Higher Ustekinumab Levels in Maintenance Therapy are Associated with Greater Mucosal Healing and Mucosal Response in Crohn's Disease: An Experience of 2 IBD Centers.

BACKGROUND: Ustekinumab (UST), a human monoclonal antibody that binds the p40 subunit of interleukin 12 (IL-12) and IL-23, is licensed for induction and maintenance therapy of moderate to severe inflammatory bowel disease (IBD). To date, there is limited data published on any potential association between ustekinumab serum trough levels and mucosal healing in order to guide treatment strategies and appropriate dosing. AIM: This study aims to identify a relationship between maintenance ustekinumab serum trough levels and mucosal healing and/or response in patients with Crohn's disease in an observational cohort study. METHODS: Ustekinumab serum trough levels and antibody titres were analyzed in patients on maintenance drug using an ELISA drug-tolerant assay. Mucosal response (MR) was defined as ≥50% reduction in fecal calprotectin level (FC) and/or ≥50% reduction in the Simple Endoscopic Score for Crohn's Disease (SES-CD score). Mucosal healing (MH) was defined as FC ≤150 µg/mL and/or global SES-CD score ≤5. Median trough levels were analyzed using the Kruskal-Wallis test, and logistic regression was used to determine sensitivity and specificity of levels predicting mucosal response. RESULTS: Forty-seven patients on maintenance ustekinumab for Crohn's disease were included in this study. The majority were female (66%), with a median age of 40 years (21-78 years). The majority of patients were biologic-experienced (89.4%, n = 42). Patients with histologically confirmed Crohn's disease represented 100% (n = 47) of the cohort. Over one-third of patients (n = 18, 38.3%) were on higher than standard dosing of 90 mg every 8 weeks. Patients with mucosal healing (n = 30) had significantly higher mean serum ustekinumab levels (5.7 µg/mL, SD 6.4) compared with those with no response (1.1 µg/mL, SD 0.52; n = 7, P < .0001). A serum ustekinumab trough level greater than 2.3 µg/mL was associated with MH, with a sensitivity of 100% and specificity of 90.6% (likelihood ratio 10.7). Similarly, for patients with MR (n = 40), we observed a higher mean serum ustekinumab trough level (5.1 µg/mL, SD 6.1) compared with those with no response (1.1 µg/mL, SD 0.52; n = 7, P < .0001). Furthermore, a serum ustekinumab trough level greater than 2.3 µg/mL was associated with a 10-fold increased likelihood of mucosal response vs mucosal nonresponse (sensitivity 100%, specificity 90.5%, likelihood ratio 10.5). CONCLUSION: This study demonstrates that higher ustekinumab serum trough levels are associated with a greater likelihood of achieving mucosal healing and mucosal response in patients with Crohn's disease regardless of prior biologic exposure. Further prospective studies are required to correlate target maintenance trough levels and the optimal time to dose-escalate in order to improve patient outcomes.

Irish data on the safety and efficacy of vedolizumab in the treatment of inflammatory bowel disease.

SUMMARY: This study reviews the safety and efficacy of treatment with vedolizumab for patients with inflammatory bowel disease across 9 Irish hospitals. It generates valuable and timely real-world data on treatment outcomes to add to the existing evidence base. Our population represents a refractory cohort with most patients previously exposed to at least one anti-TNFa agent and expressing an inflammatory phenotype. Results are reassuringly similar to larger international studies with additional insights into potential predictors of treatment response. This study further supports the safety and efficacy of vedolizumab in the treatment of inflammatory bowel disease. Key SummaryVedolizumab has growing real world data on its safety and efficacy in the treatment of IBD. Data on predictors of response are lacking. Studies such as VARSITY require new real-world data to help identify the place VDZ will occupy in the treatment algorithm for IBDThis study provides national Irish data on the safety and efficacy of VDZ in the treatment of IBD. It gives insight into various predictors of response for both UC and CD. It strengthens the available body of evidence on the use of VDZ and helps us determine its position on the treatment algorithm.

Barrett's Registry Collaboration of academic centers in Ireland reveals high progression rate of low-grade dysplasia and low risk from nondysplastic Barrett's esophagus: report of the RIBBON network.

Barrett's esophagus (BE) is the main pathological precursor of esophageal adenocarcinoma (EAC). Progression to high-grade dysplasia (HGD) or EAC from nondysplastic BE (NDBE), low-grade dysplasia (LGD) and indefinite for dysplasia (IND) varies widely between population-based studies and specialized centers for many reasons, principally the rigor of the biopsy protocol and the accuracy of pathologic definition. In the Republic of Ireland, a multicenter prospective registry and bioresource (RIBBON) was established in 2011 involving six academic medical centers, and this paper represents the first report from this network. A detailed clinical, endoscopic and pathologic database registered 3,557 patients. BE was defined strictly by both endoscopic evidence of Barrett's epithelium and the presence of specialized intestinal metaplasia (SIM). A prospective web-based database was used to gather information with initial and follow-up data abstracted by a data manager at each site. A total of 2,244 patients, 1,925 with no dysplasia, were included with complete follow-up. The median age at diagnosis was 60.5 with a 2.1:1 male to female ratio and a median follow-up time of 2.7 years (IQR 1.19-4.04), and 6609.25 person years. In this time period, 125 (5.57%) progressed to HGD/EAC, with 74 (3.3%) after 1 year of follow-up and 38 (1.69%) developed EAC, with 20 (0.89%) beyond 1 year. The overall incidence of HGD/EAC was 1.89% per year; 1.16% if the first year is excluded. The risk of progression to EAC alone overall was 0.57% per year, 0.31% excluding the first year, and 0.21% in the 1,925 patients who had SIM alone at diagnosis. Low-grade dysplasia (LGD) progressed to HGD/EAC in 31% of patients, a progression rate of 12.96% per year, 6.71% with the first year excluded. In a national collaboration of academic centers in Ireland, the progression rate for NDBE was similar to recent population studies. Almost one in two who progressed was evident within 1 year. Crucially, LGD diagnosed and confirmed by specialist gastrointestinal pathologists represents truly high-risk disease, highlighting the importance of expertise in diagnosis and management, and providing indirect support for ablative therapies in this context.

Golimumab effectiveness and safety in clinical practice for moderately active ulcerative colitis.

BACKGROUND AND AIMS: Golimumab (GLB) is an antitumour necrosis factor-α (anti-TNF) therapy that has shown efficacy as induction and maintenance therapy for ulcerative colitis (UC). We aimed to describe the outcome of GLB therapy for UC in a real-world clinical practice. PATIENTS AND METHODS: Consecutive patients receiving GLB for UC in six Irish Academic Medical Centres were identified. The primary study endpoint was the 6-month corticosteroid-free remission rate. The secondary endpoints included the 3-month clinical response, time free of GLB discontinuation and adverse events. RESULTS: Seventy-two patients were identified [57% men; median (range) age of 41.4 years (20.3-76.8); disease duration 6.6 years (0-29.9); follow-up 8.7 months (0.4-39.2)]. Sixty-four percent of patients were anti-TNF naive. The 3-month clinical response and the 6-month corticosteroid-free remission rates were 55 and 39%, respectively. Forty-four percent of patients discontinued GLB during the follow-up, median (95% confidence interval) time to GLB discontinuation 18.7 months (9.2-28.1). A C-reactive protein more than 5 mg/l at baseline was associated with failure to achieve 6-month corticosteroid-free remission and a shorter time to GLB discontinuation, odds ratio 0.2 (0.1-0.7), P=0.008, and hazard ratio (95% confidence interval) 2.8 (1.3-5.7), P=0.007, respectively. Adverse events occurred in 7% of patients (n=5), all of which were minor and self-limiting. CONCLUSION: These real-world clinical data suggest that GLB is an effective and safe therapy for a UC cohort with significant previous anti-TNF exposure. An elevated baseline C-reactive protein, likely reflective of increased inflammatory burden, is associated with a reduced likelihood of a successful outcome of GLB therapy.

Band ligation of gastric antral vascular ectasia is a safe and effective endoscopic treatment.

BACKGROUND AND AIM: Gastric antral vascular ectasia (GAVE) or 'watermelon stomach' is a rare and often misdiagnosed cause of occult upper gastrointestinal bleeding. Treatment includes conservative measures such as transfusion and endoscopic therapy. A recent report suggests that endoscopic band ligation (EBL) offers an effective alternative treatment. The aim of the present study is to demonstrate our experiences with this novel technique, and to compare argon plasma coagulation (APC) with EBL in terms of safety and efficacy. METHODS: A retrospective analysis of all endoscopies with a diagnosis of GAVE was carried out between 2004 and 2010. Case records were examined for information pertaining to the number of procedures carried out, mean blood transfusions, mean hemoglobin, and complications. RESULTS: A total of 23 cases of GAVE were treated. The mean age was 73.9 (55-89) years. Female to male ratio was 17:6 and mean follow up was 26 months. Eight patients were treated with EBL with a mean number of treatments of 2.5 (1-5). This resulted in a statistically significant improvement in the endoscopic appearance and a trend towards fewer transfusions. Of the eight patients treated with EBL, six (75%) patients had previously failed APC treatment despite having a mean of 4.7 sessions. Band ligation was not associated with any short- or medium-term complications. The 15 patients who had APC alone had a mean of four (1-11) treatments. Only seven (46.7%) of these patients had any endoscopic improvement with a mean of four sessions. CONCLUSIONS: EBL represents a safe and effective treatment for GAVE.

An incidentaloma at ileal intubation.

The authors report the case of a primary small bowel lymphoma discovered incidentally in a 33-year-old male following ileal intubation at colonoscopy. The patient subsequently underwent curative treatment with chemotherapy. This case not only highlights the importance of routine ileoscopy but also the successful use of chemotherapy in a disease for which the optimal treatment modality has not been well characterized.

Economic impact of prescreening on gastroenterology outpatient clinic practice.

BACKGROUND: Outpatient clinic activity represents a major workload for clinicians. Unnecessary outpatient visits place a strain on service provision, resulting in unnecessary delays for more urgent cases. GOALS: We sought to determine both the impact and economic benefit of employing phone follow-up and physician assistant (PA) triage systems on attendances at a gastroenterology outpatient department. STUDY: We performed a retrospective chart review of all patients attending a gastroenterology outpatient clinic over a 2-week period. Patients were categorized into new or follow-up attendees and the follow-up patients were further subcategorized into 1 of 4 groups: (1) those attending to receive results of investigations requiring no further treatment (group A); (2) those attending to receive results of investigations requiring further treatment (group B); (3) those attending with a chronic gastrointestinal disease requiring no active change in management (group C); (4) those attending with a chronic gastrointestinal disease requiring active change in management (group D). It was assumed that patients in group A could be managed by phone follow-up in place of clinic attendance and patients in group C could be triaged to see a PA. RESULTS: Out of a total of 329 outpatient attendees, 40 (12%) required no active intervention (group A) and would have been suitable for phone follow-up. A further 58 (18%) had stable disease, requiring no change in management and hence, could have been triaged to see a PA. Implementation of phone follow-up and patient review by PA could reduce salary expenses of outpatient practice by 17%. CONCLUSIONS: Our findings support routine prescreening of outpatient attendees to enhance the efficiency of gastroenterology outpatient practice.

Efficacy and safety of colonic stenting for malignant disease in the elderly.

BACKGROUND: Self-expandable metal stents (SEMS) are an accepted palliation for malignant colorectal obstruction. Outcomes of stent insertion solely in older patients are unknown. OBJECTIVE: To compare outcomes of SEMS insertion for malignant colorectal disease, in older versus younger patients. METHODS: Forty-three patients were retrospectively identified as having undergone SEMS insertion for obstructing colorectal cancer. Of these, 24 were > or = 70 years of age (older patient group) and 19 were <70 years of age (younger patient group). RESULTS: There was no significant difference in successful SEMS insertion between the groups (88% in older versus 100% in younger patients, p > 0.05). Furthermore, the complication rate was similar in both groups (12.5% versus 26%, p > 0.10). There was no difference in median survival (113 days versus 135 days, p > 0.09). CONCLUSION: Colorectal stenting for malignant disease in older patients is both safe and effective with comparative success and complication rates to a younger population.

The effect of H2 antagonists on proliferation and apoptosis in human colorectal cancer cell lines.

Cimetidine is known to enhance the survival of gastro-intestinal cancer patients, though the mechanisms involved are incompletely understood. Postulated modes of action include blocking the proliferative effect of tumors and inhibiting T suppressor cell activity, both of which are thought to be mediated by histamine type 2 receptors. Apoptotic cell death may offer an alternative explanation for reduced cell growth. We aimed to examine the effects of histamine, cimetidine, and ranitidine on in vitro proliferation and apoptosis in two human colorectal cancer cell lines, Caco-2 and LoVo. A cell proliferation assay was used as an index of cell growth. Histamine receptor status was determined by quantifying cyclic adenosine monophosphate and apoptosis via DNA fragmentation. Results show that histamine (10(-5) to 10(-9) M) had no effect on the growth of either cell line. The proliferation of Caco-2 was inhibited by ranitidine (10(-7) M) alone and in combination with histamine. Cimetidine (10(-5) M) only suppressed the growth of Caco-2 in the presence of histamine. The H2 antagonists had no effect on LoVo irrespective of histamine. There was no accumulation of cyclic adenosine monophosphate in Caco-2 cells in response to histamine at a similar concentration. Apoptosis was induced in Caco-2 by both antisecretory drugs, and only ranitidine caused apoptotic cell death in LoVo cells. We conclude that cimetidine and ranitidine inhibit Caco-2 cancer cells in vitro, independently of the H2 receptor. In addition, both drugs induce apoptosis in the same cell line. Growth inhibition and apoptosis are likely to contribute to the tumor regressive properties of cimetidine and ranitidine in vivo.

Cytokeratin 7/20 and MUC1, 2, 5AC, and 6 expression patterns in Barrett's esophagus and intestinal metaplasia of the stomach: intestinal metaplasia of the cardia is related to Barrett's esophagus.

Intestinal metaplasia (IM) in endoscopic biopsies obtained from close to the gastroesophageal junction may represent IM of the cardia (CIM) or Barrett's esophagus (BE), which have different malignant potentials despite similar morphology. This study compared cytokeratin (CK) 7/20 and mucin (MUC1, 2, 5AC, and 6) immunopatterns in biopsies from BE (n = 41), CIM (n = 35), and antral gastric IM (AIM, n = 37) to evaluate their roles as diagnostic aids. CK7 and CK20 expression was described as absent, patchy (superficial and deep), continuous superficial only, continuous deep only, and diffuse. Eleven different combinations of CK7/20 expression were seen. Since CK20 staining was positive in all cases, four main patterns were defined on the basis of the observed CK7 staining as 1, absent; 2, patchy (superficial and/or deep); 3, diffuse; and 4, continuous superficial only. Overall CK7 positivity (regardless of pattern) was higher in BE and CIM than in AIM. CK patterns 3 and 4 were also higher in BE and CIM than in AIM. For either pattern 3 or 4, the positive and negative predictive values for BE versus AIM were 95% and 67%, respectively. MUC1 was rarely expressed in BE and CIM compared with AIM, whereas the opposite was noted for MUC5AC expression. MUC2 and MUC6 expression was similar in all locations. In conclusion, diffuse or continuous superficial CK7 staining is highly characteristic of BE and CIM and contrasts with AIM. It is, however, not very sensitive. CK20 profiles have no added value. Mucin expression also differs between BE and CIM versus AIM, but the specificity of any pattern is insufficient for distinction in individual cases. Importantly, CK and MUC expression patterns in BE and CIM are virtually indistinguishable, limiting their use in this differential and raising the question of whether they are biologically related.

'Cardiac-type' (mucinous) mucosa and carditis are both associated with Helicobacter pylori-related gastritis.

BACKGROUND: Adenocarcinoma of the gastro-oesophageal junction is rapidly increasing in incidence and there is much interest in precursor lesions. The aetiology of inflammation of the gastric cardia (carditis) and the concept of the cardia as a native zone of mucinous gastric glands are disputed. AIMS: To investigate the relationship between the type of cardiac mucosa and carditis with various histological and clinical parameters. METHODS: Ninety-eight sets of gastric biopsies (cardia, corpus, incisura and antrum) were obtained prospectively in young patients (median age 40 years) who presented to the outpatient clinic with symptoms of gastro-oesophageal reflux (n = 25) or other upper gastrointestinal symptoms. Patients with neoplasia or Barrett's oesophagus were excluded. The presence (n = 19) or absence of oesophagitis at endoscopy was recorded. The degree of inflammation, Helicobacter pylori density, intestinal metaplasia and atrophy were scored according to the Sydney classification and the type of cardiac mucosa (oxyntic or mucinous) was noted. RESULTS: We found that carditis and mucinous-type cardiac mucosa were strongly associated with H. pylori-related gastritis (P = 0.00019 and P = 0.006, respectively) but not with clinical or endoscopic gastro-oesophageal reflux. Mucinous mucosa in the cardia was only seen in 17% of biopsies. CONCLUSION: H. pylori-related gastritis is associated with mucinous-type cardiac mucosa as well as with carditis. The former strongly points to expansion of mucinous cardiac mucosa in H. pylori gastritis. This probably represents metaplasia of oxyntic to mucinous mucosa and raises the possibility of a role in carcinogenesis of the gastro-oesophageal junction.

Differences in proximal (cardia) versus distal (antral) gastric carcinogenesis via the retinoblastoma pathway.

AIM: Disruption of cell cycle regulation is a critical event in carcinogenesis, and alteration of the retinoblastoma (pRb) tumour suppressor pathway is frequent. The aim of this study was to compare alterations in this pathway in proximal and distal gastric carcinogenesis in an effort to explain the observed striking epidemiological differences. METHODS: Immunohistochemistry was performed to investigate expression of p16 and pRb in the following groups of both proximal (cardia) and distal (antral) tissue samples: (a) biopsies showing normal mucosa, (b) biopsies showing intestinal metaplasia and, (c) gastric cancer resection specimens including uninvolved mucosa and tumour. RESULTS: In the antrum there were highly significant trends for increased p16 expression with concomitant (and in the group of carcinomas inversely proportional) decreased pRb expression from normal mucosa to intestinal metaplasia to uninvolved mucosa (from cancer resections) to carcinoma. In the cardia, there were no differences in p16 expression between the various types of tissue samples whereas pRb expression was higher in normal mucosa compared with intestinal metaplasia and tissue from cancer resections. CONCLUSION: Alterations in the pRb pathway appear to play a more significant role in distal gastric carcinogenesis. It may be an early event in the former location since the trend towards p16 overexpression with concomitant pRb underexpression was seen as early as between normal mucosa and intestinal metaplasia. Importantly, the marked differences in expression of pRb and p16 between the cardia and antrum strongly support the hypothesis that tumours of the two locations are genetically different which may account for some of the observed epidemiological differences.