Wolfgang Petritsch

Prophylaxis of postoperative relapse in Crohn's disease with mesalamine: European cooperative Crohn's disease study VI

BACKGROUND & AIMSnThis study investigated if long-term treatment with high-dose mesalamine reduces the risk of clinical relapse of Crohns disease after surgical resection.nnnMETHODSnIn a prospective, randomized, double-blind, multicenter study, 4 g of mesalamine (Pentasa; Ferring A/S, Vanlose, Denmark) daily was compared with placebo in 318 patients. Treatment was started within 10 days after resective surgery and continued for 18 months. Primary outcome parameter was clinical relapse as defined by an increase in Crohns Disease Activity Index, reoperation, septic complication, or newly developed fistula. Risk factors for recurrence were prospectively defined to be analyzed in a stepwise proportional hazards model.nnnRESULTSnCumulative relapse rates (+/-SE) after 18 months were 24.5% +/- 3.6% and 31.4% +/- 3.7% in the mesalamine (n = 152) and placebo (n = 166) groups, respectively (P = 0.10, log-rank test, 1-sided). Retrospective analysis showed a significantly reduced relapse rate with mesalamine only in a subgroup of patients with isolated small bowel disease (n = 124; 21.8% +/- 5.6% vs. 39.7% +/- 6.1%; P = 0.02, log-rank test). Probability of relapse was predominantly influenced by the duration of disease (P = 0.0006) and steroid intake before surgery (additional risk, P = 0.0003).nnnCONCLUSIONSnEighteen months of mesalamine, 4 g daily, did not significantly affect the postoperative course of Crohns disease. Some relapse-preventing effect was found in patients with isolated small bowel disease.

Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis.

Background: In patients with ulcerative colitis (UC), alterations of the intestinal microbiota, termed dysbiosis, have been postulated to contribute to intestinal inflammation. Fecal microbiota transplantation (FMT) has been used as effective therapy for recurrent Clostridium difficile colitis also caused by dysbiosis. The aims of the present study were to investigate if patients with UC benefit from FMT and if dysbiosis can be reversed. Methods: Six patients with chronic active UC nonresponsive to standard medical therapy were treated with FMT by colonoscopic administration. Changes in the colonic microbiota were assessed by 16S rDNA–based microbial community profiling using high-throughput pyrosequencing from mucosal and stool samples. Results: All patients experienced short-term clinical improvement within the first 2 weeks after FMT. However, none of the patients achieved clinical remission. Microbiota profiling showed differences in the modification of the intestinal microbiota between individual patients after FMT. In 3 patients, the colonic microbiota changed toward the donor microbiota; however, this did not correlate with clinical response. On phylum level, there was a significant reduction of Proteobacteria and an increase in Bacteroidetes after FMT. Conclusions: FMT by a single colonoscopic donor stool application is not effective in inducing remission in chronic active therapy–refractory UC. Changes in the composition of the intestinal microbiota were significant and resulted in a partial improvement of UC-associated dysbiosis. The results suggest that dysbiosis in UC is at least in part a secondary phenomenon induced by inflammation and diarrhea rather than being causative for inflammation in this disease.

Inflammatory Bowel Disease Is a Risk Factor for Recurrent Venous Thromboembolism

BACKGROUND & AIMSnPatients with inflammatory bowel disease (IBD) are at increased risk of a first venous thromboembolism (VTE), yet their risk of recurrent VTE is unknown. We performed a cohort study to determine the risk for recurrent VTE among patients with IBD compared with subjects without IBD.nnnMETHODSnWe assessed 2811 patients with IBD for a history of VTE, recruited from outpatient clinics at 14 referral centers (June 2006-December 2008). Patients with VTE before a diagnosis of IBD or those not confirmed to have VTE, cancer, or a VTE other than deep vein thrombosis or pulmonary embolism, were excluded. Recurrence rates were compared with 1255 prospectively followed patients without IBD that had a first unprovoked VTE (not triggered by trauma, surgery, or pregnancy). The primary end point was symptomatic, objectively confirmed, recurrent VTE after discontinuation of anticoagulation therapy after a first VTE.nnnRESULTSnOverall, of 116 IBD patients who had a history of first VTE, 86 were unprovoked. The probability of recurrence 5 years after discontinuation of anticoagulation therapy was higher among patients with IBD than patients without IBD (33.4%; 95% confidence interval [CI]: 21.8-45.0 vs 21.7%; 95% CI: 18.8-24.6; P = .01). After adjustment for potential confounders, IBD was an independent risk factor of recurrence (hazard ratio = 2.5; 95% CI: 1.4-4.2; P = .001).nnnCONCLUSIONSnPatients with IBD are at an increased risk of recurrent VTE compared to patients without IBD.

Azathioprine versus mesalazine for prevention of postoperative clinical recurrence in patients with Crohn's disease with endoscopic recurrence: efficacy and safety results of a randomised, double-blind, double-dummy, multicentre trial

Objective The aim of the study was to compare azathioprine versus mesalazine tablets for the prevention of clinical recurrence in patients with postoperative Crohns disease (CD) with moderate or severe endoscopic recurrence. Methods This was a 1 year, double-blind, double-dummy, randomised study which took place in 21 gastroenterology centres in Austria, the Czech Republic, Germany and Israel. The study participants were 78 adults with CD who had undergone resection with ileocolonic anastomosis in the preceding 6–24u2005months without subsequent clinical recurrence and with a Crohns disease activity index (CDAI) score <200, but with moderate or severe endoscopic recurrence. The study drugs were azathioprine 2.0–2.5u2005mg/kg/day or mesalazine 4u2005g/day over 1u2005year. The primary end point was therapeutic failure during 1 year, defined as a CDAI score ≥200 and an increase of ≥60 points from baseline, or study drug discontinuation due to lack of efficacy or intolerable adverse drug reaction. Results Treatment failure occurred in 22.0% (9/41) of azathioprine-treated patients and 10.8% (4/37) of mesalazine-treated patients, a difference of 11.1% (95% CI −5.0% to 27.3%, p=0.19). Clinical recurrence was significantly less frequent with azathioprine versus mesalazine (0/41 (0%) vs 4/37 (10.8%), p=0.031), whereas study drug discontinuation due to adverse drug reactions only occurred in azathioprine-treated patients (9/41 (22.0%) vs 0%, p=0.002). The proportion of patients showing ≥1 point reduction in Rutgeerts score between baseline and month 12 was 63.3% (19/30) and 34.4% (11/32) in the azathioprine and mesalazine groups, respectively (p=0.023). Conclusions In this population of patients with postoperative CD at high risk of clinical recurrence, superiority for azathioprine versus mesalazine could not be demonstrated for therapeutic failure. Clinical trial registration number NCT00946946.

Anti-cardiolipin antibodies in patients with inflammatory bowel disease.

Elevated levels of anti-cardiolipin antibodiesare associated with an increased risk for venous andarterial thrombosis. In patients with inflammatory boweldisease thrombosis is a well known complication. We determined the prevalence of elevatedanti-cardiolipin antibodies in 136 patients withinflammatory bowel disease compared with 136 healthycontrols and analyzed thromboembolic complications inpatients with increased anti-cardiolipin antibodylevels. Anti-cardiolipin antibody titers weresignificantly elevated in patients with Crohns disease(5.7 units/ml) and ulcerative colitis (5.3 units/ml)compared to the control group (2.5 units/ml). We foundno correlation between disease activity andanti-cardiolipin antibody levels. Seven patients haddeep venous thrombosis in their history, in three ofthem this was complicated by pulmonary embolism. In onlytwo of the seven patients with deep venous thrombosiswere anti-cardiolipin antibody levels increased. Inconclusion, anti-cardiolipin antibody titers were significantly increased in patients withinflammatory bowel disease. Elevated anti-cardiolipinantibody levels appear to play no role in thepathogenesis of thromboembolic events in patients withinflammatory bowel disease.

Multiplanar spiral CT enterography in patients with Crohn's disease using a negative oral contrast material: initial results of a noninvasive imaging approach

Abstract. The aim of this study was to prospectively define the role of multiplanar spiral CT enterography with a new negative oral contrast material for noninvasive assessment of the small bowel in patients with Crohns disease. Thirty patients with established Crohns disease prospectively underwent spiral CT enterography at 45–60xa0min after distension of the small bowel with 1400xa0ml of a negative oral contrast material (Mucofalk water enema). Spiral CT scans were obtained 50xa0s after administration of intravenous contrast material with the following parameters: 5-mm collimation; 7.5-mm/s table feed; and 3-mm reconstruction interval. The adequacy of bowel opacification, luminal distension, and the contribution of two-dimensional multiplanar reformatted imaging were assessed by two observers. Spiral CT imaging findings were compared with results of enteroclysis as well as endoscopic and histological findings in all patients. Spiral CT enterography with Mucofalk water enema was well tolerated in 29 of 30 patients. Findings on spiral CT enterography were comparable with those of barium studies in 25 of 30 patients, superior to those on barium studies in 4 patients, and inferior in 1 patient (p<0.05). The addition of multiplanar reformatted images to axial spiral CT scans significantly improved observers confidence in image interpretation (p<0.05) but did not reveal additional abnormalities. Multiplanar spiral CT enterography with Mucofalk excellently provides information in patients with Crohns disease. This technique accurately depicts the level of small bowel obstruction and the extent of inflammatory small bowel disease and its extraluminal complications.

A decade of infliximab: The Austrian evidence based consensus on the safe use of infliximab in inflammatory bowel disease

Infliximab (IFX) has tremendously enriched the therapy of inflammatory bowel diseases (IBD) and other immune mediated diseases. Although the efficacy of IFX was undoubtedly proven during the last decade numerous publications have also caused various safety concerns. To summarize the immense information concerning adverse events and safety issues the Austrian Society of Gastroenterology and Hepatology launched this evidence based consensus on the safe use of IFX which covers the following topics: infusion reactions and immunogenicity, skin reactions, opportunistic infections (including tuberculosis), non-opportunistic infections (bacterial and viral), vaccination, neurological complications, hepatotoxicity, congestive heart failure, haematological side effects, intestinal strictures, stenosis and bowel obstruction (SSO), concomitant medication, malignancy and lymphoma, IFX in the elderly and the young, mortality, fertility, pregnancy and breast feeding. To make the vast amount of information practicable for routine application the consensus was finally condensed into a checklist for a safe use of IFX which consists of two parts: issues to be addressed prior to anti-TNF therapy and issues to be addressed during maintenance. Both parts are further divided into obligatory and facultative items.

Intraluminal capsaicin does not affect fluid and electrolyte absorption in the human jejunum but does cause pain

Background—Stimulation of sensory nerves with capsaicin regulates ion transport in the small intestine in animal experiments. Aim—To investigate whether sensory nerves that are stimulated by capsaicin administration influence fluid and electrolyte absorption in the human jejunum in vivo. Method—Intestinal perfusion studies were performed in 12 healthy subjects using a four lumen tube with a proximal occlusion balloon and a plasma-like electrolyte solution. After an initial control period, 5 (n = 3), 10 (n = 8), or 50 (n = 1) μg/ml capsaicin was added to the perfusate, and this was followed by a final control period. Rates of absorption of water, sodium, potassium, chloride, and bicarbonate were determined in a 30 cm segment of jejunum using a non-absorbable volume marker. Results—At all three concentrations of capsaicin there were no significant changes in water and electrolyte absorption as compared with control periods. Two subjects who received 10 μg/ml and the subject receiving 50 μg/ml experienced crampy abdominal pain. Conclusion—The results do not support the hypothesis that capsaicin sensitive afferent nerves are involved in the physiological regulation of net absorption or secretion across the human jejunal mucosa. Chemical stimulation of these nerves, however, gives rise to abdominal pain.

Clinical presentation of venous thromboembolism in inflammatory bowel disease.

BACKGROUND AND AIMSnPatients with inflammatory bowel disease (IBD) are at increased risk of venous thromboembolism (VTE), but data on frequency, site of thrombosis and risk factors are limited. We sought to determine prevalence, incidence as well as location and clinical features of first VTE among IBD patients.nnnMETHODSnWe evaluated a cohort of 2811 IBD patients for a history of symptomatic, objectively confirmed first VTE, recruited from 14 referral centers. Patients with VTE before IBD diagnosis or cancer were excluded. Incidence rates were calculated based on person-years from IBD diagnosis to first VTE or end of follow-up, respectively.nnnRESULTSn2784 patients (total observation time 24,778 person-years) were analyzed. Overall, of 157 IBD patients with a history of VTE, 142 (90.4%) had deep vein thrombosis (DVT) and/or pulmonary embolism (PE), whereas 15 (9.6%) had cerebral, portal, mesenteric, splenic or internal jugular vein thrombosis. The prevalence and incidence rate of all VTE was 5.6% and 6.3 per 1000 person years, respectively. Patients with VTE were older at IBD diagnosis than those without VTE (34.4±14.8years vs 32.1±14.4years, p=0.045), but did not differ regarding sex, underlying IBD and disease duration. 121 (77.1%) VTE were unprovoked, 122 (77.7%) occurred in outpatients and 78 (60.9%) in patients with active disease. Medication at first VTE included corticosteroids (42.3%), thiopurines (21.2%), and infliximab (0.7%).nnnCONCLUSIONnVTE is frequent in IBD patients. Most of them are unprovoked and occur in outpatients. DVT and PE are most common and unusual sites of thrombosis are rare.

A systematic survey evaluating 6-thioguanine-related hepatotoxicity in patients with inflammatory bowel disease.

ZusammenfassungHINTERGRUND: Vor kurzem wurde von Leberveränderungen im Sinne einer nodulär regenerativen Hyperplasie (NRH) als Ausdruck einer 6-Thioguanin (6-TG) assoziierten Hepatotoxizität bei Patienten mit chronisch-entzündlichen Darmerkrankungen (CED) berichtet. Das Ziel dieser multi-zentrischen Internet-Studie war es, die Prävalenz der Hepatotoxizität von 6-TG in einer großen CED-Population zu untersuchen. METHODIK: Klinische Daten, Laborwerte, bildgebende Untersuchungen (Sonographie, CT, MRI) und histologische Ergebnisse von Leberbiopsien wurden bei Patienten mit CED unter Therapie mit 6-TG untersucht. Die Entscheidung zur Durchführung von bildgebenden Untersuchungen und Leberbiopsien lag ausschließlich bei den einzelnen Zentren. ERGEBNISSE: Bei 296 Patienten wurde die Anwendung von 6-TG über einen Zeitraum von 56 Wochen (Median, Spannweite < 1–207) dokumentiert. Laborveränderungen als Zeichen einer Hepatotoxizität wurden bei 43 Patienten (14,5%) beobachtet. Mittels bildgebender Verfahren wurden bei 68/176 Patienten (38,6%) pathologische Ergebnisse gefunden. An 60 Patienten erfolgte eine Leberbiopsie. Mit Durchführung einer Silber-Retikulin Färbung (n = 59) konnte bei 16 Patienten (27,1%) eine NRH gezeigt werden. Höheres Alter war der einzige unabhängige, aber schwache Risikofaktor dafür. SCHLUSSFOLGERUNG: Diese derzeit größte Studie bestätigt den starken Zusammenhang zwischen der Anwendung von 6-TG bei Patienten mit CED und dem signifikanten Risiko für die Entwicklung einer NRH. Die definitive Diagnose der NRH kann nur durch eine Leberbiopsie gestellt werden.SummaryOBJECTIVE: Drug-induced liver injury was recently reported as a major complication leading to hepatic nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease (IBD) and 6-thioguanine (6-TG) therapy. The aim of the study was to evaluate the prevalence of 6-TG-related hepatotoxicity in a large multi-centered IBD population by means of a systematic online survey. METHODS: Clinical and laboratory data, imaging techniques (sonography, CT, MRI) and histology of liver biopsies were surveyed in IBD patients treated with 6-TG. The decision on whether liver imaging and/or liver biopsy were performed was exclusively at the discretion of the investigator. RESULTS: 6-TG use was fully documented in 296 patients (median treatment duration 56 weeks, range < 1–207). Laboratory signs of drug-induced liver injury were found in 43 patients (14.5%). Liver imaging revealed pathologic results in 68/176 patients (38.6%). Liver biopsy was performed in a subset of 60 patients; using silver-reticulin staining (n = 59), NRH was considered in 16 patients (27.1%). Age was the only independent, albeit weak, risk factor for development of NRH. CONCLUSION: This large online survey confirms the strong association between 6-TG treatment and the significant risk of development of NRH in patients with IBD. The definitive diagnosis of NRH depends solely upon liver biopsy.