Tsukasa Ikeura

Recent Concepts of Autoimmune Pancreatitis and IgG4-Related Disease

Recent studies suggested the existence of two subtypes of autoimmune pancreatitis (AIP): type 1 related with IgG4 (lymphoplasmacytic sclerosing pancreatitis; LPSP) and type 2 related with a granulocytic epithelial lesion (idiopathic duct-centric chronic pancreatitis; IDCP). Apart from type 2 AIP, the pathological features of type 1 AIP with increased serum IgG4/IgE levels, abundant infiltration of IgG4+ plasmacytes and lymphocytes, fibrosis, and steroid responsiveness are suggestive of abnormal immunity such as allergy or autoimmunity. Moreover, the patients with type 1 AIP often have extrapancreatic lesions such as sclerosing cholangitis, sclerosing sialadenitis, or retroperitoneal fibrosis showing similar pathological features. Based on these findings, many synonyms have been proposed for these conditions, such as “multifocal idiopathic fibrosclerosis”, “IgG4-related autoimmune disease”, “IgG4-related sclerosing disease”, “IgG4-related plasmacytic disease”, and “IgG4-related multiorgan lymphoproliferative syndrome”, all of which may refer to the same conditions. Therefore, the Japanese Research Committee for “Systemic IgG4-related Sclerosing Disease” proposed a disease concept and clinical diagnostic criteria based on the concept of multifocal fibrosclerosis in 2009, in which the term “IgG4-related disease” was appointed as a minimal consensus on these conditions. Although the significance of IgG4 in the development of “IgG4-related disease” remains unclear, we have proposed a hypothesis for the development of type 1 AIP, one of the IgG4-related disease. The concept and diagnostic criteria of “IgG4-related disease” will be changed in accordance with future studies.

Current concept and diagnosis of IgG4-related disease in the hepato-bilio-pancreatic system.

Recently, IgG4-related disease (IgG4-RD) has been recognized as a novel clinical entity with multiorgan involvement and unknown origin, associated with abundant infiltration of IgG4-positive cells. The Japanese research committee, supported by the Ministry of Health, Labor and Welfare of Japan, unified many synonyms for these conditions to the term “IgG4-RD” in 2009. The international symposium on IgG4-RD endorsed the comprehensive nomenclature as IgG4-RD, and proposed the individual nomenclatures for each organ system manifestations in 2011. Although the criteria for diagnosing IgG4-RD have not yet been established, proposals include the International Pathological Consensus (IPC) and the Comprehensive Diagnostic Criteria (CDC) for IgG4-RD for general use, and several organ-specific criteria for organ-specialized physicians, e.g., the International Consensus Diagnostic Criteria (ICDC) and the revised clinical diagnostic criteria in 2011 by the Japan Pancreas Society (JPS-2011) for type1 AIP; the Clinical Diagnostic Criteria 2012 for IgG4-sclerosing cholangitis (IgG4-SC-2012); the diagnostic criteria for IgG4-positive Mikulicz’s disease by the Japanese Society for Sjogren’s syndrome; and diagnostic criteria for IgG4-related kidney disease by the Japanese Society of Nephrology. In cases of probable or possible IgG4-RD diagnosed by the CDC, organ-specific diagnostic criteria should be concurrently used according to a diagnosis algorithm for IgG4-RD, with referral to a specialist.

IgG4 cholangiopathy – Current concept, diagnosis, and pathogenesis

IgG4 related cholangiopathy, a distinctive type of cholangitis of unknown origin, is characterized by increased serum levels of IgG4, massive infiltration of IgG4-positive plasma cells with storiform fibrosis and/or obliterative phlebitis in the thickened bile duct wall, and good response to steroids. Patients with IgG4-cholangiopathy are frequently associated with autoimmune pancreatitis; IgG4-cholangiopathy is recognized as a biliary manifestation of IgG4-related disease. This condition can be diagnosed by a combination of imaging, serology, histopathology, and steroid responsiveness; however, cholangiographic features are often difficult to differentiate from primary sclerosing cholangitis, pancreatic cancer, or cholangiocarcinoma. The Japanese clinical diagnostic criteria for IgG4-related sclerosing cholangitis established in 2012 are useful in the diagnosis of IgG4-cholangiopathy. Although the precise pathogenic mechanism remains unclear, the development of IgG4-cholangiopathy may involve: susceptible genetic factors, abnormal innate and acquired immunity, decreased naïve regulatory T cells, and specific B cell responses. Further studies on genetic backgrounds, disease specific antigens, and the role of IgG4 are necessary to clarify the pathogenesis.

Relationship between autoimmune pancreatitis and pancreatic cancer: a single-center experience.

OBJECTIVES Ordinary chronic pancreatitis (CP), such as alcoholic CP, is well established to have the increased risk for pancreatic cancer (PaC), nevertheless an association between autoimmune pancreatitis (AIP) and PaC is still unknown. The aims of this study are to examine the frequency of patients who developed PaC during follow-up after being diagnosed with type 1 AIP and to compare the incidence rate of PaC between patients with type 1 AIP and CP. METHODS Sixty-three patients with type 1 AIP and 41 patients with CP were enrolled. We examined development of PaC during follow-up from their clinical records. RESULTS The mean follow-up period was 62.4 months in AIP group and 49.2 months in CP group. The occurrence of PaC was observed in 3 patients with AIP during the mean follow-up period of 94.7 months (range, 31-186), whereas a single CP patient developed PaC 38 months after CP diagnosis. The incident rate of PaC during follow-up was comparable between the 2 groups [4.8% (3/63) in type 1 AIP group vs. 2.4% (1/41) in CP group]. In all of 3 AIP patients who developed accompanying PaC, the clinical remission of AIP was achieved with maintenance steroid therapy, when tumors were discovered. In the histological examination of one surgical patient with PaC, lymphoplasmacytic infiltration in storiform fibrosis with abundant IgG4-positive cell infiltration was observed around the PaC area. CONCLUSIONS Similar to patients with ordinary CP, surveillance for development of PaC is needed at regular interval during follow-up in AIP patients.

Diagnostic and Therapeutic Endoscopic Retrograde Cholangiography Using a Short-Type Double-Balloon Endoscope in Patients With Altered Gastrointestinal Anatomy: A Multicenter Prospective Study in Japan

OBJECTIVES:To evaluate the utility and safety of a short-type double-balloon endoscope (DBE) in the treatment of biliary disease in patients with surgically altered gastrointestinal (GI) anatomy.METHODS:This study was conducted as a multicenter, single-arm, prospective trial at five tertiary academic care centers and three community-based hospitals in Japan. Consecutive patients with biliary disease with altered GI anatomy were prospectively included in this study.RESULTS:A total of 311 patients underwent double-balloon endoscopic retrograde cholangiography (ERC). The success rate of reaching the target site, the primary end point, was 97.7% (95% confidence interval (CI): 95.4–99.1). The success rate of biliary cannulation and contrast injection of the targeted duct, the secondary end point, was 96.4% (95% CI: 93.6–98.2), and the therapeutic success rate was 97.9% (95% CI: 95.4–99.2). Adverse events occurred in 33 patients (10.6%, 95% CI: 7.1–14.0) and were managed conservatively in all patients with the exception of 1 in whom a perforation developed, requiring emergency surgery.CONCLUSIONS:ERC using a short-type DBE resulted in an excellent therapeutic success rate and a low rate of adverse events. This treatment can be a first-line treatment for biliary disease in patients with surgically altered GI anatomy.

Application of international consensus diagnostic criteria to an Italian series of autoimmune pancreatitis

Background International consensus diagnostic criteria (ICDC) have been proposed to classify autoimmune pancreatitis (AIP) in type 1, type 2, or not otherwise specified. Objective Aim was to apply the ICDC to an Italian series of patients to evaluate the incidence and clinical profiles among different subtypes of AIP. Methods we re-evaluated and classified 92 patients diagnosed by Verona criteria, according to the ICDC. Results Out of 92 patients, 59 (64%) were diagnosed as type 1, 17 (18%) as type 2, and 15 (16%) as not otherwise specified according to the ICDC. A significant difference between type 1 and type 2 were found for age (54.5 ± 14.5 vs. 34.4 ± 13.9 respectively; p < 0.0001), male sex (76 vs. 47%; p = 0.007), jaundice (66 vs. 18%; p = 0.002) and acute pancreatitis (9 vs. 47%; p < 0.0001), elevated serum IgG4 levels (85 vs. 7%; p < 0.0001), inflammatory bowel disease (8 vs. 82%; < 0.0001), and relapse of the disease (34 vs. 6%; p = 0.058). Imaging and response to steroids in the not-otherwise-specified group were similar to type 1 and 2. Conclusions Type 1 has a different clinical profile from type 2 autoimmune pancreatitis. The not-otherwise-specified group has peculiar clinical features which are shared both with type 1 or type 2 groups.

Intrapancreatic axonal hyperbranching of dorsal root ganglia neurons in chronic pancreatitis model rats and its relation to pancreatic pain.

Objectives: Increase in number of intrapancreatic nerve bundles has been implicated in the generation of persistent pain in chronic pancreatitis. To examine the origin of these nerve fibers and the mechanisms linking neural morphological change to pain generation, we used neuronal tracing techniques in combination with immunohistochemistry in spontaneous chronic pancreatitis in the Wistar Bonn/Kobori (WBN/Kob) rats. Methods: For retrograde tracing, horseradish peroxidase was injected into the pancreas, and labeled neurons in the sensory ganglia were counted. For anterograde tracing, biotinylated dextran amine was injected into the dorsal root ganglia (DRGs), and labeled intrapancreatic sensory fibers were histochemically assessed. For assessment of pain generation, we evaluated c-Fos-positive neurons in the spinal dorsal horn and behavioral changes of the animals. Results: In WBN/Kob rats, the numbers of horseradish peroxidase-labeled neurons were decreased in the DRGs, and the numbers of biotinylated dextran amine-labeled intrapancreatic nerve fibers and terminals were increased. Biotinylated dextran amine-labeled nerve fibers contained growth-associated protein 43. The number of c-Fos-positive neurons in the dorsal horn was also increased and was correlated with intrapancreatic growth-associated protein 43 immunoreactivity. Grooming behavior was reduced in WBN/Kob rats, and this reduction was facilitated by exocrine stimulation. Conclusions: Axonal branching in DRG neurons innervating the pancreas increases in WBN/Kob rats, and these morphological changes are likely involved in pain generation in chronic pancreatitis.

Regulatory T Cells in Type 1 Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP) is a newly recognized pancreatic disorder. Recently, International Consensus Diagnostic Criteria for AIP (ICDC) was published. In this ICDC, AIP was classified into Type 1 and Type 2. Patients with Type 1 AIP have several immunologic and histologic abnormalities specific to the disease, including increased levels of serum IgG4 and storiform fibrosis with infiltration of lymphocytes and IgG4-positive plasmacytes in the involved organs. Among the involved organs showing extrapancreatic lesions, the bile duct is the most common, exhibiting sclerosing cholangitis (IgG4-SC). However, the role of IgG4 is unclear. Recently, it has been reported that regulatory T cells (Tregs) are involved in both the development of various autoimmune diseases and the shift of B cells toward IgG4, producing plasmacytes. Our study showed that Tregs were increased in the pancreas with Type 1 AIP and IgG4-SC compared with control. In the patients with Type 1 AIP and IgG4-SC, the numbers of infiltrated Tregs were significantly positively correlated with IgG4-positive plasma cells. In Type 1 AIP, inducible costimulatory molecule (ICOS)+ and IL-10+ Tregs significantly increased compared with control groups. Our data suggest that increased quantities of ICOS+ Tregs may influence IgG4 production via IL-10 in Type 1 AIP.

Primary sclerosing cholangitis with elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells

Immunoglobin G4-related sclerosing cholangitis (IgG4-SC) is recognized as one of the systemic sclerosing diseases characterized by abundant IgG4-positive plasma cells with effective steroid therapy. On the other hand, primary sclerosing cholangitis (PSC), recognized as a sclerosing cholangitis of unknown origin without steroid efficacy, has been often clinically confused with IgG4-SC. To date, the prognosis of IgG4-SC is unclear, while the prognosis of PSC is well known to be poor. Therefore, it is clinically very important to be able to distinguish IgG4-SC from PSC. However, at the present time it still remains unclear whether PSC may sometimes be misdiagnosed as IgG4-SC or not. Herein, we report three rare cases of PSC with elevated serum IgG4 levels and/or an infiltration of abundant IgG4-positive plasma cells in the liver: a young male with ulcerative colitis (UC), and elderly female and a young female, each with elevated serum IgG4 levels. The first two patients showed infiltration of abundant IgG4-positive plasma cells in the portal area of the liver without response to steroid therapy. From our experiences, we emphasize that some patients with PSC, who do not respond to steroid therapy, show elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells, although the mechanism still remains unclear.

Evaluation of endoscopic retrograde cholangiopancreatography using a newly developed short-type single-balloon endoscope in patients with altered gastrointestinal anatomy

Endoscopic approaches for pancreatobiliary diseases in patients with altered gastrointestinal anatomy had been impractical until the development of balloon‐assisted endoscope (BAE) made it feasible. The aim of the present study was to evaluate the usefulness of a newly developed short‐type single‐balloon endoscope (s‐SBE) for endoscopic retrograde cholangiopancreatography (ERCP) in patients with altered gastrointestinal anatomy.