Barry Hall

A prospective 52 week mucosal healing assessment of small bowel Crohn's disease as detected by capsule endoscopy.

BACKGROUND Mucosal healing is increasingly recognised as an important treatment goal in Crohns disease (CD). Data from colonic disease shows improved long-term outcomes in patients achieving complete mucosal healing. Little is currently known of this with regard to ileitis which is increasingly diagnosed using capsule endoscopy (SBCE). This is the first study to prospectively assess mucosal healing and deep remission rates following 52 weeks of therapy in a cohort of symptomatic small bowel CD patients commencing immunomodulator or biologic therapy. METHODS Baseline demographics, quality of life questionnaires and Harvey Bradshaw Index were collected along with C-reactive protein & calprotectin. Capsule endoscopy Crohns disease activity (CECDAI) index was used to assess ileitis severity. All parameters were reassessed at week 52. Results at baseline & week 52 were compared using univariate analysis, p < 0.05 considered significant. RESULTS In total, 108 capsule procedures were performed on 43 patients. Based on the CECDAI, 39 (90%) demonstrated active small bowel CD at baseline with 28 (65%) undergoing 52 week assessment. In total, 12 (42%) participants achieved complete mucosal healing and deep remission by 52 week assessment (p<0.0001 95% CI -0.62 to -0.22). Despite overall impressive mucosal healing rates, patients with strictures were less likely to demonstrate a decrease in CECDAI and were more likely to have symptoms. CONCLUSION In patients with active small bowel CD symptomatic and biochemical response to treatment appears to be mirrored by endoscopic remission in 42% of individuals. Strictures identified prior to therapy appear to be a poor indicator for success of treatment.

Pellino3 ubiquitinates RIP2 and mediates Nod2-induced signaling and protective effects in colitis

Mutations that result in loss of function of Nod2, an intracellular receptor for bacterial peptidoglycan, are associated with Crohns disease. Here we found that the E3 ubiquitin ligase Pellino3 was an important mediator in the Nod2 signaling pathway. Pellino3-deficient mice had less induction of cytokines after engagement of Nod2 and had exacerbated disease in various experimental models of colitis. Furthermore, expression of Pellino3 was lower in the colons of patients with Crohns disease. Pellino3 directly bound to the kinase RIP2 and catalyzed its ubiquitination. Loss of Pellino3 led to attenuation of Nod2-induced ubiquitination of RIP2 and less activation of the transcription factor NF-κB and mitogen-activated protein kinases (MAPKs). Our findings identify RIP2 as a substrate for Pellino3 and Pellino3 as an important mediator in the Nod2 pathway and regulator of intestinal inflammation.

Small bowel angiodysplasia and novel disease associations: a cohort study

Abstract Objective. Gastrointestinal angiodysplasias recurrently bleed, accounting for 3–5% of obscure gastrointestinal bleeding. The advent of small bowel capsule endoscopy (SBCE) has led to an increased recognition of small bowel angiodysplasias (SBAs) but little is known about their etiology. Previous small cohorts and case reports suggest an equal gender incidence and associations with cardiovascular disease, renal impairment, and coagulopathies. Methods. Patients with SBA were identified from our SBCE database. A control group, in whom gastrointestinal bleeding had been excluded, was also identified. Information on patient demographics, past medical/surgical/social history and medications was prospectively obtained. Results. A total of 82 patients and 95 controls were identified. Data was available from 81% (n = 66) of SBA patients. The mean age of patients and controls was 66.9 years (35–90) and 69.2 years (54–77), and 60% (n = 40) and 58% (n = 55) were females, respectively. There was a higher rate of all comorbidities in the SBA group 92% (61/66) versus controls 76% (72/95) p < 0.002. Significant associations were found with: hypertension (odds ratio [OR] 2.8), ischemic heart disease (OR 4.25), arrhythmias (OR 4.36), valvular heart disease (OR 18), congestive heart failure (OR 4.22), chronic kidney disease (CKD) (OR 8.4), chronic respiratory conditions (OR 2.0), and previous venous thromboembolism (VTE) (OR 6.4). Anticoagulant use was higher in patients with SBA, 50% (n = 33) versus 27% (n = 26) of controls, p < 0.002, specifically warfarin and asasantin retard. Conclusions. SBA occurs in elderly patients with cardiovascular disease and CKD, as previously suggested. This study identifies a previously unrecognised risk in females, patients with chronic respiratory conditions and VTE, and the use of warfarin and asasantin retard. These associations should raise awareness of possible underlying SBA in risk patients with anemia.

A prospective 12-week mucosal healing assessment of small bowel Crohn's disease as detected by capsule endoscopy.

Background Mucosal healing is increasingly recognized as an important treatment goal in Crohn’s disease (CD). Data from colonic disease shows improved long-term outcomes in patients achieving complete mucosal healing. Little is currently known of this with respect to ileitis, which is increasingly diagnosed using small bowel capsule endoscopy. The study aimed to prospectively assess mucosal healing and deep remission rates in a cohort of symptomatic small bowel CD patients commencing biologic or immunomodulator therapy. Methods Baseline demographics, quality of life questionnaires and Harvey-Bradshaw index were collected along with C-reactive protein and calprotectin. Capsule endoscopy Crohn’s disease activity (CECDAI) index was used to assess ileitis severity. All parameters were reassessed at week 12. Results at baseline and week 12 were compared using two-tailed Wilcoxon analysis, P value less than 0.05 was considered significant. Results In total, 43 patients of 71 screened underwent 80 small bowel capsule endoscopies. On the basis of the CECDAI, 39 (90%) demonstrated active small bowel CD at baseline with 37 (86%) undergoing 12-week assessment. Overall there was a statistically significant symptomatic and biochemical improvement at week 12. Furthermore, 10 (27%) had demonstrated a normalization in CECDAI (<3.5), which was statistically significant (P<0.0005, 95% confidence interval 0.12–0.15). However, no patient had achieved full mucosal healing. Conclusion In patients with active small bowel CD early symptomatic and biochemical response to treatment is not mirrored by mucosal healing. Repeat mucosal healing assessment in this cohort is warranted following a longer duration of treatment to identify potential mucosal healing and deep remission rates.

Capsule endoscopy: High negative predictive value in the long term despite a low diagnostic yield in patients with suspected Crohn's disease

Introduction The role of small bowel capsule endoscopy (SBCE) in Crohns disease (CD) has expanded with greater understanding of the technology. The ability of SBCE to differentiate CD from other causes of inflammation has been questioned. Longitudinal studies are required to assess the long-term impact and significance of SBCE findings in suspected CD. This study aimed to determine the long-term clinical accuracy of SBCE in patients referred with suspected CD. Methods A retrospective review was carried out on SBCE procedures performed for suspected CD since 2010. Only patients with at least 6 months of documented follow up were included. A chart review was undertaken to record SBCE findings/correlate with subsequent diagnosis and outcome. Results In all, 95 patients with sufficient follow up were identified. The mean follow up was 13 months (range 8–24). In total, 72 (76%) SBCEs were negative and 23 (24%) positive for CD. Of the 72 negative tests, two patients (3%) were later diagnosed with CD. The negative predictive value is 96%. There was a strong positive correlation between results of WCE and subsequent clinical diagnosis. Conclusions SBCE appears capable of safely out-ruling CD, with only 3% of negative SBCE investigations being diagnosed with CD after 15 months.

Long-acting somatostatin analogues provide significant beneficial effect in patients with refractory small bowel angiodysplasia: Results from a proof of concept open label mono-centre trial

Introduction Small bowel angiodysplasias account for over 50% of causes of small bowel bleeding and carry a worse prognosis than lesions located elsewhere in the gastrointestinal tract. Re-bleeding rates are high even after first-line endoscopic therapy and are associated with high levels of morbidity for affected patients. Small trials of long-acting somatostatin analogues have shown promising results but have not yet been assessed in patients with refractory small bowel disease. Aim The purpose of this study was to assess the effect of long-acting somatostatin analogues in reducing re-bleeding rates and transfusion requirements, and improving haemoglobin levels in patients with refractory small bowel angiodysplasia. Methods Patients with refractory small bowel angiodysplasia were treated with 20 mg of long-acting octreotide for a minimum of three months. Response was assessed according to: rates of re-bleeding, haemoglobin levels, transfusion requirements, and side effects. Results A total of 24 patients were initially treated and 20 received at least three doses. Rates of complete, partial and non-response were 70%, 20% and 10% respectively. Average haemoglobin rates increased from 9.19 g/dl to 11.35 g/dl (p = 0.0027, 95% confidence interval (CI) −3.5 to −1.1) in the group overall and 70% remained transfusion-free after a mean treatment duration of 8.8 months. The rate of adverse events was higher than previously reported at 30%. Conclusion Long-acting somatostatin analogues offer a therapeutic advantage in a significant proportion of patients with small bowel angiodysplasia. With careful patient selection and close observation, a long-acting somatostatin analogue should be considered in all patients with persistent anaemia attributable to refractory disease in conjunction with other standard treatments.

Expression of Angiogenic Factors in Patients With Sporadic Small Bowel Angiodysplasia.

Goals: To identify putative angiogenic factors associated with sporadic small bowel angiodysplasia (SBA). Background: SBAs account for 50% of obscure gastrointestinal bleeding and due to delays in diagnosis and ineffective treatments, are associated with high levels of morbidity and mortality. Treatment development is impeded by a limited knowledge of the pathophysiology behind SBA formation. Study: We identified patients with definite sporadic SBA, and fecal immunochemical–negative controls were recruited from our institution’s colorectal cancer screening program. Serum levels of VEGF, endoglin, Angiopoietin-2 (Ang-2), PDGF, Angiopoietin-1 (Ang-1), and TNF-&agr; were measured using commercially available enzyme-linked immunosorbent assay kits. On the basis of serum results, we measured gene expression of target angiogenic factors in small bowel biopsy samples from angiodysplasias and unaffected tissue by quantitative PCR assessment. Results: Serum samples were analyzed from 40 SBA patients and 40 controls. Median serum levels of Ang-2 were significantly higher in patients than controls with levels of Ang-1 and TNF-&agr; significantly lower. There were no differences in serum levels of VEGF, endoglin, or PDGF. Gene expression levels of Ang-1, Ang-2, and their receptor Tie2 were all significantly higher in biopsies from areas of angiodysplasia compared with normal small bowel. Conclusions: This study, the first to explore the role of angiogenic factors in SBA, has identified a positive association between SBA and the Angiopoietin pathway, with increased serum and mucosal expression of Ang-2, which could potentially be used as a serum biomarker and future therapeutic target to improve outcome in affected patients.

PillCam COLON 2(©) as a pan-enteroscopic test in Crohn's disease.

A recent paper by Boal Carvalho et al demonstrates the potential of PillCam COLON 2(©) (PCC2) as a pan-enteric investigation in Crohns disease (CD). Our own prospective data in patients with known CD also shows good correlation between PCC2 and small/large bowel investigations (R = 0.896, P < 0.0004/R = 0.6667, P < 0.035). Larger studies are warranted to prospectively validate the use of PCC2 in the investigation and monitoring of both small and large bowel CD.

A combined antral and corpus rapid urease testing protocol can increase diagnostic accuracy despite a low prevalence of Helicobacter pylori infection in patients undergoing routine gastroscopy

Background The effects of an increased risk of sampling error and the lower prevalence of Helicobacter pylori infection on the diagnostic accuracy of standard invasive tests needs to be considered. Despite evidence of enhanced yield with additional biopsies, combined Rapid Urease Tests (RUTs) have not been widely adopted. We aimed to compare the diagnostic efficacy of a combined antral and corpus rapid urease test (RUT) to a single antral RUT in a low prevalence cohort. Methods Between August 2013 and April 2014 adult patients undergoing a scheduled gastroscopy were prospectively recruited. At endoscopy biopsies were taken and processed for single and combined RUTs, histology and culture using standard techniques. Infection was defined by positive culture or detection of Helicobacter like organisms on either antral or corpus samples. Results In all 123 patients were recruited. H. pylori prevalence was low at 36%, n = 44. There was a significant difference in positivity between single and combined RUTs, 20% (n = 25) versus 30% (n = 37), p = 0.0094, (95% CI 0.15–0.04). The number needed to treat (NNT) for an additional diagnosis of infection using a combined versus a single RUT is 4 (95% CI 2.2–11). The only factor associated with a reduction in RUT yield was regular proton pump inhibitor (PPI) use. Overall the sensitivity, specificity, positive and negative predictive value for any RUT test was 84%, 100%, 100% and 92% respectively. Conclusion Our data suggests taking routine antral and corpus biopsies in conjunction with a combined RUT appears to optimizing H. pylori detection and overcome sampling error in a low prevalence population.

A randomized-controlled study to compare the efficacy of sequential therapy with standard triple therapy for Helicobacter pylori eradication in an Irish population.

Introduction Eradication rates for the standard first-line triple therapy for Helicobacter pylori infection have decreased in recent years. Sequential therapy has been suggested as an alternative. The efficacy of sequential therapy has not been assessed to date in an Irish population. Objective The aim of this study was to compare the efficacy of standard triple therapy with sequential therapy for H. pylori eradication. Patients and methods A prospective randomized–controlled study was carried out. Treatment-naive H. pylori-infected patients were randomized to receive either standard triple therapy or sequential therapy. Results In all, 87 eligible patients were recruited into the study, one of whom dropped out. Fifty-one per cent (N=44) patients received standard triple therapy and 49% (N=42) patients received sequential therapy. The eradication efficacy by intention-to-treat analysis was 56.8% [N=25/44; 95% confidence interval (CI) 42.2–71.4%] for standard triple therapy and 69% (N=29/42; 95% CI 55.0–83.0%) for sequential therapy. The eradication rates by per-protocol analysis for standard triple therapy and sequential therapy were 61% (N=25/41; 95% CI 46.1–76.0%) and 69% (N=29/42; 95% CI 55.0–83.0%), respectively. The differences in eradication rates for each treatment by either intention-to-treat or per-protocol analysis were not statistically significant (P=0.24 and 0.44, respectively). In addition, incidence in adverse events was not significantly different between the study groups. The most common adverse event reported was mild nausea at 15% (95% CI 7.5–22.6%). Conclusion Sequential therapy had a nonstatistically significant advantage over standard triple therapy in our patient cohort. However, eradication rates for both standard triple therapy and sequential therapy were suboptimal. Further studies are required to identify potential alternatives to standard first-line triple therapy.