Autoimmune Pancreatitis: From Pathogenesis to Treatment.

Autoimmune pancreatitis (AIP) is a rare disease. The diagnosis of AIP is difficult and should be made by a comprehensive evaluation of clinical, radiological, serological, and pathological findings. Two different types of AIP have been identified: autoimmune pancreatitis type 1 (AIP-1), which is considered a pancreatic manifestation of multiorgan disease related to IgG4, and autoimmune pancreatitis type 2 (AIP-2), which is considered a pancreas-specific disease not related to IgG4. Although the pathophysiological conditions seem to differ between type 1 and type 2 pancreatitis, both respond well to steroid medications. In this review, we focused on the pathogenesis of the disease to develop a tool that could facilitate diagnosis and lead to the discovery of new therapeutic strategies to combat autoimmune pancreatitis and its relapses. The standard therapy for AIP is oral administration of corticosteroids. Rituximab (RTX) has also been proposed for induction of remission and maintenance therapy in relapsing AIP-1. In selected patients, immunomodulators such as azathioprine are used to maintain remission. The strength of this review, compared with previous studies, is that it focuses on the clear difference between the two types of autoimmune pancreatitis with a clearly delineated and separate pathogenesis. In addition, the review also considers various therapeutic options, including biologic drugs, such as anti-tumor necrosis factor (TNF) therapy, a well-tolerated and effective second-line therapy for AIP type 2 relapses or steroid dependence. Other biologic therapies are also being explored that could provide a useful therapeutic alternative to corticosteroids and immunosuppressants, which are poorly tolerated due to significant side effects.

Plasmacytoid Dendritic Cells as a New Therapeutic Target for Autoimmune Pancreatitis and IgG4-Related Disease.

Although plasmacytoid dendritic cells (pDCs) able to produce large amounts of type 1 interferons (IFN-I) play beneficial roles in host defense against viral infections, excessive activation of pDCs, followed by robust production of IFN-I, causes autoimmune disorders including systemic lupus erythematosus (SLE) and psoriasis. Autoimmune pancreatitis (AIP), which is recognized as a pancreatic manifestation of systemic immunoglobulin G4-related disease (IgG4-RD), is a chronic fibroinflammatory disorder driven by autoimmunity. IgG4-RD is a multi-organ autoimmune disorder characterized by elevated serum concentrations of IgG4 antibody and infiltration of IgG4-expressing plasmacytes in the affected organs. Although the immunopathogenesis of IgG4-RD and AIP has been poorly elucidated, recently, we found that activation of pDCs mediates the development of murine experimental AIP and human AIP/IgG4-RD via the production of IFN-I and interleukin-33 (IL-33). Depletion of pDCs or neutralization of signaling pathways mediated by IFN-I and IL-33 efficiently inhibited the development of experimental AIP. Furthermore, enhanced expression of IFN-I and IL-33 was observed in the pancreas and serum of human AIP/IgG4-RD. Thus, AIP and IgG4-RD share their immunopathogenesis with SLE and psoriasis because in all these conditions, IFN-I production by pDCs contributes to the pathogenesis. Because the enhanced production of IFN-I and IL-33 by pDCs promotes chronic inflammation and fibrosis characteristic for AIP and IgG4-RD, neutralization of IFN-I and IL-33 could be a new therapeutic option for these disorders. In this Mini Review, we discuss the pathogenic roles played by the pDC-IFN-I-IL-33 axis and the development of a new treatment targeting this axis in AIP and IgG4-RD.

Lung cancer metastasis to the pancreas mimicking autoimmune pancreatitis.

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.

Impact of diet and genes on murine autoimmune pancreatitis.

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.

High-Dose Prednisone for Treatment of Autoimmune Pancreatitis in a Patient with Coronavirus Disease 2019 (COVID-19) due to Infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

BACKGROUND Autoimmune pancreatitis (AIP) is a rare, steroid-responsive disease of the pancreas. Concurrent treatment with immunosuppressants, including corticosteroids, increases the risk of developing a severe form of coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The World Health Organization (WHO) advises against the use of corticosteroids in patients with SARS-CoV-2 due to their poor outcomes in patients with SARS-CoV and Middle East respiratory syndrome (MERS-CoV), unless these patients require steroid treatment for a coexisting disease. CASE REPORT A 53-year old patient was admitted with symptoms and diagnostic findings consistent with AIP. Thorough etiological workup revealed an elevated IgG4 level of 361 mg/dL and significant clinical response to corticosteroid treatment, leading to a diagnosis of AIP. After finishing steroid treatment at home, the patient was readmitted with another episode of AIP complicated by development of acute necrotic collection and COVID-19 while taking a second course of high dose prednisone. The patient was continued on high dose prednisone, started on azathioprine and intravenous meropenem, and underwent CT guided percutaneous drainage. He also received supportive care for COVID-19. After significant clinical improvement, the patient was discharged to quarantine at home, which he completed uneventfully. CONCLUSIONS Despite the use of corticosteroids due to AIP, this high risk patient recovered from COVID-19 without complications. These findings support the use of corticosteroids when necessary for treatment of coexisting conditions in COVID-19 patients.

IgG4-related pancreatitis: an uncommon cause of hyperglycaemia.

Hyperglycaemia is one of the most common metabolic disturbances encountered in clinical practice, with an important differential diagnosis. We report a case of a 72-year-old woman referred to diabetes services with rapidly increasing blood glucose and weight loss despite oral hypoglycaemic therapy. She reported mild upper abdominal discomfort and liver function tests were deranged, prompting further investigation. Abdominal imaging demonstrated a diffusely enlarged pancreas and subsequent investigations noted a markedly raised serum IgG4. She was diagnosed with IgG4-related pancreatitis and swiftly responded to steroid therapy. Secondary causes of diabetes should be considered in people with atypical presentation such as weight loss or rapid progression to insulin use. While IgG4-related disease is rare, its varied clinical presentation as a result of its multiorgan involvement requires a high index of suspicion. This case highlights the importance of a detailed diagnostic work-up and describes an unusual clinical presentation of this increasingly recognised multisystem disease.

IgG4-Related Disease with Emphasis on Its Gastrointestinal Manifestation.

IgG4-related disease is an immune-mediated fibroinflammatory condition with a diverse spectrum of organ involvement, commonly in the pancreas and bile ducts among other organs such as salivary and lacrimal glands. Classic histopathologic findings are the gold standard for confirmation of diagnosis, although diagnosis remains challenging, as biomarkers to date are neither sufficient nor necessary. Glucocorticoids are the most effective initial treatment, generally having a dramatic response, although limited clinical evidence exists regarding effective maintenance therapy. This review summarizes key GI manifestations of this condition for the practicing gastroenterologist and addresses the pathology, disease mechanism, and current therapeutic recommendations.