Denmark. Patients: Forty-two patients with histologically confirmed collagenous colitis and diarrhoea (more than three stools/day). Interventions: Patients in clinical remission after 6 weeks’ open-label therapy with oral budesonide (Entocort CIR capsules, 9 mg/day) received 24 weeks’ double-blind maintenance therapy with budesonide 6 mg/day or placebo. Thereafter, patients entered the 24-week, blinded follow-up period. Main Outcome Measure: The proportion of patients in clinical remission (three or fewer stools/day) at the end of maintenance therapy. Findings: A total of 34 patients in remission at week 6 were randomly assigned to budesonide 6 mg/day (n  =  17) or placebo (n  =  17). After 24 weeks’ maintenance treatment, the proportions of patients in clinical remission were 76.5% (13 of 17) with budesonide and 12% (2 of 17) with placebo (p<0.001). At 48 weeks (the end of the follow-up period, without any treatment) these values were 23.5% (4 of 17) and 12% (2 of 17), respectively (p = 0.6). The median times to relapse after stopping active treatment (6 plus 24 weeks in the budesonide group; 6 weeks in the placebo group) were 39 and 38 days, respectively. Long-term treatment with budesonide was well tolerated. Conclusions: Long-term maintenance therapy with oral budesonide is efficacious and well tolerated for preventing relapse in patients with collagenous colitis. The risk of relapse after 24 weeks’ maintenance treatment is similar to that observed after 6 weeks’ induction therapy.

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.