Interventions for Pancreatitis-New Approaches, Knowledge Gaps, and Research Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop.

ABSTRACT: There exists no cure for acute, recurrent acute or chronic pancreatitis and treatments to date have been focused on managing symptoms. A recent workshop held by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) focused on interventions that might disrupt or perhaps even reverse the natural course of this heterogenous disease, aiming to identify knowledge gaps and research opportunities that might inform future funding initiatives for NIDDK. The breadth and variety of identified active or planned clinical trials traverses the spectrum of the disease and was conceptually grouped for the workshop into behavioral, nutritional, pharmacologic and biologic, and mechanical interventions. Cognitive and other behavioral therapies are proven interventions for pain and addiction, but barriers exist to their use. Whilst a disease specific instrument quantifying pain is now validated, an equivalent is lacking for nutrition - and both face challenges in ease and frequency of administration. Multiple pharmacologic agents hold promise. Ongoing development of Patient Reported Outcome (PRO) measurements can satisfy Investigative New Drug (IND) regulatory assessments. Despite multiple randomized clinical trials demonstrating benefit, great uncertainty remains regarding patient selection, timing of intervention, and type of mechanical intervention (endoscopic versus surgery). Challenges and opportunities to establish beneficial interventions for patients were identified.

Rationale for and Development of the Pancreatic Quantitative Sensory Testing Consortium to Study Pain in Chronic Pancreatitis.

OBJECTIVES: Abdominal pain is the primary symptom of chronic pancreatitis (CP), but pain is difficult to assess, and objective methods for pain assessment are lacking. The characterization of the sensory component of pain as a surrogate for nociception can be achieved by sensory testing using standardized stimuli. Herein, we describe the rationale for and development of an international consortium to better understand and characterize CP pain. METHODS: A collaboration was initially formed between the University of Aalborg, Johns Hopkins University, and the University of Pittsburgh. This group refined the protocol for pancreatic quantitative sensory testing (P-QST) and then expanded the collaboration with plans for incorporating P-QST into prospective studies. RESULTS: The collaboration has successfully developed a P-QST nomogram. Chronic pancreatitis patients identified with P-QST as having widespread hyperalgesia had higher pain intensity scores, higher prevalence of constant pain, and decreased quality of life. Psychiatric comorbidities were independent of pain phenotypes. Multiple studies are underway to validate these findings and evaluate their utility in clinical trials. CONCLUSIONS: Development of the P-QST Consortium will facilitate collaborative efforts to use P-QST as a means for evaluation and characterization of pain in CP patients, and optimize methods to guide individualized pain management approaches.

Post-Acute Pancreatitis Pancreatic Exocrine Insufficiency: Rationale and Methodology of a Prospective, Observational, Multicenter Cohort Study.

OBJECTIVES: We describe the methodology of Post-Acute Pancreatitis Pancreatic Exocrine Insufficiency (PAPPEI), a prospective, observational, multicenter cohort study. The objectives of PAPPEI are to estimate the incidence rate of post-acute pancreatitis (AP) pancreatic exocrine insufficiency (PEI), define factors that determine the development of post-AP PEI, and evaluate the impact of post-AP PEI on nutritional status and quality of life. METHODS: Enrollment started in June 2017 in 3 expert academic centers in the United States. Data were collected during hospitalization (baseline) at 3 and 12 months after enrollment. Fecal elastase-1 was used to assess PEI. Study questionnaires are completed by patient interview and review of electronic medical records. Blood is obtained to evaluate vitamin deficiencies and nutritional markers. RESULTS: As of August 2020, 77 subjects have completed the baseline evaluation. The median age was 58 years (interquartile range, 39-67 years), 38% were male, and 90% were white. The etiology of AP was biliary in 39 subjects (51%), and 51 subjects (66%) had mild AP. Three- and 12-month follow-up data have been collected in 29 and 13 subjects, respectively. CONCLUSION: The PAPPEI study aims to expand our understanding of post-AP PEI incidence, including its impact on nutritional status and quality of life.

Endoscopic sleeve gastroplasty plus liraglutide versus endoscopic sleeve gastroplasty alone for weight loss.

BACKGROUND AND AIMS: Endoscopic sleeve gastroplasty (ESG) has been shown to be effective for inducing weight loss. The efficacy of liraglutide, a glucagon-like peptide-1 agonist, to augment weight loss after ESG is unknown. This study aims to evaluate the efficacy of ESG and liraglutide (ESG-L) compared with ESG alone. METHODS: This was a retrospective study of prospectively collected data from patients undergoing ESG at 3 outpatient clinics in Brazil between November 2017 and July 2018. Liraglutide was offered to all patients 5 months after ESG. Patients who opted to take liraglutide (ESG-L) were matched 1:1 to patients who declined it (ESG). The primary outcome was percent total body weight loss (%TBWL), and percent excess weight loss (%EWL) 7 months after initiation of liraglutide (12 months after ESG). The secondary outcome was change in percent body fat 12 months after ESG. ESG technique and postprocedure follow-up were identical at all 3 sites. RESULTS: Propensity score matching yielded 26 matched pairs. Adjusted comparisons between the 2 groups showed that patients who opted to take liraglutide had a superior mean %TBWL 7 months after initiation of liraglutide (ESG-L) compared with those who declined it (ESG) (24.72% ± 2.12% vs 20.51% ± 1.68%, respectively; P < .001). ESG-L had a statistically greater reduction in percent body fat compared with ESG (7.85% ± 1.26% vs 10.54% ± 1.88%, respectively; P < .001) at 12 months. CONCLUSIONS: Addition of liraglutide at 5 months results in superior weight loss and improved efficacy as demonstrated by decreased body fat 12 months after ESG. Further studies are imperative to determine optimal dose, timing, and duration of liraglutide.

Efficacy of Liraglutide to Prevent Weight Regain After Retrieval of an Adjustable Intra-gastric Balloon-a Case-Matched Study.

PURPOSE: Weight regain after balloon retrieval is a concern with all intra-gastric balloons (IGBs). The aim of this study was to evaluate the efficacy of liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, to prevent weight regain following IGB retrieval. MATERIALS AND METHODS: This was a case-matched study of patients undergoing Spatz3 adjustable IGB (Spatz FGIA, Inc. NY, USA) at three outpatient clinics in Brazil between November 2015 and January 2019. Seventy-seven patients that opted to take liraglutide following IGB retrieval (IGB-L) were matched 1:1 to 198 patients that declined the medication-IGB-Alone (IGB-A). Propensity score adjustment was performed at the time of balloon retrieval on factors known to influence the choice of liraglutide. Weight and percent body fat (%BF) was measured at baseline and 9 months after IGB retrieval. % BF is defined as the total mass of fat divided by total body mass, multiplied by 100. The primary outcome was weight regain, and the secondary outcome was change in %BF 9 months after IGB retrieval. RESULTS: Propensity score matching yielded 53 matched pairs. Weight regain to the starting point was not observed in either group. There was significantly less weight regain in IGB-L compared to IGB-A, - 1.15 ± 0.94 kg versus - 0.66 ± 0.99 kg (p = 0.010) 9 months after balloon retrieval. Additionally, %BF decline in IGB-L was superior to IGB-A - 10.83 ± 1.50 versus - 7.94 ± 2.02 (p < 0.01). There was no difference in weight regain or decline in %BF based on liraglutide dose. CONCLUSION: Liraglutide has an additive benefit with respect to efficacy and a reduction in body fat when commenced after IGB retrieval. Future randomized control studies will be needed to determine the optimal dose and duration of liraglutide to achieve superior outcomes.

Risk factors for early repeat ERCP in liver transplantation patients with anastomotic biliary stricture.

INTRODUCTION: Anastomotic biliary strictures (ABS) are a significant clinical problem associated with decreased survival post-liver transplantation (LT). Contributing to the morbidity of ABS is the need for early (i.e. emergent or unplanned) repeat endoscopic retrograde cholangiopancreatographies (ER-ERCPs). Our aim was to determine clinical, operative, and endoscopic predictors of ER-ERCP in patients with ABS. MATERIAL AND METHODS: Medical records of 559 patients who underwent LT at our institution from 2000-2012 were retrospectively reviewed for pertinent data. The primary endpoint was need for ER-ERCP. Seventeen potential predictors of ER-ERCP were assessed in bivariate analyses, and those with p < 0.20 were included in multivariate regression models. RESULTS: Fifty-four LT patients developed ABS and underwent a total of 200 ERCPs, of which 40 met criteria for ER-ERCP. Predictors of ER-ERCP in bivariate analyses included balloon dilation within 3 months post-LT and donation after cardiac death (both p < 0.05). Balloon dilation within 3 months post-LT was also associated with shorter ER-ERCP-free survival (p = 0.02). Moreover, a significantly higher proportion (67%) of patients who underwent balloon dilation within 3 months post-LT subsequent experienced ≥ 1 ER-ERCP (p = 0.03), and those who experienced ≥ 1 ER-ERCP had lower stricture resolution rates at the end of endoscopic therapy compared to those who did not (79 vs. 97%, p = 0.02). In multivariate analyses, balloon dilation within 3 months post-LT was the strongest predictor of ER-ERCP (OR 3.8, 95% CI 1.7-8.6, p = 0.001). CONCLUSIONS: Balloon dilation of ABS within 3 months post-LT is associated with an increased risk of ER-ERCP, which itself is associated with lower ABS resolution rates. Prospective studies are needed to confirm these findings and their implications for endoscopic management and follow-up of post-LT ABS.

Sirolimus based immunosuppression is associated with need for early repeat therapeutic ERCP in liver transplant patients with anastomotic biliary stricture.

INTRODUCTION: Sirolimus has inhibitory effects on epithelial healing and cholangiocyte regeneration. In liver transplantation (LT) patients, these effects may be greatest at the biliary anastomosis. We therefore investigated whether sirolimus use is associated with need for early or emergent repeat therapeutic endoscopic retrograde cholangiography (ERC) in LT patients with anastomotic biliary stricture (ABS). MATERIAL AND METHODS: Medical records of patients who underwent LT from 1998-2009 at Johns Hopkins were reviewed and patients with ABS identified. Primary outcome was early repeat ERC, defined as need for unscheduled (i.e. unplanned) or emergent repeat therapeutic ERC. Univariate and multivariate logistic regression analyses (adjusting for age, sex, LT to ERC time, and stent number) were performed to assess association between sirolimus and early repeat ERC. RESULTS: 45 patients developed ABS and underwent 156 ERCs total. Early (median 26 days) repeat ERC occurred in 14/56 (25%) and 6/100 (6%) ERCs performed with and without concomitant sirolimus-based immunosuppression, respectively (OR 1.22; 95% CI 1.02-1.45; p = 0.03). In multivariate analysis, sirolimus use was associated with early repeat ERC (OR 1.24; 95% CI 1.04-1.47; p = 0.015); this association remained significant when sirolimus dose was modeled as a continuous variable (OR 1.04 for each mg of sirolimus per day; 95% CI 1.02-1.08; p = 0.038). CONCLUSIONS: Sirolimus-based immunosuppression appears to be associated with a modest but significantly increased, dose-dependent risk of early repeat ERC in LT patients with ABS. Prospective studies are needed to further investigate these findings and determine if sirolimus use or dose should potentially be reconsidered once ABS is diagnosed.

Sirolimus may be associated with early recurrence of biliary obstruction in liver transplant patients undergoing endoscopic stenting of biliary strictures.

INTRODUCTION: Recurrent biliary obstruction necessitating premature repeat endoscopic retrograde pancreatography (ERCP) remains a costly and morbid problem in patients undergoing treatment of post-orthotopic liver transplantation (OLT) biliary strictures. We evaluated the relationship between prednisone or sirolimus use and early recurrence of biliary obstruction given their negative effects on collagen production and cholangiocyte regeneration. METHODS: Medical records of adult patients who underwent OLT from 1998-2008 and developed anastomotic (ABS) and/or nonanastomotic (NABS) biliary strictures requiring endoscopic plastic stent therapy were reviewed. Outcome was early recurrence of biliary obstruction requiring repeat ERCP. Univariate and multivariable logistic regression analysis, adjusting for age, sex, and time from OLT to ERCP, were performed. RESULTS: 35 patients with ABS and 9 patients with NABS underwent a total of 157 ERCPs. Median patient age was 56 years, 68% were male, and hepatitis C was the most common OLT indication (52%). Early recurrence of biliary obstruction ocurred following 17.1% of ERCPs. In univariate analysis, neither prednisone nor sirolimus was associated with early recurrence of biliary obstruction. In multivariate analysis, however, sirolimus use was associated with increased incidence of early recurrent biliary obstruction (OR = 2.53; 95% CI: 0.77-8.32; p = 0.12); this was more pronounced at doses > 3 (OR = 4.27; 95% CI: 0.62-29.3; p = 0.14) than at ≤ 3 mg/day (OR = 2.24; 95% CI: 0.62-8.13; p = 0.22) and statistically significant in patients with ABS only (OR = 1.44 per mg increase in sirolimus dose; 95% CI 1.02-2.03; p = 0.037). CONCLUSIONS: Sirolimus use, particularly at higher doses and patients with ABS, may be associated with an increased risk of early recurrence of biliary obstruction requiring repeat ERCP for post-OLT biliary strictures. Additional studies are needed to further investigate these findings and elucidate other risk factors.