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To evaluate the efficacy and safety of rituximab in relapsing type 1 autoimmune pancreatitis especially the long-term clinical and immunologic impacts.All consecutive patients with type 1 autoimmune pancreatitis were retrospectively included. The rituximab protocol was induction therapy of 375 mg·m -2 intravenous weekly for 4 weeks, followed by 500 mg intravenous every 6 months for 2 years. The follow-up included clinical examinations, biological tests, positron emission tomography scan, and immunomonitoring of lymphocyte CD 19+.Among the 43 patients included, 15 received rituximab induction therapy, followed by maintenance in 10 cases because of 1 or more relapses after steroids (whether or not followed by immunosuppressants) and multiple organ involvement. All patients had a clinical, biological and morphological response, a deep and persistent drop in serum immunoglobulin G4 levels, an extinction of both pancreatic and extra pancreatic hypermetabolic positron emission tomography scan signals, and a depletion of B lymphocyte CD19+. No relapse occurred during the follow-up (62.8 ± standard error of the mean of 11.1 months).Rituximab is an effective treatment for type 1 autoimmune pancreatitis that provides a rapid strong clinical, biological, and morphological response, which persists after discontinuation without any safety issues.

OBJECTIVES Type 1 autoimmune pancreatitis (AIP) is a manifestation of immunoglobulin G4-related diseases (IgG4-RD). To evaluate the activity of the disease, the IgG4-RD responder index (RI) has been created. This study evaluated the IgG4-RD RI as prognostic factor of 1-year disease relapse. METHODS Patients diagnosed with type 1 AIP between January 2012 and December 2016, with available magnetic resonance imaging and IgG4 dosage, were enrolled. Immunoglobulin G4-RD RI was calculated at baseline (time 0), and at 3 to 6 and 12 to 18 months after the end of steroid therapy (time 1 and time 2, respectively). RESULTS Thirty-three patients were included in the study. Immunoglobulin G4-RD RI was 8.9 (standard deviation [SD], 3.8) at time 0, 2.4 (SD, 3.1) at time 1 (P < 0.0001 vs time 0), and 4.2 (SD, 3.9) at time 2 (P = 0.02 vs time 1). Fourteen patients who relapsed within 1 year showed a higher mean value of IgG4-RD RI at time 0 (10.9; SD, 4.3) versus 19 who did not (7.4; SD, 2.6; P = 0.012). This difference was observed also at time 2 (6.8 vs 2.1; P = 0.002). CONCLUSIONS Immunoglobulin G4-RD RI correlates with type 1 AIP disease activity, and it predicts disease relapse within 1 year.

The aim of the study was to investigate the global research levels in chronic pancreatitis (CP) fields.The term "chronic pancreatitis" was used to retrieve articles published between 2009 and 2018 from the Web of Science database. The 15 highest-output countries' gross domestic product was retrieved to analyze the correlation between output and economic development. The 5 top-ranking countries were compared in quantity and quality. The frequently used terms of all articles were retrieved to conduct co-occurrence analysis to reveal research highlights for CP.There were 6094 articles included and 6007 articles were from 15 highest-output countries. There was a positive correlation between output and gross domestic product (r = 0.928, P0.001). The United States, China, and Japan had increasing trends in total output (P = 0.022, P0.001, and P = 0.021, respectively). China and Japan had increasing trends in output per capita (P0.001 and P = 0.023). However, in average impact factor, all 5 countries did not show increasing trends (all P0.05). For research highlights, mass lesion and autoimmune pancreatitis were the notable aspects.The global output for CP will continue increasing and research quality will be stable.

Autoimmune pancreatitis (AIP) has the potential to transform into chronic pancreatitis with pancreatic stone involvement. This retrospective investigation sought to clarify the risk factors for stone formation in type 1 AIP.Questionnaires on patients with type 1 AIP were sent to 22 high-volume medical centers across Japan to compare the clinical features of patients with and without pancreatic stone formation.Of the completed records on 624 type 1 AIP patients, 31 (5%) had experienced pancreatic stones. Median follow-up duration was 1853 days. Bentiromide test values at diagnosis were significantly lower, and hemoglobin A1c values after corticosteroid treatment were significantly higher in patients with pancreatic stones. Imaging results disclosed that pancreatic atrophy and hilar or intrahepatic bile duct stenosis were significantly more frequent in patients with pancreatic stone formation. Pancreatic head swelling tended to be more frequent in this group as well. On the other hand, a shorter follow-up period was associated with the nonformation of pancreatic stones.The increased frequency of pancreatic head swelling in type 1 AIP patients exhibiting pancreatic stones indicated a propensity for pancreatic juice stasis with subsequent stone development and pancreatic dysfunction occurring over longer periods of disease duration.

OBJECTIVE The aim of this study was to critically analyze the surgical experience of managing autoimmune pancreatitis (AIP) in an era of modern diagnostics and compare these patients with those who were managed conservatively. METHODS Two prospectively maintained databases were used to retrospectively identify patients with AIP who were either managed conservatively or underwent pancreatectomy. RESULTS Eighty-eight patients were included in the study, of which 56 (63.6%) underwent resection and 32 (36.4%) were managed conservatively. Patients who underwent resection were more likely to present with jaundice (64.3% vs 18.1%, P < 0.001) and weight loss (53.6% vs 15.6%, P = 0.005). The cohort who underwent resection had a significantly higher median carbohydrate antigen 19-9 (40.0 vs 18.6 U/mL, P = 0.034) and was less likely to have elevated immunoglobulin G4 (26.1% vs 50.0%, P < 0.001). The most frequent initial diagnosis in the cohort who underwent resection was ductal adenocarcinoma (82.1%). Nine patients (28.1%) in the conservatively managed cohort experienced AIP relapse compared with 6 patients (10.7%) in the cohort who underwent resection. CONCLUSIONS The most frequent reason for surgical resection of AIP is concern for malignancy. Carbohydrate antigen 19-9 elevations were more common than immunoglobulin G4 in our cohort, suggesting that this laboratory profile is suboptimal for this population.

Objectives Oral corticosteroid treatment is the standard therapy for autoimmune pancreatitis (AIP) and is highly effective. However, relapse may occur during maintenance therapy (MT). We aimed to clarify the predictive factors for relapse after 3 years of MT for use in deciding on the continuation of long-term MT. Methods Among 56 retrospectively recruited AIP patients who received corticosteroid remission induction therapy followed by MT for a minimum of 5 years, 38 subjects were enrolled after exclusion criteria and divided into the relapse group of patients who experienced relapse after 3 years of MT and the nonrelapse group of patients who did not. Results According to multivariate analysis, at least 4 other organ involvement numbers at diagnosis (hazard ratio, 5.82; 95% confidence interval, 1.203-28.192) and IgG of 1400 mg/dL or greater at 3 years of MT (hazard ratio, 4.41; 95% confidence interval, 1.096-17.790) were predictive factors for relapse after MT for 3 years, with patients exhibiting both predictive factors having a higher cumulative relapse rate than those with 1 or fewer predictive factor. Conclusions We uncovered 2 predictive factors for AIP relapse after 3 years of MT. These findings will assist in deciding corticosteroid therapy regimens at 3 years of MT to minimize AIP relapse risk and adverse corticosteroid effects.

Objectives This study aimed to evaluate magnetic resonance imaging findings of autoimmune pancreatitis (AIP) and to find radiological patterns that could differentiate type 1 and type 2 AIP. Methods Eighty-four patients with diagnosis of AIP were enrolled. Image analysis included pancreatic signal intensity abnormalities, enhancement pattern, extrapancreatic involvement, and main pancreatic duct alterations. Results Pancreatic parenchyma resulted in hypointensity on T1-weighted images in 65 (98.5%) of 66 cases in type 1 and in 17 (94.5%) of 18 in type 2 (P > 0.05) and in hyperintensity on T2-weighted images in 41 (62%) of 66 and in 15 (83.4%) of 18, respectively (P > 0.05). Lesions were hypovascular in 64 (97%) of 66 cases in type 1 and in 16 (88.9%) of 18 in type 2 with delayed contrast retention in 56 (84.8%) of 66 and in 17 (94.5%) of 18, respectively (P > 0.05). Autoimmune cholangitis was found in 29 (43.9%) of 66 patients with type 1 and in 3 (16.7%) of 18 with type 2 (P = 0.02); renal involvement was observed in 20 (30.3%) of 66 and 1 (5.5%) of 18, respectively (P = 0.02). Both subtypes presented with multiple stenoses (P > 0.05). Dilation of upstream duct was more frequent in type 1 (P = 0.02). Conclusions Magnetic resonance imaging is useful in detecting extrapancreatic involvement, typically seen in type 1. Dilation of the upstream duct suggests type 1 AIP.

Objective To investigate the prevalence and natural history of pancreatic pseudocysts (PCs) and parenchymal necrosis in autoimmune pancreatitis (AIP). Method A search using PubMed, Embase, Scopus, and Cochrane was performed. Search terms were AIP, PC, acute fluid collection, and pancreatic necrosis. Results Fifteen studies with 17 patients were included. In 8 of 17 patients, PC was noted concurrently with the AIP diagnosis, whereas in the other half, PC appeared months or years after. In 10 of 17 cases, PC appeared as solitary. The location was variable. Pseudocysts were small ( 3 cm) in 13 cases. A normal pancreatic duct was observed in 6 of 17 cases, whereas 9 of 17 had pancreatic duct stenosis. Steroids were given to 4 of 4 small and 10 of 13 large PC. All small PC resolved with steroids, whereas only 4 of 10 large PC treated had some response. Most (9/13) of large PC underwent endoscopic or surgical procedures. None of the 17 cases developed necrosis. Conclusions Pseudocysts in AIP are rare. Pancreatic pseudocyst can present in variable number, size, and location. Small PC resolved with steroids. Large PC had poor response to steroids requiring invasive interventions. Necrosis in AIP has not been reported.

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OBJECTIVES We compared the clinical profiles and organ manifestations of the commonly encountered immunoglobulin G4-related diseases (IgG4-RDs) on either side of the diaphragm: head and neck (HN) versus pancreatobiliary (PB) in IgG4-RD. METHODS From the Mayo Clinic, Rochester, database, we identified 53 HN and 88 PB IgG4-RD based on the first affected organ manifestation. RESULTS Compared with HN IgG4-RD, subjects with PB IgG4-RD were likely to be older (median, 64.8 vs 50.2 years; P < 0.0001), male (83% vs 60.4%; P = 0.003), and with a shorter duration of follow-up (24.4 vs 48.7 months; P < 0.0001). In HN versus PB-IgG4-RD orbital, lacrimal gland, submandibular, parotid gland, asthma, and sinusitis manifestations were more common (77% vs 4.5%, 21% vs 0%, 32% vs 8%, 13% vs 0%, 36% vs 9%, and 51% vs 6.8%; P < 0.0001, respectively), whereas lung manifestations were similar (13.2% vs 5.6%; P = 0.12). In contrast, in PB versus HN IgG4-RD, pancreas and biliary were more frequent (98.8% vs 15%, 56.8% vs 3.7%; P < 0.0001), whereas renal lesions were similar (12.5% vs 7.5%; P = 0.36). CONCLUSION Pancreatobiliary and HN IgG4-RD have distinct clinical profiles. Proximity matters in other organ involvement in IgG4-RD, and organs involved tend to cluster close to each.

Autoimmune pancreatitis (AIP) is a rare disorder characterized by prompt clinical response to corticosteroids. Lost tolerance to a variety of pancreatic antigens and subsequent development of autoantibodies are presumably involved in the initiation of AIP. Even pediatric patients have been reported with features of AIP, and awareness of this disorder is increasing among different clinicians. The terms lymphoplasmacytic sclerosing pancreatitis and idiopathic duct-centric pancreatitis refer to the different histologic patterns of AIP, named type 1 and type 2, respectively. A combination of serologic, radiologic, and histologic investigations is needed to assess diagnosis of AIP and rule out neoplastic disorders. In addition, type 1 AIP can be distinguished by raised levels of serum immunoglobulin G4 and should be considered as part of systemic immunoglobulin G4-related disease. Conversely, type 2 AIP is frequently reported in younger patients and has less clear immune-mediated pathogenetic mechanisms. The natural history of pediatric AIP is obscure, and the diagnostic usefulness of different autoimmune abnormalities found in adults with AIP is limited for children. Tips to manage pediatric patients with AIP have been recently drafted through a set of recommendation statements. This review describes the current data about AIP and the pathogenic contribution of specific autoantibodies expressly in the pediatric population.

OBJECTIVES Autoimmune pancreatitis (AIP) responds well to steroid therapy but frequently relapses after discontinuing the steroid. It is difficult to know which cases are most likely to relapse. The aim of this study was to investigate the relation between the rate of decrease in serum IgG4 level after initial steroid therapy and a relapse. METHODS The subjects were 47 AIP patients who received steroid therapy. We calculated the difference between their serum IgG4 levels before and 2 months after the start of therapy, and their rate of decrease in serum IgG4 level after treatment (Δ') by dividing the difference between the 2 values by the number of days between them. RESULTS The rates of decrease were significantly higher in the nonrelapse groups than in the relapse groups. A receiver operating characteristic curve showed that the area under the curve for the Δ' value was 0.781, and that at the Δ' cutoff value of 10.7, the sensitivity and the specificity of the Δ' value for discriminating between the 2 groups were 0.846 and 0.632, respectively. CONCLUSIONS Our data suggest that the rate of decrease in serum IgG4 level may be a useful predictor of a relapse of AIP after steroid therapy.

On May 16, 2015 at the invitation of the American Gastroenterological Association Institute Council E.P.D. presented a state-of-the-art lecture at Digestive Disease Week 2015. The aims were to discuss a selection of landmark papers in chronic pancreatitis (CP) that influence modern management and to conclude by suggesting some future directions. This is based on that presentation. We will specifically review the following: duct anatomy and pancreas divisum, description of chronic relapsing pancreatitis and its differentiation from recurrent acute pancreatitis and established CP (ECP), natural histories and gene discoveries of alcoholic, idiopathic and hereditary pancreatitis, development of pancreatic cancer in CP, exocrine pancreatic insufficiency and calculation of dose and delivery of enzymes, endoscopic ultrasonography, and autoimmune pancreatitis. With some exceptions, we exclude basic science and surgery.

Eosinophil infiltration is a histological feature of autoimmune pancreatitis (AIP). However, little is known about the mechanisms underlying eosinophilic infiltration. In this study, we aimed to investigate the expression of the eosinophil chemotactic protein, eotaxin-3, in human pancreatic myofibroblasts.Enzyme-linked immunosorbent assays and quantitative polymerase chain reactions were used to quantify eotaxin-3 protein and messenger RNA levels, respectively.Eotaxin-3 expression was induced by T helper type 2 cytokines, interleukin-4 (IL-4) and IL-13, in time- and dose-dependent manners. Both IL-4 and IL-13 induced the rapid phosphorylation of STAT6 (signal transducer and activator of transcription 6), and STAT6-specific small interfering RNA significantly blocked IL-4- and IL-13-induced eotaxin-3 expression, indicating involvement of STAT6 signaling pathways in eotaxin-3 induction. In contrast, SOCS (suppressor of cytokine signaling) protein-specific small interfering RNA experiments suggested that the SOCS family proteins are negative regulators of IL-4- and IL-13-induced eotaxin-3 expression in pancreatic myofibroblasts. Interferon-γ significantly inhibited IL-4- and IL-13-induced eotaxin-3 expression, and this response was mediated by STAT1 activation.Pancreatic myofibroblasts may be a cellular source of eotaxin-3 in the pancreas. The T helper type 2 cytokines, IL-4 and IL-13, are critical factors for the induction of eotaxin-3 in the pancreas.

Introduction IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition characterised by an abundance of IgG4+ antibodies in the serum and tissue of involved organs. IgG glycosylation plays an important role in many chronic inflammatory and autoimmune conditions. We sought to assess the glycosylation status in patients with IgG4-RD and correlate with disease activity, damage and response to treatment. Methods IgG Fc and Fab glycosylation status was assessed in patients with IgG4-RD involving the bile ducts (IgG4-sclerosing cholangitis, IgG4-SC) and pancreas (autoimmune pancreatitis) (n=22), disease controls with primary sclerosing cholangitis (DC n=22) and healthy controls (HC n=22). Disease activity, organ damage and response to treatment were assessed serially using the IgG4-responder index. Serum IgG and subclasses were quantified using an ELISA and nephelometry. IgG and subclass Fc glycosylation was analysed by mass spectrometry and Fab glycosylation by lectin (SNA) affinity chromatography. Statistics were performed using Prism. Results IgG4-SC and AIP patients exhibited reduced total IgG Fc galactosylation and IgG1 Fc bisection, and increased IgG4 Fc fucosylation and IgG2/3 Fc hybrid compared with HC. There was recovery of IgG1 Fc bisection (increase) and IgG2/3 Fc hybrid (decrease) upon corticosteroid treatment. IgG Fc galactosylation and IgG2/3 Fc hybrid correlated with disease activity. IgG Fab glycosylation was higher in IgG4-RD patients, with an increase in IgG4-specific, and to a lesser extent IgG1-specific, Fab glycosylation compared to HC and DC. Conclusions In the first study to assess glycosylation status in IgG4-RD, we demonstrated alterations in both IgG Fc and Fab glycosylation, which may play a role in pathophysiology and serve as a biomarker of disease.

Objectives Serum IgG4 level is a useful diagnostic marker of autoimmune pancreatitis (AIP); however, it is difficult to predict relapse. We investigated whether a change in serum IgG4 is predictive of AIP relapse during maintenance therapy. Methods Seventy-three patients with AIP treated with steroids were divided into 3 groups according to their initial serum IgG4 levels: level 1 group (>2-fold upper limit), level 2 group (1- to 2-fold upper limit), and a normal group. The relapse rate and the prevalence of extrapancreatic lesions were compared between the 3 groups. The correlation between the relative rise of serum IgG4 levels and relapse during maintenance therapy was analyzed. Results There were no differences in serum IgG4 levels in the presence or absence of relapse. The average number of extrapancreatic lesions was 1.02, 0.47, and 0.27 in level 1, level 2, and the normal group, respectively. The relative rise of serum IgG4 levels after steroid therapy was significantly higher in relapse than in nonrelapse cases. The area under the receiver operating characteristic curve of the relative rise of IgG4 levels for discriminating between the relapse and the nonrelapse cases was 0.85. Conclusions The relative rise of serum IgG4 levels after steroid therapy may provide an indication of relapse.

Objective Differentiation between autoimmune pancreatitis (AIP) and pancreatic cancer (PC) is a clinical challenge. Emerging published data on the accuracy of serum immunoglobulin G4 (IgG4) for the differential diagnosis between AIP and PC are inconsistent. The objective of our study was to perform a meta-analysis evaluating the clinical utility of serum IgG4 in the differential diagnosis between AIP and PC. Methods We performed a systematic literature search of multiple electronic databases. The methodological quality of each study was assessed according to the Quality Assessment of Diagnostic Accuracy Studies checklist. Random-effects model was used to summarize the diagnostic odds ratio and other measures of accuracy. Results Eleven studies comprising 523 AIP patients and 771 PC patients were included in the meta-analysis. The summary estimates for serum IgG4 in distinguishing AIP from PC were as follows: diagnostic odds ratio, 57.30 (95% confidence interval [CI], 23.17-141.67); sensitivity, 0.72 (95% CI, 0.68-0.76); specificity, 0.93 (95% CI, 0.91-0.94). The area under the curve of serum IgG4 in distinguishing AIP from PC was 0.9200. Conclusions Our meta-analysis found that serum IgG4 has high specificity and relatively low sensitivity in the differential diagnosis between AIP and PC. Therefore, serum IgG4 is useful in distinguishing AIP from PC.

Before the immunoglobulin G4 (IgG4) era, autoimmune pancreatitis was proposed as a single clinical entity of autoimmune disease. In the IgG4 era, the following 2 subtypes have been proposed: type 1 is the pancreatic manifestation of IgG4-related disease and type 2 presents with granulocytic epithelial lesions. The characteristic features of type 1 are increased serum IgG4, lymphoplasmacytic sclerosing pancreatitis (abundant infiltration of IgG4+ plasmacytes and lymphocytes, storiform fibrosis, and obliterative phlebitis), other organ involvements (eg, sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis), and responsiveness to steroid. Diagnosis of both types can be made using the International Consensus Diagnostic Criteria. Different from type 2, approximately half of type 1 shows a relapse within 1 year after remission. Despite consensus for the initial steroid treatment, steroid maintenance and treatment for relapses are controversial. In the long term, approximately 10% of type 1 may develop chronic pancreatitis or pancreatic stone formation. It is controversial whether autoimmune pancreatitis is a risk factor for malignancy. Although the pathogenic mechanism remains unclear, multiple factors such as genetic background and abnormal immunity may be involved. Future studies should be conducted to identify more specific and novel biomarkers for each subtype, alternative treatment options for relapse, and the precise pathogenic mechanism.

OBJECTIVES: The aims of this study were to describe the diagnosis of autoimmune pancreatitis (AIP) in Denmark and to test the usefulness of the International Consensus Diagnostic Criteria (ICDC) on a geographically well-defined cohort.METHODS: All patients diagnosed with AIP at Odense University Hospital from 2007 to 2013 were included (n = 30; mean follow-up, 26.2 months). Data from laparoscopic or percutaneous ultrasound-guided core needle biopsy (CNB), resection specimens, endoscopic ultrasound (EUS), EUS-guided CNB, computed tomography, serum immunoglobulin G4 (IgG4), and pancreatography were retrospectively analyzed according to ICDC.RESULTS: Twenty patients were diagnosed with type 1, 8 with type 2, and 2 with not otherwise specified AIP. Twenty-eight patients (93%) could correctly be classified when ICDC were retrospectively applied. Serum IgG4 was elevated in 44% of type 1 and 0% of type 2. Other organ involvement was observed in 40% of type 1 and 13% of type 2, but inflammatory bowel disease only in type 2 (P = 0.001). One patient had IgG4-related chronic perisplenitis as a hitherto undescribed manifestation of IgG4-related disease. Nineteen (91%) of 21 biopsied patients had diagnostic CNB features of AIP. Computed tomography, EUS, and pancreatography showed features highly suggestive or supportive of AIP in 68%, 72%, and 71%, respectively.CONCLUSIONS: Laparoscopic or percutaneous ultrasound-guided CNB had the highest sensitivity for AIP. The ICDC could retrospectively correctly diagnose 93% of the patients.

Objectives To clarify the clinicoepidemiological features of autoimmune pancreatitis (AIP) in Japan, a nationwide epidemiological survey was conducted. Methods Patients with AIP who had visited selected hospitals in 2011 were surveyed. Autoimmune pancreatitis was diagnosed according to the revised clinical diagnostic criteria for AIP (Japan Pancreas Society 2011). The study consisted of 2 stage surveys; the number of patients with AIP was estimated by the first questionnaire, and their clinical features were assessed by the second questionnaire. Results The estimated total number of AIP patients in 2011 was 5745 (95% confidence interval, 5325-6164), with an overall prevalence rate of 4.6 per 100,000 population. The number of patients who were newly diagnosed as AIP was estimated to be 1808 (95% confidence interval, 1597-2018), with an annual incidence rate of 1.4 per 100,000 population. The sex ratio (male to female) was 3.2, and the mean age was 66.3 (11.5). Among the 936 patients whose detailed clinical information was obtained, 86.4% of the patients presented high serum immunoglobulin G4 levels (≥135 mg/dL), and 82.3% received steroid therapy. Conclusions The data represent the current clinical features of AIP in Japan.

OBJECTIVES The aim of this study was to assess the accuracy of key signs identified at endoscopic ultrasonography in diagnosing an autoimmune pancreatitis (AIP). METHODS Between January 2007 and December 2011, a retrospective case-control study was conducted in 177 patients with AIP (n = 30), pancreatic adenocarcinoma (n = 42), pancreatic neuroendocrine tumor (n = 21), alcoholic chronic pancreatitis (n = 32), and symptomatic common bile duct stones (n = 52). RESULTS An irregular narrowing of the main pancreatic duct in association with a wall thickening was seen in 28 of 30 AIP, 1 of 42 pancreatic adenocarcinoma, 0 of 21 pancreatic neuroendocrine tumor, 0 of 32 alcoholic chronic pancreatitis, and 0 of 52 common bile duct stones (P < 0.05). Sensitivity, specificity, positive and negative predictive values, and overall diagnostic accuracy of this sign for the diagnosis of AIP were 93%, 99.3%, 96.3%, 98.6%, and 98.3%, respectively. In type 1 AIP, hyperechoic parietal thickening was more frequent (92.3% vs 33.3%, P < 0.05). In type 2 AIP, hypoechoic parietal thickening was more frequent (83.3% vs 23.1%, P < 0.05). CONCLUSIONS An irregular narrowing of the main pancreatic duct in association with a wall thickening seen at endoscopic ultrasonography is accurate in diagnosing AIP. The type of echogenicity of the thickening is well correlated with the type of AIP.

The aim of this study was to intraindividually compare magnetic resonance pancreatography (MRP) image quality at 1.5 T and 3.0 T when demonstrating main pancreatic duct (MPD) abnormalities in patients with autoimmune pancreatitis (AIP).Thirty prospectively enrolled patients with AIP underwent MRP at both 1.5 T and 3.0 T followed by endoscopic retrograde pancreatography before treatment. Two readers independently analyzed the MRP images and graded the visualization of MPD strictures and full-length MPD, using endoscopic retrograde pancreatography as the reference standard, as well as overall image artifacts on a 4-point scale. The contrast between the MPD and periductal area was calculated using a region-of-interest measurement.Visualization scores of MPD strictures and full-length MPD, and summed scores of each qualitative analysis, were significantly greater at 3.0-T MRP than at 1.5-T MRP for both readers (P ≤ 0.02). There were less image artifacts at 3.0 T compared with 1.5 T (P ≤ 0.052). The contrast between the MPD and periductal area was significantly greater at 3.0-T MRP than at 1.5-T MRP (P0.001).The MRP at 3.0 T was superior to 1.5-T MRP for demonstrating MPD abnormalities in AIP, with better image contrast and fewer image artifacts. Consequently, 3.0-T MRP may be useful for the diagnosis and management of patients with AIP.

The risk of pancreatic and extrapancreatic cancer in autoimmune pancreatitis (AIP) has not been systematically evaluated. We compared the risk of malignancy in AIP patients and matched control subjects.We identified 116 subjects with AIP from a prospectively maintained database. From patients evaluated in primary care clinics, we selected 3 control subjects for each AIP patient matched on age, registration date, and sex (n = 344) . Risk for developing cancer after the index date was compared using a stratified Cox model.The proportion of patients diagnosed with cancer before AIP diagnosis (10.3%) was lower than that in the matched control subjects (17.4%). After a median follow-up of over 3 years, the risk of developing cancer after the index date was similar in AIP and control subjects (hazard ratio, 0.64; 95% confidence interval, 0.27-1.51). The 3 most commonly diagnosed malignancies in the AIP group were prostate cancer, lymphoma, and bladder cancer.Cancer risk before and after diagnosis of AIP is similar to that of control subjects. Specifically, there is no increased risk of cancer immediately preceding or following AIP diagnosis. Additional follow-up is needed to determine if there is a cumulative increase in cancer risk in AIP.

Objectives We attempted to clarify the mechanism underlying lower bile duct stricture in autoimmune pancreatitis. Methods Imaging and histologic finding of the bile duct were assessed for 73 patients with autoimmune pancreatitis to clarify whether IgG4-related biliary inflammation or pancreatic head swelling is associated with lower bile duct stricture. Results Lower bile duct stricture was found in 59 (81%) patients. Pancreatic head swelling was significantly more frequent among patients with lower bile duct stricture than those patients without lower bile duct stricture (53 [90%] vs 4 [29%]; P < 0.01). Intraductal ultrasonography findings revealed lower bile duct wall thickening in 21 (95%) of the 22 patients with lower bile duct stricture, and the lower bile duct wall of the patients with pancreatic head swelling was significantly thicker than those patients without pancreatic head swelling (P = 0.028). Among the 38 patients with lower bile duct biopsies, 14 (37%) exhibited abundant IgG4-bearing plasma cell infiltration. Among the patients with lower bile duct stricture, an IgG4-related inflammation seemed to exert a dominant effect under limited conditions, including concomitant middle bile duct stricture and neither pancreatic swelling nor pancreatic duct stricture in the head region. Conclusions Both pancreatic head swelling and IgG4-related biliary inflammation affect lower bile duct stricture, which may be included in IgG4-related sclerosing cholangitis. Pancreatic head swelling affects IgG4-related biliary wall thickening., Article, PANCREAS. 43(2):255-260 (2014)

To estimate the risk of malignancy in autoimmune pancreatitis (AIP).We examined resected pancreata to compare the prevalence of pancreatic intraepithelial neoplasia (PanIN) in 28 cases of AIP and 30 cases of chronic pancreatitis not otherwise specified (CP-NOS). We also reviewed a cohort of 84 AIP cases.The mean age of the AIP cohort (57 years) was significantly higher than that of the cohort of CP-NOS (47 years) (P = 0.01). Twenty-three cases (82%) of AIP showed PanIN, and 7 cases (25%) showed grade 2 PanIN. Grade 3 PanIN was identified in one case of AIP. There was no statistically significant difference in the number of cases with high-grade PanIN lesions between the cases of type 1 as opposed to type 2 AIP. In comparison to CP-NOS, a comparable percentage of patients with AIP had PanIN (82% of AIP cases vs 63% of CP-NOS cases) (P = NS) and PanIN 2 (25% AIP vs 20% CP-NOS) (P = NS). Of the 84 AIP cases at our institution (mean follow-up, 49 months), 2 cases of pancreatic carcinoma were identified 6 and 10 years after the diagnoses of AIP.These findings raise concern that AIP is associated with an elevated risk of malignancy and should prompt additional studies.

信州大学博士（医学）・学位論文・平成24年3月31日授与（甲第946号）・丸山 雅史, This is a non-final version of an article published in final form in PANCREAS. 42(1):53-59 (2013)., Objectives: Type 1 autoimmune pancreatitis (AIP) is histologically characterized by dense lymphoplasmacytic infiltration and marked storiform fibrosis, manifestations associated with pancreatic ducts. Such periductal lymphocyte recruitment is thought to be elicited by dysregulation of mechanisms governing physiological lymphocyte homing. The present study was undertaken to determine whether vascular addressins including peripheral lymph node addressin and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) play a role in type 1 AIP histogenesis. Methods: Tissue sections of type 1 AIP and tumor-associated non-AIP chronic pancreatitis, as well as normal pancreas, were subjected to immunohistochemical analysis using vascular addressin-related antibodies. Results: The number of periductal mouse endothelial cell antigen 79-positive high endothelial venule (HEV)-like vessels was increased in type 1 AIP relative to that seen in non-AIP chronic pancreatitis, whereas the number of MAdCAM-1-positive HEV-like vessels did not differ between the 2 conditions. Mouse endothelial cell antigen 79 antigens are expressed on duct-forming epithelial cells not only in pancreas but also in salivary glands, which often harbor extrapancreatic lesions in type 1 AIP. Conclusions: Type 1 AIP can be characterized by periductal induction of MECA-79-positive HEV-like vessels. MECA-79-positive 6-sulfo sialyl Lewis X-related carbohydrate antigens expressed on duct-forming epithelial cells could be associated with type 1 AIP pathogenesis., Article, PANCREAS. 42(1):53-59 (2013)

Objectives: The lack of specific biochemical markers is a major drawback for the diagnosis of autoimmune pancreatitis (AIP). The aims were to characterize the autoantibody profiles in AIP and pancreatic ductal adenocarcinoma (PDAC) and to identify circulating autoantibodies that could be diagnostic markers differentiating PDAC and the AIP subtypes. Methods: Tissue lysates obtained from the resected pancreas of patients with AIP and patients with PDAC were separated by 2-dimensional polyacrylamide gel electrophoresis subsequently immunoblotted with autologous sera. The immunoreactive spots were subjected to nanoscale liquid chromatography-electrospray ionization tandem mass spectrometry to identify serum autoantibodies to tissue-derived autoantigens associated with AIP and PDAC. Autoantibody concentrations for selected autoantigens were assessed by enzyme-linked immunosorbent assays. Results: A total of 115 immunoreactive spots were identified by 2-dimensional polyacrylamide gel electrophoresis/immunobloting. Nanoscale liquid chromatography-electrospray ionization tandem mass spectrometry-based analysis revealed 68 autoantigens in AIP, 26 in PDAC, and 21 present in both diseases. Assessment of 13 selected AIP autoantibody serum levels revealed that 7 of them had significantly higher titers in AIP versus PDAC. IgG-directed against transaldolase could significantly differentiate between the 2 AIP subtypes. Conclusions: The novel panel of AIP autoantibodies is promising to supplement the predictive tests for AIP of the currently known autoantigens and represent a basis for a combined blood test to differentiate AIP from PDAC in the future.

Because several studies for autoimmune pancreatitis (AIP) have revealed pancreatic calcification resembling that in chronic pancreatitis (CP), we sought to clarify whether AIP could transform into chronic features similar to advanced CP with severe pancreatic dysfunction.Pancreatic functions of 92 AIP patients, 47 definite CP patients, and 30 healthy controls were assessed by fecal elastase-1 concentration (FEC), fasting immunoreactive insulin (IRI), and homeostatic model assessment (HOMA)-R.The 92 AIP patients included 17 (18%) with severe calcification (SC) and 75 without. The FEC levels in AIP and CP patients were significantly lower than that in controls. Exocrine insufficiency defined as FEC less than 200 μg/g was 39% in AIP without SC, 56% in AIP with SC, and 74% in CP. Fasting IRI and C-peptide reactivity values in CP were significantly lower than those in AIP, with no significant differences between AIP subgroups. The prevalence of endocrine insufficiency according to fasting IRI less than 5.0 μU/mL was 26% in AIP without SC, 31% in AIP with SC, and 59% in CP, respectively. HOMA-R values were significantly higher in all AIP groups than in CP.Autoimmune pancreatitis can transform into a state of pancreatic insufficiency after calcification that is less severe than that in definite CP.

Objectives The aim of this study was to clarify the pancreatic blood perfusion in patients with autoimmune pancreatitis (AIP) and the changes after steroid treatment. Methods Perfusion computed tomography was performed in 11 patients with AIP and 12 control subjects. Pancreatic volumetric blood flow (F(V)), volume of distribution (V(D)), and blood transit time τ were determined from a single-compartment kinetic model. Nine patients with AIP were reexamined by perfusion computed tomography after corticosteroid administration. Results The pancreatic F(V) values of the 11 patients with AIP (82.7/min) were significantly lower than those of control subjects (163.5/min, P = 0.0006). On the other hand, the pancreatic V(D) and τ values were not significantly different between AIP and normal. After steroid treatment, the F(V) values of 9 reexamined patients with AIP (76.2/min) were significantly elevated (109.8/min, P = 0.0391). However, the changes of the values after the treatment differed in degree among individuals. The values of 4 patients were dramatically elevated to greater than 100/min, whereas those of 4 other patients did not improve well. The value of the remaining patient whose initial F(V) value was normal (168.09/min) did not change after the treatment. Conclusions Pancreatic volumetric perfusion was attenuated in AIP patients. The perfusion was improved after the steroid treatment.

Objectives Autoimmune pancreatitis (AIP) and its extrapancreatic lesions seem to be clinical manifestations of organs involved in IgG4-related systemic disease. To clarify whether the stomach is a target organ, gastric function was evaluated in patients with AIP. Methods In 6 patients with AIP, gastric emptying was assessed by Carbon 13 (¹³C) acetate breath test before and after steroid therapy. Based on 4-hour breath samples, the half ¹³CO₂ excretion time (T(1/2)) and the time of maximal excretion (T(max)) were calculated as gastric emptying parameters. Data of 20 healthy volunteers were used as controls. The number of IgG4-positive plasma cells in gastrofiberscopic biopsy specimens was counted before and after steroid therapy. Results Both T(1/2) and T(max) in patients with AIP decreased significantly after steroid therapy (T(1/2): 1.89 ± 0.21 hours vs 1.69 ± 0.15 hours, P = 0.046; and T(max): 1.1 ± 0.2 hours vs 0.96 ± 0.2 hours, P = 0.027), and became similar to those of the controls (T(1/2): 1.69 ± 0.32 hours and T(max): 0.98 ± 0.2 hour). The number of IgG4-positive plasma cells infiltrating the gastric mucosa decreased after steroid therapy. Conclusions Gastric emptying was impaired in patients with AIP and improved to the reference range after steroid therapy. The stomach may be a target organ of IgG4-related systemic disease.

To achieve the goal of developing international consensus diagnostic criteria (ICDC) for autoimmune pancreatitis (AIP).An international panel of experts met during the 14th Congress of the International Association of Pancreatology held in Fukuoka, Japan, from July 11 through 13, 2010. The proposed criteria represent a consensus opinion of the working group.Autoimmune pancreatitis was classified into types 1 and 2. The ICDC used 5 cardinal features of AIP, namely, imaging of pancreatic parenchyma and duct, serology, other organ involvement, pancreatic histology, and an optional criterion of response to steroid therapy. Each feature was categorized as level 1 and 2 findings depending on the diagnostic reliability. The diagnosis of type 1 and type 2 AIP can be definitive or probable, and in some cases, the distinction between the subtypes may not be possible (AIP-not otherwise specified).The ICDC for AIP were developed based on the agreement of an international panel of experts in the hope that they will promote worldwide recognition of AIP. The categorization of AIP into types 1 and 2 should be helpful for further clarification of the clinical features, pathogenesis, and natural history of these diseases.

To clarify the clinical and pathophysiological characteristics of autoimmune pancreatitis (AIP) in Asia.A retrospective, actual situation survey of AIP diagnosed by Asian criteria was conducted in 10 centers of Japan, Korea, Taiwan, China, and India.A total of 327 AIP cases (258 male and 69 female subjects; average age, 60.0 years) were enrolled. Obstructive jaundice was the most frequent initial symptom (46%-74%), followed by weight loss (4%-51%) and abdominal pain (19%-44%). Diffuse swelling of the pancreas was frequent in Japan (64%) and Korea (81%), but segmental swelling of the pancreas was more frequent in Taiwan (70%) and China (72%) (P0.01). Serum immunoglobulin G4 levels were elevated in 58%-100% of cases in Japan, Korea, and Taiwan. Pathologically, almost all AIPs in Asia were lymphoplasmacytic sclerosing pancreatitis. Sclerosing cholangitis was the most frequent extrapancreatic lesion (60%-81%). Steroid therapy was a major and effective therapeutic strategy in Japan, Korea, and Taiwan. However, the rate of resection or bypass operation was higher in Taiwan (40%) and China (72%) (P0.01).Features of AIP are fundamentally similar in Japan, Korea, Taiwan, and China. Knowledge of emerging AIP should be more widespread in Asia to avoid unnecessary operation.

To study the autoimmune response in MRL/Mp mice, which spontaneously develop pancreatitis in the exocrine pancreatic tissue.Six-week-old female mice were injected intraperitoneally with polyinosinic polycytidylic acid at a dose of 5 mg/kg of body weight twice a week for up to 12 weeks. The mice were serially killed, and the severity of their pancreatitis was graded with a histological scoring system. Immunohistological examinations were performed, and the serum levels of autoantibodies were measured by enzyme-linked immunosorbent assay.The administration of polyinosinic polycytidylic acid accelerated the development of pancreatitis, with abundant infiltration of B220 B cells and CD138 plasmacytes. Various autoantibodies directed against autoantigens, including carbonic anhydrase II and lactoferrin, were detected but none against glutamic acid decarboxylase. Of these, autoantibodies directed against the pancreatic secretory trypsin inhibitor (PSTI; 91.7%) were more prevalent than those against carbonic anhydrase II (33.3%) or lactoferrin (45.8%). Determination of the epitope of the anti-PSTI antibody showed that most immunoreactivity was directed at the site on PSTI that is active in the suppression of trypsin activity.The autoimmune response to PSTI protein may induce a failure of PSTI activity, resulting in the activation of trypsinogen and the subsequent disease progression.

To clarify the frequency and clinical significance of extrapancreatic lesions in autoimmune pancreatitis (AIP).The frequency and clinical characteristics of extrapancreatic lesions during the clinical course of AIP were investigated retrospectively in 64 patients with AIP. The predictive factors for relapse of AIP at clinical onset were also examined.Extrapancreatic lesions occurred in 95% (61/64) during the clinical course of AIP. The frequencies of sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis, and mediastinal or hilar lymphadenopathy were 84% (54/64), 23% (15/64), 16% (10/64), and 77% (27/35), respectively. Patients with sclerosing sialadenitis or extrapancreatic bile duct sclerosing cholangitis had a significantly higher serum immunoglobulin G concentration than those without (P = 0.005 and P = 0.016, respectively). Univariate analysis revealed that sclerosing sialadenitis (P = 0.005), diffuse pancreatic ductal changes (P = 0.028), and a high serum immunoglobulin G concentration (P = 0.030) at clinical onset of AIP were significant predictive factors for relapse. Multivariate analysis revealed that diffuse pancreatic ductal changes (P = 0.005) and sclerosing sialadenitis (P = 0.012) were significant independent predictive factors for relapse of AIP.The frequency of extrapancreatic lesions with AIP during the clinical course was high. The presence of sclerosing sialadenitis at clinical onset is a significant predictive factor for relapse of AIP.

A 74-year-old male patient presented with progressive anorexia, cholestatic liver function tests, and a diffuse enlarged pancreas suggestive of a pancreatic carcinoma. There was a marked elevation of total immunoglobulin G4 (IgG4) in serum. Further investigation led to the diagnosis of IgG4-related sclerosing disease with involvement of the pancreas, retroperitoneal fibrosis, and bilateral focal nephritis. To our knowledge, this is the first report on these 3 clinical entities occurring in the same patient. A short review of the literature concerning autoimmune pancreatitis and retroperitoneal fibrosis is made, with special interest to the concept of IgG4-related pathology. This systemic disease can have several clinical manifestations: IgG4-positivity not only can be found in the pancreas, but also at the level of extrahepatic biliary ducts, gallbladder, salivary glands, retroperitoneal tissue, kidneys, ureters, and lymph nodes. Although further investigation is required to determine its exact pathophysiologic role, IgG4 seems to be an important key player.