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.

Autoimmune pancreatitis and micronutrients.

INTRODUCTION: Nutritional deficiencies, including fat-soluble vitamins and minerals have been detected in many autoimmune diseases, including those involving the digestive system, but have yet to be assessed in autoimmune pancreatitis (AIP). The aim of the present study was to determine the prevalence of micronutrient deficiencies in patients with AIP as well as to investigate their relationship with relapse. PATIENTS AND METHODS: We retrospectively analysed medical records of patients treated for AIP. Demographic and clinical data were collected. RESULTS: One hundred patients were included in the final analysis. The male-to-female ratio was 2.5:1; median age at diagnosis was 57 years (range 19-85). Median follow-up was 53 months, and during this time, 38% of patients suffered from at least one micronutrient deficiency. The most prevalent micronutrient deficiencies were vitamin D (16.1%) and zinc (25.5%). Relapse was observed in 37% of the AIP patients. Initial analysis showed that AIP relapse was associated with any micronutrient deficiency as well as zinc and vitamin D deficiency, but after stratifying for AIP type 1 and adjusting for PEI and elevated IgG4 levels, the association ceased to be statistically significant. CONCLUSION: Zinc and vitamin D deficiencies may be common in patients with AIP, indicating that these micronutrients might play a role in the natural course of AIP. Importantly, any micronutrient deficiency may be prevalent even in the light of treated PEI, which emphasizes the potential of micronutrients as an additional tool in the workup and follow-up of AIP patients.

Fatal bleeding due to an aorto-esophageal fistula: A case report and literature review.

BACKGROUND: Aorto-esophageal fistula is an extremely rare cause of acute upper gastrointestinal bleeding (UGIB). CASE SUMMARY: We present a case of an 80-year-old woman with esophageal cancer who was admitted to our department with hemorrhagic shock due to UGIB. During the diagnostic procedure, emergency computed tomography angiography was performed and confirmed aorto-esophageal fistula. Interventional radiologists inserted a stent graft into the aorta, successfully closing the fistula. Unfortunately, the patient later died of heart failure following irreversible hemorrhagic shock. Autopsy confirmed the aorto-esophageal fistula, which formed 1 cm below the distal edge of the stent previously inserted into the esophagus for a malignant stricture. CONCLUSION: There are very rare causes of UGIB. Although clinical decisions are made during the diagnostic workup of these patients, we must be aware of the limitations of various therapeutic options, even the most contemporary.

Exocrine and Endocrine Insufficiency in Autoimmune Pancreatitis: A Matter of Treatment or Time?

BACKGROUND: Autoimmune pancreatitis (AIP) is a specific form of chronic pancreatitis with a high relapse rate after treatment. AIP patients are burdened with an increased risk of long-term sequelae such as exocrine and endocrine insufficiency. Our objective was to investigate if pharmacological treatment affects both endocrine and exocrine pancreatic function in patients with AIP. METHODS: We included 59 patients with definite AIP in the final analysis. Screening for diabetes mellitus (DM) and pancreatic exocrine insufficiency (PEI) was performed at the time of AIP diagnosis and during follow-up. RESULTS: There were 40 (67.8%) males and 19 (32.2%) females; median age at diagnosis was 65 years. Median follow-up after the diagnosis of AIP was 62 months. PEI prevalence at diagnosis was 72.7% and was 63.5% at follow-up. The cumulative incidence of DM was 17.9%, with a prevalence of DM at diagnosis of 32.8%. No strong association was found between pharmacological treatment and occurrence of PEI and DM. Univariate analysis identified potential risk factors for PEI (other organ involvement and biliary stenting) and for DM (overweight, blue-collar profession, smoking, weight loss or obstructive jaundice as presenting symptoms, imaging showing diffuse pancreatic enlargement, smoking). In a multivariate analysis, only obstructive jaundice was identified as a risk factor for DM both at diagnosis and during follow-up. CONCLUSIONS: Our results suggest that the prevalence of endocrine and exocrine insufficiency in AIP is high at diagnosis with an additional risk of PEI and DM during follow-up despite pharmacological treatment.

Unraveling the relationship between autoimmune pancreatitis type 2 and inflammatory bowel disease: Results from two centers and systematic review of the literature.

INTRODUCTION: The relationship between autoimmune pancreatitis (AIP) type 2 and inflammatory bowel disease (IBD) has been established and previously described within International Consensus Diagnostic Criteria. However, it is unknown if the presence of IBD changes the natural disease course of AIP type 2. Our aim was to investigate the association between AIP type 2 and IBD as well as to systematically summarize all the existing evidence in the literature. METHODS: Electronic medical record analysis was conducted in two centers (in Stockholm, Sweden, and Milan, Italy; records dated between January 2001 and June 2021). Additionally, we conducted a systematic review of the literature. RESULTS: A total of 35 patients (18 females, 51.4%) fulfilled the diagnostic criteria of AIP type 2 and were included in the study. A diagnosis of IBD was established in 29 patients (82.8%), ulcerative colitis in 17 (58.6%) and Crohn's disease in 11 (37.9%). Median follow-up was 54 months. AIP patients with IBD commonly presented with abdominal pain and/or acute pancreatitis at diagnosis, the latter was prevailing in concomitant and later IBD onset. These patients more frequently used steroids, but there were no differences in relapse rates. Concomitant onset of IBD was associated with the development of diabetes mellitus. There were no cases of colon or pancreatic malignancy during follow-up. In our systematic analysis, a total of 693 AIP type 2 patients were included from 24 single-center retrospective studies and 8 multicenter retrospective studies. A diagnosis of IBD was reported in 330 (47.8%) patients. Relapse rate was 20.0%. CONCLUSIONS: Clinical and radiological remission of AIP type 2 was high, while the cumulative incidence of relapse is around 20%. Our results show that concomitance of IBD imposes no obvious risk of a different disease course for AIP type 2.

Surgery in Autoimmune Pancreatitis.

INTRODUCTION: Autoimmune pancreatitis (AIP) is a disease that may mimic malignant pancreatic lesions both in terms of symptomatology and imaging appearance. The aim of the present study is to analyze experiences of surgery in patients with AIP in one of the largest European cohorts. PATIENTS AND METHODS: We performed a single-center retrospective study of patients diagnosed with AIP at the Department of Abdominal Diseases at Karolinska University Hospital in Stockholm, Sweden, between January 2001 and October 2020. RESULTS: There were 159 patients diagnosed with AIP, and among them, 35 (22.0%) patients had surgery: 20 (57.1%) males and 15 (42.9%) females; median age at surgery was 59 years (range 37-81). Median follow-up period after surgery was 50 months (range 1-235). AIP type 1 was diagnosed in 28 (80%) patients and AIP type 2 in 7 (20%) patients. Malignant and premalignant lesions were diagnosed in 8 (22.9%) patients for whom AIP was not the primary differential diagnosis, but in all cases, it was described as a simultaneous finding and recorded in retrospective analysis in histological reports of surgical specimens. CONCLUSIONS: Diagnosis of AIP is not always straightforward, and in some cases, it is not easy to differentiate it from the malignancy. Surgery is generally not indicated for AIP but might be considered in patients when suspicion of malignant/premalignant lesions cannot be excluded after complete diagnostic workup.

Efficacy and safety of rituximab in autoimmune pancreatitis type 1: our experiences and systematic review of the literature.

INTRODUCTION: Autoimmune pancreatitis (AIP) is a special form of pancreatitis that responds well to glucocorticoid (GC) treatment. Relapses of AIP are common. The anti-CD20 antibody rituximab (RTX) has shown promising results in GC refractory cases, but long-term data are scarce. The study aims to determine the clinical and imaging response to RTX and summarize the existing data on RTX therapy in patients with AIP type 1 in the literature. PATIENTS AND METHODS: Retrospective analysis of electronic medical records was conducted. Additionally, we conducted a systematic review of the literature concerning RTX use in AIP type 1. RESULTS: Twelve (11.7%) of 103 patients with AIP type 1 were treated with RTX during the study period: eight (66.7%) achieved complete and four (33.3%) partial remission. RTX was discontinued in one patient who developed fever and reactivation of latent tuberculosis. None of the remaining 11 patients relapsed during a median follow-up of 17 months. No significant differences were detected in baseline clinical characteristics or history of relapse between the patients who obtained complete and partial remission. Altogether, eight studies with 110 AIP type-1 patients treated with RTX were analyzed. Adverse effects ranged from 11-43% and the relapse-free period during follow-up (range 2-173 months) ranged from 38-94%. CONCLUSIONS: Our results confirm that RTX is efficacious in the treatment of AIP type 1 by inducing remission and preventing relapse. In addition, there are few adverse effects of the treatment.

Clinical importance of main pancreatic duct variants and possible correlation with pancreatic diseases.

Background: Except for pancreas divisum (PD), the prevalence of anatomic variants of the main pancreatic duct (MPD) seems to be insufficiently investigated. To date, their role in the occurrence of pancreatic exocrine insufficiency (PEI) and morphological changes suggestive of chronic pancreatitis (CP) has remained unclear.Methods: A systematic review was performed, searching MEDLINE and Web of Science, limited to articles published between 1960 and 1 June 2019.Results: Our review included a total number of 3234 subjects. The most common variant of MPD was type 3, followed by type 1, indicating MPD drainage pattern into major papilla (MP) as the most frequent. A sub-variant of type 3, known as 'reverse pancreas divisum' had a prevalence of 2.2%. Type 4 variant- PD, was found in 6.4% of all cases. The most common sub-variant of PD was complete PD, followed by incomplete PD and variant with MPD as only pancreatic duct. Type 5 variant (including ansa pancreatica) was present in 2.9% of subjects. Apart from one study with a significantly higher frequency of morphological changes suggestive of CP in patients with ansa pancreatica, the studies stated no significant association between pancreatic disease and MPD variants. Furthermore, only one study examined the influence of MPD variants on exocrine pancreatic function. Although equivocal, this association is most likely found to be insignificant.Conclusion: To elucidate linkage between MPD variants and the occurrence of chronic pancreatitis and impairment of pancreatic exocrine function, further clinical investigations are warranted.

Cardiovascular and Lung Involvement in Patients with Autoimmune Pancreatitis.

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is a systemic immune-mediated disease characterised pathologically by the infiltration of IgG4-bearing plasma cells into the involved organs. Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis with a heavy lymphocytic infiltration and two distinct histopathological subtypes, namely: lymphoplasmacytic sclerosing pancreatitis (AIP type 1) and idiopathic duct-centric pancreatitis (AIP type 2). Lung involvement and aortic involvement have been reported in 12% and 9% of patients with systemic IgG4-RD, respectively. In series including patients with AIP, both lung and aortic involvement were described in 2% of the patients. Most of the epidemiological data come from Japan, and there is a lack of information from Europe, especially the Scandinavian countries. PATIENTS AND METHODS: We performed a single-centre retrospective study on a prospectively collected cohort of patients diagnosed with AIP at the Department for Digestive Diseases at Karolinska University Hospital in Stockholm, Sweden, from 2004 to 2019. Demographic and clinical data were collected from the medical charts. RESULTS: One hundred and thirty-three patients with AIP were analysed. Six patients were excluded because they lacked some of the clinical data relevant to the study. Demographic and clinical features of 127 patients were presented. There were 98 patients with AIP type 1-35 (35.7%) female and 63 (64.3%) male, with a mean age of 55.4 ± 18.2. Among them, 15 (15.3%) patients had lung and/or cardiovascular involvement-11 (11.2%) patients had lung involvement, 10 (10.2%) patients had cardiovascular involvement (six patients had both). Most of them (67.0%) had never smoked. The mean follow-up time of the patients with AIP type 1 was 49 months. CONCLUSIONS: Lung and/or cardiovascular involvement were diagnosed in 15 (15.3%) patients in our historical cohort of patients with AIP type 1. Most of the lung involvement was presented in the form of nodular lesions in the lungs, non-specific infiltrates, "ground-glass" appearance with pleura thickening, and effusion. Aortic involvement was a major form of vascular involvement in patients with AIP, as in previous published studies on patients with IgG4-RD.

Chronic pancreatitis and the heart disease: Still terra incognita?

BACKGROUND: It has been suggested that chronic pancreatitis (CP) may be an independent risk factor for development of cardiovascular disease (CVD). At the same time, it seems that congestive heart failure (CHF) and CP share the responsibility for the development of important clinical conditions such as sarcopenia, cachexia and malnutrition due to development of cardiac cachexia and pancreatic exocrine insufficiency (PEI), respectively. AIM: To explore the evidence regarding the association of CP and heart disease, more specifically CVD and CHF. METHODS: A systematic search of MEDLINE, Web of Science and Google Scholar was performed by two independent investigators to identify eligible studies where the connection between CP and CVD was investigated. The search was limited to articles in the English language. The last search was run on the 1st of May 2019. The primary outcomes were: (1) Incidence of cardiovascular event [acute coronary syndrome (ACS), chronic coronary disease, peripheral arterial lesions] in patients with established CP; and (2) Incidence of PEI in patients with CHF. RESULTS: Out of 1166 studies, only 8 were eligible for this review. Studies regarding PEI and CHF showed an important incidence of PEI as well as associated malabsorption of nutritional markers (vitamin D, selenium, phosphorus, zinc, folic acid, and prealbumin) in patients with CHF. However, after substitution of pancreatic enzymes, it seems that, at least, loss of appetite was attenuated. On the other side, studies investigating cardiovascular events in patients with CP showed that, in CP cohort, there was a 2.5-fold higher incidence of ACS. In another study, patients with alcohol-induced CP with concomitant type 3c diabetes had statistically significant higher incidence of carotid atherosclerotic plaques in comparison to patients with diabetes mellitus of other etiologies. Earlier studies demonstrated a marked correlation between the clinical symptoms in CP and chronic coronary insufficiency. Also, statistically significant higher incidence of arterial lesions was found in patients with CP compared to the control group with the same risk factors for atherosclerosis (hypertension, smoking, dyslipidemia). Moreover, one recent study showed that PEI is significantly associated with the risk of cardiovascular events in patients with CP. CONCLUSION: Current evidence implicates a possible association between PEI and malnutrition in patients with CHF. Chronic pancreatic tissue hypoxic injury driven by prolonged splanchnic hypoperfusion is likely to contribute to malnutrition and cachexia in patients with CHF. On the other hand, CP and PEI seem to be an independent risk factor associated with an increased risk of cardiovascular events.

Subendocardial viability ratio and ejection duration as parameters of early cardiovascular risk in children.

AIM: The purpose of this study was to investigate subendocardial viability ratio (SEVR) and ejection duration (ED) in children and adolescents with common cardiovascular risk factors such as arterial hypertension, obesity, and hypercholesterolemia. METHODS: Four groups of pediatric patients were analyzed: 31 children and adolescents had hypertension, 36 were overweight, 49 were overweight and had hypertension, and 70 had hypercholesterolemia. The patients were compared to a control group of 50 healthy individuals. Subjects were sampled by opportunity sampling at the Department of Pediatrics Maribor, Slovenia. In each patient, blood pressure, anthropometrical parameters, and pulse wave analysis (PWA) measurements using applanation tonometry technique were performed and calculated. RESULTS: The results show a statistically-significant difference in ED (p = 0.013) but not in SEVR (p = 0.074) in the hypercholesterolemia group in comparison to the control group. In other research groups, no statistically-significant differences were found. In all study groups, SEVR correlated significantly with age (positive, moderate) and heart rate (negative, strong) as well as with central mean pressure (CMP). CONCLUSIONS: Our study does not show a significant role of SEVR and ED in early cardiovascular risk determination in children. However, some results do indicate a potential role of both, at least in hypercholesterolemia, and should be further investigated.
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Arterial Compliance Measurement in Overweight and Hypertensive Children.

OBJECTIVES: To investigate the pulse wave velocity (PWV) and augmentation index (Alx), measures of arterial stiffness, in relation to hypertension and obesity, the main risk factors for cardiovascular diseases. METHODS: Two groups of pediatric patients, 31 children and adolescents with hypertension and 85 with overweight, were analysed and compared to the control group (50 healthy individuals). Subjects were sampled by opportunity sampling at the Department of Pediatrics, Maribor. In each patient, blood pressure, anthropometrical parameters and PWV measurements using the applanation tonometry technique were performed. RESULTS: There was a significant correlation between PWV and age (r = 0.461, p = 0.001) in the control group, whereas no correlation was obtained between PWV and body mass index (BMI) or central mean arterial pressure (CMAP). In the hypertensive group, PWV only correlated with CMAP (r = 0.496, p = 0.005). A significant correlation was found in the overweight group between PWV and both age and BMI (r = 0.484, p < 0.001 and r = 0.347, p = 0.001, respectively). Alx results were not taken into consideration. CONCLUSIONS: The results of this pilot study show that overweight and hypertensive children and adolescents are associated with less compliant arteries than their healthy peers, which could be used for screening of patients with expected early cardiovascular risk.

The influence of bisoprolol dose on ADP-induced platelet aggregability in patients on dual antiplatelet therapy.

PURPOSE: Dual antiplatelet therapy is recommended after acute coronary syndrome or after percutaneous coronary intervention with coronary stent implantation. Many of the patients on dual antiplatelet therapy receive ß-blockers; some of them could have antiaggregatory effect. Bisoprolol is a highly selective adrenoceptor-blocker, which is often used in the settings of percutaneous coronary intervention or acute coronary syndrome in patients on dual antiplatelet therapy. Its antiaggregative effect has not been extensively studied. Therefore, the aim of this study is to investigate the effect of bisoprolol on ADP-induced platelet aggregation in patients on dual antiplatelet therapy. METHODS: Platelet aggregability has been measured in 100 patients on dual antiplatelet therapy with multiplate analyzer using ADP test in blood samples anticoagulated with heparin. ADP test values have been expressed by arbitrary units/minute. In univariate and multivariate regression analyses, we have investigated the influence of bisoprolol and its dose and also different factors, such as risk factors, concomitant drugs and their dosage, laboratory findings, on ADP test values. RESULTS: Univariate regression analysis showed significant correlation between the bisoprolol dose and the ADP test value (P=0.046, B=52.55, 95% confidence interval 0.87-104.23), which was also shown in the multivariate regression analysis (P=0.018; B=57.011; 95% confidence interval 10.455-103.567). CONCLUSION: We have identified a positive correlation between bisoprolol dose and ADP-induced platelet aggregability in patients on dual antiplatelet therapy.