Paul Rutgeerts

Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease

OBJECTIVES:A primary defect of the tight junctions and, hence, increased intestinal epithelial permeability has been proposed as a basic pathogenic event in Crohns disease. Challenge of the mucosal immune system by the commensal gut flora would then result in chronic inflammation. Alternatively, increased permeability could be the result of inflammation. Our aim was to study intestinal permeability in refractory Crohns disease before and after treatment with monoclonal chimeric antibodies directed against tumor necrosis factor (TNF) to investigate whether the abnormal permeability persists after control of inflammation.METHODS:Twenty-three patients with active Crohns disease were evaluated before and 4 wk after a single infusion of 5 mg/kg infliximab. Intestinal permeability was studied by measurement of urinary excretion of 51Cr-EDTA after oral intake.RESULTS:The increased permeation of 51Cr-EDTA through the small intestine (1.63% interquartile range [IQR] 1.06–2.07) and the overall permeation (3.27% IQR 2.40–4.38) before therapy decreased significantly after infliximab infusion to values (1.04% IQR 0.74–1.54 and 2.42% IQR 2.03–2.80, respectively) in the range of those found in normal volunteers (1.12% IQR 0.85–1.58 and 2.28% IQR 1.88–2.86, respectively).CONCLUSION:Inhibiting the proinflammatory cytokine tumor necrosis factor dramatically reduces gut inflammation and largely restores the gut barrier in Crohns disease. Our data confirm the central role of TNF in gut barrier modulation in inflammatory conditions in vivo.

Caspase Activation and Apoptosis Induction by Adalimumab: Demonstration In Vitro and In Vivo in a Chimeric Mouse Model

Background: Adalimumab is a fully human monoclonal antibody to tumor necrosis factor (TNF), which was recently introduced as a therapy for Crohns disease and rheumatoid arthritis. Besides neutralization, induction of apoptosis of monocytes/macrophages and T cells is thought to be an important mechanism of action of the anti‐tumor necrosis factor monoclonal antibody infliximab, at least in Crohns disease therapy. Aim: To study caspase activation and the induction of apoptosis by adalimumab and the effect of a caspase inhibitor in vivo. Methods: For in vitro studies, THP‐1 cells (human monocytic cell line) were incubated with adalimumab, infliximab, or human immunoglobulin G, and annexin V + propidium iodide, Apo2.7, and 7‐amino actinomycin‐D were used to study apoptosis on the cell membrane, mitochodrial, and DNA level, respectively. Active caspase‐3 was detected by intracellular staining. For in vivo studies, a chimeric human‐mouse model was used, in which THP‐1 cells were injected intraperitoneally in SCID‐Beige mice followed by treatment with adalimumab, infliximab, or human immunoglobulin G. Effects of a pan‐caspase inhibitor N‐benzyloxycarbonyl‐Val‐Ala‐Asp‐fluoromethyketone on apoptosis induction were evaluated. Results: In vitro analysis revealed that apoptosis could be induced in THP‐1 cells by both adalimumab and infliximab. Activation of caspase‐3 after incubation with adalimumab was demonstrated by intracellular staining. In addition, in the chimeric mouse model, a higher percentage of residual THP‐1 cells were apoptotic, and lower cell numbers were recovered in the adalimumab‐ or infliximab‐treated mouse. Apoptosis induction by adalimumab could be abrogated through in vivo pretreatment of mice with the pan‐caspase inhibitor. Conclusions: Adalimumab, besides neutralizing tumor necrosis factor, also induces apoptosis of transmembrane tumor necrosis factor‐positive THP‐1 cells by activating intracellular caspases. This activity is likely to be important for the clinical effect of this biodrug.

Success and failure after repair of rectovaginal fistula in Crohn's disease: analysis of prognostic factors.

To compare the healing rate after several types of surgical repair of rectovaginal fistula (RVF) in Crohn’s disease, and to identify factors predicting a successful outcome.

Hyperresponsiveness of the mucosal barrier in Crohn's disease is not tumor necrosis factor-dependent

Background: Crohns disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti‐inflammatory drugs. We studied whether reducing inflammation and restoring gut barrier dysfunction with anti‐tumor necrosis factor (TNF) antibody treatment also antagonizes the permeability increase by oral nonsteroidal anti‐inflammatory drug intake in patients with CD. Methods: Thirty‐one healthy control subjects and 25 patients with active CD were studied. The 31 controls performed intestinal permeability testing for 51Cr‐EDTA before (baseline) and after oral intake of indomethacin (50 + 75 mg). Twenty‐five patients carried out a baseline and indomethacin‐mediated permeability test before infliximab infusion. The patients repeated either the indomethacin test (12/25) or baseline and indomethacin tests (13/25), 1 month after this treatment. Intestinal permeability was studied by measurement of urinary excretion of 51Cr‐EDTA after oral intake. Results: Increased whole gut permeation before treatment (3.16%; interquartile range [IQR], 2.92‐5.72) was restored to normal values (2.47%; IQR, 1.97‐2.78) by anti‐TNF treatment. Indomethacin increased whole gut permeability significantly more in patients with CD (before anti‐TNF: 6.50%; IQR, 4.84‐10.38; after anti‐TNF: 5.50%; IQR, 3.97‐10.09) compared with the healthy subjects (4.66%; IQR, 3.51‐5.64). Eleven of 25 patients (44%) had an abnormal whole gut permeability response to indomethacin before anti‐TNF, and 9 of them remained hyperresponsive after infusion, despite clinical remission. Conclusions: Although anti‐TNF treatment suppresses inflammation and restores gut barrier function in patients with CD, it does not antagonize the barrier hyperresponsiveness to indomethacin. These data support the notion of an underlying intestinal mucosal barrier hyperresponsiveness in a subset of patients with CD, independent of inflammation.

Genetic Evidence Supporting the Association of Protease and Protease Inhibitor Genes with Inflammatory Bowel Disease: A Systematic Review

As part of the European research consortium IBDase, we addressed the role of proteases and protease inhibitors (P/PIs) in inflammatory bowel disease (IBD), characterized by chronic mucosal inflammation of the gastrointestinal tract, which affects 2.2 million people in Europe and 1.4 million people in North America. We systematically reviewed all published genetic studies on populations of European ancestry (67 studies on Crohns disease [CD] and 37 studies on ulcerative colitis [UC]) to identify critical genomic regions associated with IBD. We developed a computer algorithm to map the 807 P/PI genes with exact genomic locations listed in the MEROPS database of peptidases onto these critical regions and to rank P/PI genes according to the accumulated evidence for their association with CD and UC. 82 P/PI genes (75 coding for proteases and 7 coding for protease inhibitors) were retained for CD based on the accumulated evidence. The cylindromatosis/turban tumor syndrome gene (CYLD) on chromosome 16 ranked highest, followed by acylaminoacyl-peptidase (APEH), dystroglycan (DAG1), macrophage-stimulating protein (MST1) and ubiquitin-specific peptidase 4 (USP4), all located on chromosome 3. For UC, 18 P/PI genes were retained (14 proteases and 4protease inhibitors), with a considerably lower amount of accumulated evidence. The ranking of P/PI genes as established in this systematic review is currently used to guide validation studies of candidate P/PI genes, and their functional characterization in interdisciplinary mechanistic studies in vitro and in vivo as part of IBDase. The approach used here overcomes some of the problems encountered when subjectively selecting genes for further evaluation and could be applied to any complex disease and gene family.

A Rule for Determining Risk of Colorectal Cancer in Patients With Inflammatory Bowel Disease

BACKGROUND & AIMSnSurveillance guidelines for inflammatory bowel disease-associated colorectal cancer (IBD-CRC) are based on findings from retrospective studies. We aimed to create and validate a prediction rule to assist clinicians in identifying patients with IBD who are at low and high risk for CRC.nnnMETHODSnWe performed a retrospective case-control study of 2 cohorts of patients from tertiary care centers (the University Hospital of Leuven, Belgium, and 7 University Medical Centers in The Netherlands). Multivariate Cox regression was used to select independent risk factors for CRC in the Leuven cohort. Based on their regression coefficients (β), we created a rule to predict risk for CRC. In validation studies, the predictive strength was tested by C-statistic analysis and then validated externally in the Dutch cohort.nnnRESULTSnIn total, we identified 50 patients with IBD-CRC (cases) and 136 patients with IBD without CRC (controls) in Leuven, and 138 cases and 206 controls in the Dutch cohort. From the Leuven cohort we created the CRC risk prediction rule based on 4 risk factors: IBD-type ulcerative colitis (β = 1.2), primary sclerosing cholangitis (β = 1.1), extent of colonic disease ≥50% (β = 1.1), and postinflammatory polyps (β = 0.8). The prediction rule consisted of a total score for each individual patient calculated from the presence or absence of these 4 risk factors. For example, a score of 13 represented patients who had extensive Crohns disease without PSC or postinflammatory polyps, who had a 15% likelihood of CRC in the Leuven cohort and a 24% likelihood of CRC in the Dutch cohort. Scores of 0, 13, 23, 27, and 37 represented patients with Crohns disease, and scores 15, 25, 28, 38, 42, and 52 represented patients with ulcerative colitis. The total score per patient had a C-statistic of 0.75. In the Dutch cohort this score had a C-statistic of 0.67.nnnCONCLUSIONSnUlcerative colitis, primary sclerosing cholangitis, disease extent ≥50%, and postinflammatory polyps were found to determine risk for CRC in patients with IBD. A surveillance guideline that incorporates the relative weights of these risk profiles would identify patients at risk for CRC more accurately than algorithms in current guidelines.

Eldelumab [anti-interferon-γ-inducible protein-10 antibody] Induction Therapy for Active Crohn's Disease: a Randomised, Double-blind, Placebo-controlled Phase IIa Study

Background and AimsnThis 11-week Phase IIa induction study evaluated the efficacy and safety of eldelumab in patients with active Crohns disease.nnnMethodsnAdults with Crohns Disease Activity Index 220-450 were randomised 1:1:1 to placebo or eldelumab 10 or 20 mg/kg intravenously on Days 1 and 8, and alternate weeks thereafter. All patients underwent ileocolonoscopy at baseline. Patients with active inflammation according to the Simplified Endoscopic Score for Crohns Disease criteria [the originally planned endoscopy cohort] underwent another ileocolonoscopy at Week 11 at the investigators discretion. All ileocolonoscopies were centrally read. The primary objective was identification of the eldelumab target exposure for induction of remission [absolute Crohns Disease Activity Index score < 150]. Rates of clinical response [reduction of ≥ 100 from baseline or absolute score < 150 Crohns Disease Activity Index], remission, and endoscopic improvements were also assessed.nnnResultsnA total of 121 patients were randomised. The eldelumab exposure-remission relationship was not significant at Week 11. Numerically higher remission and response rates were reported with eldelumab 20 mg/kg [29.3% and 41.5%, respectively] and 10 mg/kg [22.5% and 47.5%] versus placebo [20.0% and 35.0%]. A higher proportion of patients with a baseline Simplified Endoscopic Score for Crohns Disease > 2 who received eldelumab achieved a 50% improvement in score and greater reductions from baseline endoscopy scores overall versus placebo. Adverse events were comparable across treatment groups.nnnConclusionsnNo exposure-remission relationship was seen with eldelumab. Eldelumab induction treatment demonstrated trends towards clinical and endoscopic efficacy. Safety was consistent with that reported previously. ClinicalTrials.gov identifier: NCT01466374.

W1092 Maintenance of Long-Term Remission in Patients with Moderately to Severely Active Crohn's Disease Treated for 3 Years with Adalimumab: Results from the Open-Label ADHERE Study

The Impact of Concomitant Treatment with Immuno-Modulators and Antibiotics On the Outcome of C. difficile-Associated Inflammatory Bowel Disease Exacerbation: A European Multi-Center Retrospective Study Shomron Ben-Horin, Maya Margalit, Peter J. Bossuyt, Jochen Maul, Yami Shapira, Daniela Bojic, Irit Chermesh, Ahmad Al-Rifai, Alain Schoepfer, Matteo Bosani, Matthieu Allez, Peter L. Lakatos, Fabrizio Bossa, Alexander Eser, Tommaso Stefanelli, Franck Carbonnel, Konstantinos Katsanos, Davide Checchin, Ines Saenz de Miera, Yehuda Chowers, Gordon W. Moran

European Experience with ND: YAG and Argon Laser for Therapy of Upper Gastrointestinal Bleeding

On the pioneering work of Kiefhaber with the Neodymium-YAG laser and Fruhmorgen with the Argon laser, both lasers are now being used for hemostasis of gastrointestinal bleeding in at least 50 European centers. More centers have employed the laser in the past but used it only for experimental work. The YAG laser is more widely used than the Argon laser because most investigators feel it has a higher hemostatic capacity. Despite its widespread applications, the clinical contribution of laser photocoagulation for upper gastrointestinal bleeding remains in some doubt. Evaluation of the uncontrolled data is difficult for several reasons. Firstly most upper gastrointestinal bleeding is self limited and abates without any therapeutic intervention. Secondly a lot of the uncontrolled data gives information only regarding initial hemostasis. A more important question is the effect of laser photocoagulation on the overall outcome in a particular patient. However the overall data of uncontrolled studies using lasers for the therapy of gastrointestinal bleeding present impressive results.

Long-term outcome of endoscopic dilatation in patients with Crohn's disease is not affected by disease activity or medical therapy (vol 59, pg 320, 2010)

it is a fact and needs to be pointed out, that only one third of our identified IAR (80 of 205) participated in the recommended screening programme. A pilot study on 32 of these IAR using standard questionnaires and interviews (Beck Depression Inventory (BDI) and Brief Symptom Inventory (BSI)) around counselling (days 7, 0, +30) conducted by a psychiatrist revealed, that these IAR were critically biased by cognitive coping strategies (unpublished data). Pancreatic cancer (PC) screening is clearly different from other cancer screening programmes, given the disastrous prognosis of PC, the unknown true penetrance in the different settings of hereditary PC, the lack of a major gene defect, the lack of reliable imaging or biomarkers, the lack of evidence to improve prognosis or to save lives by any screening, and the high risk of morbidity and mortality of potential preventive surgery. Some authors even advocate that at present ‘doing nothing’ provides the greatest remaining quality of life-adjusted years and the lowest costs. We fully agree that we need to gain much more knowledge about hereditary PC to draw a definite conclusion about the true value of PC screening in IAR. However, based on our data, we strongly believe, in accordance with the recommendations of the Fourth International Symposium of Inherited Diseases of the Pancreas, that all screening procedures should be performed as part of peer-reviewed protocols combined with a scientific appraisal of the screening methods and human subject protection. At present there is no data, that would justify a general PC screening even of high risk individuals outside of such protocols as suggested by Harinck et al. In contrast, it has to be feared that uncritical use and interpretation of screening results obtained with the presently available tools on a healthcare basis may cause unnecessary physical harm and psychological distress. On the other hand over-estimation of the power of our present screening tools may lead to a deceptive, unjustified and potentially dangerous level of safety, if done uncritically and uncontrolled. The message of our paper thus is not ‘to do nothing’, but to carefully evaluate screening methods for IAR from familial pancreatic cancer (FPC) families in the setting of board approved clinical trials, to continuously improve our knowledge and strategies.