Type 1 Autoimmune Pancreatitis in Europe: Clinical Profile and Response to Treatment.

BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. METHODS: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. RESULTS: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054-3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. CONCLUSIONS: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.

Quality of life after endoscopic procedures for chronic pancreatitis: A multicentre study.

BACKGROUND: Chronic Pancreatitis (CP) causes morphological changes in the pancreatic tissue, leading to complications and pain, which may require endoscopic interventions. OBJECTIVE: Our aim was to determine the frequency of endoscopic procedures (EP) in CP patients and to analyse pain and quality of life (QoL) in these patients after their EP. METHODS: This study included 1327 CP patients from the Scandinavian Baltic Pancreatic Club (SBPC) database including four countries and eight centres. We analysed patients undergoing EPs and gathered information on the EP, pancreatic function, pain, disease and duration. The EORTC C-30 QoL questionnaire was gathered prospectively and multivariable analysis was conducted on independent parameters between the groups. The reference population had no interventions (n = 870). RESULTS: 260 CP patients (22%) underwent EPs, median one year (range 0-39 years) after CP diagnosis. 68% were males. The median age was 59 (20-90) years. Most common aetiological factors were alcohol in 65% and smoking in 71%. Extracorporeal shock wave lithotripsy (ESWL) was used in 6% of the CP population and in 21% of the EP group. Biliary duct stenting was performed on 37% and pancreatic stenting was performed on 56% of the patients. There was no difference in pain patterns between patients who had pancreatic stenting and the reference population. The EP group had slightly better QoL (p = 0.047), functioning and fewer symptoms than the reference population, in the multivariable analysis there was no interaction effect analysis between the groups. The pancreatic stent group had better QoL and the same amount of pain than the reference group. The patients who needed later surgery (23%) had more pain (p = 0.043) and fatigue (p = 0.021). CONCLUSIONS: One in five of the CP patients underwent EP. These patients scored higher on QoL responses and had better symptom scores. CP patients who had pancreatic stenting performed had the same pain patterns as the reference population. Randomised prospective trials are needed to determine the effect of endoscopy procedures on CP patients.

Surgical strategies for chronic pancreatitis in a 1,327- patient Scandinavian Baltic pancreatic Club (SBPC) register.

BACKGROUND: Chronic pancreatitis (CP) may cause intermittent or continuous pain and complications requiring invasive interventions. No specific recommendations for surgical interventions have been presented. Our aim was to determine the surgical treatment strategies for the treatment of CP in the Scandinavian and Baltic countries. METHODS: This multi-centre cross sectional study included 1327 CP patients from eight centres. The data was gathered from the Scandinavian Baltic Pancreatic Club (SBPC) database. Patients who underwent pancreatic surgery were analysed. The baseline CP population from the eight centres was used as a reference. The information registered included comorbidities, pancreatic function, previous interventions, time and type of surgery and the EORTC-30 quality of life (QOL) questionnaire. RESULTS: Overall, 95/1327 (7%) patients underwent pancreatic surgery. Fifty-one (54%) of these underwent pancreatic surgery for chronic pain (PSCP) and formed the final study group. Median follow-up time was two (range 0-8) years after surgery and seven (1-46) years after diagnosis. The most common surgical procedures were pancreatic resection combined with drainage (54%) followed by pancreatic resections (32%) and drainage procedures (14%). Postoperatively, 47% of the patients were pain free with or without pain medication while 16% had chronic pain episodes, this did not differ from the base CP population. In QOL questionnaires, PSCP patients reported the same QOL but worse social functioning and more symptoms compared to the CP population. CONCLUSIONS: Pancreatic surgery for CP is rare: surgical procedures were performed on only 7% of the CP patients in the SBPC database. In half of the patients the indication was pain. Most of these patients underwent endoscopic procedures before surgery. Half of the patients reported being pain-free after surgery.

PrescrAIP: A Pan-European Study on Current Treatment Regimens of Auto-Immune Pancreatitis.

Introduction: Treatment of autoimmune pancreatitis (AIP) is based solely on consensus and has yet to become standardized. Consequently, therapeutic regimens vary greatly between countries and centers, and largely depend on the experience of the physician. At this moment, the optimal regimen for inducing disease remission and preventing relapse is unknown. Objectives: The primary objective of this study is to describe current treatment regimens used in Europe, and to compare their effectiveness in inducing remission and preventing and treating relapse. The secondary objectives are: to identify risk factors for relapse; to assess the diagnostic accuracy of the Unified-AIP criteria; to assess the performance of the M-ANNHEIM score for predicting relapse; and to assess long-term outcomes including pancreatic exocrine insufficiency and pancreatic cancer. Methods: This is an international, retrospective, observational cohort study, performed in over 40 centers from 16 European countries. Eligible are all patients diagnosed with AIP from 2005 onwards, regardless of the used diagnostic criteria. Data on study subjects will be retrieved from the hospital's electronic medical records and registered with a standardized, web-based, electronic case report form (eCRF). To compare the effectiveness of treatment regimens in inducing remission, preventing relapse, and treating relapse, subjects will be stratified in groups based on: type of therapy; initial therapy dose; cumulative therapy dose; therapy tapering speed and duration; and having received maintenance therapy or not. Ethics and Dissemination: Ethical and/or institutional review board approvals are obtained by all participating centers according to local regulations. The study complies with the General Data Protection Regulation (GDPR). All manuscripts resulting from the study will be submitted to peer-reviewed journals. Conclusion: This is the first pan-European retrospective registry for AIP. It will produce the first large-scale data on treatment of European patients with AIP, providing answers on the use and effectiveness of treatment regimens. In the future, this collaboration may provide a network for continuation into a prospective European registry.

Multiple risk factors for diabetes mellitus in patients with chronic pancreatitis: A multicentre study of 1117 cases.

BACKGROUND: Diabetes mellitus is a common complication of chronic pancreatitis. It is traditionally considered to develop as a consequence of beta cell loss, but there might be additional factors. Recent studies have highlighted the importance of type 2 diabetes-related risk factors in this context and population-based studies show increased risk of diabetes following acute pancreatitis. The aim of this study was to explore multiple risk factors for diabetes in patients with chronic pancreatitis. METHODS: We conducted a multicentre, cross-sectional study of patients with definitive chronic pancreatitis according to the M-ANNHEIM criteria. We used multivariable logistic regression models to determine risk factors independently associated with diabetes. RESULTS: The study included 1117 patients of whom 457 (40.9 %) had diabetes. The mean age was 52.8 ± 14.2 years and 67% were men. On multivariate analysis, parameters indicative of beta cell loss (pancreatic calcification, exocrine insufficiency, pancreatic resection) were confirmed as independent risk factors for diabetes (all p ≤ 0.02). In addition, type 2 diabetes-related risk factors (dyslipidaemia and overweight/obesity) were associated with the presence of diabetes (all p ≤ 0.002). Patients with a history of pancreatic fluid collections (indicative of previous attacks of acute pancreatitis) had a marginally increased risk of diabetes (p = 0.07). CONCLUSION: In patients with chronic pancreatitis the presence of diabetes is associated with multiple risk factors including type 2 diabetes-related factors. Our observations attest to the understanding of this entity and may have implications for treatment.

Chronic Pancreatitis Is Characterized by Distinct Complication Clusters That Associate With Etiological Risk Factors.

OBJECTIVES: Chronic pancreatitis (CP) is characterized by several disease-related complications and multiple etiological risk factors. Past studies of associations between complications and risk factors have mostly been limited to single complications or highly focused on single etiologies. Using an objective data-driven approach (cluster analysis), we characterized complication clusters and their associations with etiological risk factors in a large cohort of patients with CP. METHODS: This was a multicenter, cross-sectional study including 1,071 patients with CP from the Scandinavian and Baltic countries. Complications to CP were classified according to the M-ANNHEIM system, and treelet transform was used to derive complication clusters. Cluster complication frequencies were analyzed for their association with main etiological risk factors (smoking and alcohol). RESULTS: The mean age of participants was 57 years and 66% were men. Alcohol (55%) and smoking (53%) were the most common etiological risk factors and seen in combination in 36% of patients. Cluster analysis identified 3 distinct complication clusters characterized by inflammation, fibrosis, and pancreatic insufficiencies. An independent association between inflammatory complications and alcoholic etiology was seen (odds ratio [OR] 2.00 [95% CI [confidence interval], 1.38-2.90], P < 0.001), whereas smoking was associated with fibrosis-related complications (OR 2.23 [95% CI, 1.56-2.3.20], P < 0.001) and pancreatic insufficiencies (OR 1.42 [95% CI, 1.00-2.01], P = 0.046). DISCUSSION: Three distinctive clusters of complications to CP were identified. Their differing associations with alcoholic and smoking etiology indicate distinct underlying disease mechanisms.

The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction.

BACKGROUND AND AIMS: Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co-administration of the peripherally acting µ-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo. METHODS: In a double-blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale. RESULTS: During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (-45.9 vs -38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01). CONCLUSIONS: In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process.

Colorectal Transit and Volume During Treatment With Prolonged-release Oxycodone/Naloxone Versus Oxycodone Plus Macrogol 3350.

BACKGROUND/AIMS: Opioid-induced constipation (OIC) is the most common gastrointestinal (GI) side effect to opioid treatment. Opioid receptor antagonists against OIC have been introduced, but their efficacy has not been directly compared to conventional laxatives. Our aim was to compare symptoms and objective parameters of gut function in an experimental model of OIC during treatment with the opioid antagonist naloxone and oxycodone in prolonged-release (PR) formulation versus oxycodone plus macrogol 3350. METHODS: In this randomized, double-blind, crossover trial 20 healthy men received a 5-day treatment of combined PR oxycodone/naloxone or PR oxycodone plus macrogol 3350. Regional GI transit times and segmental colorectal transit were assessed with the Motilis 3D-Transit electromagnetic capsule system. Colorectal volumes were determined by MRI. OIC symptoms were assessed with validated questionnaires, along with stool frequency and consistency. RESULTS: Total colorectal volume did not change after 5 days' treatment with PR oxycodone/naloxone (941 vs 1036 mL; P = 0.091), but increased significantly after PR oxycodone plus macrogol treatment (912 vs 1123 mL; P < 0.001). Neither regional GI transit times nor segmental colorectal transit differed between the treatments (all P > 0.05). The Patient Assessment of Constipation Symptom Questionnaire abdominal symptoms score was lower during PR oxycodone/naloxone compared to PR oxycodone plus macrogol (0.2 vs 3.2; P = 0.002). Stool frequency was lower during PR oxycodone/naloxone compared to PR oxycodone plus macrogol (4.2 vs 5.4; P = 0.035). CONCLUSIONS: PR oxycodone plus macrogol increases colorectal volume, but does not improve GI transit compared to PR oxycodone/naloxone. However, PR oxycodone/naloxone results in a lower abdominal symptom burden, despite higher stool frequency during macrogol treatment.

The Scandinavian baltic pancreatic club (SBPC) database: design, rationale and characterisation of the study cohort.

OBJECTIVES: Chronic pancreatitis (CP) is a multifaceted disease associated with several risk factors and a complex clinical presentation. We established the Scandinavian Baltic Pancreatic Club (SBPC) Database to characterise and study the natural history of CP in a Northern European cohort. Here, we describe the design of the database and characteristics of the study cohort. METHODS: Nine centres from six different countries in the Scandinavian-Baltic region joined the database. Patients with definitive or probable CP (M-ANNHEIM diagnostic criteria) were included. Standardised case report forms were used to collect several assessment variables including disease aetiology, duration of CP, preceding acute pancreatitis, as well as symptoms, complications, and treatments. The clinical stage of CP was characterised according to M-ANNNHEIM. Yearly follow-up is planned for all patients. RESULTS: The study cohort comprised of 910 patients (608 men: 302 women; median age 58 (IQR: 48-67) years with definite 848 (93%) or probable CP 62 (7%). Nicotine (70%) and alcohol (59%) were the most frequent aetiologies and seen in combination in 44% of patients. A history of recurrent acute pancreatitis was seen in 49% prior to the development of CP. Pain (69%) and exocrine pancreatic insufficiency (68%) were the most common complications followed by diabetes (43%). Most patients (30%) were classified as clinical stage II (symptomatic CP with exocrine or endocrine insufficiency). Less than 10% of the patients had undergone pancreatic surgery. CONCLUSION: The SBPC database provides a mean for future prospective, observational studies of CP in the Northern European continent.

Acupuncture for Pain in Chronic Pancreatitis: A Single-Blinded Randomized Crossover Trial.

OBJECTIVES: Many patients with painful chronic pancreatitis (CP) have insufficient effect of treatment, and the prevalence of adverse effects is high. Consequently, alternatives to conventional management are needed. We aimed to study the effect of acupuncture in painful CP. METHODS: This was a prospective, single-blinded, randomized crossover trial. Fifteen patients with CP were assigned to a session of acupuncture followed by sham stimulation or vice versa. Patients rated clinical pain scores daily on a 0 to 10 visual analogue scale (VAS) and completed the Patient Global Impression of Change. For mechanistic linkage, resting state electroencephalograms were recorded and quantified by spectral power analysis to explore effects on central pain processing. RESULTS: Acupuncture, compared with sham stimulation, caused more pain relief (2.0 ± 1.5 VAS vs 0.7 ± 0.8 VAS; P = 0.009). The effect, however, was short, and after 1-week follow-up, there was no difference in clinical pain scores between groups (P = 1.0) or the rating of Patient Global Impression of Change (P = 0.8). Electroencephalogram spectral power distributions between sham and acupuncture were comparable between groups (all P > 0.6). CONCLUSIONS: The study presents proof-of-concept for the analgesic effect of acupuncture in pancreatic pain. Although the effect was short lasting, the framework may be used to conceptualize future trials of acupuncture in visceral pain.

The Impact of Opioid Treatment on Regional Gastrointestinal Transit.

BACKGROUND/AIMS: To employ an experimental model of opioid-induced bowel dysfunction in healthy human volunteers, and evaluate the impact ofopioid treatment compared to placebo on gastrointestinal (GI) symptoms and motility assessed by questionnaires and regional GItransit times using the 3-dimensional (3D)-Transit system. METHODS: Twenty-five healthy males were randomly assigned to oxycodone or placebo for 5 days in a double blind, crossover design. AdverseGI effects were measured with the bowel function index, gastrointestinal symptom rating scale, patient assessment of constipationsymptom questionnaire, and Bristol stool form scale. Regional GI transit times were determined using the 3D-Transit system, and segmental transit times in the colon were determined using a custom Matlab(®) graphical user interface. RESULTS: GI symptom scores increased significantly across all applied GI questionnaires during opioid treatment. Oxycodone increased median total GI transit time from 22.2 to 43.9 hours (P < 0.001), segmental transit times in the cecum and ascending colon from 5.7 to 9.9 hours (P = 0.012), rectosigmoid colon transit from 2.7 to 9.0 hours (P = 0.044), and colorectal transit time from 18.6 to 38.6 hours (P= 0.001). No associations between questionnaire scores and segmental transit times were detected. CONCLUSIONS: Self-assessed GI adverse effects and increased GI transit times in different segments were induced during oxycodone treatment. This detailed information about segmental changes in motility has great potential for future interventional head-to-head trials of different laxative regimes for prevention and treatment of constipation.

Opioid-induced bowel dysfunction in healthy volunteers assessed with questionnaires and MRI.

OBJECTIVE: Opioid treatment is associated with numerous gastrointestinal adverse effects collectively known as opioid-induced bowel dysfunction (OIBD). Most current knowledge of the pathophysiology derives from animal studies limited by species differences and clinical studies, which have substantial confounders that make evaluation difficult. An experimental model of OIBD in healthy volunteers in a controlled setting is therefore highly warranted. The aim of this study was to assess bowel function in healthy volunteers during opioid treatment using subjective and objective methods. METHODS: Twenty-five healthy men were assigned randomly to oxycodone or placebo for 5 days in a cross-over design. The analgesic effect was assessed with muscle pressure algometry and adverse effects were measured using questionnaires including the bowel function index, gastrointestinal symptom rating scale, patient assessment of constipation symptoms and the Bristol stool form scale. Colorectal volumes were determined using a newly developed MRI method. RESULTS: Compared with baseline, oxycodone increased pain detection thresholds by 8% (P=0.02). Subjective OIBD was observed as increased bowel function index (464% increase; P<0.001), gastrointestinal symptom rating scale (37% increase; P<0.001) and patient assessment of constipation symptoms (198% increase; P<0.001). Objectively, stools were harder and drier during oxycodone treatment (P<0.001) and segmental colorectal volumes increased in the caecum/ascending colon by 41% (P=0.005) and in the transverse colon by 20% (P=0.005). No associations were detected between questionnaire scores and colorectal volumes. CONCLUSION: Experimental OIBD in healthy volunteers was induced during oxycodone treatment. This model has potential for future interventional studies to discriminate the efficacies of different laxatives, peripheral morphine antagonists and opioid treatments.