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.

The optimal management of anti-drug antibodies to infliximab and identification of anti-drug antibody values for clinical outcomes in patients with inflammatory bowel disease.

PURPOSE: Secondary loss of response (LOR) to infliximab (IFX) commonly occurs. One cause is the development of anti-drug antibodies (ADAs). Evidence regarding the optimal management of ADAs is lacking. We aim to identify the best practice of management of ADAs to IFX to avoid discontinuation of therapy and to determine specific ADA cut-off values to determine pre-specified clinical outcomes. METHODS: This is a 3-year study of patients receiving IFX who developed ADAs > 8µg/ml. We reviewed the management strategies and subsequent outcomes in patients who developed ADAs. RESULTS: A total of 132 patients are included. Baseline characteristics include 54% male patients and mean age of 39.4 years. Fifty-two percent (n = 69) of patients discontinued IFX following the development of ADAs, 33.3% (n = 44) sited as secondary to LOR. Both an increase in IFX and adjustments to combination therapy were associated with lower rates of discontinuation of IFX vs no intervention (p value < 0.001, p value < 0.001). An increase in IFX resulted in a significant difference in ADAs/IFX trough levels pre- and post-intervention (p value < 0.001, p value = 0.032). ROC curve analysis yielded significant cut-off values for ADAs and treatment failure (ADA >16µg/ml, AUC 0.642, p value 0.003), steroid use (ADA >19 µg/ml, AUC 0.61, p value 0.048) development of infusion reactions (ADA> 37 µg/ml, AUC 0.68, p value 0.045) and switch to another biologic (ADA >45 µg/ml, AUC 0.739, p value <0.001). CONCLUSION: Both escalation of IFX and combination therapy resulted in lower rates of LOR. ROC curve analysis identified significant cut-off values for ADA trough levels and important clinical 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.

Assessment of the value of gastroenterologists' activity in the outpatient setting: applying the "Moneyball" approach to clinical care.

BACKGROUND: With the emergence of alternative payment systems replacing the traditional funding models, the value of physician activity is scrutinized more closely. Attempts have been made to quantify the value of endoscopists' activity; there is little in the medical literature describing gastroenterologists' value in the outpatient setting. AIMS: To characterize the value of clinical activity of gastroenterologists in the outpatient setting. METHODS: The value of clinical activity of ten gastroenterologists in an academic medical center was estimated. Value was defined as Q (quality of clinical care) divided by TA (duration of outpatient visit adjusted for complexity level); TA served as a surrogate measure of the cost of the clinician's services. Medical records of each patient's clinical visit were reviewed and graded independently by three staff gastroenterologists; each reviewer was blinded to the identity of the physician and to other reviewers' scores. RESULTS: Over consecutive weeks, the clinical records of 307 patients who were seen by ten gastroenterologists were reviewed and graded for quality (Q) and complexity (C); the duration of each visit (T) was recorded. Each physician saw a mean of 31 patients; mean physician value varied from 0.28 to 0.87. More senior physicians demonstrated higher levels of value. CONCLUSION: Measurement of the value of clinical activity represents an important component of gastroenterologists' performance. There was a threefold variation among physician levels of value with more experienced clinicians demonstrating higher value levels. Further studies will be required to more clearly define valid metrics for physician value.

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.

Measuring the value of endoscopic retrograde cholangiopancreatography activity: an opportunity to stratify endoscopists on the basis of their value.

INTRODUCTION: As finite healthcare resources come under pressure, the value of physician activity is assuming increasing importance. The value in healthcare can be defined as patient health outcomes achieved per monetary unit spent. Even though some attempts have been made to quantify the value of clinician activity, there is little in the medical literature describing the importance of endoscopists' activity. This study aimed to characterize the value of endoscopic retrograde cholangiopancreatography (ERCP) performance of five gastroenterologists. PATIENTS AND METHODS: We carried out a retrospective-prospective cohort study using the databases of patients undergoing ERCP between September 2014 and March 2017. We collected data from 1070 patients who underwent ERCP comparing value among the ERCPists at index ERCP. Procedure value was calculated using the formula Q/(T/C), where Q is the quality of procedure, T is the duration of procedure and C is the adjusted for complexity level. Quality and complexity were derived on a 1-4 Likert scale on the basis of American Society for Gastrointestinal Endoscopy criteria; time was recorded (in min) from intubation to extubation. Endoscopist time calculated from procedure time was considered a surrogate marker of cost as individual components of procedure cost were not itemized. RESULTS: In total, 590 procedures were analysed: 465 retrospectively over 24 months and 125 prospectively over 6 months. There was a 32% variation in the value of endoscopist activity in a more substantial retrospective cohort, with an even more considerable 73% variation in a smaller prospective arm. CONCLUSION: In an analysis of greater than 1000 ERCPs by a small cohort of experienced ERCPists, there was a wide variation in the value of endoscopist activity. Although the precision of estimating procedural costs needs further refinement, these findings show the ability to stratify ERCPists on the basis of the value their activity. As healthcare costs are scrutinized more closely, such value measurements are likely to become more relevant.

Covered self-expanding metal stents for the management of common bile duct stones.

BACKGROUND AND AIMS: Little medical literature exists for the use of fully covered self-expanding metal stents (CSEMSs) in the management of retained common bile duct (CBD) stones. Our aim was to assess the safety and efficacy of CSEMSs for the indication of retained "difficult" CBD stones. METHODS: This retrospective cases series included 44 patients (30 women; median age, 69 years [range, 24-88]) who underwent CSEMS insertion for the indication of retained "difficult" CBD stones in 2 tertiary referral centers. Patients underwent temporary placement of CSEMSs after incomplete stone clearance at ERCP. Follow-up ERCP was arranged for stent removal and subsequent attempt at duct clearance. Procedure-related adverse events were also recorded. RESULTS: Successful biliary drainage was achieved in all cases after CSEMS placement. Forty-two stents were removed with successful duct clearance achieved in 36 cases (82%) after a median in-stent duration of 8 weeks. There were 10 cases (22.7%) of stent migration, all noted incidentally during follow-up. One patient died of nonbiliary causes before attempted removal. CONCLUSION: This is the largest published retrospective case series for use of CSEMSs for management of retained CBD stone disease to date. We have shown high success rates for this indication. A well-designed, multicenter, randomized controlled trial might address the uncertainty of cost-to-benefit ratio and appropriate duration for CSEMSs to be left in situ. Specific stent modification for this indication, including wider distal flare and retrieval purse string loop, may also be useful.

The Inappropriate Prescription of Oral Proton Pump Inhibitors in the Hospital Setting: A Prospective Cross-Sectional Study.

UNLABELLED: Proton pump inhibitors (PPIs) are used to treat upper gastrointestinal tract disorders. Their efficacy and perceived safety have led to widespread prescription. This is not without effect, in terms of adverse events and resource utilization. AIM: To prospectively assess oral PPI prescription in hospitalized patients. METHODS: PPI prescription in consecutive hospitalized patients was assessed. Indication and dose were assessed by patient interview and medical record review. Comparisons with current published prescribing guidelines were made. RESULTS: Four hundred and forty-seven patients were included. 57.5 % were prescribed PPIs. 26.8 % prescriptions were for inappropriate or unclear indications. 68.4 % were on higher doses than guidelines recommended, of which 41.6 % could have undergone dose reduction, and 26.5 % discontinued. In a multivariate analysis, age, gender, and length of stay had no association with PPI prescription. Although aspirin use was appropriately associated with PPI prescription (RR: 1.8, 95 % CI 1.127-3.69; p < 0.05), the PPI was often given at higher than recommended doses (p < 0.001). This may reflect older age and multiple risk factors in this subset. Surgical patients commenced more PPIs and at higher dosages (p < 0.001). Omeprazole and lansoprazole were most often inappropriately prescribed (p < 0.01, p < 0.001, respectively). CONCLUSION: Inappropriate PPI therapy is still a problem in hospitals, though it appears to be at a lower level compared with previous studies. Awareness of evidence-based guidelines and targeted medicine reconciliation strategies are essential for cost-effective and safe use of these medications.

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.

Inter-endoscopist agreement in diagnosis of Barrett's oesophagus.

OBJECTIVE: To assess how interpretation of abnormalities at the oesophago-gastric junction (OGJ) when making a diagnosis of Barrett's oesophagus (BO) varies between endoscopists and to examine the impact of the endoscopy experience on these decisions. DESIGN/SETTING: Members of the Irish Society of Gastroenterology who regularly perform gastroscopy were invited to participate in a web based image assessment study. INTERVENTIONS: Questions were posed to ascertain level of endoscopy experience, and participants were asked to indicate the presence or absence of BO in 12 endoscopic images of the OGJ. OUTCOME MEASURES: Primary outcome was overall level of agreement in responses and relationship to endoscopy experience. RESULTS: The responses of 65 clinicians regularly performing gastroscopy were analysed. In 3/12 images, showing typical long segment BO, there was a strong consensus on the endoscopic diagnosis (>95% agreement). However, agreement was fair to poor (κ for multiple raters, 0.31) on the presence or absence of short BO segments at endoscopy. Minimal differences were observed between experienced endoscopists (individuals with >10 years' endoscopy experience) and less experienced counterparts in the threshold for BO diagnosis. Inter-endoscopist agreement overall was not significantly better within the more experienced group. CONCLUSION: The study demonstrates low interobserver agreement in endoscopic diagnosis of (short segment) BO, even among experienced endoscopists. Given the costs associated with endoscopic surveillance of BO, prompt efforts to promote consensus diagnosis and improve agreement are required as an important quality improvement measure in this area.

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.