Gert Van Assche

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.

Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept

Background :u2002Adalimumab, a fully human monoclonal antibody to tumour necrosis factor, was recently introduced for therapy of Crohns disease.

The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis

BACKGROUND & AIMSnInterobserver differences in endoscopic assessments contribute to variations in rates of response to placebo in ulcerative colitis (UC) trials. We investigated whether centralized review of images could reduce these variations.nnnMETHODSnWe performed a 10-week, randomized, double-blind, placebo-controlled study of 281 patients with mildly to moderately active UC, defined by an Ulcerative Colitis Disease Activity Index (UCDAI) sigmoidoscopy score ≥2, that evaluated the efficacy of delayed-release mesalamine (Asacol 800-mg tablet) 4.8 g/day. Endoscopic images were reviewed by a single expert central reader. The primary outcome was clinical remission (UCDAI, stool frequency and bleeding scores of 0, and no fecal urgency) at weekxa06.nnnRESULTSnThe primary outcome was achieved by 30.0% of patients treated with mesalamine and 20.6% of those given placebo, a difference of 9.4% (95% confidence interval [CI],xa0-0.7% to 19.4%; Pxa0= .069). Significant differences in results from secondary analyses indicated the efficacy of mesalamine. Thirty-one percent of participants, all of whom had a UCDAI sigmoidoscopy score ≥2 as read by the site investigator, were considered ineligible by the central reader. After exclusion of these patients, the remission rates were 29.0% and 13.8% in the mesalamine and placebo groups, respectively (difference of 15%; 95% CI, 3.5%-26.0%; Pxa0= .011).nnnCONCLUSIONSnAlthough mesalamine 4.8 g/day was not statistically different from placebo for induction of remission in patients with mildly to moderately active UC, based on an intent-to-treat analysis, the totality of the data supports a benefit of treatment. Central review of endoscopic images is critical to the conduct of induction studies in UC; ClinicalTrials.gov Number, NCT01059344.

Increasing incidence of Clostridium difficile -associated diarrhea in inflammatory bowel disease

INTRODUCTION AND AIMnOver the last decade a rise in Clostridium difficile-associated diarrhea (CDAD) has been observed. A higher incidence of CDAD has also been suggested in patients with inflammatory bowel disease (IBD), and may be a challenging factor in the differential diagnosis of flares. It is unclear if the increase is caused by the enhanced use of immunosuppressive therapy in IBD. We investigated if CDAD infection is increasing in IBD patients and evaluated outcome and possible predisposing factors.nnnMETHODSnThrough an electronic database of the Laboratory of Microbiology of our hospital (tertiary referral center), all stool samples from patients admitted for diarrhea and hospitalized on gastroenterology wards between January 2000 and January 2008 were reviewed for diagnosis of CDAD. For analysis, we compared two periods of equal duration.nnnRESULTSnA total of 57 patients were diagnosed with CDAD, of whom 26.3% had concomitant IBD. A 3.75-fold increase in CDAD was observed between period 1 and period 2, irrespective of underlying IBD and with a comparable total number of analyzed stool samples between both periods. Non-IBD patients were significantly older. Antibiotic use three months prior to the infection was higher in non-IBD (29/42 or 69%) than in IBD patients (6/15 or 42%) (p = 0.047). Nine IBD patients were on concomitant immunomodulators, and this was not different between period 1 and period 2. Most patients had a successful outcome and only one patient with ulcerative colitis needed semi-urgent colectomy. Two patients died in the non-IBD group. The duration of hospital stay was significantly lower in IBD patients.nnnCONCLUSIONnWe observed a significant rise in CDAD in both IBD and non-IBD. The clinical outcome was favorable with only one IBD patient needing semi-urgent colectomy. Because C. difficile can mimic an IBD flare, it is essential that clinicians are vigilant to this complication. The use of immunosuppressive drugs in IBD does not influence the risk.

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.

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.

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.

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.