Autoimmune-related Pancreatitis Research Articles

THU378 Presentation Of Autoimmune Destruction Of Pancreatic Beta Cells By Pembrolizumab In The Setting Of Existing Type 2 Diabetes

Abstract Disclosure: J. Seidenberg: None. M.J. Ansari: None. Background: Prembrolizumab, like other immunotherapies, have become a commonplace treatment for certain cancers. Its method of action is binding of the programmed cell death I receptor that blocks the binding of the programmed cell death ligand 1. PD1-1 receptors have been reported to cause autoimmune endocrinopathies including type 1 diabetes. Many patients who present with the adverse reaction of autoimmune diabetes type 1 present with ketoacidosis. However, patients already diagnosed with diabetes type 2 on insulin could have this strong initial presentation masked. Clinical Case: Patient is a 76 year old female who was recently diagnosed with bladder cancer and started on Pembrolizumab. She presented to the endocrinology clinic due to new onset poor blood sugar control with self-tested glucose levels ranging from 300-400. This patient was previously diagnosed with diabetes type II and was taking metformin, Levemir 18 units daily, Humalog 6 units AC. A C peptide level was obtained during euglycemia, which was undetectable, indicating autoimmune destruction of pancreas. Patient was continued on Pembrolizumab due to her clinical response to it and a low probability of pancreatic beta cells functioning again. Patient’s C peptide continued to be undetectable 1 year after her presentation. Conclusion: Autoimmune destruction of pancreatic beta cells from Pembrolizumab is a rare but important adverse effect. Pembrolizumab has been reported to be associated with autoimmune-related pancreatitis leading to type 1 diabetes in only 0.1% of all patients in clinical trials. We present this patient, who was already being treated with insulin for type 2 diabetes and thus was being tested for elevated glucose regularly. She was able to notice a significant change in glucose control prior to onset of symptoms. All patients who take Pembrolizumab, especially those with underlying diabetes, should be regularly evaluated for interference with pancreatic beta cells with regular glucose labs and if hyperglycemia occurs, with a C peptide level should then be ordered. Presentation: Thursday, June 15, 2023

Autoimmune pancreatitis in Japan: overview and perspective

Since the rediscovery and definition of autoimmune pancreatitis (AIP) by Yoshida et al. in 1995, the disease has been attracting attention because of its unique clinical features and practical issues. This disease shows very impressive imaging findings, serological changes, and characteristic histopathology. It occurs most commonly in elderly males with painless jaundice or mild abdominal pain; resemblance in imaging findings between AIP and pancreatobiliary cancers poses an important practical issue of differentiation. With increasing recognition of AIP and accumulation of cases, another important feature of this disease has been revealed, i.e., association of extrapancreatic organ involvements. Initially misunderstood because it can be accompanied by other autoimmune disorders, such as Sjögren's syndrome or primary sclerosing cholangitis (PSC), AIP is now known to be associated with unique types of sialadenitis and cholangitis distinct from Sjögren's syndrome or PSC. Now the concept of "IgG4-related sclerosing disease" has become widely accepted and the list of organs involved continues to increase. With worldwide recognition, an emerging issue is the clinical definition of other possible types of autoimmune-related pancreatitis called "idiopathic duct-centric chronic pancreatitis (IDCP)" and "AIP with granulocyte epithelial lesion (GEL)" and their relation to AIP with lymphoplasmacytic sclerosing pancreatitis (LPSP). The time has arrived to establish clinical diagnostic criteria of AIP based on international consensus and to discuss regional and racial differences in the clinicopathological features of AIP. Consensus guidelines are also required for the ideal use of steroids in the treatment of AIP to suppress recurrence efficiently with minimal side effects. There are many issues to be settled in AIP; international collaboration of experts in the pancreas field is necessary to clarify the entire picture of this unique and important disease.

Endoscopic Ultrasonography of Autoimmune-Related Pancreatitis in Five Cases: The Reticular Pattern Disappears After Steroid Therapy?

Background & Aim: Although imaging features of autoimmune-related pancreatitis (AIP) have recently been established, there have been only a few reports of investigation of pancreatic parenchyma by endoscopic ultrasonography (EUS). The aim of this study was to clarify the EUS features of AIP. Methods: The study was performed in 5 patients (4 males and 1 female aged 51-74 years with a mean age of 61.4 years old) diagnosed with AIP and treated at our hospital between July 2002 and June 2004. AIP was diagnosed according to the criteria established by the Japan Pancreas Society and the criteria reported by Okazaki et al (GUT, 2002). All of the patients underwent EUS before therapy, and the EUS findings mainly in the body of the pancreas were investigated with regard to the following items: 1) Findings in the margin of the pancreas (smooth or irregular), 2) Findings in pancreatic ducts (dilatation or narrowing), and 3) Findings in pancreatic parenchyma (hypertrophy or atrophy, homogenous or heterogeneous, and reticular pattern or strand). In one patient, EUS was repeated 1 month after prednisolone therapy, and changes in EUS findings were investigated. Results: The margin of the pancreas was uneven and irregular, and some nodule-like protrusions were imaged in 4 patients. In all of the patients, no dilatation was noted in the main or side branches of the pancreatic duct. Swelling of the pancreas was noted in all of the patients, and was heterogeneous at a hypoechoic level. Hyperechoic strands were imaged as a reticular pattern in the pancreatic parenchyma, and hyperechoic foci were scattered inside the reticular pattern. In the patient who underwent EUS after therapy, the reticular pattern disappeared, and hyperechoic foci were partially imaged. Conclusion: As an EUS finding of AIP, a reticular pattern was noted, as reported in the early stage of chronic pancreatitis. It was suggested that steroid therapy may resolve the reticular pattern in AIP.

Acute tubulointerstitial nephritis associated with autoimmune-related pancreatitis

Various etiologic factors have been identified in tubulointerstitial nephritis (TIN), including allergic drug reaction, infection, and immune-mediated disease. Immune-mediated TIN without significant glomerular involvement has been reported to occur as a renal complication secondary to Sjögren's syndrome, lupus nephritis, and antitubular basement membrane antibody-related disease. We present a first case of acute TIN associated with autoimmune-related pancreatitis (AIP). A 64-year-old man was referred to our division from a surgeon for the close examination of renal dysfunction. The pancreatic and biliary imaging showed segmental narrowing of the pancreatic duct with localized swelling of the pancreatic head, suggesting the carcinoma of the pancreatic head at that time. However, the laboratory findings also showed renal dysfunction with high level of serum immunoglobulin G and hypocomplemetemia. Renal biopsy was performed to investigate the etiology of the renal dysfunction. The renal biopsy specimen showed acute TIN. The patient had no drug history, which may cause TIN. Oral corticosteroid therapy improved the renal function as well as histological damage, the pancreatic imaging study, and the laboratory tests of pancreatic and hepatobiliary enzyme. Although the pancreatic biopsy has not performed in our patient, his clinical course confirmed us that AIP was the final diagnosis for his pancreatic lesion. Despite further examination, there was no evidence of other autoimmune-related diseases such as Sjögren's syndrome. To our knowledge, this is the first report of acute TIN associated with AIP. We suggest that AIP may be an etiologic factor in some cases of TIN.

Ultrasonographic evaluation in patients with autoimmune-related pancreatitis.

The concept of autoimmune-related pancreatitis (AIP) has recently been described. It is important to exclude pancreaticobiliary malignancy in patients with AIP who develop distal bile duct strictures. The aim of this study was to evaluate distal common bile duct strictures in AIP patients by endoscopic ultrasonography (EUS), intraductal ultrasonography (IDUS), and contrast-enhanced EUS (ceEUS). Five patients with AIP, encountered from January 2000 through December 2001, underwent EUS, IDUS, and ceEUS, using Levovist as a contrast medium. EUS and ceEUS were used to follow changes in distal bile duct strictures in three of these five patients following a trial of steroid therapy. Of the five patients, four had cholestatic biochemical profiles, three were positive for autoantibodies, and three had elevated serum immunoglobulin G (IgG) or IgG4. A diffusely enlarged pancreas, narrowing of the main pancreatic duct (MPD), and strictured common bile duct in the pancreatic head were features common to all patients. Pretherapy EUS or IDUS imaging showed concentric wall thickening of the distal common bile duct causing bile duct stenosis. ceEUS showed diffuse strong enhancement of the thickened bile duct wall, possibly due to inflammation. After the steroid therapy, the stenotic lesions in both the MPD and distal common bile duct were rapidly attenuated, with a decline in biochemical cholestatic enzymes and serum IgG or IgG4 levels. On EUS and IDUS imaging, concentric bile duct wall thickening and its strong enhancement by Levovist was characteristic in AIP patients.

Kinetic analysis of the development of pancreatic lesions in mice infected with a murine retrovirus

Sjögren's syndrome (SjS)-like sialoadenitis and exocrine pancreatitis were induced in mice infected with LP-BM5 murine leukemia virus, which induces a severe immunodeficiency termed murine AIDS (MAIDS). All mice with MAIDS showed advancing cellular infiltration around the pancreatic ducts as well as systemic exocrinopathy. The primary target tissue of the pancreas was acinar cells, and the pancreatic islets were well preserved until a late phase of the disease. Immunofluorescence and flow cytometry demonstrated that CD4 + T cells, Mac-1 + cells, and B220 + cells were major inflammatory components, and IFN-γ and IL-10 were mainly detected on CD4 + T and Mac-1 + cells in the pancreas. Both Th1 and Th2 cells were found. TUNEL + apoptotic cells were mostly detected among pancreas-infiltrating cells. Fas ligand and TNF-α were also detected among pancreas-infiltrating cells, whereas Fas was rarely expressed in the pancreatic acinar cells. Thus, MAIDS mice could be valuable for analyzing the pathogenesis of autoimmune-related pancreatitis associated with SjS.

Evaluation of contrast enhancement patterns in pancreatic tumors by coded harmonic sonographic imaging with a microbubble contrast agent.

The purpose of the study was to assess patterns of primary pancreatic lesions by contrast-enhanced sonography for differentiating ductal carcinomas from other pancreatic tumors. One hundred six consecutive patients with pancreatic masses, consisting of 83 ductal carcinomas, 7 endocrine carcinomas, 5 intraductal papillary mucinous tumors, 3 cases of autoimmune-related pancreatitis, 3 solid pseudopapillary tumors, 2 cases of chronic pancreatitis, 1 serous cystadenoma, 1 osteoclastoid giant cell tumor, and 1 follicular lymphoma, were examined by contrast-enhanced sonography with coded harmonic imaging in a phase inversion harmonic technique. The contrast enhancement patterns were assessed, and specimens removed during pancreatectomy were subjected to pathologic examination. Internal tumoral vascularity was detected in 47 (56.6%) of the 83 ductal carcinomas. Vascular image spreading and homogeneous staining throughout the tumors were observed in all endocrine carcinomas. Two of the 5 intraductal papillary mucinous tumors were positive for enhancement effects. Enhancement effects were observed in all 3 cases of autoimmune-related pancreatitis, but the degree varied. There was a significant correlation between the intensity of enhancement effects and the ratio of patent vessels in the tumors (P < .05). Vascularity was detected by contrast-enhanced sonography in only about half of the ductal carcinomas, confirming the difficulty in distinguishing those tumors from other pancreatic tumors. There was a correlation between the patency of the vessels in the tumors and their vascularity.

Clinical relevance of autoimmune-related pancreatitis

Recently, a concept of ‘autoimmune pancreatitis’ (AIP) was proposed. Computed tomography, magnetic resonance imaging or ultrasonography show a diffusely enlarged pancreas with a so-called ‘sausage-like’ appearance. Hypergammaglobulinaemia, increased serum levels of total IgG or IgG4, positive autoantibodies such as antinuclear antibody, anti-lactoferrin antibody, anti-CA-II antibody, rheumatoid factor and anti-smooth muscle antibody, were often observed in patients with AIP. Microscopic findings showed fibrotic changes with infiltration of lymphocytes, plasmacytes and sometimes eosinophils in the pancreas. Major subgroups of lymphocytes infiltrating areas around pancreatic ducts were CD4+ T-cells producing IFN-γ. HLA-DR was expressed on pancreatic duct cells as well as CD4+ cells. The diagnosis is made by a combination of clinical, laboratory and morphological findings. Laboratory data, pancreas images and diabetes mellitus in most patients do respond to steroid treatment. In conclusion, autoimmune-related pancreatitis appears to be a unique clinical entity. However, its importance in clinical practice needs further characterization.

Experimental Immune-Mediated Pancreatitis in Neonatally Thymectomized Mice Immunized with Carbonic Anhydrase II and Lactoferrin

We previously reported that autoantibodies against carbonic anhydrase II and lactoferrin are frequently identified in patients with autoimmune-related pancreatitis. To clarify the role of carbonic anhydrase II and lactoferrin, we created animal models of autoimmune pancreatitis by immunizing neonatally thymectomized mice with carbonic anhydrase II and lactoferrin and also by transferring immunized spleen cells to nude mice. Neonatally thymectomized BALB/c mice were immunized with carbonic anhydrase II or lactoferrin followed by three booster injections (n = 10 in each group). We transferred whole, CD4+, or CD8+ spleen cells prepared from immunized neonatally thymectomized mice to nude mice (n = 5 in each group). Gene expression of IFN-γ and IL-4 was investigated using semiquantitative reverse transcription-polymerase chain reaction. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling staining was used to examine apoptosis. In immunized neonatally thymectomized mice, the prevalence of inflammation was significantly higher in the pancreas. Inflammation was present in all mice receiving whole or CD4+ cells. There was no change in any of the mice receiving CD8+ cells or nonimmunized spleen cells. Carbonic anhydrase II or lactoferrin-immunized mice had apoptotic duct cells or acinar cells, respectively. Expression of the IFN-γ gene was up-regulated in each group. Similar findings were observed in the salivary glands and liver. An immunologic mechanism against carbonic anhydrase II or lactoferrin is involved in the pathogenesis of these pancreatitis models, in which the effector cells are Th1-type CD4+ T cells.

Autoimmune-related Pancreatitis.

The treatment of patients with autoimmune pancreatitis poses a challenge to the clinician. Prednisone, in an initial dosage of 30 to 40 mg/d, is used in patients with moderate abdominal and back pain, obstructive jaundice, or sclerosing cholangitis. Antacid or anticholinergic agents may be used to minimize stimulation of pancreatic exocrine function. Patients with quiescent disease may not need pharmacologic medication. In patients with complications such as obstructive jaundice and infection, biliary drainage and administration of antibiotics are recommended prior to steroid therapy. Steroid therapy occasionally ameliorates diabetes mellitus associated with autoimmune pancreatitis.

Recent concept of autoimmune-related pancreatitis.

Recent concept of autoimmune-related pancreatitis.

Clinical analysis of diabetes mellitus in patients with autoimmune-related pancreatitis

Clinical analysis of diabetes mellitus in patients with autoimmune-related pancreatitis

Clinical analysis of diabetes mellitus in patients with autoimmune-related pancreatitis

Clinical analysis of diabetes mellitus in patients with autoimmune-related pancreatitis

Analysis of an animal model of autoimmune-related pancreatitis using neonatally thymectomized mice

Analysis of an animal model of autoimmune-related pancreatitis using neonatally thymectomized mice

Analysis of an animal model of autoimmune-related pancreatitis using neonatally thymectomized mice

Analysis of an animal model of autoimmune-related pancreatitis using neonatally thymectomized mice

Clinical analysis of autoimmune-related pancreatitis

OBJECTIVE: Several investigators have reported on autoimmune-related pancreatitis, but the clinical findings and pathophysiology still remain unclear. To clarify it, we analyzed eight patients with autoimmune pancreatitis. METHODS: We evaluated clinical findings in eight patients (four men and four women) with autoimmune-related pancreatitis. Patients were aged 45–73 yr (mean, 57.5 yr). We examined blood chemistry and immunological studies, including autoantibodies against lactoferrin or carbonic anhydrase II, and compared ERCP images with clinical findings. In two patients, we studied the subset of lymphocytes infiltrating in the pancreas by immunohistochemistry and flow cytometry. RESULTS: Four of eight patients had jaundice, two had renal dysfunction, two had abdominal pain, and two had back pain. Three patients were complicated with other autoimmune diseases. Three patients showed abnormal pancreatic exocrine function by an N-benzoyl- L-tyrosyl- para-aminobenzoic acid excretion test. Antinuclear antibody was detected in four of eight patients, antilactoferrin antibody in three of six, anticarbonic anhydrase II antibody in two of six, antismooth muscle antibody in two of seven, and rheumatoid factor in one of eight. All eight patients showed segmental stenosis of the main pancreatic duct by ERCP. Four patients showed stenosis of the common bile duct as well as the pancreatic duct. Microscopic findings showed infiltration of CD4-positive lymphocytes around the pancreatic duct, and HLA-DR was expressed on both CD4-positive cells and pancreatic duct cells. In two patients, stenosis of the pancreatic duct improved by prednisolone. CONCLUSIONS: Autoimmune mechanism may be involved in some patients with idiopathic pancreatitis associated with hypergammaglobulinemia.

Clinical analysis of autoimmune-related pancreatitis.

Several investigators have reported on autoimmune-related pancreatitis, but the clinical findings and pathophysiology still remain unclear. To clarify it, we analyzed eight patients with autoimmune pancreatitis. We evaluated clinical findings in eight patients (four men and four women) with autoimmune-related pancreatitis. Patients were aged 45-73 yr (mean, 57.5 yr). We examined blood chemistry and immunological studies, including autoantibodies against lactoferrin or carbonic anhydrase II, and compared ERCP images with clinical findings. In two patients, we studied the subset of lymphocytes infiltrating in the pancreas by immunohistochemistry and flow cytometry. Four of eight patients had jaundice, two had renal dysfunction, two had abdominal pain, and two had back pain. Three patients were complicated with other autoimmune diseases. Three patients showed abnormal pancreatic exocrine function by an N-benzoyl-L-tyrosyl-para-aminobenzoic acid excretion test. Antinuclear antibody was detected in four of eight patients, antilactoferrin antibody in three of six, anticarbonic anhydrase II antibody in two of six, antismooth muscle antibody in two of seven, and rheumatoid factor in one of eight. All eight patients showed segmental stenosis of the main pancreatic duct by ERCP. Four patients showed stenosis of the common bile duct as well as the pancreatic duct. Microscopic findings showed infiltration of CD4-positive lymphocytes around the pancreatic duct, and HLA-DR was expressed on both CD4-positive cells and pancreatic duct cells. In two patients, stenosis of the pancreatic duct improved by prednisolone. Autoimmune mechanism may be involved in some patients with idiopathic pancreatitis associated with hypergammaglobulinemia.

Autoantibodies and Th1/Th2 cellular responses in patients with autoimmune-related pancreatitis

Autoantibodies and Th1/Th2 cellular responses in patients with autoimmune-related pancreatitis

Carbonic anhydrase II and th1 type CD4-positive cells are involved in the development of autoimmune-related pancreatitis in an animal model

Carbonic anhydrase II and th1 type CD4-positive cells are involved in the development of autoimmune-related pancreatitis in an animal model

Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response

Background & Aims: Although autoimmunity may be involved in some cases of pancreatitis, the mechanism is still unknown. To clarify this, we studied serum autoantibodies, subsets of lymphocytes, and the Th1/Th2 balance of cellular immune responses in patients with autoimmune-related pancreatitis (AIP). Methods: Seventeen patients with AIP (8 men and 9 women; age, 53.2 ± 13.0 years) were studied. Autoantibodies including antilactoferrin (ALF) or carbonic anhydrase II antibody (ACA-II) were examined using the enzyme-linked immunosorbent assay (ELISA) or the indirect fluorescein antibody method. Intracellular cytokines (interferon gamma and interleukin 4) and subtypes of peripheral blood lymphocytes were examined by flow cytometry and ELISA. Results: More than one autoantibody was observed in all 17 patients. Serum antinuclear antibody was detected in 13 of 17 patients, ALF antibody in 13, ACA-II antibody in 10, rheumatoid factor in 5, and anti–smooth muscle antibody in 3, but antimitochondrial antibody in none. The serum levels of ACA-II and LF antibody were not correlated. HLA-DR +CD8 + and HLA-DR +CD4 + cells were significantly increased in peripheral blood ( P < 0.05). CD4 + cells producing interferon gamma and the secreted levels were significantly increased compared with those in controls ( P < 0.05), but interleukin 4 was not increased. Conclusions: An autoimmune mechanism against CA-II or LF, and Th1-type immune response, may be involved in AIP. GASTROENTEROLOGY 2000;118:573-581