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Autoimmune pancreatitis (AIP) and inflammatory bowel disease (IBD) are categorized into immune-mediated inflammatory disorders (IMIDs). While AIP is a pancreato-biliary IMID with an increased incidence and prevalence among patients with IBD, its features are still unclear. This systematic review and meta-analysis aims to assess the prevalence and clinical characteristics of AIP-IBD patients.Electronic databases were searched to identify observational studies assessing AIP and IBD. The primary outcome was the prevalence of IBD among AIP patients, and vice versa. Secondary outcomes included clinical findings and outcomes of each IMID in AIP-IBD patients. The pooled rate of each outcome was determined using a random effects model.For primary outcomes, 40 observational studies with 4031 AIP patients were included and the pooled prevalence of IBD was 10.5% (95% CI 7.2-15.0%). Meanwhile, five studies with 10,551 IBD patients were included and the pooled prevalence of AIP was 0.6% (95% CI 0.2-1.9%). For secondary outcomes, 53 observational studies with 469 AIP-IBD patients were assessed. The rates of type 2 AIP and ulcerative colitis were 79.2% (95% CI 69.1-86.6%) and 74.8% (95% CI 68.2-80.4%), respectively. We also demonstrated AIP-IBD patients were at a significant increased risk of AIP recurrence and colectomy compared with patients with either AIP or IBD (RR = 1.9, 95% CI 1.1-3.1 and P = 0.014 and RR = 3.7, 95% CI 1.9-6.9, P 0.001, respectively).Our meta-analysis reported the prevalence of AIP-IBD patients and demonstrated patients with both IMIDs had a high risk of poor outcomes.

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.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.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%.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.

BACKGROUND The survival rate of pancreatic ductal adenocarcinoma (PDAC) is very poor because early detection is difficult. Extracellular vesicles (EVs) are released from cells associating with the cellular condition and circulated in the blood. We aimed to identify EV proteins from endoscopic ultrasound-fine needle aspiration (EUS-FNA) biopsy samples in order to develop novel biomarkers for PDAC. METHODS Extracellular vesicles were isolated from EUS-FNA samples of 40 PDAC patients and six autoimmune pancreatitis (AIP) patients to be used as a control. EV proteins were identified using nanoLC-MS/MS. RESULTS Intact EVs approximately 200 nm in diameter were detected from EUS-FNA samples. We identified 2059 or 1032 EV proteins in PDAC or AIP, respectively, and 1071 EV proteins were detected only in PDAC. One hundred and fifty-three EV proteins were significantly different between PDAC and AIP: 64 proteins were down-regulated in PDAC whereas 89 EV proteins were up-regulated in PDAC including mucins, keratins, Ras-related proteins, and olfactomedin-4, which proteins have been reported to be elevated in PDAC tissue/blood, or cultured pancreatic cancer cell lines. Notably, in the 89 up-regulated PDAC EV proteins we identified novel proteins including ADP-ribosylation factor 3, CD55, pyruvate kinase, and lipopolysaccharide-induced tumor necrosis factor. Out of 89 proteins, a total of 13 proteins including Ras-related proteins were significantly elevated in PDAC stages II-IV compared to PDAC stage I, including Ras-related proteins, moesin, and CD55. CONCLUSIONS The EV proteins obtained from EUS-FNA samples contain a PDAC-specific protein barcode. The EV proteins identified from EUS-FNA samples include promising biomarkers for the diagnosis and clinical staging of PDAC.

Acute recurrent pancreatitis (ARP) is defined as two distinct episodes of acute pancreatitis (AP), whereas chronic pancreatitis (CP) is caused by persistent inflammation of the pancreas. In children they are caused by genetic mutations, autoimmune pancreatitis, congenital pancreatic abnormalities, and other conditions. Acute recurrent pancreatitis is frequently a precursor to CP, and both are thought to be on the same disease continuum. In particular, genetic factors are associated with early progression of ARP to CP. The diagnosis of CP, as in AP, is based on clinical findings, biochemical tests, and imaging studies. Findings of exocrine pancreatic dysfunction are also important in the diagnosis of CP. A step-up strategy has become increasingly standard for the treatment of patients with CP. This strategy starts with endoscopic treatment, such as pancreatic sphincterotomy and stenting, and progresses to surgery should endoscopic therapy fail or prove technically impossible. Non-opioid (e.g. ibuprofen / naproxen) and opioid (e.g. oxycodone) forms of analgesia are widely used in pediatric patients with AP or CP, whereas pancreatic enzyme replacement therapy may be beneficial for patients with abdominal pain, steatorrhea, and malnutrition. Despite the disparity in the age of onset, pediatric CP patients display some similarities to adults in terms of disease progress. To reduce the risk of developing pancreatic exocrine inefficiency, diabetes and pancreatic cancer in the future, clinicians need to be aware of the current diagnostic approach and treatment methods for ARP and CP and refer them to a pediatric gastroenterologist in a timely manner.

Aims Types 1 and 2 autoimmune pancreatitis (AIP) can mimic pancreatic neoplasia. Due to the small quantity of tissue in mass-targeted pancreas biopsies, inflammatory features may raise the differential of AIP. However, the frequency of AIP-like histology in neoplastic pancreas is not well characterised. Therefore, the specificity of inflammatory lesions on biopsy with respect to the diagnosis of AIP is uncertain. Methods and results Neoplastic pancreas resections performed at our institution between 2008 and 2019 were retrospectively reviewed. Features of AIP types 1 and 2 were assessed in the non-neoplastic areas. If features of immunoglobulin (Ig)G4-associated AIP were seen, IgG4 immunohistochemistry was performed. We identified 163 neoplastic pancreas resections. Of these, 34 had one or more types of inflammatory lesions in non-neoplastic pancreatic tissue. Dense lymphoplasmacytic inflammation mimicking type 1 AIP was found in six cases with mild to moderately increased IgG4-positive plasma cells. Neutrophilic infiltrates in small intralobular ducts were found in 20 cases. Mild extralobular ductitis or duct microabscess was found in 10 specimens. Marked neutrophilic duct destruction that resembled granulocytic epithelial lesions was found in 12 cases. Some cases showed multiple features. Conclusion Approximately 20% of neoplastic pancreas resections showed focal areas that could raise the differential of AIP. More cases showed neutrophilic predominant inflammation as seen in type 2 autoimmune pancreatitis, compared to dense lymphoplasmacytic infiltrates seen in type 1 AIP. Pathologists must be cautious when making a diagnosis of AIP on biopsy tissue based on histological findings alone.

Background/purpose Epidemiological data on immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) are scarce. Method We randomly selected healthcare facilities from a list of all facilities in Japan. The selection rate was determined according to a stratification based on the facility characteristics and scale. We sent questionnaires to the selected facilities enquiring about the number and sex of patients with IgG4-SC in 2018. Among responding facilities, we further inquired about the clinical characteristics of the patients with IgG4-SC. Results We selected 1,180 departments from health centers across Japan. Of them, 532 (45.1%) responded to the questionnaires. The number of reported patients with IgG4-SC was 1,045, and the estimated point prevalence was 2.18 (95% confidence interval, 2.13-2.23) per 100,000 population. In addition, we enrolled 1,096 patients with IgG4-SC, combining data from previously and newly registered patients. Male patients comprised 79.5% of the population and patients aged 60-80 years had the highest risk for developing the disease. The follow-up period was 5.1±4.0 years and the 5- and 10-year overall survival rates were 95.3% and 89.0%, respectively. Conclusions The point prevalence of IgG4-SC was 2.18 per 100,000 population. The epidemiological features were similar to those observed in previous studies.

The biopsy-based diagnosis of autoimmune pancreatitis (AIP) is difficult but is becoming imperative for pathologists due to the increased amount of endoscopic ultrasound-guided biopsy tissue. To cope with this challenge, we propose guidance for the biopsy diagnosis of type 1 AIP. This guidance is for pathologists and comprises three main parts. The first part includes basic issues on tissue acquisition, staining, and final diagnosis, and is intended for gastroenterologists as well. The second part is a practical guide for diagnosing type 1 AIP based on the AIP clinical diagnostic criteria 2018. Inconsistent histological findings, tips for evaluating IgG4 immunostaining and key histological features including the ductal lesion and others are explained. Storiform fibrosis and obliterative phlebitis are diagnostic hallmarks but are sometimes equivocal. Storiform fibrosis is defined as spindle-shaped cells, inflammatory cells and fine collagen fibers forming a flowing arrangement. Obliterative phlebitis is defined as fibrous venous obliteration with inflammatory cells. Examples of each are provided. The third part describes the differentiation of AIP from pancreatic ductal adenocarcinoma (PDAC), focusing on histological features of acinar-ductal metaplasia in AIP, which is an important mimicker of PDAC. This guidance will help standardize pathology reports of pancreatic biopsies for diagnosing type 1 AIP.

Background and Aims Imaging tools for predicting pancreatic atrophy after steroid therapy in autoimmune pancreatitis (AIP) have not been established. As delayed equilibrium‐phase contrast enhancement in computed tomography (CE‐CT) may reflect interstitial fibrosis, we evaluated the ability of equilibrium‐phase CT imaging for predicting pancreatic atrophy. Methods Forty‐six steroid‐treated AIP patients who underwent contrast‐enhanced CT at our university hospital were included in this retrospective study. CT attenuation (Hounsfield units [HU]) values in noncontrast images (NC) and equilibrium‐phase images (EP) and the differences in HU values between NC and EP images (SUB) were measured. Pancreatic volume was measured in CE‐CT before (Volpre) and after (Volpost) steroid therapy. The volume reduction rate was calculated. The relationships of CT values with pancreatic atrophy, Volpost, volume reduction rate, and diabetes exacerbation were investigated. Results CT values in the EP and SUB images before steroid therapy were associated with pancreatic atrophy after steroid therapy (atrophy vs nonatrophy 114.5 ± 12.8 vs 99.5 ± 11.1, P = 0.0002; 70.9 ± 14.72 vs 57.2 ± 13.1, P = 0.003, respectively), but CT values in NC images were not (P = 0.42). CT values in EP and SUB images before steroid therapy were correlated with Volpost (EP images r = −0.70, P = 0.002; SUB images r = −0.68, P = 0.03) and volume reduction rate after steroid therapy (EP images: r = −0.55, P, Pancreatic atrophy is often observed after steroid therapy for AIP and is associated with exacerbation of diabetes. However, it has not been possible to predict pancreatic atrophy before the start of therapy. This time, we have found a method to predict pancreatic atrophy using CT values, and we introduce it here.

The impact of environmental factors, such as diet, and the genetic basis of autoimmune pancreatitis (AIP) are largely unknown. Here, we used an experimental murine AIP model to identify the contribution of diet to AIP development, as well as to fine‐map AIP‐associated genes in outbred mice prone to develop the disease. For this purpose, we fed mice of an autoimmune‐prone intercross line (AIL) three different diets (control, calorie‐reduced and western diet) for 6 months, at which point the mice were genotyped and phenotyped for AIP. Overall, 269 out of 734 mice (36.6%) developed AIP with signs of parenchymal destruction, equally affecting mice of both sexes. AIP prevalence and severity were reduced by approximately 50% in mice held under caloric restriction compared to those fed control or western diet. We identified a quantitative trait locus (QTL) on chromosome 4 to be associated with AIP, which is located within a previously reported QTL. This association does not change when considering diet or sex as an additional variable for the mapping. Using whole‐genome sequences of the AIL founder strains, we resolved this QTL to a single candidate gene, namely Map3k7. Expression of Map3k7 was largely restricted to islet cells as well as lymphocytes found in the exocrine pancreas of mice with AIP. Our studies suggest a major impact of diet on AIP. Furthermore, we identify Map3k7 as a novel susceptibility gene for experimental AIP. Both findings warrant clinical translation.

Background and aim We examined the differences in the risks and characteristics of pancreatic relapse (PR) and pancreatic cancer (PC) in patients with autoimmune pancreatitis (AIP). Methods We retrospectively reviewed 123 type 1 AIP patients with a median follow-up of 55 months (interquartile range, 27-98). The following items were evaluated: (i) cumulative relapse rates and risk factors, (ii) the incidence of PC, (iii) PR versus PC, and (iv) outcomes after the appearance of morphological changes in the pancreas (focal enlargement, apparent mass lesions, or main pancreatic duct dilation). Results (i) The cumulative PR rates were 1.7% within 1 year, 11.5% within 3 years, and 22.6% within 5 years. Lack of maintenance therapy, IgG4-related sclerosing cholangitis, and IgG4-related kidney disease were identified as independent predictors of relapse. (ii) Two patients (1.6%) were diagnosed with PC at 17 and 22 months after initial AIP diagnosis. (iii) Thirteen (59.1%) and four (18.2%) patients with PR had focal enlargement and main pancreatic duct dilation, respectively. The median CA19-9 level at initial diagnosis was significantly higher in PC patients (21 vs 220.5 U/mL, P = 0.014). (iv) Eight PR patients underwent endoscopic ultrasound-guided fine-needle aspiration, none of whom had malignant findings. PC was diagnosed by ultrasound-guided fine-needle aspiration in both cancer patients. Conclusions Although the incidence of PC is low, it may mimic PR in AIP patients. Surveillance is important, and when morphological changes occur, biopsy and evaluation of serum IgG4 and CA19-9 levels (particularly if the levels were high before) should be considered.

BACKGROUND: Autoimmune pancreatitis (AIP) is a rare, and relatively new, form of chronic pancreatitis. The management of AIP can vary considerably among different centres in daily clinical practice. OBJECTIVES: The aim of this study is to present a picture of epidemiological, clinical characteristics, outcomes, and the real-life practice in terms of management in several academic and non-academic centres in Italy. METHODS: Data on the clinical presentation, diagnostic work-up, treatments, frequency of relapses, and long-term outcomes were retrospectively collected in a cohort of AIP patients diagnosed at 14 centres in Italy. RESULTS: One hundred and six patients were classified as type 1 AIP, 48 as type 2 AIP, and 19 as not otherwise specified. Epidemiological, clinical, radiological, and serological characteristics, and relapses were similar to those previously reported for different types of AIP. Endoscopic cytohistology was available in 46.2% of cases, and diagnostic for AIP in only 35.2%. Steroid trial to aid diagnosis was administered in 43.3% cases, and effective in 93.3%. Steroid therapy was used in 70.5% of cases, and effective in 92.6% of patients. Maintenance therapy with low dose of steroid (MST) was prescribed in 25.4% of cases at a mean dose of 5 (±1.4) mg/die, and median time of MST was 60 days. Immunosuppressive drugs were rarely used (10.9%), and rituximab in 1.7%. Faecal elastase-1 was evaluated in only 31.2% of patients, and was pathological in 59.2%. CONCLUSIONS: In this cohort of AIP patients, diagnosis and classification for subtype was frequently possible, confirming the different characteristics of AIP1 and AIP2 previously reported. Nevertheless, we observed a low use of histology and steroid trial for a diagnosis of AIP. Steroid treatment was the most used therapy in our cohort. Immunosuppressants and rituximab were rarely used. The evaluation of exocrine pancreatic insufficiency is underemployed considering its high prevalence.

Autoimmune pancreatitis, a derivative of chronic pancreatitis, frequently causes acute episodes with clinical symptoms parallel to those of acute pancreatitis. Corticosteroids are effective in the treatment of 90% of autoimmune pancreatitis cases, but for the remaining 10%, options are limited. Due to their significant immunomodulatory capabilities, mesenchymal stromal cells (MSCs) have been proposed as a novel treatment strategy for various immune and inflammatory pathologies including those with autoimmune origins. Here, we not only highlight the most recent MSC live‐cell experiments to address acute pancreatitis, but also discuss the opportunities afforded by the emergence of the newly identified field of MSC necrobiology. We conclude that the putative employment of MSC derivatives provides a newer and simpler therapeutic approach that could have significant advantages over the use of cells themselves., Autoimmune pancreatitis frequently causes acute episodes with clinical symptoms parallel to those of acute pancreatitis. Due to their significant immunomodulatory capabilities, mesenchymal stromal cells (MSCs) have been proposed as a novel treatment strategy for various immune and inflammatory pathologies including those with autoimmune origins. Here, we not only highlight the most recent MSC live‐cell experiments to address acute pancreatitis, but also discuss the opportunities afforded by the emergence of the newly identified field of MSC necrobiology.

BACKGROUND AND AIMS: Steroid therapy is the first-line treatment for autoimmune pancreatitis but relapses are frequent. The aims were to assess the efficacy and the safety of immunomodulator treatments for relapsing autoimmune pancreatitis and rituximab in particular and to identify relapsing risk factors. METHODS: Patients followed for autoimmune pancreatitis from 2000 to 2016 were included. Data were retrospectively analysed regarding autoimmune pancreatitis treatment. RESULTS: In total, 162 patients with autoimmune pancreatitis type 1 (n = 92) and type 2 (n = 70) were included (median follow-up: 3 years (0.5–14). Relapse occurred in 46.5% of patients with autoimmune pancreatitis type 1 (vs 19.3% in autoimmune pancreatitis 2; p

Background To investigate whether the relative computed tomography (CT) value (rCT) of adjacent pancreatic parenchyma can distinguish focal‐type autoimmune pancreatitis (fAIP) from pancreatic ductal adenocarcinoma (PDAC). Methods A total of 13 patients with fAIP and 20 patients with PDAC were included in this study. The rCT was calculated as the ratio of the CT value of adjacent pancreatic parenchyma to that of muscle. The diagnostic performance of rCT for discriminating fAIP from PDAC was evaluated using receiver operating characteristic (ROC) analysis. Results Both fAIP and PDAC presented hyper‐fibrosis histologically and delayed enhancement on CT examination. Moreover, the pancreatic parenchyma of fAIP presented serious inflammation. The mean rCT of the parenchyma was significantly lower in fAIP than in PDAC in all phases. The best diagnostic performance of the rCT value was found in the pancreatic phase, with an area under the ROC curve of 0.912, while the areas under the ROC curve of the portal and delayed phases were 0.812 and 0.754, respectively. The optimal cut‐off value for distinguishing fAIP from PDAC was 1.62 in the pancreatic phase. Conclusions The rCT of the pancreatic parenchyma during the pancreatic phase may be a feasible CT feature for differentiating fAIP from PDAC., Similar imaging features such as regional enlargement of the pancreas and delayed enhancement became a big challenge to differentiate focal‐type autoimmune pancreatitis (fAIP) from PDAC. In this study, we found that the pancreatic parenchyma of fAIP presented severe inflammation. Moreover, the mean relative computed tomography values of the pancreatic parenchyma were lower in fAIP than that in PDAC in all phases.

Purpose To perform a radiomics analysis with comparisons of multidomain features and a variety of feature selection strategies and classifiers, with the goal of evaluating the value of quantified radiomics method for noninvasively differentiating autoimmune pancreatitis (AIP) from pancreatic ductal adenocarcinoma (PDAC) in 18 F-fluorodeoxglucose positron emission tomography/computed tomography (18 F FDG PET/CT) images. Methods We extracted 251 expert-designed features from 2D and 3D PET/CT images of 111 patients, and recombined these features into five feature sets according to their modalities and dimensions. Among the five feature sets, the optimal one was found leveraging four feature selection strategies and four machine learning classifiers based on the area under the receiver operating characteristic curve (AUC). The feature selection strategies include spearman's rank correlation coefficient, minimum redundancy maximum relevance, support vector machine recursive feature elimination (SVM-RFE), and no feature selection, while the classifiers are random forest, adaptive boosting, support vector machine (SVM) with the Gaussian radial basis function, and SVM with the linear kernel function respectively. Based on the optimal feature set, these feature selection strategies and classifiers were comparatively studied to achieve the best differentiation. Finally, the quantified radiomics prediction model was developed based on the best combination of the feature selection strategy and classifier, and it was compared with two clinical factors based prediction models, and human doctors using nested cross-validation in terms of AUC, accuracy, sensitivity, and specificity. Results Comparison experiments demonstrated that CT features and three-dimensional (3D) features performed better than positron emission tomography (PET) features and three-dimensional (2D) features respectively, and multidomain features were superior to single domain features. In addition, the combination of SVM-RFE feature selection strategy and Linear SVM classifier had the highest diagnostic performance (i.e., AUC = 0.93 ± 0.01, ACC = 0.85 ± 0.02, SEN = 0.86 ± 0.03, SPE = 0.84 ± 0.03). The quantified radiomics model developed is significantly superior to both human doctors and clinical factors based prediction models in terms of accuracy and specificity. Conclusions Our preliminary results confirmed that the quantified radiomics method could aid the noninvasive differentiation of AIP and PDAC in 18 F FDG PET/CT images and the integration of multidomain features is beneficial for the differentiation.

Type 2 autoimmune pancreatitis (AIP) typically presents with diffuse or focal enlargement of the pancreas; however, its diverse clinical presentation has not yet been clarified. We herein described a 46-year-old man with a 1-month history of ulcerative colitis who presented with imaging features of a mass-like lesion in the pancreatic body with upstream duct dilatation and serum CA19-9 elevation. He underwent laparoscopic distal pancreatectomy with splenectomy for suspected malignancy. Histologically, the area radiologically suspected to be duct dilatation consisted of necrotic tissue, in which the disrupted main pancreatic duct was involved. The area radiologically suspected to be the mass lesion showed features of pancreatitis without discrete mass. In addition, several ducts showed neutrophilic duct injury similar to granulocytic epithelial lesions observed in type 2 AIP. Immunohistochemistry revealed the aberrant expression of IL-8 in the pancreatic ductules and infiltrating CD3-positive T-lymphocytes, findings recently identified in type 2 AIP. The present case is not typical for either type 2 AIP or other known conditions, but extreme examples of type 2 AIP may present with ductal obstruction because of severe neutrophilic duct injury. IL-8 immunostaining may also assist in establishing a diagnosis of type 2 AIP with an atypical presentation.

Background and aim Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) presents as isolated proximal-type sclerosing cholangitis (i-SC). The present study sought to clarify the imaging differences between i-SC and Klatskin tumor. Differences between i-SC and IgG4-SC associated with autoimmune pancreatitis (AIP-SC) were also studied. Methods Differentiating factors between i-SC and Klatskin tumor were studied. Serum IgG4 level, CA19-9 level, computed tomography (CT) findings, cholangiography findings (symmetrical smooth long stricture extending into the upper bile duct [SSLS]), endosonographic features (continuous symmetrical mucosal lesion to the hilar part [CSML]), endoscopic biopsy results, treatment, relapse, and survival were also compared between patients with i-SC and those with AIP-SC. Results For a differential diagnosis between i-SC (N = 9) and Klatskin tumor (N = 47), the cut-off value of serum IgG4 level was 150 mg/dL (sensitivity, 0.857, specificity, 0.966). Logistic regression analysis indicated that serum IgG4 level, presence of SSLS, presence of CSML, and presence of swollen ampulla are independent factor for identifying i-SC. Relapse rate was significantly higher in the IgG4-SC with AIP group than in the i-SC group (log rank, P = 0.046). Conclusion Isolated proximal-type sclerosing cholangitis presents as a nodular lesion with SSLS and/or CSML mimicking a Klatskin tumor. Those endoscopic features might provide a diagnostic clue for i-SC. i-SC is likely to have a more favorable prognosis than IgG4-SC with AIP.

The immunopathogenesis of autoimmune pancreatitis (AIP) is poorly understood. Here, we have used MRL/MpJ mice, a model of spontaneous AIP, to address the role of cellular autoimmune processes in the initiation and progression of the disease. Therefore, different T cell subpopulations were adoptively transferred from sick to still healthy (but susceptible) MRL/MpJ mice. Unpurified splenocytes and CD3+ T cells both efficiently induced AIP, while CD4+ and CD8+ T cells alone, as well as splenocytes from healthy mice, were insufficient to trigger the disease. Strikingly, CD4+ CD44high memory T cells, although transferred at lower numbers than other T cells, also induced AIP in recipient mice. Employing a modified experimental design, we also evaluated the effects of regulatory T cells (Tregs ) on the progression of AIP in already diseased mice. Under the given experimental conditions, there was no significant suppressive effect of adoptively transferred Tregs on pancreatic histopathology. The results of our studies suggest a key role of T cell-mediated processes in murine AIP. The effects of CD4+ CD44high memory T cells are in accordance with genetic studies of our group, which had previously implicated this cell type into the pathogenesis of AIP. In follow-up studies, we will focus on the interplay of cellular and humoral autoimmunity in the context of AIP.

Aims Xanthogranulomatous cholecystitis (XGC), an unusual histologic variant of chronic cholecystitis, is characterized by mixed foamy histiocytic and lymphoplasmocytic infiltration and fibrosis. Radiologically, the poorly defined nodular growth pattern often leads to the misinterpretation of XGC as gallbladder cancer. In this study, we aimed to identify the relationship of XGC with IgG4-related cholecystitis, Methods and Results We re-evaluated 57 surgically resected XGCs and 104 conventional chronic cholecystitis cases, according to the histologic features observed in IgG4-related disease, including lymphoplasmocytic infiltration, storiform fibrosis, obliterative phlebitis, and IgG4-positive plasma cells. XGCs contained a significantly increased mean number of IgG4-positive plasma cells (34.8/high-power field [HPF]), compared with conventional chronic cholecystitis (4.8/HPF; P 50 IgG4-positive cells per HPF. Nine XGCs (16%), including one case with IgG4-related autoimmune pancreatitis, exhibited “the histological features suggestive of IgG4-related disease”, as described in the consensus statement regarding this condition. Extracholecystic inflammatory extension (7 cases, P = .009) and mass-forming lesions (8 cases, P < .001) were more frequently seen in XGC cases with histological features suggestive of IgG4-related disease than in cases without those microscopic changes. Conclusions XGCs with IgG4-positive cell infiltration are considered mimickers, as xanthogranulomatous inflammation generally contradicts a diagnosis of IgG4-related disease and is weakly associated with other typical organ manifestations of IgG4-related disease. However, XGC may be a concurrent condition, particularly in patients with IgG4-related disease in other organs. This article is protected by copyright. All rights reserved.

The unique radiological manifestation mimicking autoimmune pancreatitis caused by lung cancer metastasis to the pancreas has not previously been reported. The incidence of pancreatic secondary tumors has previously been reported to be approximately 15% in autopsy cases of malignant tumors, and it is unusual for thoracic oncologists to find that the second common primary tumor site of metastatic pancreas tumor is the lung.

Background and Purpose Pancreatitis is a common inflammation of the pancreas with rising incidence in many countries. Despite improvements in diagnostic techniques, the disease is associated with high risk of severe morbidity and mortality and there is an urgent need for new therapeutic interventions. In this study we evaluated whether histone deacetylases (HDACs), key epigenetic regulators of gene transcription, are involved in the development of the disease. Experimental Approach We analyzed HDAC regulation during cerulein-induced acute, chronic and autoimmune pancreatitis using different transgenic mouse models. The functional relevance of class I HDACs was tested with the selective inhibitor MS-275 in vivo upon pancreatitis induction and in vitro in activated macrophages and primary acinar cell explants. Key Results HDAC expression and activity were up-regulated in a time-dependent manner following induction of pancreatitis, with the highest abundance observed for class I HDACs. Class I HDAC inhibition did not prevent the initial acinar cell damage. However, it effectively reduced the infiltration of inflammatory cells, including macrophages and T cells, in both acute and chronic phases of the disease, and directly perturbed macrophage activation. In addition, MS-275 treatment reduced DNA damage in acinar cells and limited acinar de-differentiation into acinar-to-ductal metaplasia in a cell-autonomous manner by impeding the EGFR signaling axis. Conclusions and Implications These results demonstrate that class I HDACs are critically involved in the development of acute and chronic forms of pancreatitis and suggest that blockade of class I HDAC isoforms is a promising target to improve the outcome of the disease.

The International Consensus Diagnostic Criteria (ICDC) for the diagnosis of autoimmune pancreatitis (AIP) include the histological criterion that is based on either pancreatic core needle biopsies (CNBs) or surgical specimens. However, CNBs are difficult to obtain by endoscopic ultrasound (EUS). EUS fine-needle aspiration (EUS-FNA) cytology is usually not sufficient for the diagnosis of AIP, but may sometimes contain tissue microfragments. Another approach is EUS-guided histological fine-needle biopsy (EUS-FNB), using needles such as the SharkCore or ProCore needle. Published data regarding EUS-guided SharkCore FNB for the diagnosis of AIP are lacking. We aimed to describe our histological findings in one type 1 and two type 2 AIP patients who underwent EUS SharkCore FNB. The EUS-FNBs of two patients fulfilled the histological level 2 ICDC for type 1 AIP or type 2 AIP. The EUS-FNB of one patient fulfilled the histological level 1 ICDC for type 2 AIP. The tissue cylinders and fragments measured 55, 28 and 17 mm in total. At least histological level 2 ICDC were fulfilled in all cases, and our findings regarding the utility of EUS SharkCore FNB for the diagnosis of AIP are therefore promising, but further studies based on larger numbers of patients are warranted.

IgG4-related disease (IgG4-RD) is a systemic, multi-organ disorder with heterogeneous clinical features but distinctive presentations.1, 2 The classic onset of this disease is subacute, taking the form of tumor-like lesions that develop gradually. These lesions are generally identified either on physical examination (e.g., salivary gland enlargement) or imaging (e.g., a renal, lung, or pancreatic mass), frequently at a time when the patient feels well. In the first years following recognition of IgG4-RD, the diagnosis was often made by pathologists in the complete absence of clinical suspicion for the disease. More recently, because of growing familiarity with typical IgG4-RD presentations and the use of blood IgG4 testing, presumptive diagnoses are often rendered by clinicians before the performance of diagnostic tests. Biopsy confirmation of the diagnosis remains important in most cases. IgG4-RD is not a new disease. Cases of the disease are well documented in medical history going back at least to the late 1800s3 , but the individual organ manifestations were considered to be distinct disease entities for more than a century, each confined to single organs and given eponymic designations: e.g., Riedel’s thyroiditis (circa 1883), Kuttner’s tumor (dacryoadenitis involving the submandibular gland, circa 1896), and Ormond’s disease (circa 1960).4, 5, 6 In 2001, Hamano, Kawa, and colleagues demonstrated that an elevated serum IgG4 level was useful in distinguishing “sclerosing pancreatitis,” now termed type 1 (IgG4-related) autoimmune pancreatitis, from other diseases of the pancreatic and biliary tract.7 In 2003, Kamisawa and Nakajima recognized similar pathology findings in extra-pancreatic organs of patients with sclerosing pancreatitis.8 They described a disease typified by elevated serum IgG4 levels, responsiveness to glucocorticoids, multi-organ involvement, and a fibroinflammatory infiltrate. The name “IgG4-related autoimmune disease” was given to this disorder initially because of the abundance of IgG4-expressing plasma cells within affected tissues, thereby unifying seemingly disparate conditions. The involvement of bile ducts, major salivary glands, lymph nodes, and retroperitoneal tissue was also described in this original case series. Since that time, IgG4-RD has been reported to affect virtually every organ in the body. The lacrimal gland, lung, and kidney are other common sites of disease involvement [Figure 1, A–B].2 The aorta, pachymeninges, and bile ducts comprise exceptions to the tumefactive clinical presentation, presumably because of their tubular structures and/or thin walls.9, 10, 11 Open in a separate window Open in a separate window Figure 1 (A) Head and neck illustration highlighting involvement of the lacrimal and major salivary glands. Lacrimal and salivary gland enlargement is most often bilateral in distribution. (B) Abdomen illustration highlighting typical organ involvement including the pancreas, bile ducts, kidneys, and retroperitoneal tissue. Radiographically, the retroperitoneal fibrosis often extends inferiorly to encase the iliac vessels. Not depicted here, the aorta and lung are other common sites of disease involvement.

Objectives The aim of this study was to review the suitability of endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) for ruling out malignancy in autoimmune pancreatitis patients. Methods We retrospectively reviewed 40 autoimmune pancreatitis patients (type 1:37 patients; type 2: two patients; possible autoimmune pancreatitis: one patient) who received EUS-FNA. Among the 40 autoimmune pancreatitis patients, 34 were not histopathologically diagnosed with autoimmune pancreatitis by EUS-FNA, and they were followed up for more than 6 months in our hospital. Moreover, 14 pancreatic cancer patients who were not diagnosed by EUS-FNA were selected as a control group. These 14 patients constituted 3.9% of the 360 pancreatic cancer patients who received EUS-FNA. We evaluated the prognoses of the 34 autoimmune pancreatitis patients and the clinical differences between these 34 autoimmune pancreatitis patients and the 14 pancreatic cancer patients. Results All 34 autoimmune pancreatitis patients showed reduced pancreatic swelling. The main pancreatic duct dilation ( > 3 mm), the diameter of the main pancreatic duct, the capsule-like rim sign, and serum CA19-9 levels were significantly different between the autoimmune pancreatitis and pancreatic cancer patients (2.9% versus 69.2%, P

IgG4-related disease (IgG4-RD) is an increasingly prevalent protean multisystem disorder characterized by single or multi-organ infiltration of IgG4-bearing plasma cells. Skin involvement has been recognized and is relevant to proper diagnosis. A systematic literature review of 50 cases involving the skin reveals that patients with IgG4-related skin disease show predominant involvement of the head and neck and have a distinct pattern of systemic involvement, also favoring the head and neck - lymphatics, orbit, salivary, and lacrimal glands - but generally lacking pancreaticobiliary involvement (16% of cases), which by contrast is a predominant manifestation in systemic IgG4-RD (60% with pancreaticobiliary involvement). We summarize clinical and pathologic descriptive data from this systematic review. We review differential diagnosis and propose a diagnostic scheme for stratifying probability of disease based upon comprehensive integration of clinical, histopathologic, and laboratory data. Plasmacyte infiltration and storiform fibrosis are prominent in IgG4-related skin disease, but obliterative venulitis is less common than in the prototypical IgG4-related disease manifestation of autoimmune pancreatitis. IgG4 tissue and serum values, with a mean (±95% CI) in the reviewed cases of 132.8 ± 32.6 IgG4-positive plasma cells per high-power field and 580 ± 183.8 mg/dl, respectively, are incorporated into the suggested criteria. The distinct set of manifestations identified by this systematic review and the proposed diagnostic considerations, while requiring further validation in prospective studies, highlight the need to consider that IgG4-related skin disease defines a unique systemic disease complex along the spectrum of IgG4-RD.

PURPOSE To evaluate the diagnostic value of apparent diffusion coefficient (ADC) and intravoxel incoherent motion (IVIM) parameters in differentiating patients with either a normal pancreas (NP), pancreatic ductal adenocarcinoma (PDAC), neuroendocrine tumor (NET), solid pseudopapillary tumor (SPT), acute pancreatitis (AcP), vs. autoimmune pancreatitis (AIP). MATERIALS AND METHODS In all, 84 pathologically confirmed pancreatic tumors (60 PDACs, 15 NETs, 9 SPTs), 20 pancreatitis (13 AcPs, 7 AIPs), and 30 NP subjects underwent IVIM diffusion-weighted imaging using 10 b-values (0-900 sec/mm2 ) at 1.5T. The ADC, pure molecular diffusion coefficient (Dslow ), perfusion fraction (f), and perfusion-related diffusion coefficient (Dfast ) were calculated and compared using a Kruskal-Wallis test and post-hoc Dunn procedure. Receiver operating characteristic (ROC) analysis was performed to assess diagnostic performance. RESULTS The f and Dfast of the PDAC were significantly lower than that of the NP (f = 0.10 vs. 0.24; Dfast = 42.21 vs. 71.74 × 10-3 mm2 /sec; P < 0.05). In ROC analysis, f showed the best diagnostic performance (area-under-the-curve, 0.919) among all parameters in differentiating PDAC from NP (P ≤ 0.001). The f values of AcP (0.11) and AIP (0.13) and the Dfast values of SPT (20.48 × 10-3 mm2 /sec) and AcP (24.49 × 10-3 mm2 /sec) were significantly lower compared with NP (f = 0.24; Dfast = 71.74 × 10-3 mm2 /sec; P < 0.05). For NET, the f (0.21) was significantly higher than that of PDAC (0.10, P < 0.01). CONCLUSION Perfusion-related parameters f and Dfast are more helpful in characterizing pancreatic diseases than ADC or Dslow . The PDCA, SPT, AcP, and AIP were characterized by reduced f and Dfast values compared with normal pancreas. The f value might help in differentiating between PDAC and NET. LEVEL OF EVIDENCE 3 J. Magn. Reson. Imaging 2017;45:260-269.

We reported three cases of mass-forming type 1 autoimmune pancreatitis (AIP) that were preoperatively suspected to be pancreatic cancer, and reviewed their clinicopathological features. Radiological findings in the patients revealed hypoattenuating masses in the early phase or a stricture of the main pancreatic duct with upstream dilatation, which was consistent with the diagnosis of pancreatic cancer. Histopathologically, the lesions were well demarcated and met all diagnostic criteria for immunoglobulin G4 (IgG4)-related AIP, including the presence of periductal lymphoplasmacytic infiltration, obliterative phlebitis, storiform fibrosis and abundant IgG4-positive plasma cells. However, the adjacent uninvolved pancreatic duct and lobular structures were well preserved. And in all patients, none or some of the aforementioned characteristics were observed. We suggest that some cases of focal AIP may progress to more severe grades and exhibit mass formation, although remaining localized. These focal cases of AIP are difficult to distinguish from pancreatic cancer. To our knowledge, this report is the first to present a histopathological comparison of mass-forming AIP with the adjacent uninvolved pancreatic tissues.

Background and aim Pancreatic cysts have been reported in cases with autoimmune pancreatitis (AIP) and are often treated by corticosteroid; however, their response to steroid has not been determined fully. We aimed to see the incidence and steroid response of pancreatic cysts and the features of cysts without proper response in cases with AIP. Methods Fifty-eight AIP cases were analyzed for the incidence and associated factors of pancreatic cystic lesions (≥ 10 mm). Of these, 47 cases, determined for steroid response, were retrospectively investigated for the factors associated with cyst change by corticosteroid therapy. Results At initial diagnosis, 17 pancreatic cystic lesions were recognized in 13 cases (22.4%) of AIP, with an average size of 30 mm (range: 11-130 mm), associated with higher incidence of elevated serum amylase (38.5% vs 11.1%, P = 0.02). Of these 13 cases, nine cases with 10 cystic lesions underwent steroid therapy in our hospital. All of seven unilocular cysts were dramatically shrunken or vanished in a few months; meanwhile, three cases with multilocular cysts showed scarcely any steroid response (P = 0.008). Of these three cases, two cases were revealed to accompany pancreatic ductal carcinoma, in contrast to null of seven unilocular cysts (P = 0.07). Conclusions Pancreatic cystic lesions are sometimes recognized in cases with AIP, and most unilocular cysts can be minimized by corticosteroids. However, clinicians must be alert for atypical pancreatic cysts, such as multilocular cysts or cysts without obvious steroid response.

Immunoglobulin G4 (IgG4)-associated autoimmune hepatitis (AIH) is a new disease entity with elevated levels of serum IgG4 and marked IgG4 positive plasma cell infiltration of the liver, and its clinical course remains unknown. A patient with IgG4-associated AIH who later developed autoimmune pancreatitis (AIP) is reported. A 73-year-old man was admitted to our hospital due to elevated liver transaminase levels, hypergammaglobulinemia and positive antinuclear antibody. A liver biopsy specimen showed severe interface hepatitis with marked lymphoplasmacytic infiltration without damage to the interlobular bile ducts, and a diagnosis of AIH was made. Abdominal computed tomography showed no abnormalities in the pancreas. Prednisolone therapy normalized the transaminase levels. Two years later, the patient developed AIP, which recurred after 5 years due to a reduction in the prednisolone dose. Three years later, he had a recurrence of AIH after discontinuation of prednisolone treatment. Evaluation of serum IgG4 levels and IgG4-bearing plasma cell infiltration of the liver at both the onset and recurrence of AIH showed that the serum IgG4 levels were 284 and 208 mg/dL, respectively, and the IgG4-bearing plasma cell infiltration levels were 30-40 cells/high-power field (HPF) per portal area and 4-10 cells/HPF per portal area, respectively. From these results, this case was finally diagnosed as IgG4-associated AIH. The course of this patient demonstrates two important clinical lessons: (i) IgG4-associated AIH can later be complicated by AIP; and (ii) discontinuation of prednisolone treatment can cause recurrence of IgG4-associated AIH.

Immunoglobulin G4-related disease (IgG4-RD) is a regional or systemic fibro-inflammatory disease of unknown etiology. It presents a distinctive histopathological appearance of dense lymphoplasmacytic infiltrates with abundant IgG4-positive plasma cells, storiform fibrosis and obliterative phlebitis with the appearance of inflammatory swelling or tumefactive lesions. This new disease entity includes a wide variety of diseases such as Mikulicz disease, autoimmune pancreatitis, Riedel thyroiditis, interstitial nephritis and retroperitoneal fibrosis. Glucocorticoid therapy can resolve the clinical and pathological abnormalities and impaired organ function. IgG4-RD was recognized internationally in 2011, and new evidence has accumulated regarding its pathogenesis, clinical features and treatment. In this review, we outline our present understanding of IgG4-RD.

Background and Aim Autoimmune pancreatitis (AIP) is a distinct disease entity. Whether the genes involved in pancreatic acinar cell injury, cationic trypsinogen gene (protease, serine, 1 [trypsin 1] [PRSS1]) and the pancreatic secretory trypsin inhibitor gene (serine peptidase inhibitor, Kazal type 1 [SPINK1]), are associated with AIP remains to be explored. Methods Genetic analyses of PRSS1 variants (exon 2 and 3) and SPINK1 variants (exon 1, 2, and 3) including the intronic areas in 118 patients with AIP and 200 control subjects were performed by direct DNA sequencing. Clinical features including imaging, histology, serology, response to steroid, and extra-pancreatic organ involvement in AIP patients with and without variants were compared. Results A total of 19 PRSS1 variants and one SPINK1 variant were identified in 20 (16.9%) out of 118 AIP patients. They included one K92N, nine R116C, seven T137M, one C139S, and one C139F of PRSS1 and one 2(IVS3 + 2) of SPINK1. No PRSS1 or SPINK1 variant was identified in the control group. Patients with PRSS1 variants had an increased risk of AIP with odds ratio 22.37 (95% confidence interval: 2.96–168.8, P = 0.003) and higher frequency of serum IgG4 above 280 mg/dL. Using immunosuppressive agent and PRSS1 variant were predictors of less disease relapse in univariate analysis. Presence of PRSS1 variants was the only negative predictor for disease relapse in multivariate analysis. Conclusions We found a significantly higher frequency of PRSS1 variants in AIP patients than in geographically and ethnically matched control subjects. PRSS1 variants are associated with less disease relapse in AIP.