Pancreatic Enzyme Replacement Therapy in Patients with Non-pancreatic Digestive Conditions: A Nationwide Claims Analysis.

BACKGROUND AND AIMS: Pancreatic enzyme replacement therapy (PERT) is most commonly used to treat exocrine insufficiency related to pancreatic diseases, but can be used for non-pancreatic digestive conditions (NPDC). We aimed to determine the prevalence of PERT use and describe prescription patterns in individuals with NPDC. METHODS: A nationally representative claims database of 48.6 million enrollees was used to identify individuals who received PERT prescription(s) in the absence of any pancreas-related diagnosis. Data on demographics, enrolment, comorbidities, exocrine function testing, treatment and potential indications for PERT were retrieved, and compared with individuals who received PERT for primary diagnosis of chronic pancreatitis (CP). RESULTS: A total of 29,234 individuals (64.1% female, mean age 52.4 ± 16.5 years) received PERT for NPDC. The overall estimated US population prevalence rate for PERT use for NDPC was 60.2/100,000 persons. Rates increased significantly with age and were higher in women in all age groups except 1-20 years old. When compared with CP, individuals with NPDC receiving PERT were more likely to be older (52.4 vs. 50.1 years), female (64.1% vs. 51.0%), have lower prevalence of alcoholism (3.6% vs. 25.0%), tobacco abuse (8.4% vs. 30.1%), and received PERT for shorter mean duration (5.3 vs. 8.2 months) (all p < 0.001). Median dose of PERT in individuals with NPDC was 2880 lipase units/day. CONCLUSIONS: Although proportionally low, a sizable population receives PERT for NPDC. PERT for NPDC is usually prescribed at a low dose and for shorter duration, suggesting it is used mostly as a trial for or until resolution of symptoms.

A phase 1/2 trial to evaluate the pharmacokinetics, safety, and efficacy of NI-03 in patients with chronic pancreatitis: study protocol for a randomized controlled trial on the assessment of camostat treatment in chronic pancreatitis (TACTIC).

BACKGROUND: Chronic pancreatitis (CP) is a progressive, fibro-inflammatory disease characterized by enzymatic autoactivation and subsequent fibrotic replacement of acinar cells. A significant proportion of patients develop pain, which may be due to many causes, including perineural inflammation, altered central processing of pain signals, parenchymal structural changes, and ductal obstruction. Currently there are no approved medical treatment options for CP-associated pain. NI-03 (camostat mesilate) is an orally administered serine protease inhibitor that reduces pancreatic enzyme activity and has been widely used for the treatment of CP-associated pain in Japan. The current study will assess the safety and efficacy of NI-03 for reduction of CP-associated pain in the USA. METHODS: The current study consists of two phases. First, a phase I study will be performed to establish the pharmacokinetics and safety profile over a 1-week period following a single dose (100, 200, or 300 mg). Subsequently, a phase II study will be performed consisting of a double-blind, randomized, controlled trial (RCT). This RCT will evaluate the efficacy of each of the three doses of NI-03 given three times daily compared to placebo over 28 days. A 7-day, single-blind, run-in period will precede the double-blind phase to assess baseline pain characteristics. The primary efficacy outcome is the average of worst daily pain scores (numeric rating scale of 0-10) over the terminal 7 days of the study period compared to baseline. Secondary efficacy outcomes include change in opioid dose and quality of life measures, and time to first rescue intravenous analgesic. Adverse events will be recorded. DISCUSSION: NI-03 has been used successfully and safely in Japan to treat CP-associated pain. The aim of the current study is to assess the safety and efficacy of NI-03 using a rigorous RCT in a population in the USA. This study may fill an important clinical gap to provide an effective medical treatment option for CP-associated pain. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02693093 . Registered through the National Institutes of Health on 26 February 2016.

Total pancreatectomy with islet autotransplantation: summary of a National Institute of Diabetes and Digestive and Kidney diseases workshop.

A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases focused on research gaps and opportunities in total pancreatectomy with islet autotransplantation (TPIAT) for the management of chronic pancreatitis (CP). The session was held on July 23, 2014, and structured into 5 sessions: (1) patient selection, indications, and timing; (2) technical aspects of TPIAT; (3) improving success of islet autotransplantation; (4) improving outcomes after total pancreatectomy; and (5) registry considerations for TPIAT. The current state of knowledge was reviewed; knowledge gaps and research needs were specifically highlighted. Common themes included the need to identify which patients best benefit from and when to intervene with TPIAT, current limitations of the surgical procedure, diabetes remission and the potential for improvement, opportunities to better address pain remission, gastrointestinal complications in this population, and unique features of children with CP considered for TPIAT. The need for a multicenter patient registry that specifically addresses the complexities of CP and total pancreatectomy outcomes as well as postsurgical diabetes outcomes was repeatedly emphasized.

Recent advances in autoimmune pancreatitis: type 1 and type 2.

Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis characterised clinically by frequent presentation with obstructive jaundice, histologically by a lymphoplasmacytic infiltrate with fibrosis, and therapeutically by a dramatic response to steroids. When so defined, AIP can be sub-classified into two subtypes, 1 and 2. Recent international consensus diagnostic criteria for AIP have been developed for diagnosis of both forms of AIP. Type 1 AIP is the pancreatic manifestation of a multiorgan disease, recently named IgG4-related disease. Little is known about the pathogenesis of either form of AIP. Despite frequent association of type 1 AIP with elevated serum IgG4 levels and infiltration with IgG4-positive plasma cells, it is unlikely that IgG4 plays a pathogenic role in AIP. Type 1 AIP responds to steroids, but there needs to be consensus on treatment regimens for induction and therapeutic end points. Relapses are common, but can be reduced by long-term use of low-dose steroids. Recent reports suggest that immunomodulators (azathioprine, 6-mercaptopurine and mycophenolate mofetil), as well biological agents (the antibody to CD20, rituximab) may have a role in maintaining remission in relapsing type 1 AIP. Future studies should clarify the best management options for treatment of relapses and maintenance of remission. Type 2 AIP is a pancreas-specific disorder not associated with IgG4. It presents in younger individuals equally with obstructive jaundice and pancreatitis. The inflammatory process responds to steroid therapy; relapses are uncommon. The clinical spectrum and long-term outcomes of medically treated type 2 AIP are still being evaluated.

Cost-effectiveness analysis of pancreatin minimicrospheres in patients with pancreatic exocrine insufficiency due to chronic pancreatitis.

OBJECTIVE: Chronic pancreatitis (CP) is the most common cause of pancreatic exocrine insufficiency (PEI). Management of PEI due to CP is achieved through lifelong treatment with pancreatic enzyme replacement therapy (PERT). To the authors' knowledge, no cost-effectiveness analysis on the benefit of PERT in CP patients with PEI has been performed to date. The objective of this analysis was to examine the cost-effectiveness of Creon (pancreatin minimicrospheres [MMS]), one of the main PERTs available in Poland, in treating patients with CP-related PEI. METHODS: The cost-effectiveness of pancreatin MMS in the treatment of patients with CP-related PEI vs no PERT treatment was estimated using a decision analysis based on clinical data from relevant studies. The model horizon was 20 years. Main outcomes included the percentage of patients with controlled PEI, survival, total medical costs, number of quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). All costs were analysed from the Polish payer perspective. RESULTS: The model included clinical data from 176 patients treated in five pancreatin MMS randomized trials. Treatment with pancreatin MMS resulted in a considerably higher proportion of patients with controlled PEI compared to those not treated with any PERT. Over a horizon of 20 years, the total treatment cost and the ICER for pancreatin MMS was €8223 and €6312 per QALY, respectively. LIMITATIONS: Important limitations include the lack of long-term and comparative clinical data available. The use of 'no PERT treatment' as a comparator against pancreatin MMS treatment may not accurately reflect current practice in Poland. CONCLUSIONS: Treatment of CP-related PEI with pancreatin MMS is cost-effective from a Polish payer perspective, with an ICER below the accepted 'willingness to pay' threshold of 3-times gross domestic product (GDP) per capita. These results are likely to apply to other European countries.

Assessment of the protective effects of oral tocotrienols in arginine chronic-like pancreatitis.

Tocotrienols exhibit anti-inflammatory properties over macrophages and promote cytotoxicity in activated pancreatic stellate cells, suggesting that they may limit chronic pancreatitis progression. We aimed to quantitate the effect of oral tocotrienols on a rat model of chronic pancreatic injury. Chronic-like pancreatitis was induced by repeated arginine pancreatitis. Palm oil tocotrienol-rich fraction (TRF) was given by gavage before and after pancreatitis inductions. Amylase and hydroxyproline were determined in pancreatic homogenates; collagen, fibronectin, α-smooth muscle actin (SMA), glial fibrillary acidic protein (GFAP), and phosphorylated Smad3 were assessed by Western blotting. Transforming growth factor (TGF)-ß1 was measured in plasma. Morphological assessment included light microscopy, fibrosis area fraction, and collagen network fractal analysis. Arginine pancreatitis induced pancreatic atrophy and increased hydroxyproline that ameliorated after TRF. Arginine increased TGF-ß1 (185 ± 40 vs. 15 ± 2 ng/ml; P <0.01) that was blunted by TRF (53 ± 19; P < 0.01). TRF reduced protease and Smad3 activation, collagen, and fibronectin. α-SMA increased and GFAP diminished in arginine pancreatitis, consistent with long-term stellate cell activation, and TRF reverted these changes to basal. Arginine pancreatitis increased fibrosis area fraction (4.5 ± 0.3% vs. 0.2 ± 0.2%), collagen network complexity (fractal dimension 1.52 ± 0.03 vs. 1.42 ± 0.01; P < 0.001), and inhomogeneity (lacunarity 0.63 ± 0.03 vs. 0.40 ± 0.02; P < 0.001), which were all reduced by TRF (1.3 ± 0.4%, 1.43 ± 0.02%, and 0.51 ± 0.03%, respectively; P < 0.01). Best correlation coefficients were obtained when comparing fibrosis area fraction with lacunarity (r = 0.88) and both parameters with pancreatic weight (r = -0.91 and -0.79, respectively). TRF administered only before pancreatitis best, but not fully, recapitulated the beneficial effects of TRF. Tocotrienols improve quantitative measures of chronic pancreatic damage. They may be of benefit in human chronic pancreatitis.

Quality of life assessment in patients with chronic pancreatitis receiving antioxidant therapy.

AIM: To undertake a baseline study comparing quality of life (QoL) in patients with chronic pancreatitis (CP) on Antox to those with CP, matched for disease duration, who were not on this medication. METHODS: CP was defined according to the Zurich classification. Sixty eight consecutive patients with CP who were taking Antox (antioxidants) were compared with 69 consecutive control CP patients not on Antox. European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core questions 30 and Pancreatic Modification (28 questions) were used to assess QoL. Out of a total of 137 patients 28 in each group were matched for disease duration (within 12 mo). Median disease duration was 8 (1-22) years in the Antox group and 7 (1-23) years in the Non-Antox cohort (P = NS, Mann-Whitney U-test). Other parameters (age, gender, etiology, endocrine and exocrine insufficiency) were similar between groups. RESULTS: Median visual analogue pain score in the Antox group was 3 (0-8) compared with 6 (0-8) in the Non-Antox group (P < 0.01). Perceptions of cognitive, emotional, social, physical and role function were impaired in the Non-Antox group compared to Antox patients (P < 0.0001, P = 0.0007, P = 0.0032 and P < 0.005 and P < 0.001, respectively). Analgesics and opiate usage was significantly lower in the Antox group (P < 0.01). Overall physical health and global QoL was better in the Antox group (P < 0.0001, 95% CI: 1.5-3). CONCLUSION: Contemporary quality of life assessments show that after correction for disease duration and cigarette smoking, patients with CP taking antox had better scores than non-antox controls.

Assessment of oxidative stress in chronic pancreatitis patients.

AIM: To assess the levels of antioxidant capacity and oxidative damage in blood of chronic pancreatitis (CP) patients in comparison with those in healthy control subjects, by using several different analytical techniques. METHODS: Thirty-five CP patients and 35 healthy control subjects were investigated prospectively with respect to plasma levels of thiols, ferric reducing ability of plasma (FRAP, i.e. antioxidant capacity), levels of protein carbonyls and thiobarbituric acid reactive substances (TBARS). Additionally, we evaluated the production of reactive oxygen species (ROS) in whole blood. RESULTS: The antioxidative thiols including cysteine, cysteinylglycine and glutathione were significantly lower in CP patients. In addition, the non-enzymatic antioxidant capacity was significantly lower in CP patients, which correlated with the amount of oxidative protein (protein carbonyls) and the extent of lipid damage (TBARS), both were significantly higher in CP patients. The ROS production in whole blood after stimulation with phorbol 12-myritate 13-acetaat, demonstrated a strong tendency to produce more ROS in CP patients. CONCLUSION: Oxidative stress may contribute to the pathogenesis of chronic pancreatitis by decreasing antioxidant capacity and increasing oxidative damage in CP patients may be a rationale for intervention with antioxidant therapy.