IgG4-related Autoimmune Disease Research Articles

IgG4-related autoimmune liver disease.

The term IgG4-related autoimmune liver disease (AILD) refers to hepato-biliary manifestations of Immunoglobin G4-related disease (IgG4-RD) including IgG4-related sclerosing cholangitis and IgG4-related pseudotumor. The association of some forms of autoimmune hepatitis to IgG4-RD remains controversial. Although autoimmune phenomena have not been clearly observed in IgG4-AILD, perturbation of the adaptive immune system and activation of the humoral response represent established pathophysiological hallmarks and potential therapeutic targets. Clinical manifestations of IgG4-AILD are virtually indistinguishable from bile duct cancer or primary sclerosing cholangitis and are due to mass forming lesions and thickening of the biliary tract that progressively lead to biliary ducts obstruction. There are no current reliable biomarkers for IgG4-AILD and diagnosis should rely on the integration of clinical, serological, radiological, and histological findings. In analogy to most IgG4-RD manifestations, and in contrast to its major mimickers, IgG4-AILD promptly responds to glucocorticoids but frequently relapses, thus requiring long-term maintenance therapy to avoid progressive fibrosclerotic disease and liver cirrhosis. Accumulating evidence on the efficacy of B-cell depletion therapy in patients with systemic IgG4-RD is gradually changing the treatment paradigm of IgG4-AILD and biologics will be increasingly used also for gastroenterological manifestations of IgG4-RD to spare glucocorticoids and traditional immunosuppressive agents. Looking ahead, identification of reliable biomarkers and of mini-invasive strategies to obtain informative biopsies from the biliary tree represent unavoidable priorities to optimize diagnosis and management of IgG4-AILD.

IgG4-related autoimmune liver disease.

The term IgG4-related autoimmune liver disease (AILD) refers to hepato-biliary manifestations of IgG4-related disease (IgG4-RD) including IgG4-related sclerosing cholangitis and IgG4-related pseudotumors. The association of some forms of autoimmune hepatitis to IgG4-RD remains controversial. Although autoimmune phenomena have not been clearly observed in IgG4-AILD, perturbation of the adaptive immune system and activation of the humoral response represent established pathophysiological hallmarks and potential therapeutic targets. Clinical manifestations of IgG4-AILD are virtually indistinguishable from bile duct cancer or primary sclerosing cholangitis, and are due to mass forming lesions and thickening of the biliary tract that progressively lead to biliary ducts obstruction. There are no current reliable biomarkers for IgG4-AILD and diagnosis should rely on the integration of clinical, serological, radiological, and histological findings. In analogy to most IgG4-RD manifestations, and in contrast to its major mimickers, IgG4-AILD promptly responds to glucocorticoids but frequently relapses, thus requiring long-term maintenance therapy to avoid progressive fibrosclerotic disease and liver cirrhosis. Accumulating evidence on the efficacy of B-cell depletion therapy in patients with systemic IgG4-RD is gradually changing the treatment paradigm of IgG4-AILD and biologics will be increasingly used also for gastroenterological manifestations of IgG4-RD to spare glucocorticoids and traditional immunosuppressive agents. Looking ahead, identification of reliable biomarkers and of miniinvasive strategies to obtain informative biopsies from the biliary tree represent unavoidable priorities to optimize diagnosis and management of IgG4-AILD.

Update on IgG4-mediated autoimmune diseases: New insights and new family members

Antibodies of IgG4 subclass are exceptional players of the immune system, as they are considered to be immunologically inert and functionally monovalent, and as such may be part of classical tolerance mechanisms. IgG4 antibodies are found in a range of different diseases, including IgG4-related diseases, allergy, cancer, rheumatoid arthritis, helminth infection and IgG4 autoimmune diseases, where they may be pathogenic or protective. IgG4 autoimmune diseases are an emerging new group of diseases that are characterized by pathogenic, antigen-specific autoantibodies of IgG4 subclass, such as MuSK myasthenia gravis, pemphigus vulgaris and thrombotic thrombocytopenic purpura. The list of IgG4 autoantigens is rapidly growing and to date contains 29 candidate antigens. Interestingly, IgG4 autoimmune diseases are restricted to four distinct organs: 1) the central and peripheral nervous system, 2) the kidney, 3) the skin and mucous membranes and 4) the vascular system and soluble antigens in the blood circulation. The pathogenicity of IgG4 can be validated using our classification system, and is usually excerted by functional blocking of protein-protein interaction.

IgG4 associated autoimmune hepatitis: A rare entity

Background: IgG4-related disease is an immune mediated multisystem disorder fibroinflammatory condition. Two types of hepatic involvement in IgG4 related disease have been described: IgG4 hepatopathy and IgG4 related autoimmune disease,1 which is rare with only few cases reported. Case report: We present a case of 50-year-old lady who presented with a history of malaise and nausea, and had deranged LFTs, raised IgG4 and serum lipase levels, and positive ANA and SMA antibodies. Abdominal CT showed no bile duct abnormality. Liver biopsy showed features of autoimmune hepatitis with grade III activity. Unusually, a significant amount of pericapsular tissue was present which showed fibroinflammatory reaction with infiltration of IgG4 bearing plasma cells. No significant bile duct damage was seen. The patient fulfilled the diagnostic criteria for definite AIH using IAIHG scoring system and responded well with steroid therapy. Conclusion: The diagnostic criteria for IgG4 associated autoimmune hepatitis are not well defined and additional studies are needed to clarify the clinical significance and diagnostic guidelines.2

Sclerosing sialadenitis of the submandibular gland is rarely an immunoglobulin G4-related disease in theFinnish population.

Chronic sclerosing sialadenitis may represent one of many manifestations of an immunoglobulin G4-related disease. However, existing studies typically consist of small patient cohorts rarely conducted in Western populations. The clinical behavior of chronic sclerosing sialadenitis, including follow-up data, warrants further study. Thus, we aimed to determine whether chronic sclerosing sialadenitis always presents as IgG4-related disease or associates with autoimmune diseases and to determine which additional examinations patients may require. Between 2000 and 2017, 51 patients undergoing submandibular gland resection within the Helsinki University Hospital area were diagnosed with chronic sclerosing sialadenitis. We re-evaluated all specimens and performed immunostaining for IgG4. IgG and CD31 stainings were performed for IgG4-positive specimens. IgG4-related disease diagnosis was defined by the Boston consensus statement criteria. We revised clinical data, distributing a follow-up questionnaire to patients to register symptoms of IgG4-related disease or autoimmune disease during follow-up. The chronic sclerosing sialadenitis criteria were fulfilled in 34 patients, whereby 17 were diagnosed as non-sclerosing chronic sialadenitis. In 19 cases, a sialolith associated with a salivary gland lesion. In total, 12 of 51 cases were recognized as IgG4-positive, while two met the criteria for IgG4-related disease. These two cases belonged to the non-sclerosing chronic sialadenitis group, and both involved other organs. The histopathological features between chronic sclerosing sialadenitis and non-sclerosing chronic sialadenitis overlapped regarding the degree of fibrosis and inflammatory infiltrates. In the Finnish population, chronic sclerosing sialadenitis of the submandibular gland does not appear to present as IgG4-related disease. Non-sclerosing chronic sialadenitis can associate with IgG4-related disease. A histopathological distinction between chronic sclerosing sialadenitis and non-sclerosing chronic sialadenitis is not always unequivocal and the presence of a sialolith does not exclude IgG4-positivity. Therefore, immunostaining for IgG4 should be performed when dense plasma cell infiltration is present in either non-sclerosing chronic sialadenitis or chronic sclerosing sialadenitis.

DIAGNOSIS OF ENDOCRINE DISEASE: IgG4-related thyroid autoimmune disease.

IgG4-related disease (IgG4-RD) is fibro-inflammatory, immune-mediated, systemic disease recognized as a defined clinical condition only in 2001. The prevalence of IgG4-RD is 6/100 000, but it is likely to be underestimated due to insufficient awareness of the disease. The diagnostic approach is complex because of the heterogeneity of clinical presentation and because of rather variable diagnostic criteria. Indeed, high concentrations of IgG4 in tissue and serum are not a reliable diagnostic marker. The spectrum of IgG4-RD also includes well-known thyroid diseases including Riedel's thyroiditis, Hashimoto's thyroiditis and its fibrotic variant, Graves' disease and Graves' orbitopathy. Results from clinical studies indicate that a small subset of patients with the above-mentioned thyroid conditions present some features suggestive for IgG4-RD. However, according to more recent views, the use of the term thyroid disease with an elevation of IgG4 rather than IgG4-related thyroid diseases would appear more appropriate. Nevertheless, the occurrence of high IgG4 levels in patients with thyroid disease is relevant due to peculiarities of their clinical course.

Emerging Treatment Models in Rheumatology: IgG4‐Related Disease: Insights Into Human Immunology and Targeted Therapies

IgG4-related disease (IgG4-RD) is a systemic, multi-organ disorder with heterogeneous clinical features but distinctive presentations.1, 2 The classic onset of this disease is subacute, taking the form of tumor-like lesions that develop gradually. These lesions are generally identified either on physical examination (e.g., salivary gland enlargement) or imaging (e.g., a renal, lung, or pancreatic mass), frequently at a time when the patient feels well. In the first years following recognition of IgG4-RD, the diagnosis was often made by pathologists in the complete absence of clinical suspicion for the disease. More recently, because of growing familiarity with typical IgG4-RD presentations and the use of blood IgG4 testing, presumptive diagnoses are often rendered by clinicians before the performance of diagnostic tests. Biopsy confirmation of the diagnosis remains important in most cases. IgG4-RD is not a new disease. Cases of the disease are well documented in medical history going back at least to the late 1800s3 , but the individual organ manifestations were considered to be distinct disease entities for more than a century, each confined to single organs and given eponymic designations: e.g., Riedel’s thyroiditis (circa 1883), Kuttner’s tumor (dacryoadenitis involving the submandibular gland, circa 1896), and Ormond’s disease (circa 1960).4, 5, 6 In 2001, Hamano, Kawa, and colleagues demonstrated that an elevated serum IgG4 level was useful in distinguishing “sclerosing pancreatitis,” now termed type 1 (IgG4-related) autoimmune pancreatitis, from other diseases of the pancreatic and biliary tract.7 In 2003, Kamisawa and Nakajima recognized similar pathology findings in extra-pancreatic organs of patients with sclerosing pancreatitis.8 They described a disease typified by elevated serum IgG4 levels, responsiveness to glucocorticoids, multi-organ involvement, and a fibroinflammatory infiltrate. The name “IgG4-related autoimmune disease” was given to this disorder initially because of the abundance of IgG4-expressing plasma cells within affected tissues, thereby unifying seemingly disparate conditions. The involvement of bile ducts, major salivary glands, lymph nodes, and retroperitoneal tissue was also described in this original case series. Since that time, IgG4-RD has been reported to affect virtually every organ in the body. The lacrimal gland, lung, and kidney are other common sites of disease involvement [Figure 1, A–B].2 The aorta, pachymeninges, and bile ducts comprise exceptions to the tumefactive clinical presentation, presumably because of their tubular structures and/or thin walls.9, 10, 11 Open in a separate window Open in a separate window Figure 1 (A) Head and neck illustration highlighting involvement of the lacrimal and major salivary glands. Lacrimal and salivary gland enlargement is most often bilateral in distribution. (B) Abdomen illustration highlighting typical organ involvement including the pancreas, bile ducts, kidneys, and retroperitoneal tissue. Radiographically, the retroperitoneal fibrosis often extends inferiorly to encase the iliac vessels. Not depicted here, the aorta and lung are other common sites of disease involvement.

A Case of Idiopathic Retroperitoneal Fibrosis Associated With Sjögren's Syndrome.

After presenting with nonspecific symptoms, a 52-year-old female was found to have a 3.4 × 2.6 cm retroperitoneal mass resulting in hydronephrosis on abdominal computed tomography scan. After extensive workup including surgical debulking, excisional biopsy, and autoimmune panel, she was found to have idiopathic retroperitoneal fibrosis (IRF) with negative staining for immunoglogulin G4 (IgG4). Two years after presentation, the patient developed dyspnea, cough, and xerostomia. Repeat anti-Sjögren Syndrome A and anti-Sjögren Syndrome B titers and labial gland biopsy confirmed the diagnosis of concomitant Sjögren's syndrome (SS). The patient was treated with mycophenolate mofetil with improvement in her symptoms. Most cases of retroperitoneal fibrosis are associated with IgG4-related disease or other autoimmune disease. To our knowledge, this is only the second reported case of SS associated with IRF. Because symptoms of IRF are nonspecific, there is often a delay in diagnosis resulting in end-organ disease such as ureteral obstruction or hydronephrosis. Although IRF is uncommon, it should be considered in patients presenting with abdominal or flank pain, especially in patients with concomitant autoimmune disorders. Early recognition of disease can prevent end-organ damage and, as more cases are diagnosed, its relationship to SS may be elucidated leading to further advances in treatment and surveillance.

Overlapping IgG4 Responses to Self- and Environmental Antigens in Endemic Pemphigus Foliaceus.

The etiology of human autoimmune diseases in general remains largely unknown, although the genetic and environmental interplay may be relevant. This applies to the autoimmune diseases of the skin such as the pemphigus phenotypes and others. In this group, there is an endemic form of pemphigus foliaceus (also known as fogo selvagem [FS]) in which the pathogenic IgG4 autoantibody response to the self-antigen desmoglein 1 (Dsg1) cross-reacts with the LJM11 sand fly salivary gland Ag. In this investigation, we dissected the IgG4 autoantibody repertoires used by FS patients in response to endogenous self-Dsg1 and exogenous LJM11 sand fly Ag. Based on analyses of the genetic clonal signatures of these Abs, our results indicate that there is a significant overlap between these two responses, as all identified IgG4 mAbs cross-react to both Dsg1 and LJM11 Ags. Germline H- and L-chain V gene Abs generated according to mutated cross-reactive mAbs preserved their reactivity to both Ags. Our findings suggest that both Dsg1 autoantigen and LJM11 environmental Ag could be the initial antigenic stimulants for the IgG4 autoimmune responses in FS. These results support our hypothesis that LJM11 Ag plays a substantial role in triggering the IgG4 autoantibody development in FS and provide new insights on how noninfectious environmental Ag(s) may drive the generation of autoantibodies in IgG4-related autoimmune diseases.

Isolated Mass-Forming IgG4-Related Cholangitis as an Initial Clinical Presentation of Systemic IgG4-Related Disease.

IgG4-related disease (IgG4-RD) may involve multiple organs. Although it usually presents as diffuse organ involvement, localized mass-forming lesions have been occasionally encountered in pancreas. However, the same pattern has been seldom reported in biliary tract. A 61-year-old male showed a hilar bile duct mass with multiple enlarged lymph nodes in imaging studies and he underwent trisectionectomy under impression of cholangiocarcinoma. Gross examination revealed a mass-like lesion around hilar bile duct. Histopathologically, dense lymphoplasmacytic infiltration and storiform fibrosis were identified without evidence of malignancy. Immunohistochemical stain demonstrated rich IgG4-positive plasma cell infiltration. Follow-up imaging studies disclosed multiple enlarged lymph nodes with involvement of pancreas and perisplenic soft tissue. The lesions have been significantly reduced after steroid treatment, which suggests multi-organ involvement of systemic IgG4-RD. Here, we report an unusual localized mass-forming IgG4-related cholangitis as an initial presentation of IgG4-RD, which was biliary manifestation of systemic IgG4-related autoimmune disease.

The prevalence of IgG4-positive plasma cell infiltrates in inflammatory bowel disease patients without autoimmune pancreatitis.

IgG4-related autoimmune disease can exist in other organs even when there is no evidence of autoimmune pancreatitis. The aim of our study was to determine the prevalence of IgG4-positive plasma cells in the histopathological evaluations of colon biopsy specimens in IBD patients. The number of IgG4-positive plasma cells with strong cytoplasmic immunoreactivity was counted in each colon biopsy from inflammatory bowel disease patients who had no evidence of autoimmune pancreatitis. Five high power fields (HPFs) in the highest density plasma cell infiltration area were counted and were then averaged. An average >10 cells/HPF was considered significant for IgG4-related disease. We detected IgG4-positive plasma cell staining in the colon of 21 of 119 patients (17.6%). Of these 21 patients, 5 had elevated serum IgG4 levels (>140 mg/dL). Of the total, 4.2% (5/119) had both IgG4-immunstaining and elevated IgG4 serum levels. The demographic features, disease type and activity, and response to treatment (especially to steroid treatment) were similar between the IgG4-negative and IgG4-positive groups. In our study, 4.2% of patients with the diagnosis of IBD had elevated IgG4 serum levels and significant IGg4 immunostaining. Together, these two parameters indicate the possible diagnosis of an IgG4-related systemic disease.

Characteristics of autoimmune pancreatitis based on serum IgG4 level

Background Autoimmune pancreatitis is categorized as an IgG4-related autoimmune disease, mostly associated with serological alterations, however characteristics of autoimmune pancreatitis based on serum markers have not been fully evaluated. Methods We evaluated demographics, symptoms, imaging and therapeutic outcome in 27 cases of autoimmune pancreatitis stratified by serum IgG4 level. Results Twenty patients (74%) had elevated serum IgG4 and 7 (26%) had normal IgG4 levels. Compared to patients with normal serum IgG4 levels, patients with elevated IgG4 had higher incidence of jaundice at onset (14.3% vs. 80%, respectively; P = 0.002), more frequent diffuse pancreatic enlargement at imaging (14.3% vs. 60%, respectively; P = 0.04), significantly higher 18F-2-fluoro-2-deoxy- d-glucose uptake of pancreatic lesions (SUV max: 4.0 vs. 5.7, respectively; P = 0.02), more frequent extrapancreatic lesions (42.9% vs. 85%, respectively; P = 0.03). Response to steroids was recognized regardless of serum IgG4 level, however maintenance therapy was required more frequently amongst patients with elevated compared to normal IgG4 (85.7% vs. 33.3%, respectively; P = 0.04). Conclusions Clinical features of autoimmune pancreatitis are different based on level of serum IgG4. Further studies are needed to clarify if normal serum IgG4 cases are a precursor of active type 1 or type 2 autoimmune pancreatitis.

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.

IgG4-related sclerosing cholangitis: liver biopsy findings

IgG4-related autoimmune disease is a recently recognized clinical entity associated with autoimmune pancreatitis, various systemic extrapancreatic lesions and an elevated serum IgG4 level.1 IgG4-related sclerosing cholangitis (IgG4-SC) is one of the extrapancreatic manifestations of this entity, which needs to be differentiated from primary sclerosing cholangitis (PSC) as these two diseases appear similar at presentation, but follow different clinical courses. In this issue, we will discuss the histopathologic findings of IgG4-SC based on a liver biopsy case of a 65-year-old patient with autoimmune pancreatitis.

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.

IgG4 Syndrome: Old Disease, New Perspective

In the last few decades, the evolution of biomedical sciences has contributed to a better understanding of the pathogenesis of human disease, the description of new clinical entities, sorting out of disease subgroups, and development of targeted therapeutic interventions1. A new syndrome was identified recently, called IgG4 syndrome. Many terms such as “IgG4-related systemic sclerosing disease,” “IgG4-related autoimmune disease,” “IgG4-related systemic disease,” “IgG4-positive multiorgan lymphoproliferative syndrome,” and others have been used to identify the disease. IgG4 syndrome has various clinical manifestations, such as sclerosing pancreatitis, sclerosing cholangitis, prostatitis, tubulointerstitial nephritis, interstitial pneumonia, and enlargement of salivary glands. In previous years, these clinical entities appeared to be unrelated. Recent studies, however, revealed that they share some common denominators, such as elevated serum IgG4 levels and tissue infiltration by IgG4-positive plasma cells, accompanied by tissue fibrosis and sclerosis2. These serological and histopathological features are considered hallmarks for diagnosis of IgG4 syndrome. Thus, the enlargement of salivary glands, accompanied by high serum IgG4 concentrations and IgG4-positive plasma cells in the infiltrates of the salivary glands, previously called … Address correspondence to Dr. Moutsopoulos. E-mail: hmoutsop{at}med.uoa.gr

A case of Mikulicz’s disease complicated with severe interstitial nephritis associated with IgG4

A 48-year-old woman who had bilateral swelling in the eyelids and submandibular region was admitted. Clinical findings suggested that her renal function had deteriorated. Laboratory data showed renal insufficiency (2.52 mg/dl), hypergammaglobulinemia (IgG 3,729 mg/dl, IgA 124 mg/dl, IgM 73 mg/dl). Gallium-67 scintigram indicated abnormal uptake in bilateral lacrimal glands, submandibular glands, and kidneys. A diagnosis of Mikulicz's disease and interstitial nephritis was made, since biopsy specimens of her lacrimal gland and minor salivary gland showed diffuse infiltration of lymphocytes. In addition, renal biopsy specimens showed diffuse severe interstitial infiltration of IgG4-positive mononuclear cells. Symptoms and laboratory data normalized in response to methylprednisolone semi-pulse therapy and prednisolone 50 mg/day. Mikulicz's disease was recently reported to be IgG4 associated disease. In our case, Mikulicz's disease complicated with diffuse severe interstitial nephritis was successfully treated by corticosteroid. The present case supports the hypothesis that IgG4-related autoimmune disease could be causes of Mikulicz's disease and interstitial nephritis.

Salivary duct carcinoma arising in IgG4-related autoimmune disease of the parotid gland

Hyper IgG4 disease or IgG4-related sclerosing/autoimmune disease is a multisystem condition characterized histologically by fibrosis, lymphoplasmacytic infiltration, and abundant IgG4 plasma cells associated with raised serum IgG4 levels. We present a case of salivary duct carcinoma of the parotid gland in a background of chronic sclerosing sialadenitis that also involved the submandibular gland with associated regional lymphadenopathy. The serology showed raised total IgG levels of 16.3 g/L (reference range, 6.0-15.0) and raised IgG4 levels of 3.41 g/L (reference range, 0.07-1.70). The salivary duct carcinoma contained areas of dense fibrosis and abundant IgG4-positive plasma cells (>100 per high-power field [hpf]). The adjacent noncarcinomatous areas, submandibular gland, and regional lymph nodes also contained plasma cells immunoreactive to IgG4 with densities higher than 100/hpf. To the best of our knowledge, this case is the first documentation of malignancy occurring in a background of IgG4-related autoimmune disease of the salivary gland.

Autoimmune Pancreatitis Associated with Various Extrapancreatic Lesions during a Long-term Clinical Course Successfully Treated with Azathioprine and Corticosteroid Maintenance Therapy

Autoimmune pancreatitis (AIP) is often associated with systemic extrapancreatic lesions, and the concept of IgG4-related autoimmune disease has been proposed. We report a 62-year-old woman with AIP associated with various extrapancreatic lesions during a long-term clinical course. These extrapancreatic lesions occurred after the withdrawal of steroid therapy. Sclerosing sialadenitis occurred before AIP, whereas autoimmune sensorineural hearing loss, allergic purpura and endocapillary proliferative glomerulonephritis occurred after AIP. However, no relapse was observed for 5 years after the start of maintenance therapy with prednisolone and azathioprine.

Two Cases of Pulmonary Involvement of Immunoglobulin G4 Related Autoimmune Disease

Immunoglobulin G4 (IgG4) related autoimmune diseases are characterized by high serum IgG4 concentrations, sclerosing inflammation of numerous IgG4-positive lymphoplasma cells of varying origin, and a positive response to steroid treatment. Autoimmune pancreatitis, sclerosing cholangitis, and retroperitoneal fibrosis are representative presentations of IgG4 related autoimmune disease. Herein, we describe 2 patients (40-years-old woman and 47-years-old man) diagnosed with pulmonary involvement of IgG4-related autoimmune disease. The patients were admitted for an evaluation of the lung mass or multiple lung nodules found on chest radiography. Surgical lung biopsies were performed and pathologic finding revealed lymphoplasmacytic sclerosing inflammation with numerous IgG4 positive cells. The patients had elevated serum total IgG and IgG4 levels. Treatment consisted of high dose methylpredinisolone (1 mg/kg/day) and demonstrated good responsiveness. However, one patient experienced 2 relapses while being tapered off of steroid treatment.