Preexposition Prophylaxis With Truvada (Tenofovir/Emtricitabine) as Potential Cause of Celiac Disease-Like Enteropathy.

We present here a case of a 39-year-old patient who presented with celiac-disease-like symptoms and MARSH 3a histology in duodenal biopsies under normal diet. Interestingly, HLA genotyping and celiac-specific serology were negative, primarily leading to exclusion of celiac disease. However, biopsies from a second endoscopy a couple of months later (still under normal diet) showed histologic progression of the disease to MARSH 3b and led to the re-evaluation of the out-of-hospital-obtained histological samples by a pathologist experienced in celiac disease. The second biopsy described previously as MARSH 3b turned out to be non-specific and was therefore re-classified as MARSH 0. After all known causes of duodenal villous atrophy were excluded by a thorough evaluation, a correlation between the first biopsy (MARSH 3a) and Truvada intake could be established. After Truvada discontinuation and under normal diet, normalisation of duodenal mucosa was observed, leading to the assumption that Truvada could lead to celiac-like enteropathy.

PMA - Zeolite (Clinoptilolite) in the Management of Irritable Bowel Syndrome - a Non-Interventional Study.

In clinical practice, the treatment of patients with irritable bowel syndrome (IBS) can be very challenging. The aims of the present non-interventional study (NIS) were to investigate the tolerability and efficacy of PMA-zeolite under everyday conditions in patients with diarrheic IBS type (IBS-D) or constipated type (IBS-C) or mixed type (IBS-M). METHODS: To document prospective data on tolerability and symptom frequency in the frame of a nationwide NIS, we recruited 204 IBS patients. The study focused on the IBS-related quality of life (measured by the SF-36 questionnaire) and improvements of IBS-related symptoms according to specific ROM-III criteria and stool consistency (Bristol stool scale). The participants documented their abdominal pain, bloating, number of bowel movements, and stool consistency through a web-based internet platform (initial and exit questionnaires) and daily diary entries over the period of intake (8 weeks). RESULTS: A total of 82.2% of the recruited patients had filled in the questionnaires before and after the 8-week treatment with PMA-zeolite. Seven of the eight subscales of the SF-36 improved significantly (p<0,001); the reduction in abdominal pain was especially significant (p<0,001). The diary entries confirmed the reduction in abdominal pain and revealed a significant reduction in days with bloating (p<0,001). The Bristol-stool-scale analysis showed improvements; particularly, patients with IBS-D benefited from the treatment (p<0,001). CONCLUSION: The treatment duration of 8 weeks was well tolerated by most patients. Under everyday life conditions, PMA-zeolite alleviated the global IBS-related symptoms and raised the quality of life (QOL). The PMA-zeolite, thus, may represent a good adjuvant therapeutic option for patients with irritable bowel syndrome.

Higher vs Standard Adalimumab Induction and Maintenance Dosing Regimens for Treatment of Ulcerative Colitis: SERENE UC Trial Results.

BACKGROUND & AIMS: SERENE UC (Study of a Novel Approach to Induction and Maintenance Dosing With Adalimumab in Patients With Moderate to Severe Ulcerative Colitis) evaluated the efficacy of higher adalimumab induction and maintenance dose regimens in patients with ulcerative colitis. METHODS: This phase 3, double-blind, randomized trial included induction and maintenance studies, with a main study (ex-Japan) and Japan substudy. Eligible patients (18-75 years, full Mayo score 6-12, centrally read endoscopy subscore 2-3) were randomized 3:2 to higher induction regimen (adalimumab 160 mg at weeks 0, 1, 2, and 3) or standard induction regimen (160 mg at week 0 and 80 mg at week 2); all received 40 mg at weeks 4 and 6. At week 8, all patients were rerandomized 2:2:1 (main study) to 40 mg every week (ew), 40 mg every other week (eow), or exploratory therapeutic drug monitoring; or 1:1 (Japan substudy) to 40 mg ew or 40 mg eow maintenance regimens. RESULTS: In the main study, 13.3% vs 10.9% of patients receiving the higher induction regimen vs standard induction regimen achieved clinical remission (full Mayo score ≤2 with no subscore >1) at week 8 (induction primary end point; P = .265); among week-8 responders, 39.5% vs 29.0% receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (maintenance primary end point; P = .069). In the integrated (main + Japan) population, 41.1% vs 30.1% of week-8 responders receiving 40 mg ew vs 40 mg eow achieved clinical remission at week 52 (nominal P = .045). Safety profiles were comparable between dosing regimens. CONCLUSION: Although primary end points were not met, a >10% absolute difference in clinical remission was demonstrated with higher adalimumab maintenance dosing. Higher dosing regimens were generally well tolerated and consistent with the known safety profile of adalimumab in ulcerative colitis. CLINICALTRIALS: gov, Number: NCT002209456.

Role of fecal calprotection in predicting endoscopic recurrence in postoperative Crohn's disease.

BACKGROUND AND AIMS: Fecal calprotectin (fCP) has been shown to correlate with endoscopic disease activity in Crohn's disease (CD). The aim of this study was to evaluate its role in predicting early endoscopic recurrence in postoperative CD. METHODS: Patients who underwent CD-related intestinal resection with ileocolonic anastomosis were prospectively followed up until ileocolonoscopy was performed around 12 months post-surgery. Endoscopic recurrence (ER) was defined as modified Rutgeerts score i2b or higher. Endoscopic still images were reviewed by 2 independent reviewers blinded to fCP results. Stool specimens were collected 6 months post-surgery and a multivariate logistic regression model was established to explore the predictive value of fCP for ER. RESULTS: 79 patients were included. FCP was significantly associated with endoscopic recurrence (p = .036). A cut-off value of fCP of 267 µg/g at 6 months post-surgery predicted ER with a sensitivity of 61.8% and a specificity of 72.7% (AUC 0.669). A prediction model subsuming age at diagnosis and fCP 6 months post-surgery were significantly associated with ER (fCP at 6 months [p = .007] and age at diagnosis [p = .004], multivariate analysis). CONCLUSIONS: FCP 6 months after surgery and age at diagnosis predict early ER at 1 year postoperatively. However, the low sensitivity of fCP still suggests the necessity of endoscopy as a gold standard for the assessment of postoperative recurrence of CD.KEY SUMMARYWhat is already known? Fecal calprotectin (fCP) correlates with endoscopic disease activity. Endoscopic recurrence occurs in up to 70% of patients after intestinal resection within 1 year.What are the significant and/or new findings of this study? Fecal calprotectin 6 months post-surgery and age at diagnosis significantly predict endoscopic recurrence at 1 year. Due to low sensitivity fCP cannot replace the necessity of endoscopy for accurate assessment of postoperative recurrence.

Crohn's disease: prevalence, MR features, and clinical significance of enteric and colonic sinus tracts.

OBJECTIVES: Enteric and colonic sinus tracts are inflammatory complications that precede intestinal fistulas in patients with Crohn's disease (CD). The aim of this study was to retrospectively determine the prevalence, morphologic features, and outcome of sinus tracts using MR imaging. METHODS: A consecutive cohort of 642 patients with known CD, referred for MR enterography or MR enteroclysis (study period 01/2014-09/2019), was evaluated retrospectively for the presence of sinus tracts, their locations, presence and length of coexisting strictures, bowel wall thickness, CDMI score, upstream dilation, and bowel distension. Clinical outcome was assessed using medical records. For metric data, means and standard deviation, as well as one-way ANOVA and Pearson's correlation coefficient, were calculated. RESULTS: In 36/642 patients with CD undergoing MRE, 49 sinus tracts (forty in small intestine, nine in left-sided colon) were detected with a prevalence of 6.9% in patients with MR-visible signs of CD (n = 519, overall prevalence of 5.6%). Mean segmental bowel wall thickness was 8.9 mm, and mean CDMI score was 9.3. All sinus tracts were located within a stenotic segment, showing mesenteric orientation within the small bowel and upstream dilation in 13 patients. Of 36 patients, 19 underwent immediate surgery and seven developed clinical progression within the segment containing the sinus tract. CONCLUSIONS: Sinus tracts occur in 6.9% of patients with visible signs of CD. They are located within stenotic, severely thickened bowel segments with high MR inflammation scores. Their detection is clinically important, because they indicate a more aggressive phenotype and, if left untreated, may show severe progression. KEY POINTS: • Sinus tracts occur in 6.9% of patients with MR-visible signs of Crohn's disease. • Sinus tracts are a radiological indicator of early penetrating Crohn's disease, with a high risk of progression, and require dedicated treatment. • Sinus tracts can be recognized by characteristic findings and typically occur in stenotic, severely thickened bowel segments with high MR inflammation scores.

[Second Austrian consensus on the safe use of anti-TNFα-antibodies in patients with inflammatory bowel diseases]. / Zweiter österreichischer Konsensus zur sicheren Anwendung von anti-TNF-α-Antikörpern bei chronisch-entzündlichen Darmerkrankungen.

Anti-TNFα-antibodies have revolutionized the therapy of inflammatory bowel diseases and other immune-mediated inflammatory diseases. Due to the increasing application of these substances, the Working Group of Inflammatory Bowel Diseases of the Austrian Association of Gastroenterology and Hepatology intended to update their consensus report on the safe use of Infliximab (published in 2010) and to enlarge its scope to cover all anti-TNFα-antibodies. The present consensus report summarizes the current evidence on the safe use of anti-TNFα-antibodies and covers the following topics: general risk of infection, bacterial infections (i. e., Clostridium difficile, Tuberculosis, food hygiene), Pneumocystis jiroveci, viral infections (i. e., Hepatitis B, Hepatitis C, HIV, CMV, VZV), vaccination in general and recommendation for vaccines, gastrointestinal aspects (i. e., perianal fistula, abdominal fistula, intestinal strictures, stenosis and bowel obstruction), dermatologic aspects (skin malignancies, eczema-like drug-related skin eruption), infusion reactions and immunogenicity, demyelinating diseases, hepatotoxicity, haematotoxicity, congestive heart failure, risk and history of malignancies, and pregnancy and breast feeding. For practical reasons, the relevant aspects are summarized in a checklist which is divided into two parts: issues to be addressed before therapy and issues to be addressed during therapy.

Platelets Toll-like receptor-4 in Crohns disease.

BACKGROUND: Platelets are activated in Crohn's disease (CD) and interplay with leukocytes. Engagement of Toll-like receptor-4 (TLR-4), which is expressed in human platelets, may be involved in crosstalks between platelets and leukocytes leading to their mutual activation for host defense. MATERIALS AND METHODS: Human neutrophil peptides (HNPs), lipoprotein binding peptides, and sCD14 were determined by enzyme-linked immunosorbent assays in 42 patients with active CD, in 43 patients with CD in remission, and in 30 healthy individuals. Neutrophil-platelet aggregates and binding of the TLR-4 monoclonal antibody to platelets were determined by flow cytometry. RESULTS: Levels of HNPs were higher in patients with CD than in controls (P = 0.0003 vs. active CD and P = 0.01 vs. CD in remission). Likewise, neutrophils with adhering platelets were higher in patients with active CD than in controls (P = 0.004). Binding of the TLR-4 antibody in patients with active CD was similar to that in controls, while patients in remission had significantly higher binding capacities (P = 0.59 and P = 0.003). Incubation of plasma from patients with active disease or patients in remission with platelets from healthy controls confirmed lower binding of the TLR-4 antibody in the presence of plasma from active diseased patients compared to controls (P = 0.039), possibly due to high levels of lipopolysaccharides, as suggested by high levels of sCD14 and lipoprotein binding protein. CONCLUSION: Our study indicates involvement of platelet TLR-4 in enhancing the secretion of antimicrobial peptides from neutrophils. While platelet aggregation can be due to a variety of mechanisms in inflammatory disease, the mutual activation of platelets and neutrophils may augment host defense.

Anogenital Human Papillomavirus Prevalence is Unaffected by Therapeutic Tumour Necrosis Factor-alpha Inhibition.

Patients receiving tumour necrosis factor alpha (TNF-α) inhibitors are at increased risk of exacerbation of (myco-)bacterial and some viral infections. However, information on anogenital human papillomavirus (HPV) infection in these patients is sparse or conflicting. In this study 222 patients with psoriasis or inflammatory bowel disease (IBD), who received either anti-TNF-α inhibitors or alternatives (purine-, folic acid analogues, phototherapy, fumaric ester, mesalazine) continuously for at least 6 months, were evaluated for the presence of anogenital HPV-induced lesions, mucosal HPV DNA, and serological status of mucosal low-risk HPV6 and high-risk HPV16/HPV18. Hallmarks of anogenital HPV infection were more frequently detected in patients with psoriasis than in those with IBD. HPV-induced lesions, viral DNA, and seroprevalence were not elevated in participants with psoriasis or IBD, who received TNF-α inhibitors for a mean duration of 31.4 months (range 6-96 months) compared with recipients of alternative or no treatment. TNF-α blockade for a mean period of 31.4 months does not increase detectable anogenital HPV infection or disease.

Usefulness of recombinant γ-gliadin 1 for identifying patients with celiac disease and monitoring adherence to a gluten-free diet.

BACKGROUND: Celiac disease (CD) is an inflammatory disease of the small intestine caused by an immunologic hypersensitivity reaction to dietary wheat gluten. OBJECTIVES: We sought to clone, express, and perform IgA epitope mapping of a CD-specific wheat antigen and to study its usefulness for identifying patients with CD and monitoring adherence to a gluten-free diet. METHODS: A synthetic gene coding for γ-gliadin 1 (GG1) was expressed in Escherichia coli. Recombinant γ-gliadin 1 (rGG1) was purified and characterized biochemically, structurally, and immunologically by using sera from patients with CD and control subjects. Overlapping GG1 peptides were synthesized for IgA and IgG epitope mapping. GG1 and peptide-specific antibodies were raised for tracing GG1 in cereals and dietary wheat products and to study its resistance to digestion. RESULTS: rGG1 was expressed and purified. rGG1-based IgA ELISAs performed in populations of patients with CD and control subjects showed a specificity of 92.9%, which was higher than that of gliadin extract (e). Furthermore, it allowed monitoring of adherence to a gluten-free diet in patients. A 26-amino-acid peptide from the proline-glutamine-rich repetitive N-terminal region was identified as the immunodominant IgA epitope. GG1-related antigens were found in rye, barley, and spelt but not in oat, rice, or maize. GG1 was detected in dietary wheat products after baking, and in particular, the major IgA epitope-containing region was resistant against digestion. CONCLUSIONS: rGG1 and its epitope might be useful for identifying patients with CD, monitoring treatment, and studying the pathomechanisms of CD and development of preventive and therapeutic strategies.

A 1-year trial of repeated high-dose intravenous iron isomaltoside 1000 to maintain stable hemoglobin levels in inflammatory bowel disease.

OBJECTIVE: Iron isomaltoside 1000 (Monofer®) is a high-dose intravenous (IV) iron, which in a recent 8 weeks trial in inflammatory bowel disease (IBD) subjects with iron deficiency anemia (IDA) demonstrated good tolerability and efficacy. The present trial is an extension to this trial, which evaluates the need for additional high IV iron doses to maintain a stable hemoglobin (Hb) ≥12.0 g/dl. MATERIAL AND METHODS: This was a prospective, open-label, 12 months trial of European IBD subjects willing to participate after completing the lead-in trial. Subjects were allowed re-dosing with 500-2000 mg single doses of iron isomaltoside 1000 infused over ∼15 min at 3 months intervals depending on a predefined algorithm. Outcome measures included Hb, safety parameters and need for additional iron dosing. RESULTS: A total of 39 subjects were enrolled of which 34 subjects required re-dosing with a median cumulative 1-year dose of 1.8 g (mean cumulative dose 2.2 g). The mean (SD) Hb was 12.3 (1.5) g/dl at baseline, 12.8 (1.6) g/dl at 3 months, 12.8 (1.6) g/dl at 6 months, 12.9 (1.4) g/dl at 9 months and 12.9 (1.6) g/dl at 12 months. Seventy-four percent of subjects who had an Hb ≥12.0 g/dl at baseline were able to maintain Hb ≥12.0 g/dl till the end of the trial at 12 months. Nonserious probably related hypersensitivity reactions without significant hypotension were reported at the beginning of the infusion in two subjects, who recovered without sequelae. CONCLUSION: Repeated treatment of iron deficiency with iron isomaltoside 1000 could avoid episodes of IDA without major safety issues.

Early recognition of possible pitfalls in histological diagnosis of celiac disease.

OBJECTIVE: A state-of-the-art assessment of duodenal biopsies by the pathologist in the diagnosis of celiac disease (CelD) is of highest importance. However, inaccurate characterization of specific features can lead to misdiagnosis. Our hypothesis is that a detailed histological report guarantees a good quality and helps in the primary diagnostic process by preventing false-positive diagnosis of CelD. MATERIAL AND METHODS: A total of 52 patients primarily diagnosed with CelD and suspicion of misdiagnosis were selected for this retrospective study. External histological reports of duodenal biopsies were obtained and later reassessed by an experienced in-house pathologist. For an objective evaluation a histology quality score (HQS) was created. Both pathological reports were compared and causes for a possible misdiagnosis were analyzed. Diagnostic systems by Catassi and Korponay-Szabo were compared with each other. RESULTS: The original diagnosis had been confirmed in 27% by our pathologist. The HQS was significantly lower (worse) in cases where the original diagnosis were dismissed than in confirmed CelD (p = 0.018). The new diagnostic approach by Catassi and Korponay-Szabo showed a sensitivity of 89% and 83%, respectively, a specificity of 97%, a positive predictive value of 94% and a negative predictive value of 94% and 92%, respectively. CONCLUSIONS: A low quality of the histological evaluation can lead to a high probability of misdiagnosing CelD. By applying the HQS the physician can estimate whether the report is fraught with uncertainty. Ideally the score minimizes false-positive results and prevents a delay of the correct diagnosis.

Withdrawal of long-term maintenance treatment with azathioprine tends to increase relapse risk in patients with Crohn's disease.

BACKGROUND AND AIM: Many patients with quiescent Crohn's disease are maintained on long-term treatment with azathioprine (AZA), but controlled data are limited. We aimed to evaluate the efficacy of AZA therapy for more than 4 years to maintain clinical remission. METHODS: We performed a randomized double-blind placebo-controlled AZA withdrawal trial with a follow-up period of 24 months. Patients had to have continuous AZA therapy ≥ 4 years without exacerbation of disease during the 12 months before enrollment, and a Crohn's disease activity index < 150 at baseline. Patients were randomized to continue on AZA or switch to placebo. The primary endpoint was time to clinical relapse during follow-up. RESULTS: After inclusion of 52 patients, the trial was stopped prematurely due to slow recruitment. During the 2-year follow-up, clinical relapse occurred in 4 of 26 (15 %) patients on continued AZA and in 8 of 26 (31 %) patients on placebo. Time to clinical relapse averaged 22.3 months (95 % CI 20.6-24.0) on AZA and 19.2 months (95 % CI 16.4-22.1) on placebo (p = 0.20). According to life-table analysis, the proportion of patients in remission after 12 and 24 months was 96 ± 4 and 86 ± 7 % in patients receiving AZA versus 76 ± 8 and 68 ± 9 % in patients receiving placebo (month 12, p = 0.035; month 24, p = 0.30). A higher AZA dose at enrollment was an independent predictor for relapse (p < 0.05). CONCLUSIONS: AZA withdrawal resulted in a significantly increased relapse risk after 1 year and a nonstatistically significant trend for relapse after 2 years. Our results are in line with previous observations.

Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment.

BACKGROUND: We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor α (TNF-α) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD). DESIGN: Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab. RESULTS: Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohn's disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-γ-secreting Th1 cells and IFN-α-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab. CONCLUSIONS: New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions.

Follow-up of pediatric celiac disease: value of antibodies in predicting mucosal healing, a prospective cohort study.

BACKGROUND: In diagnosing celiac disease (CD), serological tests are highly valuable. However, their role in following up children with CD after prescription of a gluten-free diet is unclear. This study aimed to compare the performance of antibody tests in predicting small-intestinal mucosal status in diagnosis vs. follow-up of pediatric CD. METHODS: We conducted a prospective cohort study at a tertiary-care center. 148 children underwent esophohagogastroduodenoscopy with biopsies either for symptoms ± positive CD antibodies (group A; n = 95) or following up CD diagnosed ≥ 1 year before study enrollment (group B; n = 53). Using biopsy (Marsh ≥ 2) as the criterion standard, areas under ROC curves (AUCs) and likelihood-ratios were calculated to estimate the performance of antibody tests against tissue transglutaminase (TG2), deamidated gliadin peptide (DGP) and endomysium (EMA). RESULTS: AUCs were higher when tests were used for CD diagnosis vs. follow-up: 1 vs. 0.86 (P = 0.100) for TG2-IgA, 0.85 vs. 0.74 (P = 0.421) for TG2-IgG, 0.97 vs. 0.61 (P = 0.004) for DPG-IgA, and 0.99 vs. 0.88 (P = 0.053) for DPG-IgG, respectively. Empirical power was 85% for the DPG-IgA comparison, and on average 33% (range 13-43) for the non-significant comparisons. Among group B children, 88.7% showed mucosal healing (median 2.2 years after primary diagnosis). Only the negative likelihood-ratio of EMA was low enough (0.097) to effectively rule out persistent mucosal injury. However, out of 12 EMA-positive children with mucosal healing, 9 subsequently turned EMA-negative. CONCLUSIONS: Among the CD antibodies examined, negative EMA most reliably predict mucosal healing. In general, however, antibody tests, especially DPG-IgA, are of limited value in predicting the mucosal status in the early years post-diagnosis but may be sufficient after a longer period of time.

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

BACKGROUND & AIMS: We evaluated the gastrointestinal permeability and bacterial translocation in cirrhotic patients with portal hypertension (PHT) prior to and after non-selective betablocker (NSBB) treatment. METHODS: Hepatic 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. RESULTS: Fifty 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. CONCLUSIONS: Abnormal 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.

A combined biochemical, biophysical and immunological approach towards the identification of celiac disease-specific wheat antigens.

Celiac disease (CD) is an inflammatory affliction of the small bowel caused by an immunological hypersensitivity to ingested wheat antigens affecting almost 1 % of the population. The gliadin fraction of wheat has been shown to contain the pathogenic antigens which react with antibodies and T cells. However, there is only limited knowledge regarding the precise nature of the wheat antigens recognized by IgA antibodies from CD patients and diagnostic tests based on the gliadin fraction have been demonstrated to give frequently false positive results. The aim of this study was the characterization of wheat antigens specifically recognized by IgA antibodies of CD patients. We developed a combined biochemical, biophysical, and immunological approach for the identification of celiac disease-specific wheat antigens. It is based on sub-fractionation of the wheat gliadin fraction using two ion exchange chromatography steps, the localization of CD-specific antigens by immunoblotting with IgA antibodies from CD patients, subsequent digestion followed by electro spray ionization-liquid chromatography/mass spectrometry (LC-ESI-MS/MS) and N-terminal sequencing by Edman degradation. Through the sub-fractionation procedure it was possible to separate CD-specific IgA-reactive wheat antigens from other wheat antigens which were also recognized by IgA antibodies of individuals without CD or by CD patients on gluten-free diet. Analysis by LC-ESI-MS/MS and N-terminal sequencing of the sub-fractions and the proteins specifically recognized by CD patients identified certain γ-gliadins with molecular mass of 37,000 and 45,000 as CD-specific wheat antigens. The CD-specific γ-gliadins with the molecular mass of 37,000 and 45,000 should be useful to study pathomechanisms of the disease and to improve the specificity of diagnostic tests for CD.

Selective Granulocyte and Monocyte Apheresis as a Non-Pharmacological Option for Patients with Inflammatory Bowel Disease.

Ulcerative colitis and Crohn's disease are the two most prevalent inflammatory bowel diseases. In both cases, the medically refractory and steroid-dependent type presents a therapeutic challenge. To help resolve this problem, a mainly Japanese team developed a new therapeutic option. There are two systems, both of which are able to selectively remove the main mediators of the disease, namely the activated pro-inflammatory cytokine-producing granulocytes and monocytes/macrophages, from the patient's blood circulation (GMA = granulocyte monocyte apheresis). One of the two systems is the Adacolumn( (®) ) (Immunoresearch Laboratories, Takasaki, Japan) consisting of the ADA-monitor and a single-use column, which contains approximately 35,000 cellulose acetate beads. The exact mode of action is not yet sufficiently understood, but however, a modulation of the immune system takes place. As a result, less pro-inflammatory cytokines are released. Furthermore, the production of anti-inflammatory interleukin-1 receptor antagonist is increased, and the apoptosis of granulocytes boosted. The decreased LECAM-1-expression on leukocytes impedes the leukotaxis to the inflamed tissue, and CD10-negative immature granulocytes appear in the peripheral blood. Another effect to be mentioned is the removal of the peripheral dendritic cells and the leachate of regulatory T cells (T-regs). The second system is the Cellsorba( (®) ) FX Filter (Asahi Medical, Tokyo, Japan). The range of efficiency, the indication, and the procedure are very similar to the Adacolumn. Solely the additional removal of lymphocytes can possibly limit the implementation since lymphopenia can increase the risk of autoimmune disease. Both systems provide a low-risk therapy with few adverse reactions. ASFA recommendations for GMA in inflammatory bowel disease are 2B due to the fact that not enough randomized double-blind studies are available to proof the efficacy of this treatment.

Atypical enteropathogenic E. coli are associated with disease activity in ulcerative colitis.

With increasing urbanization and industrialization, the prevalence of inflammatory bowel diseases (IBDs) has steadily been rising over the past two decades. IBD involves flares of gastrointestinal (GI) inflammation accompanied by microbiota perturbations. However, microbial mechanisms that trigger such flares remain elusive. Here, we analyzed the association of the emerging pathogen atypical enteropathogenic E. coli (aEPEC) with IBD disease activity. The presence of diarrheagenic E. coli was assessed in stool samples from 630 IBD patients and 234 age- and sex-matched controls without GI symptoms. Microbiota was analyzed with 16S ribosomal RNA gene amplicon sequencing, and 57 clinical aEPEC isolates were subjected to whole-genome sequencing and in vitro pathogenicity experiments including biofilm formation, epithelial barrier function and the ability to induce pro-inflammatory signaling. The presence of aEPEC correlated with laboratory, clinical and endoscopic disease activity in ulcerative colitis (UC), as well as microbiota dysbiosis. In vitro, aEPEC strains induce epithelial p21-activated kinases, disrupt the epithelial barrier and display potent biofilm formation. The effector proteins espV and espG2 distinguish aEPEC cultured from UC and Crohn's disease patients, respectively. EspV-positive aEPEC harbor more virulence factors and have a higher pro-inflammatory potential, which is counteracted by 5-ASA. aEPEC may tip a fragile immune-microbiota homeostasis and thereby contribute to flares in UC. aEPEC isolates from UC patients display properties to disrupt the epithelial barrier and to induce pro-inflammatory signaling in vitro.