IgG<Subscript>4</Subscript>-Related Sclerosing Disease: A Novel Mimic of Inflammatory Bowel Disease

High levels of IgG4-positive plasma cells are commonly seen in autoimmune pancreatitis. It has recently become evident that autoimmune pancreatitis is one component of a larger multi-system disease. IgG4-positive plasma cells have been identified in many extrapancreatic tissues, including the colon, biliary tract, liver, and lungs, and thus the term “IgG4-related sclerosing disease” has been proposed. Awareness of IgG4-related sclerosing disease is important, as it has been shown to mimic other conditions like malignancy. This review discusses IgG4-related colitis and its potential for mimicking inflammatory bowel disease.     

Refractory gastric ulcer with abundant IgG4-positive plasma cell infiltration: A case report

We describe a 77-year-old man with refractory gastric ulcer that worsened after Helicobacter pylori eradication therapy.Pathology showed marked infiltration of IgG4-positive plasma cells in the gastric lesions,which led us to suspect IgG4-related sclerosing disease.To the best of our knowledge,this is the first report of IgG4-related gastric ulcer without the main manifestation of autoimmune pancreatitis.     

IgG4-related sclerosing disease

Based on histological and immunohistochemical exami- nation of various organs of patients with autoimmune pancreatitis （AIP）, a novel clinicopathological entity of IgG4-related sclerosing disease has been proposed. This is a systemic disease that is characterized by extensive IgG4-positive plasma cells and T-lymphocyte infiltration of various organs. Clinical manifestations are apparent in the pancreas, bile duct, gallbladder, salivary gland, retroperitoneum, kidney, lung, and prosrate, in which tissue fibrosis with obliterative phlebitis is pathologically induced. AlP is not simply pancreatitis but, in fact, is a pancreatic disease indicative of IgG4- related sclerosing diseases. This disease includes AlP, sclerosing cholangitis, cholecystitis, sialadenitis, retro-peritoneal fibrosis, tubulointerstitial nephritis, interstitial pneumonia, prostatitis, inflammatory pseudotumor and lymphadenopathy, all IgG4-related. Most IgG4-related sclerosing diseases have been found to be associated with AlP, but also those without pancreatic involvement have been reported. In some cases, only one or two organs are clinically involved, while in others, three or four organs are affected. The disease occurs predominantly in older men and responds well to steroid therapy. Serum IgG4 levels and immunos-taining with anti-IgG4 antibody are useful in making the diagnosis. Since malignant tumors are frequently suspected on initial presentation, IgG4-related sclerosing disease should be considered in the differential diagnosis to avoid unnecessary surgery.     

Autoimmune pancreatitis as the initial presentation of systemic lupus erythematosus

Pancreatitis is a relatively rare complication in systemic lupus erythematosus (SLE). Here we present a case of SLE associated with autoimmune pancreatitis. A 37-year old woman was admitted to our hospital because of fever, skin rash, proteinuria and abdominal pain. A diagnosis of SLE was made based on her clinical, laboratory and renal histological findings showing diffuse proliferative lupus nephritis. Elevated serum amylase, typical radiographic findings and selective increase in serum IgG4 all suggested that the patient also had autoimmune pancreatitis. Systemic administration of glucocorticoid successfully induced remission of pancreatitis and nephritis along with the reduction of IgG4. Autoimmune pancreatitis is a newly recognized type of pancreatitis, in which IgG4 immune response is thought to participate pathophysiologically. Although the disease has been observed to develop in patients having various connective tissue diseases, our report is the first to describe IgG4-related autoimmune pancreatitis in a patient with SLE.     

Recent advances in the concept and diagnosis of autoimmune pancreatitis and IgG4-related disease

Recent studies have suggested the existence of two subtypes of autoimmune pancreatitis (AIP): type 1 AIP, related to IgG4 (lymphoplasmacytic sclerosing pancreatitis); and type 2 AIP, related to a granulocytic epithelial lesion (idiopathic duct-centric chronic pancreatitis). Compared with type 2 AIP, the clinicopathological features of type 1 AIP, with increased serum IgG4/IgE levels, abundant infiltration of IgG4 + plasmacytes and lymphocytes, autoantibodies, and steroid responsiveness, are more suggestive of abnormal immunity such as allergy or autoimmunity. Moreover, patients with type 1 AIP often have extrapancreatic lesions, such as sclerosing cholangitis, sclerosing sialadenitis, or retroperitoneal fibrosis, showing pathological features similar to those of the pancreatic lesions. Based on these findings, an international concept of and diagnostic criteria for AIP have been proposed recently. Of interest, many synonyms have been proposed for the conditions of AIP and extrapancreatic lesions associated with IgG4, such as "multifocal idiopathic fibrosclerosis," "IgG4-related autoimmune disease," "IgG4-related sclerosing disease," "systemic IgG4-related plasmacytic syndrome (SIPS)," 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 fibrosclerosing disease, in 2009, in which the term "IgG4-related disease" was agreed upon as a minimal consensus to cover 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 diseases. The concept and diagnostic criteria of "IgG4-related disease" will be changed in accordance with future studies.     

Autoimmune pancreatitis that developed over a 3-month observation period for IgG4-related dacryoadenitis and sialadenitis

Autoimmune pancreatitis (AIP) that developed in a short period in a patient with IgG4-related dacryoadenitis and sialadenitis is reported. A 67-year-old man was diagnosed as having IgG4-related dacryoadenitis and sialadenitis histologically, serologically, and radiologically. At that time, the pancreas was normal on computed tomographic scanning, magnetic resonance imaging, and 18F-fluorodeoxyglucose positron emission tomography. However, AIP occurred in the pancreatic body and tail during the 3-month period of observation of the initial diseases. All IgG4-related lesions improved promptly after steroid therapy. This report emphasizes that, since IgG4-related disease can develop in other organs within a short period in a patient with IgG4-related disease, periodic imaging follow-up is necessary.     

Recent Advances in the Concept and Pathogenesis of IgG4-Related Disease in the Hepato-Bilio-Pancreatic System

Recent studies have proposed nomenclatures of type 1 autoimmune pancreatitis (AIP) (IgG4-related pancreatitis), IgG4-related sclerosing cholangitis (IgG4-SC), IgG4-related cholecystitis, and IgG4-related hepatopathy as IgG4-related disease (IgG4-RD) in the hepato-bilio-pancreatic system. In IgG4-related hepatopathy, a novel concept of IgG4-related autoimmune hepatitis (AIH) with the same histopathological features as AIH has been proposed. Among organs involved in IgG4-RD, associations with pancreatic and biliary lesions are most frequently observed, supporting the novel concept of “biliary diseases with pancreatic counterparts.” Targets of type 1 AIP and IgG4-SC may be periductal glands around the bile and pancreatic ducts. Based on genetic backgrounds, innate and acquired immunity, Th2-dominant immune status, regulatory T (Treg) or B cells, and complement activation via a classical pathway may be involved in the development of IgG4-RD. Although the role of IgG4 remains unclear in IgG4-RD, IgG4-production is upregulated by interleukin 10 from Treg cells and by B cell activating factor from monocytes/basophils with stimulation of toll-like receptors/nucleotide-binding oligomerization domain-like receptors. Based on these findings, we have proposed a hypothesis for the development of IgG4-RD in the hepato-bilio-pancreatic system. Further studies are necessary to clarify the pathogenic mechanism of IgG4-RD.     

Sclerosing Cholangitis Related to IgG4: Not Always a Curable Entity

IgG4-related disease is a recently-described fibro-inflammatory condition with characteristic histopathological findings in the organs involved. The most commonly affected organs are pancreas, lymph nodes, and retroperitoneum. Liver disease usually involves bile structures and therefore IgG4-related disease is considered a cause of secondary sclerosing cholangitis. One out of three patients with IgG4 sclerosing cholangitis also presents autoimmune pancreatitis, although it can be associated with manifestations in other organs. One of the main features of IgG4-related disease is its good prognosis due to the great response to glucocorticoid therapy. However, relapse of the disease is not uncommon, especially when steroid therapy is decreased or stopped. Rituximab seems to be an effective treatment to achieve remission of the disease. We report the case of a 74 year-old man diagnosed with IgG4-related disease based on increase of serum IgG4 levels, imaging and histopathological findings, with systemic involvement including sclerosing cholangitis. Despite the absence of liver fibrosis at onset, the early use of glucocorticoids and rituximab therapy, the patient presented clinical and analytical deterioration, leading to secondary biliary cirrhosis. In conclusion, this clinical case highlights the importance of prompt diagnosis and therapeutics for sclerosing cholangitis secondary to IgG4-related disease in order to avoid progression of the disease and development of liver cirrhosis, as well as the refractory, aggressive nature of the disease in some cases as this one.     

Current approach to the diagnosis of IgG4-related disease – Combination of comprehensive diagnostic and organ-specific criteria

IgG4-related disease (IgG4-RD) is a fascinating clinical entity proposed by Japanese investigators, and includes a wide variety of diseases, formerly diagnosed as Mikulicz's disease (MD), autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis, retroperitoneal fibrosis, etc. Although all clinicians in every field of medicine may encounter this new disease, a unifying diagnostic criterion has not been established. In 2011, the Japanese IgG4 team, organized by the Ministry of Health, Labor and Welfare (MHLW) of Japan, published comprehensive diagnostic criteria for IgG4-RD. Several problems with these criteria have arisen in clinical practice, however, including the difficulty obtaining biopsy samples from some patients, and the sensitivity and the specificity of techniques used to measure serum IgG4 concentrations. Although serum IgG4 concentration is an important clinical marker for IgG4-RD, its diagnostic utility in differentiating IgG4-RD from other diseases, called IgG4-RD mimickers, remains unclear. This review describes the current optimal approach for the diagnosis of IgG4-RD, based on both comprehensive and organ-specific diagnostic criteria, in patients with diseases such as IgG4-related pancreatitis (AIP), sclerosing cholangitis, and renal, lung and orbital diseases.     

Peripheral T-cell lymphoma that developed during the follow-up of IgG4-related disease

IgG4-related disease is a recently recognized fibroinflammatory disorder characterized by extensive IgG4-positive plasma cell and lymphocyte infiltration of various organs. The pancreatic manifestation of IgG4-related disease is called autoimmune pancreatitis (AIP), in which autoimmune mechanisms are likely involved. On the other hand, some autoimmune and chronic inflammatory disorders, such as Sj?gren's syndrome and rheumatoid arthritis, are associated with increased risks of non-Hodgkin lymphoma (NHL). There have been a few reports of cases with IgG4-related disease that had subsequently developed NHL, however, all of them suffered from B-cell lymphoma. We describe the first case of NHL, compatible with a subtype of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), which arose in IgG4-related sclerosing cholangitis. As patients with IgG4-related disease may be at an increased risk of developing NHL, such presentation during the follow-up of IgG4-related disease should be carefully scrutinized to exclude NHL.     

Autoimmune Pancreatitis: Updated Concepts of a Challenging Diagnosis

Autoimmune pancreatitis is a benign process characterized by inflammation and fibrosis. It is now known that cases of “autoimmune pancreatitis” actually consist of two distinct pathologic entities. Type 1 autoimmune pancreatitis is a manifestation of a systemic process, immunoglobulin G subclass 4 (IgG4)-related disease. IgG4-related disease can affect virtually every organ system in the body. Type 1 affects older patients and is characterized by an elevated serum IgG4 level and sites of extrapancreatic disease. Type 2 autoimmune pancreatitis is a disease process confined to the pancreas. It affects younger patients and is associated with inflammatory bowel disease. Type 2 is not associated with elevated IgG4 levels or extrapancreatic disease. Both subtypes can mimic malignancy, particularly pancreatic cancer. Awareness of the clinical and imaging features of the subtypes of autoimmune pancreatitis is important to avoid an incorrect diagnosis of malignancy.     

IgG4-related retroperitoneal fibrosis: the first reported case in a Chinese population

Immunoglobulin G4 (IgG4)-related sclerosing disease is a newly recognized clinicopathological entity characterized by lymphoplasmacytic infiltration and varying degrees of fibrosis in various organs, with abundant IgG4-positive plasma cells in tissues. Patients usually exhibit multisystem involvement and often respond well to steroid and immunosuppressive therapy. However, this disease has been rarely reported in a Chinese population. We herein report a case of IgG4-related sclerosing disease solely presenting with retroperitoneal fibrosis that was effectively treated with systemic steroid therapy. To the best of our knowledge, this is the first reported case of IgG4-related retroperitoneal fibrosis in a Chinese population.     

Immunoglobulin G4-Related Disease Mimicking Unresectable Gallbladder Cancer

Immunoglobulin G4 (IgG4)-related disease is a novel disease entity that can involve diverse organs, causing specific diseases, including autoimmune pancreatitis, sclerosing cholangitis, cholecystitis, inflammatory aortic aneurysm, and inflammatory pseudotumor. IgG4-related disease is characterized by elevated serum IgG4 concentrations, abundant IgG4 lymphoplasmacytic infiltration, and dramatic steroid responses. It is clinically important to differentiate this rare disease from primary sclerosing cholangitis and cholangiocarcinoma, because the treatment and prognosis of these two diseases are completely different. However, the preoperative diagnosis is challenging, and the disease is frequently misdiagnosed. If the serum level of IgG4 is within the normal range, the diagnosis of IgG4-related disease is more difficult. This article reports on a 59-year-old man with IgG4-related disease mimicking unresectable gallbladder cancer with normal serum IgG4 concentrations.     

The successful treatment of IgG4-positive colitis with adalimumab in a patient with IgG4-related sclerosing disease – a new subtype of aggressive colitis?

We present the case of a 16 year old girl who developed an aggressive colitis in the context of a prior biopsy proven autoimmune pancreatitis, which presented with obstructive jaundice at the age of 13 year. This history prompted prospective investigation and the discovery of compelling evidence to make a diagnosis of IgG4-related sclerosing disease with extra-pancreatic colonic involvement on the basis of raised serum IgG4 levels and a florid colonic IgG4 plasma cell infiltrate with over 20 IgG4 positive plasma cells/hpf. The colitis was resistant to conventional therapy but responded dramatically to treatment with the anti-TNFα monoclonal antibody, adalimumab. This is the first case to report both the effectiveness of adalimumab in treating IgG4 positive colitis in a patient with IgG4-related sclerosing disease, and to prospectively record resolution of an IgG4 positive colonic infiltrate with immunosuppression.     

Revisión de la enfermedad relacionada con la IgG4

IgG4-related disease is a fibrous-inflammatory process related to immunomodulation. The most commonly affected organs are: the pancreas, bile duct, major salivary glands, lacrimal glands, retroperitoneum and lymphatic ducts.In recent decades, this disease has been recognised as a systemic disorder that includes many single organ disorders, previously unrelated and known as independent entities.The common characteristics shared by the different entities that make up the IgG4-related disease are: raised serum IgG4 levels, alterations in the imaging tests with neoplastic-like swelling of the affected organs, specific histopathological characteristics and in immunostaining, as well as good response to treatment with glucocorticoids.In this work, we will review this pathology with a special emphasis on the characteristics of autoimmune pancreatitis, sclerosing cholangitis related to IgG4 and the involvement of the retroperitoneum, mesenterium and the digestive tract.     

IgG4-positive pulmonary disease

We report herein high-resolution computed tomography findings from a patient with IgG4-related pulmonary disease for the first time. The 61-year-old male patient complained of low-grade fever, dry mouth, and night sweats. He was diagnosed as having autoimmune pancreatitis, Sj?gren syndrome, and elevated serum IgG4. High-resolution computed tomography of the lungs showed dense alveolar consolidation and air bronchograms in bilateral perihilar regions. IgG4-positive lymphoplasmacytes were detected in pulmonary lesions by immunostaining of biopsy samples. IgG4-related pulmonary disease can be associated with various radiologic findings.     

IgG4-related respiratory disease

Abstract

IgG4-related diseases (IgG4-RDs), such as autoimmune pancreatitis and IgG4-related Mikulicz disease, are often accompanied by intrathoracic lesions, which are called IgG4-related respiratory disease (IgG4-RRD). IgG4-RRD has few subjective symptoms, and is usually detected during workup of patients with extra-thoracic lesions of IgG4-RD. IgG4-RRD is characterized by various conditions, including masses, nodules, thickening, and infiltration at numerous sites in the thorax through lymphatic routes. Although elevated serum IgG4 concentrations and pathologic evidence of lymphoplasmacytic infiltrates with abundant IgG4-positive plasma cells are characteristic findings of IgG4-RD, other intrathoracic diseases, such as multicentric Castleman disease and malignancy, may present with similar findings. Developing diagnostic criteria for IgG4-RRD, including clinicoradiological and pathological characteristics, is necessary for its appropriate diagnosis.