IgG4-related disease of the ureter: report of two cases and review of the literature

IgG4-related disease (IgG4-RD) is a recently recognized multi-organ fibro-inflammatory lesion characterized by elevated IgG4 serum levels and mass-forming lesions. This condition shows similar histological features independently of the site of origin including storiform fibrosis, obliterative phlebitis, and dense lymphoplasmacytic infiltrate with a conspicuous IgG4-positive plasma cell component. Since this disease has only recently been categorized as a single specific nosologic entity, lesions with these typical morphological features have previously been named in different ways, creating some confusion and making it difficult to identify cases published in the literature. Lesions with features suggesting IgG4-RDs have very rarely been reported in the ureter, and they have been named using the terms “inflammatory pseudotumor” and “idiopathic segmental ureteritis.” Herein, we describe the clinicopathological features of ureteral IgG4-RD found in two different patients. An 82-year-old female and a 77-year-old male underwent ureteral resection due to severe ureteral wall thickness and lumen stenosis suggestive of urothelial carcinoma. However, histological examinations showed transmural fibro-inflammatory lesions, with abundant IgG4 plasma cells intermixed with histiocytes, lymphocytes, fibroblasts, and scattered eosinophils. We have also accurately reviewed the literature in order to identify, among lesions diagnosed with different names, examples of ureteral IgG4-related lesions to give the reader a comprehensive overview of this relatively rare inflammatory disease. We suggest using the name “ureteral IgG4-RD” for those lesions showing the same morphological features as IgG4-RDs located elsewhere.     

IgG4-related disease

IgG4-related disease (IgG4-RD) is considered a fibro-inflammatory condition with a marked propensity to form mass forming lesions, characterized by a dense lymphoplasmacytic infiltrate, the presence of abundant IgG4+ plasma cells, frequent elevation of serum IgG4 and a dramatic initial response to glucocorticoid. Nowadays, IgG4-RD has been described in almost every organ system: the pancreatobiliary tract, liver, salivary glands, nasopharynx, bone marrow, lacrimal gland, extra-ocular muscles and retrobulbar space, kidneys, lungs, lymph nodes, meninges, aorta and arteries, skin, breast, prostate, thyroid gland and pericardium. Although the common diagnostic features of all these regional involvements cannot be defined with certainty, and slight differences have been noted in different organs, many histopathological features are shared. Consensus has not yet been reached regarding criteria that have to be fulfilled for a new IgG4-RD. The proposed criteria include appropriate clinical and histopathological findings, presence of abundant tissue-infiltrating IgG4+ plasma cells, high serum IgG4 concentrations, response to steroid therapy, other autoimmune diseases or other organ involvement. The two hallmark features for diagnosis are histopathological characteristics and the presence of infiltrating IgG4+ plasma cells. In this review, we will focus on the histopathological features of IgG4-RD in specific organs and discuss the relationship with inflammatory pseudotumour and malignancy, IgG4 counting methods, and diagnosis using biopsy specimens. IgG4-related disease (IgG4-RD) is a multi-organ system disease that has been recognized in the last 10 years. IgG4-RD has a marked propensity to present as mass-forming lesions. The two hallmark features for diagnosis are histopathological characteristics and the presence of infiltrating IgG4+ plasma cells. Correct identification is crucial to avoid unnecessary major surgical procedures and initiate corticosteroid therapy.     

IgG4-related kidney disease

IgG4-related disease (IgG4-RD) is a recently recognized systemic immune-mediated disease that can affect nearly any organ or tissue. The most common manifestation in the kidney is IgG4-related tubulointerstitial nephritis (IgG4-TIN), which can present as renal insufficiency, renal mass lesions, or both. Histologically, IgG4-TIN is a plasma cell-rich interstitial inflammatory infiltrate with mononuclear cells, eosinophils, and increased IgG4+ plasma cells, along with expansile interstitial fibrosis that often has a “storiform” appearance. Tubular basement membrane immune complex deposits, best visualized on immunofluorescence staining, are present in most cases. IgG4-TIN usually shows a rapid response to steroid therapy. Glomeruli may be affected by IgG4-RD, usually in the form of membranous glomerulonephritis; other glomerular lesions have also been described. This review describes the different histopathologic patterns of renal involvement by IgG4-RD, with associated clinical, radiographic, and serologic features.     

Diagnostic guidelines for IgG4-related disease with a focus on histopathological criteria

IgG4-related disease (IgG4-RD) is an under recognized, protean, multiorgan fibro-inflammatory condition of unknown aetiology that is defined by its unique histopathological features, that are fairly similar regardless of the affected organ. Patients with IgG4-RD also share certain clinical features: a tendency for formation of mass lesion(s), frequent elevations in their serum IgG4 concentration, as well as an excellent response to glucocorticoid treatment. The 3 key histologic features of IgG4-RD are: 1) dense lymphoplasmacytic infiltrate, 2) fibrosis, arranged at least focally in a storiform pattern, and 3) obliterative phlebitis. The diagnosis of IgG4-RD requires both these characteristic histologic features as well as elevated numbers of IgG4 positive plasma cells. Neither elevations in serum IgG4 concentrations nor increased tissue IgG4-plasma cells are in themselves sufficient for the diagnosis, and histopathology remains the key to the accurate diagnosis of IgG4-RD.     

Immunoglobulin G4-related hepatobiliary disease

Immunoglobuline G4-related disease (IgG4-RD) is a systemic disease that can involve virtually any organs including the biliary tract and liver. The biliary tract involvement of IgG4-RD is known as IgG4-sclerosing cholangitis (IgG4-SC) and may or may not present with an inflammatory pseudotumor. Large bile ducts such as extrahepatic, hilar, and perihilar ducts are typically affected and demonstrate marked bile duct wall thickening and develop strictures. Histologically, the involved ducts show transmural dense lymphoplasmacytic infiltrates with storiform fibrosis extending into peribiliary glands and periductal soft tissue. The luminal epithelium is usually preserved. Tissue eosinophilia and obliterative phlebitis are also frequently noted. Liver biopsy findings of IgG4-SC are heterogeneous and rather nonspecific, but two features specific to IgG4-SC have been described: >10 IgG4-positive plasma cell/HPF and small portal-based fibroinflammatory nodules. Secondary changes, due to downstream bile duct obstruction are often appreciated. When considering the differential diagnosis, primary sclerosing cholangitis and cholangiocarcinoma are great clinical and histologic mimics of IgG4-SC. Liver involvement in IgG4-RD has not been well characterized and includes IgG4-hepatopathy and IgG4-related autoimmune hepatitis (AIH). IgG4-hepatopathy is a generic term covering hepatic lesions related to IgG4-RD and /or IgG4-SC. It includes primary liver parenchymal changes inherent to IgG4-RD, liver parenchymal involvement of IgG4-SC, and secondary changes related to IgG4-SC. IgG4-related AIH is characterized by clinical and histologic features of classical AIH but with prominent (>10/HPF) IgG4-positive plasma cells. It is unclear whether this represents a hepatic manifestation of IgG4-RD or a subset of AIH with increased IgG4-positive plasma cells at the present time. Synchronous or metachronous involvement of other organs, offers a clue to make this distinction. IgG4 immunohistochemistry has an important role in diagnosing IgG4-RD. But the diagnosis cannot be made solely based on the number of IgG4-positive plasma cells, and results need to be interpreted with caution as increased IgG4-positive plasma cells can be seen in other inflammatory conditions or even in malignancy.     

IgG4-related lymphadenopathy and IgG4-related lymphoma: moving targets

IgG4 is the least common of all the IgG subclasses. In recent years an uncommon systemic disease characterized by variable manifestations that may include the presence of tumour-like sclerosing lesions in a variety of extranodal sites, lymphadenopathy, presence of increased numbers of IgG4+ plasma cells in affected tissues, elevated serum IgG4 level, frequent presence of autoantibodies and often, a good response to steroid therapy or Rituximab has been described. The disorder has been called IgG4-related sclerosing disease, IgG4-related systemic disease and IgG4-related autoimmune disease; currently the preferred designation is IgG4-related disease (IgG4-RD). In addition to other changes that may be found in association with IgG4-RD, some investigators have suggested that IgG4-RD may serve as a substrate for the development of lymphoma.This review focuses on lymphadenopathy associated with IgG4-RD and also explores the significance of isolated lymphadenopathy with increased numbers of IgG4+ plasma cells. Emerging data on lymphomas arising in association with IgG4-RD and the possibility of an increased risk of lymphoma in patients with IgG4-RD are also discussed.     

Immunoglobulin G4-related disease: case report and literature review

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a rare and chronic progressive clinical entity, characterized by elevated serum IgG4 along with tissue infiltration by IgG4 + plasma cells. It is an immune-mediated fibro-inflammatory condition that can affect virtually any organ and tissue. IgG4-related lung disease (IgG4-RLD) occupies 14% of all IgG4-RD, with nonspecific symptoms and various abnormal radiographic patterns. Published data on IgG4-related hypertrophic pachymeningitis (IgG4-RHP), an increasingly recognized central nervous system manifestation of IgG4-RD, is also limited. Both lung and cranial dura involvement have not yet been reported until now. We further entail a review of the literature on the clinicopathologic features and differential diagnosis of this uncommon disease. We herein report an interesting case of a 70-year-old male patient admitted due to headache and fever. A magnetic resonance imaging (MRI) of the brain revealed extensive dural thickening with marked enhancement. Chest computed tomography (CT) scan showed nodular or mass-like consolidation and focal interstitial change. Thoracoscopic lung biopsy and lumbar puncture were conducted. After careful histopathological observation and consideration of alternative differential diagnoses, he was diagnosed with IgG4-related disease with lung and cranial dural involvement based upon significant elevation of serum and cerebrospinal fluid (CSF) IgG4 concentration. The patient was started on oral prednisolone 60 mg/day (1.0 mg/kg/day) for 14 days, and a tapering dose of 5 mg every 2 weeks followed by maintenance therapy at low dose for 3 months. His clinical manifestations, and serologic and imaging findings improved with steroid treatment. Currently, the patient remains well without disease progression. IgG4-RD should be considered as a differential when diagnosing other similar multisystemic lesions. Clinical examination, careful histological observation, and immunostaining for appropriate markers are essential in establishing the diagnosis. Clinicians should become familiar with this alternative differential diagnosis.

     

Antineutrophil cytoplasmic antibody-associated vasculitides and IgG4-related disease: A new overlap syndrome

Objective

Atypical manifestations have been described in patients with ANCA-associated vasculitides (AAV), such as pachymeningitis, orbital mass or chronic periaortitis. Because these manifestations have been associated to the spectrum of IgG4-related disease (IgG4-RD), we hypothesized that both diseases could overlap.

IgG4-related sclerosing mesenteritis: a rare mesenteric disease of unknown etiology

Sclerosing mesenteritis is a rare inflammatory and fibrosing disorder of unknown etiology, while IgG4-related disease (IgG4-RD) consists of mass-forming, fibroinflammatory lesions characterized by high serum IgG4 levels and tissue infiltration of many IgG4-positive plasma cells; obliterative phlebitis is common. This report describes a case of sclerosing mesenteritis that was considered a manifestation of IgG4-RD. A 53-year-old man underwent right hemicolectomy because of an ileocecal mass that did not improve with conservative therapy. The ill-defined fibroinflammatory lesion extended in the mesentery with storiform fibrosis, obliterative phlebitis, and infiltration of many IgG4-positive plasma cells. The ratio of IgG4-positive/IgG-positive cells was 64%, and the ratio of forkhead box protein 3 (FOXP3)-positive/CD4-positive cells was elevated (13%). It is likely that at least some cases of sclerosing mesenteritis are a manifestation of IgG4-RD. It is important to investigate this relationship because steroid therapy may benefit such cases.     

Usefulness of minor salivary gland biopsy in the diagnosis of IgG4-related disease: a case report

Although considered essential for diagnosing IgG4-related disease (IgG4-RD), biopsy of target organs is often difficult to perform. Such was the case of a 56-year-old man admitted with general malaise and weight loss. Computed tomography revealed swelling of the submandibular gland, mild dilatation of the main pancreatic duct, renal involvement, periaortitis, and swelling of the lymph nodes in the abdominal cavity. Laboratory testing revealed elevated serum IgG4 level. These findings were suggestive of IgG4-RD; however, the patient refused consent for biopsy of the target organs for a definitive diagnosis for the invasiveness. Therefore, we tried to perform a biopsy from minor salivary gland, which revealed no sign of clinical abnormality because the biopsy is not an invasive diagnostic procedure. As a result, the biopsy revealed significant IgG4-positive plasma cell infiltration, allowing for definitive IgG4-RD diagnosis. Administration of oral prednisolone (30 mg/day) effectively improved all symptoms. These findings indicate that minor salivary gland biopsy is an effective means of IgG4-RD diagnosis in patients for whom biopsy of target organs is difficult even if there were no sign of clinical abnormality in appearance.     

Mediators of angiogenesis and fibrosis in IgG4-related disease

IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory condition that can affect almost any organ, characterized by tumefactive lesions and often by eosinophilia and elevated serum IgG4 concentrations. The aim of the study is to analyze in IgG4-RD patients the serum levels of a group of cytokines and growth factors potentially involved in the regulation of fibrotic processes. In the sera of 12 patients affected by IgG4-RD and of 15 normal healthy subjects (NHS), pro-fibrogenic mediators (TGF-β1 and periostin) and pro- (VEGF and angiogenin-1) and anti- (endostatin and thrombospondin-1) angiogenic mediators were measured by sandwich enzyme immunoassay. Among mediators regulating fibrosis and angiogenesis, endostatin levels were significantly higher in IgG4-RD patients compared to NHS (p < 0.0001). No differences in the levels of TGF-β1, periostin, VEGF, angiogenin-1 and thrombospondin-1 were observed between groups. Our study suggests that among the mediators mainly involved in fibrosis and angiogenesis endostatin might play a role in the pathogenetic processes of IgG4-RD.     

IgG4-related disease involving polyserous effusions with elevated serum interleukin-6 levels: a case report and literature review

Immunoglobulin G4-related disease (IgG4-RD) is a recently described immune-mediated fibroinflammatory disease with a characteristic histopathologic appearance that can affect various organs. We report a 43-year-old Chinese female patient with IgG4-RD involving polyserous effusions with reports of worsening exertional dyspnea for 3 months. Laboratory blood tests revealed that serum interleukin (IL)-6, carbohydrate antigens (CA-199 and CA-125), and alpha-fetoprotein levels were significantly increased, but serum IgG4 levels were normal. Repeat pleural effusion and ascite analysis showed lymphocyte-predominant exudates. In addition, computed tomography scan showed massive pleural effusion in the right pleural cavity, abdominal effusion, and some pericardial effusion with a partial compression atelectasis. Further, medical thoracoscopy was performed to examine the pleural cavity and found multiple nodules on the pleura and partly thickened pleura with a reddish color. Histopathologic and immunohistochemical examination revealed marked lymphocytes and IgG4-positive plasma cell infiltration. The patient was finally diagnosed with IgG4-RD according to the comprehensive diagnostic criteria, although the patient presented similar serological and pathological manifestations of Castleman disease (CD). Our case suggests that IgG4-RD may be one of the causes of polyserous effusions and shows the difficulties in differentiating between IgG4-RD and CD.     

Abdominal aortic aneurysm as an IgG4-related disease

The objectives of this study were to evaluate patients with aortic abdominal aneurysm (AAA) with regard to immunoglobulin (Ig)G4-related disease (IgG4-RD). IgG4-RD represents a recently defined condition comprised of a collection of disorders characterized by IgG4 hypergammaglobulinemia, the presence of IgG4-positive plasma cells in organs affected with fibrotic or sclerotizing changes and typical histopathological features. It was identified as a possible cause of vasculitis in large vessels. Studies have been published on a possible association between inflammatory aortic or cardiovascular disease and IgG4-RD. We examined 114 patients with AAA requiring surgery in order to identify findings which are characteristic of IgG4-RD. Aneurysm samples from seven patients showed histopathological features consistent with IgG4-RD and the presence of IgG4⁺ plasma cells. Only two of these seven patients showed elevated IgG4 serum levels higher 1·35 g/l. In five of the patients, the concentration of serum IgG4 was lower than 1·20 g/l, with the number of IgG4⁺ plasma cells being higher than 50/high-power field. These findings were consistent with AAA being a heterogeneous group of inflammatory diseases with different pathogenesis.     

A Case of IgG4-Related Disease with Bronchial Asthma and Chronic Rhinosinusitis in Korea

IgG4-related disease (IgG4-RD) is characterized by a systemic involvement of tumor-like lesions with IgG4-positive plasmacytes. We experienced a case of IgG4-RD developed in a patient with bronchial asthma (BA) and chronic rhinosinusitis (CRS). A 55-yr-old female patient with BA and CRS complained of both eyes and neck swelling as well as a recurrent upper respiratory infection in recent 1 yr. The serum levels of IgG4, creatinine, and pancreatic enzymes were elevated. A biopsy of the submandibular gland showed an abundant infiltration of IgG4-positive plasmacytes. Her symptoms remarkably improved after the treatment of a systemic steroid that has been maintained without recurrence. We report a rare case of IgG4-RD developed in a patient with BA and CRS.

Graphical Abstract

相似文献   

The immunobiology and clinical characteristics of IgG4 related diseases

Having the characteristic features of elevated serum IgG4 levels and prominent infiltration of IgG4-positive plasma cells with fibrosis in lesions, Mikulicz's disease (MD) has been recognized as an IgG4-related disease (IgG4-RD). Although incidence of autoimmune pancreatitis (AIP), one of the organ characteristics of IgG4-RD, has been internationally reported, there are only a few such reports of IgG4-related MD. The limited number of reports might be attributable to the low recognition of IgG4-related MD as a clinical entity as well as its misdiagnosis as Sj?gren's syndrome (SS). Thus, we compared several clinical features of MD with SS to improve proper clinical diagnosis of MD in the clinical setting. A total of 70 SS and 70 MD cases evaluated at Sapporo Medical University Hospital were retrospectively analyzed. In SS patients, sicca symptoms were the most frequent (87%), followed by articular symptoms (23%), while lacrimal and salivary gland swelling were a rare (10%) and transient manifestation. In contrast, lacrimal or salivary gland swelling was observed in all patients with MD. Although nearly 60% of MD patients complained of sicca syndrome, skin rash and arthralgia were rare symptoms. Hypergammaglobulinemia was recognized in both SS and MD patients, but the occurrence of autoantibodies in patients with IgG4-related MD was low. Extraglandular organ involvement, often involving the retroperitoneum, pancreas, kidney and lung, was often discovered at the time of IgG4-related MD diagnosis. Although corticosteroid therapy tended to delay the hypofunction of salivary gland in SS patients, recovery of decreased function of salivary glands were observed in IgG4-related MD patients. These results suggest the beneficial effect of aggressive corticosteroid intervention in patients with IgG4-related MD. Although SS and MD are both chronic inflammatory diseases affecting the lacrimal and salivary glands, their clinical features and corticosteroid responsiveness are different. Thus, differential diagnosis of these conditions is warranted.     

IgG4-associated inflammatory pseudotumor of ureter: clinicopathologic and immunohistochemical study of 3 cases

Inflammatory pseudotumors are lesions characterized by proliferation of fibroblasts/myofibroblasts with variable chronic inflammatory cell infiltration. Recent studies have suggested that inflammatory pseudotumor with abundant IgG4-positive plasma cells may be a unique entity associated with systemic IgG4-related sclerosing disease and should be distinguished from other similar lesions such as inflammatory myofibroblastic tumor and fibrohistiocytic-type inflammatory pseudotumor. Localized inflammatory pseudotumor has been rarely reported in the ureter, and IgG4-associated inflammatory pseudotumor of ureter has not been described. We describe herein 3 cases of ureteral inflammatory pseudotumor of IgG4-associated lymphoplasmacytic type, focusing on density of IgG4-positive plasma cells; infiltration pattern of eosinophils and histiocytes; presence of obliterative phlebitis; and immunohistochemical profiles of smooth muscle actin, anaplastic lymphoma kinase, and CD68. Three patients, 45- and 47-year-old men and 84-year-old woman, all presented with flank pain and ureteral narrowing by a mass effect. Microscopic examination of the resected ureters showed suburothelial masslike lesions with fibroblasts/myofibroblasts without atypia, abundant plasma cells, and scattered eosinophils and histiocytes. The lesion of the 47-year-old man showed obliterative phlebitis in addition to the above findings. The lesion of the 84-year-old woman was accompanied by urothelial carcinoma in situ in the overlying urothelium. Spindle cells were diffusely or focally positive for smooth muscle actin but negative for anaplastic lymphoma kinase in all 3 cases. For each case, respectively, an average of 154, 112, and 50 plasma cells per high-power fields were immunoreactive for IgG4, a diagnostic feature of IgG4 inflammatory pseudotumor. We described 3 cases of IgG4-associated inflammatory pseudotumor of ureter with pathologic and immunohistochemical features that are compatible for lymphoplasmacytic type of inflammatory pseudotumor. Further study is needed to characterize any relationship between this entity and systemic sclerosing disease and/or urothelial carcinogenesis.     

Idiopathic vs. secondary retroperitoneal fibrosis: a clinicopathological study of 12 cases, with emphasis to possible relationship to IgG4-related disease

Retroperitoneal fibrosis (RF) is a rare disease characterized by inflammation and fibrosis of retroperitoneal soft tissues. It is classified into two types: idiopathic (iRF) and secondary (sRF). The aim of the study was to investigate the relationship between iRF and IgG4-related disease (IgG4-RD) and to eventually extend the clinicopathological features of this condition by analysis of the sample comprising six iRF and six sRF patients. The iRF patients included four males and two females, aged 12–62 years (median 55 years). Two lesions were periaortic, one was periureteral, and three cases showed both periaortic and periureteral localization. Two patients had increased serum levels of IgG4. None of the patients developed any manifestation of IgG4-RD during the follow-up period ranging for 15–133 months (median 43 months). Microscopically, in two iRF cases, fibrosis was highly cellular encircling the vessels, nerves, and paraganglia. Phlebitis was found in all cases and being obliterative in four. Lymphocytic inflammation with formation of follicles and plasma cell infiltration were scored as severe in five iRF cases. The numbers of IgG-positive plasma cells ranged 0–373 per 1 HPF (high power field; median 132) and of IgG4-positive plasma cells 0–238 per 1 HPF (median 91). The IgG4/IgG ratio values ranged 0.38–0.74 (median 0.68). Two of the iRF cases were diagnosed as definite and three cases as probable IgG4-RD. To the contrary, none of the sRF cases met the diagnostic criteria for either definite, probable, or possible IgG4-related disease. Our results indicate that a substantial portion of iRF cases, including some of very rare pediatric cases, is a manifestation of IgG4-RD.     

Enterocolic lymphocytic phlebitis of the cecal pole and appendix vermiformis with increase of IgG4-positive plasma cells

Here we describe the clinicopathological course of a 20-year-old female patient with enterocolic lymphocytic phlebitis (ELP) of the appendix vermiformis and cecal pole with increase of IgG4-positive plasma cells. The patient presented with acute abdomen, suspicious of acute appendicitis. Diagnostic laparoscopy showed tumefaction of the cecal pole and appendix vermiformis. Histologic examination revealed mural thickening and a dense lymphoplasmocytic, partly obliterative infiltrate of the veins with sparing of the arteries, diagnostic of ELP. In addition, we found an elevated number of IgG4-positive plasma cells blended in with the lymphocytes. The IgG4-to-IgG ratio accounted for >40 %. This case meets the histopathological criteria requested for IgG4-related disease (IgG4-RD) and thus opens the possibility that ELP might be part of the IgG4-RD spectrum.     

The clinical spectrum of IgG4-related disease

IgG4-related disease (IgG4-RD) is an emerging immune-mediated disease with the capability of involving essentially any organ. The epidemiology of this disease has not been explored in detail. A majority of patients reported in the literature to date are from Japan, but the condition has been described all across the world and there is no strong evidence to suggest a predilection for Asian populations. The mean age at diagnosis is approximately 60 years and there is a decided male predominance for many clinical features, with an overall male:female ratio of 8:3. A cardinal feature of IgG4-RD is single or multiple organ swelling that often raises concern for malignancy. IgG4-RD should be suspected in patients presenting with unexplained enlargement or swelling of one or more organs. Presenting features vary substantially according to the specialty to which patients present first; in addition, the disease can be diagnosed unexpectedly in pathological specimens or identified incidentally on radiology studies. Involvement of major organs is common and IgG4-RD may lead to organ failure, particularly in the pancreas, liver and biliary tree, kidneys, thyroid gland, lungs, and aorta. The diagnosis of IgG4-RD relies on the coexistence of various clinical, laboratory and histopathological findings, although none is pathognomonic by itself.     

Consideration concerning similarities and differences between ANCA-associated vasculitis and IgG-4-related diseases: case series and review of literature

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and immunoglobulin G4-related diseases (IgG4-RD) are regarded as entirely different disease types with different etiological mechanisms. However, we experienced two cases that had clinical features of both AAV and IgG4-RD. The first case is an 81-year-old woman who showed periaortitis and retroperitoneal fibrosis and periarteritis with elevation of myeloperoxidase-anti-neutrophil cytoplasmic antibody and IgG4 levels. The second case is a 63-year-old woman who had dura mater, ear, nose, lung, and kidney involvement with serum negative for ANCA and elevated IgG4. Renal biopsy revealed tubulointerstitial nephritis involving IgG4⁺ plasma cells (IgG4⁺/IgG⁺ cell ratio of ≥ 40%). On the other hand, lung biopsy showed features of granulomatosis with polyangiitis (GPA). These two cases suggested that AAV and IgG4-RD might overlap. To investigate the similarities and differences between AAV and IgG4-RD, we retrospectively analyzed 13 cases of typical GPA, a subtype of AAV, and 13 cases of typical IgG4-RD at our hospital for comparison of clinical features and found some differences that can be useful in the differential diagnosis between the two diseases. Although AAV and IgG4-RD are distinguishable based on characteristic findings in many cases, the diagnosis can be unclear in rare cases, in which clinicians should consider possible coexistence of AAV and IgG4-RD when performing further workup. Here, we discuss the similarities and differences between AAV and IgG4-RD on the basis of our results and past literature.