P. Rutgeerts

Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD.

BACKGROUND Healing of mucosal lesions appears to offer significant benefit and is an important end point in clinical trials of treatment for Crohns disease. The only validated endoscopic activity score at present is the Crohns Disease Endoscopic Index of Severity, which is complicated and time consuming and, hence, is unsuitable for routine use. The aim of this study was to develop and to prospectively validate a simpler endoscopic score of disease activity, the Simple Endoscopic Score for Crohns Disease. METHODS Selected endoscopic parameters (ulcer size, ulcerated and affected surfaces, stenosis) were scored from 0 to 3. Reproducibility for scoring of these parameters was evaluated through 71 examinations in which the endoscopist was paired with an observer. The simplest score (Simple Endoscopic Score for Crohns Disease) that was highly correlated with both the Crohns Disease Endoscopic Index of Severity and Crohns Disease Activity Index was derived for 70 patients and then was prospectively validated in 121 different patients with Crohns disease. RESULTS The interobserver agreement for all selected endoscopic variables was excellent (kappa coefficient 0.791-1.000). Based on multiple linear regression, the Simple Endoscopic Score for Crohns Disease resulted in the sum of the scores for ulcer size, ulcerated surface, affected surface, and luminal narrowing. In the validation phase of the study, a strong correlation was demonstrated for the Simple Endoscopic Score for Crohns Disease with Crohns Disease Endoscopic Index of Severity (r = 0.920). In addition, the Simple Endoscopic Score for Crohns Disease was correlated to clinical parameters and serum C-reactive protein level. CONCLUSIONS Simple Endoscopic Score for Crohns Disease is a simple, reproducible, and easy-to-use endoscopic scoring system for Crohns disease.

Laboratory markers in IBD: useful, magic, or unnecessary toys?

Laboratory markers have been investigated in inflammatory bowel disease (IBD) for diagnostic and differential diagnostic purposes, for assessment of disease activity and risk of complications, for prediction of relapse, and for monitoring the effect of therapy. The introduction of biological therapies in IBD has renewed interest in inflammatory markers (especially C reactive protein (CRP)), given their potential to select responders to these treatments. Of all the laboratory markers, CRP is the most studied and has been shown to have the best overall performance. CRP is an objective marker of inflammation and correlates well with disease activity in Crohns disease (CD). Increased CRP levels are associated with better response rates and normal CRP levels predict high placebo response rates in clinical trials with biologicals. However, despite the advantages of CRP over other markers, it is still far from ideal. Furthermore, CRP correlates less well with disease activity in patients with ulcerative colitis (UC) as compared with CD. Other laboratory markers, including erythrocyte sedimentation rate (ESR), leucocyte and platelet count, albumin, and 1 acid glycoprotein (orosomucoid), have been studied either less extensively in IBD or have proven to be less useful than CRP. Faecal markers seem promising and may be more specific in detecting gut inflammation in patients with established IBD. Promising results have been reported with the use of faecal calprotectin in CD as well as in UC. Recent data however suggest that the performance of the faecal calprotectin test is superior for UC than for CD. Taken together, laboratory markers are useful and should be part of the global management of our IBD patients. They are however not magic and until more data become available, the use of CRP and other laboratory markers should be seen as an additive tool to clinical observation and physical examination rather than a replacement.

Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort

Background and aims: This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn’s disease (CD) from a single centre during a median follow-up of 55 months (interquartile range (IQR) 27–83). Methods: The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed. Results: 10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group. Conclusions: In this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery.

The risk of post-operative complications associated with infliximab therapy for Crohn's disease: a controlled cohort study

Background : By temporarily suppressing the immune response, the anti‐tumour necrosis factor agent, infliximab, may increase the risk of peri‐operative complications.

Inflammatory Bowel Disease A Positive Response to Infliximab in Crohn Disease: Association with a Higher Systemic Inflammation Before Treatment But Not With -308 TNF Gene Polymorphism

Background: Two-thirds to three-fourths of patients with either refractory luminal or fistulizing Crohn disease respond to infliximab treatment. The ability or inability to respond seems to persist over time. Biological characteristics and/or genetic background can influence the response to treatment. The aim was to assess the value of C-reactive protein and TNF- α serum levels before treatment as well as the TNF -308 gene polymorphism in the prediction of response to infliximab treatment in Crohn disease. Methods: Two-hundred-and-twenty-six Crohn disease patients treated in the setting of an expanded access programme to infliximab in Belgium were studied. There were 136 refractory luminal diseases and 90 refractory fistulizing diseases. Luminal diseases were treated with one single infusion; fistulizing diseases with three infusions at weeks 0, 2 and 6. A clinical response to treatment was defined as either a Crohn disease activity index <150 (complete) or a drop of 70 points (partial) at week 4, for luminal disease, and as either complete fistula healing (complete) or a decrease of at least 50% of the number of draining fistulas on two consecutive visits between weeks 0 and 18, for fistulizing disease. CRP and serum TNF- α levels were measured at week 0 before treatment and were compared between responders and non-responders. Patients were genotyped for the-308 TNF gene polymorphism, and allelic as well as genotype frequencies were compared between responders and non-responders. Results: There were 73.2% responders (46.4% complete and 26.8% partial) and 26.8% non-responders. Response rates were similar in luminal and fistulizing diseases. CRP level before treatment was significantly higher in responders than in non-responders (16.8 mg/l (5-160) versus 9.6 mg/l (5-143); P = 0.02). Furthermore, response rate was significantly higher in patients with elevated CRP (>5 mg/l) than in patients with a normal CRP value (<5 mg/l) before treatment (76% versus 46%; P = 0.004; OR: 0.26 (0.11-0.63)). Allelic and genotype frequencies for-308 TNF gene polymorphism were not significantly different between responders and non-responders - with the exception of a slightly higher TNF2 frequency in nonresponders in luminal disease (22.1% versus 11.6%; P = 0.04). However, this was not associated with a significant difference in genotype frequencies. Conclusion: A positive clinical response to infliximab was associated with a higher CRP level before treatment in our population of Crohn disease patients, but there was no relevant association with-308 TNF gene polymorphism. We therefore suggest that CRP level may help to identify better candidates for infliximab treatment.

A dose escalating, placebo controlled, double blind, single dose and multidose, safety and tolerability study of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease

Introduction: This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon γ antibody, in patients with moderate to severe Crohn’s disease (CD). Patients and methods: Forty five patients with a CD activity index (CDAI) of 250–450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates. Results: Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn’s disease endoscopic index of severity (p = 0.02) and serum C reactive protein (p<0.001) was observed in the 4.0 mg/kg (n = 14) fontolizumab cohort compared with placebo (n = 10). Pharmacodynamic effects were observed by immunohistochemistry. Conclusions: Fontolizumab was well tolerated with minimal immunogenicity at doses of up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested.

Switch from systemic steroids to budesonide in steroid dependent patients with inactive Crohn's disease

BACKGROUND Steroid dependent patients with Crohns disease are at high risk of developing glucocorticosteroid induced side effects. AIMS We evaluated the possibility of switching from systemic steroids to budesonide (Entocort) in prednisolone/prednisone dependent patients with inactive Crohns disease affecting the ileum and/or ascending colon. PATIENTS Steroid dependent patients with a Crohns disease activity index ⩽200 were included. METHODS In a double blind multicentre trial, 120 patients were randomly assigned to receive budesonide 6 mg once daily or placebo. Prednisolone was tapered to zero during the first 4–10 weeks and budesonide or placebo was given concomitantly and for a further 12 weeks. Relapse was defined as an index >200 and an increase of 60 points from baseline or withdrawal due to disease deterioration. RESULTS After one and 13 weeks without prednisolone, relapse rates were 17% and 32%, respectively, in the budesonide group, and 41% and 65% in the placebo group (95% confidence intervals for the difference in percentages −41%, −8% and −51%, −16%; p=0.004 and p<0.001, respectively). The number of glucocorticosteroid side effects was reduced by 50% by switching from prednisolone and was similar in the budesonide and placebo groups. Basal plasma cortisol increased in both groups. CONCLUSIONS The majority of patients with steroid dependent ileocaecal Crohns disease may be switched to budesonide controlled ileal release capsules 6 mg without relapse, resulting in a sharp decrease in glucocorticosteroid side effects similar to placebo, and with an increase in plasma cortisol levels.

JC viral loads in patients with Crohn’s disease treated with immunosuppression: can we screen for elevated risk of progressive multifocal leukoencephalopathy?

Background and aims: Anti-α4 integrin therapy with natalizumab is efficacious in refractory Crohn’s disease and in multiple sclerosis, but carries an estimated 1/1000 risk of progressive multifocal leukoencephalopathy (PML) caused by reactivation of latent JC virus infection. Athough anti-α4 integrin therapies are likely to be introduced in the clinic, screening for the risk of PML has not been developed. Methods: We prospectively collected urine, serum, plasma and buffy coats from 125 patients with Crohn’s disease, 100 control subjects with gastrointestinal (GI) disease, and 106 healthy volunteers. Four to eight weeks after this first sample collection, we additionally collected a set of urine, serum, plasma and buffy coat samples from the 125 patients with Crohn’s disease, and a next set of samples was collected 12–16 weeks after the first collection. JC viral loads were determined with quantitative real-time polymerase chain reaction (PCR), and JC virus seroprevalence with a specific enzyme-linked immunosorbant assay (ELISA). Results: The overall JC virus seroprevalence was 65%. JC virus DNA copies were detected in the urine from 29–44% of subjects, both those with Crohn’s disease and controls. Median viral loads were significantly higher in patients with Crohn’s disease who were immunosuppressed (7.36×106 copies/ml) compared to healthy volunteers (2.77×105 copies/ml) and compared to GI controls (1.8×106 copies/ml). Clearance at any time point occurred in 4/107 (3.7%) subjects only. JC viraemia was found in two patients with Crohn’s disease. Conclusions: The natural history of JC virus in patients with Crohn’s disease is still unknown. Our study results show that JC virus latency and urine viral shedding is frequent in immunosuppressed patients with Crohn’s disease. More prospective studies are needed in order to agree on possible recommendations concerning the exclusion of patients with JCV viraemia from anti-α4 integrin treatment.

Effect of dietary intervention with different pre- and probiotics on intestinal bacterial enzyme activities

Objective:To investigate the influence of different pre- and probiotics on faecal β-glucuronidase and β-glucosidase activity, as one of the claimed beneficial effects of pre- and probiotics is the hypothesis that these substrates are able to reduce the production of toxic and carcinogenic metabolites by suppressing specific enzyme activities in the colon.Setting:Department of Gastrointestinal Research, University Hospital Gasthuisberg, KU Leuven, Belgium.Design and subjects:The effect was evaluated in a randomized, crossover study in 53 healthy volunteers who were randomly assigned to one of five treatment groups.Interventions:At the start and after a 4-week treatment period, the healthy volunteers collected faeces during 72 h. Lactulose and oligofructose-enriched inulin (OF-IN) were chosen as prebiotics, whereas Lactobacillus casei Shirota, Bifidobacterium breve and Saccharomyces boulardii were selected as probiotics. Two synbiotic combinations were evaluated as well. The enzyme activity was assessed spectrophotometricly.Results:Lactulose and OF-IN significantly decreased β-glucuronidase activity, whereas a tendency to a decreased β-glucuronidase activity was observed after L. casei Shirota and B. breve intake. To the contrary, B. breve increased β-glucosidase levels. Supplementation with the synbiotic did not appear to be more beneficial than either compound alone. No influence of S. boulardii was noted.Conclusions:Administration of lactulose, OF-IN, L. casei Shirota or B. breve resulted in a decrease of the β-glucuronidase activity, which is considered beneficial for the host.

Epithelioid granulomas, pattern recognition receptors, and phenotypes of Crohn’s disease

Introduction: Crohn’s disease is a chronic inflammatory disorder of the gut. It is assumed that a defective interaction between the bacterial flora of the gut and the innate immune system plays a key role in the pathogenesis of the disease. This may lead to specific histological lesions. The epithelioid granuloma is particularly interesting in this regard as it is also observed in several bacterial infections of the gut. Aims and methods: We hypothesised that genetic or environmental factors with a known influence on inflammation or immunity would lead to an increased prevalence of granulomas. Therefore, surgical specimens from 161 patients were evaluated for the presence of granulomas. Patients were genotyped for the three single nucleotide polymorphisms in caspase recruitment domain 15 (CARD15)/NOD2 associated with CD and for Asp299Gly in Toll-like receptor 4 (TLR4). Results: The overall prevalence of granulomas was 68.9%. We did not find a significant correlation between granulomas and TLR4 or CARD15 variants. The frequency of granulomas increased with more distal disease (63% small bowel, 72% right colon, 88% left colon, 90% rectum; p = 0.01). Granulomas were more frequent in younger patients (odds ratio 0.95 (95% confidence interval 0.92–0.98) p = 0.007). Conclusion: In this study of 161 well documented CD patients, we found no significant association between CARD15 and TLR4 variants and granulomas. This finding seems to refute our initial hypothesis. However, it may be that additional factors are needed for granuloma development. Granulomas may develop only when specific bacterial components are present. Therefore, future research on granuloma pathogenesis should be orientated towards detection and identification of bacterial components in these lesions.