INTRODUCTION: Chronic pancreatitis (CP) remains difficult to manage with few treatment options. Prior studies have implicated prostaglandin E₂ (PGE₂) in mediating chronic inflammation in the pancreas. Therefore, we aimed to evaluate whether indomethacin, a cyclooxygenase-2 enzyme inhibitor, would reduce PGE₂ 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 PGE₂ 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 PGE₂ 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 PGE₂ 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 PGE₂ levels, further studies are needed to determine the effect of indomethacin on the inflammatory pathway of CP and patient-centered outcomes.

INTRODUCTION: Pancreatitis-associated osteopathy is a clinically significant but mechanistically underexplored complication of pancreatic disease. We aimed to characterize stage-specific alterations in bone remodeling biomarkers across the spectrum of disease: recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP). METHODS: In a cross-sectional analysis of North American Pancreatitis Study 2 participants, we measured serum mechanistic (sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin), hormonal (fibroblast growth factor 23, insulin, and leptin), and modulatory (osteopontin, oncostatin, and osteoactivin) markers in controls (n = 30), RAP (n = 40), and CP (n = 40) using a multiplex assay. Group differences were assessed with ANOVA, Fisher exact test, and Kruskal-Wallis; multivariable regression identified predictors of biomarker variation. RESULTS: Eight of 10 biomarkers differed significantly among groups. Sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin were elevated in RAP and CP vs controls, with the highest values in CP. The RANKL/OPG ratio was greatest in CP. Fibroblast growth factor 23 was increased in RAP, while insulin was reduced in CP. Osteopontin and oncostatin were elevated in pancreatitis groups, with osteopontin increasing progressively from control to RAP to CP. Several bone biomarker patterns varied by sex, tobacco, and alcohol use. Stepwise regression identified several significant predictors. DISCUSSION: These findings represent the most comprehensive bone metabolism biomarker profiling in pancreatitis to date, revealing stage-specific dysregulation of bone remodeling. Findings suggest a shift toward increased bone resorption and impaired formation with disease progression. Larger longitudinal studies are needed for marker validation, to clarify mechanisms, and guide targeted interventions to reduce bone loss and fracture risk in this high-risk population.

Objective: We previously validated a short endoscopic test with pancreas fluid enzyme activity in pediatrics and young adults. We assessed the role of pancreatic fluid enzyme activity as a candidate to address the lack of a diagnostic biomarker for chronic pancreatitis (CP). Methods: In this pilot study, we assessed pancreatic fluid samples collected endoscopically 30-minute post-secretin injection from adult controls (n=10) and CP subjects (n=20). Protein-normalized enzymatic activity for amylase, lipase, trypsin, chymotrypsin, and elastase was compared between CP and control groups using logistic regression, and diagnostic performance was evaluated by ROC analysis. Results: Acinar cell enzyme levels were decreased in pancreatic fluid from CP subjects compared with controls, with significant differences observed for lipase and trypsin activity (AUC≥0.82; p’s=0.01). Eighty-six percent of controls had normal enzymatic activity across all five analytes, compared with only 43% of CP subjects, who more frequently exhibited multi-enzyme abnormalities. A graded pattern of reduction was observed from controls to equivocal (Eq) CP to definitive (Def) CP, indicating that enzyme activity generally shifts with advancing CP disease, although Eq and Def CP did not differ significantly from one another. Conclusions: This pilot study explored the potential of pancreatic fluid enzymatic activity as a functional assessment of exocrine activity in CP, with potential correlation to disease severity. Pancreatic fluid represents a promising, proximal biomarker source; however, larger prospective studies are needed to validate pancreas fluid biomarkers and define their relationship to disease stage, EPD, and other CP-related clinical outcomes.