Harald Vogelsang

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.

Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis

BACKGROUND & AIMSnWe evaluated the gastrointestinal permeability and bacterial translocation in cirrhotic patients with portal hypertension (PHT) prior to and after non-selective betablocker (NSBB) treatment.nnnMETHODSnHepatic venous pressure gradient (HVPG) was measured prior to and under NSBB treatment. Gastroduodenal and intestinal permeability was assessed by the sucrose-lactulose-mannitol (SLM) test. Anti-gliadin and anti-endomysial antibodies were measured. Levels of LPS-binding protein (LBP) and interleukin-6 (IL-6) were quantified by ELISA, and NOD2 and toll-like receptor 2 (TLR2) polymorphisms were genotyped.nnnRESULTSnFifty cirrhotics were included (72% male, 18% ascites, 60% alcoholic etiology). Abnormal gastroduodenal and intestinal permeability was found in 72% and 59% of patients, respectively. Patients with severe portal hypertension (HVPG ≥20 mm Hg; n=35) had increased markers of gastroduodenal/intestinal permeability (urine sucrose levels p=0.049; sucrose/mannitol ratios p=0.007; intestinal permeability indices p=0.002), and bacterial translocation (LBP p=0.002; IL-6 p=0.025) than patients with HVPG <20 mm Hg. A substantial portion of patients showed elevated levels of anti-gliadin antibodies (IgA: 60%, IgG: 34%) whereas no anti-endomysial antibodies were detected. A significant correlation of portal pressure (i.e., HVPG) with all markers of gastroduodenal/intestinal permeability and with LBP and IL-6 levels was observed. NOD2 and TLR2 risk variants were associated with abnormal intestinal permeability and elevated markers of bacterial translocation. At follow-up HVPG measurements under NSBB, we found an amelioration of gastroduodenal/intestinal permeability and a decrease of bacterial translocation (LBP - 16% p=0.018; IL-6 - 41% p<0.0001) levels, which was not limited to hemodynamic responders. Abnormal SLM test results and higher LBP/IL-6 levels were associated with a higher risk of variceal bleeding during follow-up but not with mortality.nnnCONCLUSIONSnAbnormal gastroduodenal/intestinal permeability, anti-gliadin antibodies, and bacterial translocation are common findings in cirrhotic patients and are correlated with the degree of portal hypertension. NSBB treatment ameliorates gastroduodenal/intestinal permeability and reduces bacterial translocation partially independent of their hemodynamic effects on portal pressure, which may contribute to a reduced risk of variceal bleeding.

Anastomotic recurrence of Crohn’s disease after ileocolic resection: comparison of MR enteroclysis with endoscopy

The purpose of this study was to assess the accuracy of MR enteroclysis in patients with Crohn’s disease recurrence after ileocolic resection and to establish an MR scoring sytem. MR enteroclysis and endoscopy were performed in 30 patients with suspected Crohn’s disease recurrence after ileocolic resection. Findings were evaluated by three radiologists, using an MR score based on image quality, contrast enhancement, and mural and extramural bowel-wall changes: MR0 (no abnormal features), MR1 (minimal mucosal changes), MR2 (diffuse aphtoid ileitis, moderate recurrence), and MR3 (severe recurrence with trans- and extramural changes). The endoscopic Rutgeerts score defines changes at the ileum on a scale from I0 to I4. In 3/30 (10%) patients, evaluation was not possible. The mean overall image quality was rated as 1.7 (kappa 0.78). Comparing MR and Rutgeerts score, the mean observer agreement for the total score rating was 77.8% (kappa 0.67). When comparing only scores below or above MR2—the threshold indicative of the necessity of medical treatment—there was a total agreement of 95.1% (kappa 0.84). MR enteroclysis allows assessment of Crohn’s disease recurrence after ileocolic resection. The MR score is reproducible and shows high agreement with the approved endoscopic Rutgeerts score.

Endoscopy and MR enteroclysis: Equivalent tools in predicting clinical recurrence in patients with Crohn's disease after ileocolic resection

Background: Ileocolonoscopy poses the gold standard in the evaluation of postoperative recurrence of Crohns disease (CD) at the site of ileocolonic anastomosis. Magnetic resonance enteroclysis (MRE) on the other hand is a promising technique for small bowel imaging. The aim was to compare MRE and ileocolonoscopy for predicting clinical recurrence in CD patients who have undergone ileocolonic resection. Methods: We included 29 patients in the study. The median time since index operation was 35 months and between ileocolonoscopy and MRE was 3 days. Patients were followed up for a maximum of 2 years unless clinical recurrence occurred earlier. Endoscopic findings were evaluated on a 5‐grade scale (i0–i4), whereas MRE findings on the neoterminal ileum and anastomosis were assessed according to a previously validated 4‐grade scale MR score (MR0‐MR3). Results: By classifying patients into subgroups of endoscopic severity of postoperative recurrence using as a threshold an endoscopic score of i3, we found that 10% of patients in the i0 to i2 group had a clinical recurrence during the 2‐year follow‐up period as compared to 52.6% of subjects with i3 to i4 (P = 0.043). The corresponding clinical exacerbation rates in the subgroups based on MRE severity assessment were 12.5% for MR0 to MR1 and 50% for MR2 to MR3 (P = 0.09). Conclusions: Our data suggest that colonoscopy and MR enteroclysis are of similar value to predict the risk of clinical recurrence in postoperative patients with Crohns disease. Inflamm Bowel Dis 2009

Long-term follow-up of babies exposed to azathioprine in utero and via breastfeeding ☆

BACKGROUNDnRecommendations on breastfeeding under thiopurines are inconsistent due to limited data.nnnAIMnTo assess the risk of infections in offspring breastfed by mothers receiving azathioprine (AZA) for inflammatory bowel disease (IBD).nnnMETHODSnBabies, who were breastfed from their mothers treated either with or without AZA were included from a local pregnancy-registry. Women were asked by structured personal interview on general development, infections, hospitalisations and vaccinations of their offspring.nnnRESULTSnA group of 11 mothers taking AZA (median 150 mg/d) during pregnancy and lactation and another of 12 patients without using any immunosuppressive therapy breastfed 15 babies each for median 6 months and 8 months, respectively. Median age of children at time of interview was 3.3 and 4.7 years, respectively. All offspring showed age-appropriate mental and physical development. Infections were commonly seen childhood diseases. Similar rates were observed for most of the various infections between offspring with and without azathioprine exposure during breastfeeding. However, common cold more than two episodes/year and conjunctivitis were numerically more often reported in the group without AZA exposure. In an exploratory analysis no difference in the rate of hospitalisations was seen between exposed (0.06 hospitalisations/patient year) versus non-exposed children (0.12 hospitalisations/patient year, p=0.8)nnnCONCLUSIONnOur study which reports the largest number of babies breastfed with exposure to AZA suggests that breastfeeding does not increase the risk of infections.

The Impact of Thiopurines on the Risk of Surgical Recurrence in Patients With Crohn's Disease After First Intestinal Surgery

OBJECTIVES:Smoking and a lack of immunosuppressive (IS) therapy are considered risk factors for intestinal surgery in Crohns disease (CD). Good evidence for the latter is lacking. The objective of this study was to evaluate the impact of thiopurine treatment on surgical recurrence in patients after first intestinal resection for CD and its possible interaction with smoking.METHODS:Data on 326 patients after first intestinal resection were retrieved retrospectively, and subjects were grouped according to their postoperative exposure to thiopurines. Treatment with either azathioprine (AZA) or 6-mercaptopurine (6-MP) was recorded on 161 patients (49%). Smoking status was assessed by directly contacting the patients.RESULTS:Surgical recurrence occurred in 151/326 (46.3%) patients after a median time of 71 (range 3–265) months. Cox regression revealed a significant reduction of re-operation rate in patients treated with AZA/6-MP for ⩾36 months as compared with patients treated for 3–35 months, for less than 3 months, and to those without postoperative treatment with AZA/6-MP (P=0.004). Cox regression analysis revealed treatment with thiopurines for ⩾36 months (hazard ratio (HR) 0.41; 95% confidence interval (CI) 0.23–0.76, P=0.004) and smoking (HR 1.6; 95% CI 1.14–2.4, P=0.008) as independent predictors for surgical recurrence. Furthermore, longer duration of disease tended to be protective (HR 0.99; 95% CI 0.99–1.0, P=0.067).CONCLUSIONS:Long-term maintenance treatment with AZA/6-MP reduces the risk of surgical recurrence in patients with CD. We also identified smoking as a risk factor for surgical recurrence.

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.

Factors impacting the results of interferon‐γ release assay and tuberculin skin test in routine screening for latent tuberculosis in patients with inflammatory bowel diseases

Background: Screening for latent tuberculosis (LTB) including chest x‐ray, tuberculin skin test (TST), and facultative whole blood interferon‐&ggr; assay (IGRA) is part of routine management in inflammatory bowel disease (IBD) patients before starting therapy with tumor necrosis factor (TNF)‐&agr; inhibitors. However, in patients with immunomodulators (IM) TST and IGRA might show limitations. Methods: We aimed to evaluate the results from an IGRA (QuantiFERON‐TB Gold in Tube) and TST as well as their concordance in 208 consecutive IBD patients with indications for anti‐TNF‐&agr; therapy. Associations of both tests with risk factors for LTB were determined by logistic regression. Results: During screening, 149 patients (71.6%) were under IM therapy. In 26 (12.5%) patients TST was positive, whereas 15 (7.2%) patients showed a positive result from IGRA. IGRA failed on samples from 16/208 (7.7%) patients, resulting in 192/208 (92.3%) patients in whom results from both screening tests were available. Correlation between IGRA and TST results was fair (84.9%, &kgr; = 0.21). The presence of risk factors for LTB showed association with positive results of TST (odds ratio [OR] 3.7, 1.5–9.6) and IGRA (OR 3.5, 1.2–11.3). TST was associated furthermore with age (OR 1.06, 1.02–1.10) and signs indicative of LTB in chest x‐ray (OR 4.9, 1.1–19.9). The IGRA was negatively influenced by IM therapy (OR 0.3, 0.1–0.9). Conclusion: Our study reveals that results of IGRA are negatively affected by IM therapy. Thus, current guidelines for TB screening prior anti‐TNF‐&agr; therapy appear inaccurate in patients under IM. Therefore, LTB screening might be best performed prior to initiation of IM treatment. (Inflamm Bowel Dis 2011;)

Safety and Efficacy of an Oral Inhibitor of the Purinergic Receptor P2X7 in Adult Patients with Moderately to Severely Active Crohn's Disease: A Randomized Placebo-controlled, Double-blind, Phase IIa Study.

Background:AZD9056 is a selective orally active inhibitor of the purinergic receptor P2X7, which is a key player in the generation and secretion of several proinflammatory cytokines involved in the pathogenesis of Crohns disease (CD). The aim of this phase IIa study was to assess the efficacy and safety of AZD9056 for the treatment of moderately to severely active CD. Methods:We conducted a placebo-controlled, multicenter, double-blind phase IIa study in patients with moderately to severely active CD as defined by a CD Activity Index (CDAI) of at least 220. Patients were randomized in a 2:1 mode either to 200 mg of AZD9056 administered orally as a tablet once daily for 28 days or matching placebo. Primary endpoint was the change in CDAI from baseline at day 28, and secondary endpoints included clinical remission (CDAI < 150) and CDAI 70 response and improvement in the quality of life measures Short Form 36 and Inflammatory Bowel Disease Questionnaire. Changes in serum C-reactive protein and fecal calprotectin were assessed. Results:In total, 34 patients were enrolled, 24 to AZD9056 and 10 to placebo. The CDAI dropped in AZD9056-treated subjects from a baseline mean of 311 to 242 and from 262 to 239 in placebo-treated subjects (P = 0.049). Remission and response rates were numerically higher with AZD9056 versus placebo, (n = 5, 24% versus n = 1, 11%, P = 0.43 and n = 11, 52% versus n = 2, 22%, P = 0.13, respectively). Marked decrease in disease activity was observed for the CDAI subcomponents, pain and general well-being. Apart from a statistically significant improvement in the Mental Component Score of Short Form 36 for AZD9056 versus placebo (P = 0.017), no other differences in measurements of quality of life could be observed. There was no decrease in concentrations of serum C-reactive protein and fecal calprotectin during treatment. AZD9056 was well-tolerated, and no serious adverse events were reported. Conclusions:Our data suggest that the purinergic receptor P2X7 antagonist AZD9056 has the potential to improve symptoms in patients with moderate-to-severe CD combined with a beneficial risk profile. Although the lack in change of inflammatory biomarkers questions its anti-inflammatory potential, the results obtained in this study rather suggest P2X7 antagonism for the treatment of chronic abdominal pain.

Retesting for latent tuberculosis in patients with inflammatory bowel disease treated with TNF-α inhibitors

Patients treated with TNF‐α inhibitors (TNFi) are at high risk of reactivation of latent tuberculosis (LTB). Prospective studies on monitoring of TB reactivation and/or infection in this risk group are lacking.