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Abstract Purpose Validate the semiquantitative (SQ)-MRI score for chronic pancreatitis (CP) diagnosis in an independent, multicenter cohort. Methods We analyzed MRIs performed at baseline in 337 participants with acute (AP) or recurrent AP (RAP) and 67 with non-calcific chronic pancreatitis (NCCP) enrolled in the PROCEED study from 6/2017 to 3/2023. MRIs were performed at multiple clinical centers using site-specific clinical protocols and a variety of MRI vendors to evaluate the SQ-MRI score in a real-world setting. The SQ-MRI score was calculated using the T1 signal intensity ratio of the pancreas to the spleen (T1 score), arteriovenous enhancement ratio (AVR), and pancreatic body diameter (PBD). We adjusted for confounding by participant characteristics via propensity score weighting. Results Median AVR was higher in AP/RAP (1.18, IQR: 0.97–1.44) than in the NCCP group (1.03, IQR: 0.78–1.22, p = 0.007). Pancreatic body diameters were larger in AP/RAP than in the NCCP group − 7–14 mm (10% vs 25%), 14–20 mm (40% vs 54%), and > 20 mm (50% vs 21%), respectively ( p < 0.01). Median T1 score was higher in AP/RAP (1.18, IQR: 0.96–1.40) than in the NCCP group (1.04, IQR: 0.86–1.32, p = 0.10). Median SQ-MRI score in the AP/RAP group was significantly lower, 1.91 (IQR: 0.97, 2.95), than in the NCCP group, 2.74 (IQR: 2.04–4.03) ( p < 0.001). The propensity score-adjusted AUC for SQ-MRI to distinguish AP/RAP from NCCP was 0.64, which was higher than for individual parameters. Conclusion We have validated the SQ-MRI score in a multicenter cohort using an independent, real-world MRI dataset.

The adult chronic pancreatitis (CP) working group, formed at the inception of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC), has developed a robust framework and infrastructure to conduct clinical, translational, and mechanistic studies of CP. At its core is PRO spective Evaluation of C hronic Pancreatitis for E pid E miologic and Translational Stu D ies (PROCEED), the first longitudinal cohort study of CP in US adults, launched in 2017. PROCEED has developed a well-annotated clinical data set of over 2000 deeply-phenotyped participants, a biorepository and an imaging repository. Investigators have published promising data on blood-based and imaging-based biomarkers of CP diagnosis and pain, which are awaiting validation. Clinical observations include classification of patients into mechanism-based pain phenotypes using responses to PROMIS questionnaires, prevalence and predictors of opioid use, prevalence of psychological comorbidity, and osteopathy in CP patients. Pilot clinical trials have evaluated the effect of oral indomethacin on pancreatic fluid prostaglandin E2 levels and Internet-based cognitive behavioral therapy (CBT) for chronic pain. Results of pilot trials have led to an ongoing definitive randomized clinical trial for CBT. The rich environment and resources have facilitated mentorship and academic development of many early-stage investigators. Investigators outside of the consortium have opportunities for collaboration. In the next 5 years, the working group plans to further strengthen the research platform, complete primary and key secondary analyses of PROCEED and ancillary studies, continue efforts to develop biomarkers for diagnosis and prognosis of CP, and complete ongoing clinical trials to address unanswered questions in the field.

Background: Pancreatitis significantly alters the microbial composition of the oral and intestinal compartments, causing dysbiosis that may contribute to disease mechanisms and potentially serve as a basis for diagnosis or treatment. Objective: To determine whether the oral or gut microbial signature can classify chronic pancreatitis (CP). Methods: Stool samples (n=707) were collected from participants in the Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED). Samples were distributed among 200 healthy (HC), 310 CP, 49 acute pancreatitis (AP), and 148 recurrent acute pancreatitis (RAP). In addition, saliva samples were collected for a subset of participants (n=156). Whole genome sequencing was performed to assess microbiome composition. Machine learning algorithms were utilized to identify a signature with microbial features predictive of CP. Results: Gut alpha diversity was significantly decreased in AP, RAP, and CP compared with HC, with CP exhibiting the lowest diversity. In contrast, oral microbial diversity showed no significant variation across groups. Beta diversity analysis revealed distinct gut microbiome compositions between HC and pancreatitis subtypes, with CP showing the most pronounced differences. Random forest models using gut microbial species demonstrated robust predictive performance for CP using a minimum of 10 species (Area under the curve—AUC: 0.834; accuracy: 0.774). Despite similarities in gut microbiome composition across pancreatitis subtypes, a unique gut microbial signature for CP was identified highlighting the microbiome’s potential in CP diagnosis. Conclusion: Our study reveals a gut microbial signature predictive of CP using machine learning models in a large US multi-institutional cohort.

Objectives: Smoking is a key risk factor for pancreatitis, contributing to pathogenesis and disease progression. Data regarding second-hand smoking, or passive smoking (PS) exposure, are lacking. We therefore aimed to assess the impact of PS exposure across the pancreatitis spectrum. Methods: We analyzed baseline data from the PROCEED study, a multicenter study in the United States including patients with acute (AP), recurrent acute (RAP), and chronic (CP) pancreatitis. Participants detailed their individual smoking history and PS exposure, which was compared between AP, RAP, and CP subgroups. Participant factors and clinical characteristics were compared by level of individual and PS exposure. Results: Among 1369 participants (190 AP, 498 RAP, 681 CP), 346 (25.3%) were current and 409 (29.9%) were former smokers. The CP subgroup had the highest proportion of current smokers (36.7% CP vs 15.1% RAP, 11.1% AP, P < 0.001). PS exposure was also significantly higher in the CP subgroup (68.6% CP vs 58.2% RAP, 55.3% AP, P < 0.001). A minority (16.3%) with CP reported no smoking exposure (by self or passive) while nearly half smoked ≥20 pack-years. The mean PS duration was significantly higher in CP participants (21.8 y) compared with those with AP (17.8 y) or RAP (18.9 y) ( P < 0.0166). Conclusions: In this multicenter study, we affirmed an association with smoking use and intensity with CP-related complications. For the first time, we report a high prevalence of prior exposure to passive smoking in all pancreatitis subtypes, which requires further study to understand the impact on disease outcomes.

Objectives: Participant retention is essential in prospective studies to minimize bias and maintain validity. This study aimed to estimate retention rates and identify factors influencing attrition in a multicenter cohort (PROCEED) of US adults with acute/recurrent acute pancreatitis (AP/RAP) and chronic pancreatitis (CP). Methods: Participants from the PROCEED study with AP/RAP or CP eligible for follow-up within the designated visit window were included. Retention was defined as completing at least one follow-up visit during the observation period. Retention was analyzed by follow-up mode (in-person and/or medical record review) and disease type (AP/RAP and CP). Retention factors were assessed using univariate analyses (Wilcoxon rank-sum for continuous variables, χ 2 /Fisher's exact for categorical) and multivariable logistic regression. Missing data were adjusted using multiple imputations in statistical modeling. Results: Among 1279 participants (AP/RAP: n=632, median age 47, 48.9% female; CP: n=647, median age 54, 46.5% female), we observed high cumulative and annualized retention rates, with improved retention when incorporating medical record reviews. In multivariable regression analyses, older age was statistically significantly associated with in-person retention in the AP/RAP group ( P =0.0001), while a higher self-reported physical health (assessed with PROMIS Global Health Physical Health T-score) was a key predictor of retention in CP ( P =0.034). Conclusions: Integrating medical records review substantially enhanced retention rates, enabling robust analyses of pancreatitis outcomes and disease progression. Older age and better self-reported physical health were key predictors of retention, highlighting the need for targeted strategies to enhance engagement among younger participants and those with poorer health in long-term studies.

Background: The impact of multiple substance use on the risk of pancreatitis remains underexplored. Objective: To systematically review peer-reviewed observational studies assessing the association of multiple substance use with the risk of acute pancreatitis (AP) or chronic pancreatitis (CP) in adults. Design: We conducted a systematic review informed by the Preferred Reporting Items for Systematic Review and Meta-Analyses guideline. Data sources and methods: EMBASE, MEDLINE, and PsycINFO were searched up to March 2024. Reference lists of included studies were reviewed. From 5205 records identified, 181 relevant records were evaluated in full text. Studies evaluating the association of ⩾2 substances, including tobacco, alcohol, cannabis, and illicit substances, with AP or CP were included. Data were extracted by one reviewer, with quality control by a second reviewer. Quality assessments were independently conducted by two reviewers, with differences resolved by a third. Results: Of 11 included studies, 6 investigated AP as the outcome and 5 examined CP. Among AP studies, 5 comparing smoking and alcohol to alcohol-only use showed high heterogeneity ( I 2 = 90.9%), with relative risks (RRs) from 1.40 to 11.40. One study examining cannabis and alcohol versus alcohol found a lower risk of AP in cannabis users. Among CP studies, four comparing smoking and alcohol to alcohol-only use were heterogeneous ( I 2 = 81%) with odds ratios 1.21–31.50. Where examined, smoking increases the risk of AP and CP in a dose-dependent fashion. Heavy alcohol users demonstrated a significant increase in CP risk across all smoking categories in one study. Conclusion: Combined alcohol and tobacco use increases pancreatitis risk compared to single substance use, despite heterogeneity in RRs and exposure definitions. Evidence suggests a dose-dependent impact of smoking on pancreatitis risk when added to alcohol. Studies on the impact of a combination of other substance use on pancreatitis risk are needed. Trial registration (PROSPERO): CRD42024503677.

INTRODUCTION: Chronic pancreatitis (CP) is a disease associated with chronic inflammation, fibrosis, and pain. There is a lack of tools available that facilitate early diagnosis, when intervention could prevent irreversible damage. Pilot data suggested prostaglandin E2 (PGE2) as a candidate biomarker for early CP. PGE2 activates signaling pathways that promote inflammation, pain, and fibrosis. METHODS: We assessed PGE2, metabolites, and downstream targets in pancreatic fluid collected endoscopically 0–10 (n = 110) and 10–20 (n = 111) minutes after intravenous secretin administration. PGE2 and metabolites were measured in plasma (n = 75) and urine (n = 71) from the same subjects. Subjects were enrolled in the PROCEED study and classified symptomatic controls, acute/recurrent acute pancreatitis (AP/RAP), or CP. RESULTS: A significant main effect was detected in 10–20 minutes pancreas fluid ( P = 0.027) and plasma ( P = 0.046); post hoc testing showed PGE2 was lower in the AP/RAP group compared with symptomatic controls. There was also trend toward lower PGE2 in urine ( P = 0.062). To elucidate the active downstream pathways, calcitonin gene-related peptide, substance P, and matrix metalloproteinases (MMPs) 1, 2, 3, 7, 9, and 13 were measured in pancreas fluid. A significant difference between the 3 groups was detected for both MMP7 and MMP9. MMP7 was elevated in individuals with CP vs AP/RAP ( P = 0.012) for samples collected early but both time points for MMP9 ( P = 0.027, P = 0.002). DISCUSSION: While PGE2 is detectable in pancreas fluid, these data suggest that it may not be sensitive enough to distinguish between AP/RAP and CP. However, MMPs may distinguish between stages of pancreatitis and require further testing as potential diagnostic biomarkers.

Pancreatogenic or type 3c diabetes, which occurs as a consequence of pancreatitis, may have several mechanisms. Mechanisms overlapping with those of type 2 diabetes have been explored, including insulin resistance and insulin deficiency. However, autoimmune mechanisms in response to unmasking β-cell antigens, similar to those of type 1 diabetes (T1D), have not been thoroughly examined. We performed cross-sectional T1D autoantibody profiling in a large prospective cohort (N = 927) of adults with acute, recurrent acute, or chronic pancreatitis. We examined correlations of prevalence of autoantibodies against GAD (GAD antibody), IA-2 (IA-2 antibody), zinc transporter 8 (ZnT8; ZnT8 antibody), and insulin (insulin autoantibody [IAA]) with clinical and demographic features, including presence of diabetes, diabetes treatment, and family history of diabetes. Diabetes was present in 11 (12%) of 94 participants with acute pancreatitis, 69 (27%) of 273 with recurrent acute pancreatitis, and 235 (43%) of 560 with chronic pancreatitis. Among these groups, islet autoantibodies were respectively found in five (5.3%) of 94, 48 (17.6%) of 273, and 127 (22.6%) of 560. The proportions of individuals with diabetes who were autoantibody positive were 45%, 70%, and 54%, respectively (most commonly IAA, which may reflect exogenous insulin use). However, across the entire cohort, 27 participants (2.9%) had two, two (0.2%) had three, and one (0.1%) had four T1D-associated autoantibodies, respectively, suggesting a potential pathogenic link that should be further explored. ARTICLE HIGHLIGHTS Type 1 diabetes–associated autoimmune mechanisms have not been thoroughly examined in pancreatitis-associated diabetes. We assessed the prevalence of four islet autoantibodies in serum from a large prospective cohort of patients with acute, recurrent acute, or chronic pancreatitis. Diabetes was present in 11 (12%) of 94 participants with acute pancreatitis, 69 (27%) of 273 with recurrent acute pancreatitis, and 235 (43%) of 560 with chronic pancreatitis. Excluding those with only insulin autoantibody positivity, which is confounded by insulin treatment, islet autoantibodies were identified in 51 (5.5%) of 927 participants, and 30 (3.2%) of 297 were positive for two or more autoantibodies. Our findings suggest pancreatitis may elicit islet autoimmunity in a subset of patients, necessitating prospective longitudinal follow-up.

INTRODUCTION: Chronic pancreatitis (CP) remains difficult to manage with few treatment options. Prior studies have implicated prostaglandin E 2 (PGE 2 ) in mediating chronic inflammation in the pancreas. Therefore, we aimed to evaluate whether indomethacin, a cyclooxygenase-2 enzyme inhibitor, would reduce PGE 2 levels in CP. METHODS: In this pilot multicenter randomized controlled trial, participants with CP received oral indomethacin (50 mg) or placebo twice daily for 28 days. Measurement of PGE 2 levels in pancreatic fluid collected endoscopically after secretin administration at baseline and posttreatment (day 28) was performed. Quality of life and pain were also assessed at baseline and posttreatment. RESULTS: A total of 27 participants were randomized (indomethacin = 13, placebo = 14). Although PGE 2 levels decreased after treatment in pancreas fluid, plasma, and saliva in the indomethacin group, there was no significant difference in mean change in pancreas fluid PGE 2 levels between the indomethacin and placebo groups (−457.7 pg/mL vs −840.4 pg/mL, P = 0.25). There was also no significant change in pain severity composite score (−1.3 indomethacin vs −0.5 placebo, P = 0.33), but the improvement in pain interference score (−2.9 indomethacin vs −0.4, P = 0.058) trended toward significance. There was no difference in adverse events between the 2 groups. DISCUSSION: In this phase 1/2 study, oral indomethacin was safe and well tolerated by patients with CP. Although there was no significant difference in change in PGE 2 levels, further studies are needed to determine the effect of indomethacin on the inflammatory pathway of CP and patient-centered outcomes.

INTRODUCTION: Opioids are used to treat pain in chronic pancreatitis (CP), but little is known about current use patterns. The aim of this study was to characterize the utilization of opioids and associations with clinical characteristics in adult patients with CP. METHODS: This cross-sectional analysis used baseline data from participants with definite CP enrolled in a cohort study in the United States (PROspective Evaluation of CP for EpidEmiologic and Translational StuDies). Data on demographics, pain medication use, healthcare utilization, disability, and pain patterns were systematically collected in case report forms while quality of life was assessed with patient-reported outcome instruments. Opioid use was classified according to strength (weak or strong) and frequency (scheduled or as-needed). RESULTS: A total of 681 participants (n = 364, 53% male) were included: 299 (44%) were current opioid users (22% only weak opioids and 22% at least 1 strong opioid). Increasing frequency and severity of pain was associated with increase of weak, strong, as-needed, or scheduled opioids. Neuromodulators were used by ∼40% of participants; increasing use was associated with increasing frequency and severity of pain. On multivariate analysis, independent predictors associated with strength and frequency of current opioid use were pain patterns (odds ratios [ORs] 1.84–8.32 and ORs 1.92–8.52, respectively, P < 0.001) and prior celiac plexus block (OR 3.54, 95% confidence intervals 1.82–6.87 and OR 3.42, 95% confidence intervals 1.76–6.64, respectively). Participants using opioids had higher prevalence of disability, healthcare utilization, and poorer quality of life. DISCUSSION: Opioid use in CP is common and associated with increased pain severity and constancy. These data provide foundational estimates for future trials that can elucidate the complex interactions between patient factors, pain, and interventions.