Clinical characteristics of autoimmune pancreatitis with IgG4 related kidney disease

PurposeTo clarify the clinical characteristics of autoimmune pancreatitis (AIP) in immunoglobulin (Ig)G4-related kidney disease (IgG4-RKD).Patients and methodsA total of 92 patients with AIP were divided into an IgG4-RKD-positive group (RKD-P group, n = 13) and an IgG4-RKD-negative group (RKD-N group, n = 79) on the basis of the diagnostic criteria for IgG4-RKD. Clinical characteristics, including: age; sex; the presence of extrapancreatic lesions other than renal lesions, proteinuria, and hematuria; serum concentrations of IgG, IgG4, IgE, and creatinine; and urinary concentrations of liver-type fatty acid binding protein, α1-microglobulin, β2-microglobulin, and N-acetyl-β-d-glucosaminidase were compared between the RKD-P and RKD-N groups. The clinical course of the RKD-P group was also characterized.ResultsThe prevalence of extrapancreatic lesions other than renal lesions was significantly higher in the RKD-P group (84.6% vs 43.0%,p < 0.01). Serum creatinine (1.19 mg/dl versus 0.74 mg/dl, p < 0.05), urinary β2-microglobulin (6609.8 μg/l vs 265.8 μg/l, p < 0.05), and the prevalence of proteinuria (30.7% vs 7.6%, p < 0.05) were significantly higher in the RKD-P group. Nine out of thirteen patients in the RKD-P group had multiple low-density renal lesions on enhanced computed tomography, 3 patients had multiple high-intensity lesions on diffusion-weighted magnetic resonance images, and 1 patient had diffuse thickening of the renal wall, with a smooth intra-luminal surface.ConclusionsPatients who had AIP with IgG4-RKD were more likely to have extrapancreatic lesions other than those in the kidney, and their serum creatinine and urinary β2-microglobulin concentrations were significantly higher than in those without IgG4-RKD.     

IgG4相关性疾病的研究进展

IgG4相关性疾病是一个新的独立疾病,临床表现复杂多样,可以浸润多种器官,出现器官弥漫性肿胀或局部肿块形成,病理可见IgG4+浆细胞为主的淋巴浆细胞浸润、闭塞性静脉炎、组织席纹状纤维化改变,血清IgG4浓度升高.此病多见于老年男性,对类固醇激素反应敏感.临床常见的受累器官有:浸润唾液腺、泪腺的米库利兹病,浸润下颌下腺的Küttner肿瘤,Riedel's甲状腺炎,腹膜后纤维化,自身免疫性胰腺炎1型等全身多系统疾病.本文从概念,流行病学概况、发病机制,病理特征,临床表现,诊断和治疗作一综述.     

IgG4-related prostatitis progressed from localized IgG4-related lymphadenopathy

Immunoglobulin G4-related disease (IgG4-RD) is a recently described inflammatory disease involving multiple organs. Prostate involvement with IgG4-RD is very rare. In this report, we describe a case of IgG4-related prostatitis progressed from localized IgG4-related lymphadenopathy. This patient was present with urine retention symptoms. MRI and CT examination revealed the prostatic enlargement and the multiple lymphadenopathy. Serum IgG4 levels were elevated. Prostatic tissue samples resected both this time and less than 1 year earlier showed the same histological type of prostatitis with histopathologic and immunohistochemical findings characteristic of IgG4-RD. The right submandibular lymph nodes excised 2 years earlier were eventually proven to be follicular hyperplasia-type IgG4-related lymphadenopathy. This is the first case of IgG4-RD that began as localized IgG4-related lymphadenopathy and progressed into a systemic disease involving prostate and multiple lymph nodes. This patient showed a good response to steroid therapy. This leads us to advocate a novel pathogenesis of prostatitis, and a novel therapeutic approach against prostatitis. Pathologists and urologists should consider this disease entity in the patients with elevated serum IgG4 levels and the symptoms of prostatic hyperplasia to avoid ineffective medical or unnecessary surgical treatment.     

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.     

IgG4相关性涎腺炎的临床病理特点

IgG4相关性疾病作为一种全身系统性疾,可累及多个器官及组织.发生于涎腺的IgG4相关性涎腺炎容易与干燥综合征、慢性非特异性涎腺炎、淋巴瘤等多种疾病混淆,延误治疗并给患者带来诸多不必要的手术负担.因此有必要提高对IgG4相关性涎腺炎的认识.本文就IgG4相关性涎腺炎的临床及病理组织学等特点进行综述.     

IgG4相关性淋巴结病的临床病理特点

IgG4相关性疾病作为一种全身系统性疾病,可累及多个器官及组织。发生于淋巴结的IgG4相关性淋巴结病由于其临床病理特点缺乏特异性,需与多种病变鉴别,如Castleman’s病样、淋巴滤泡反应性增生、淋巴瘤等。尽管IgG4相关性疾病经激素治疗效果显著,但是某些患者可发展成淋巴瘤。因此有必要提高对IgG4相关性淋巴结病的认识。本文就IgG4相关性淋巴结病的临床及病理组织学等特点进行综述。     

IgG4-related systemic sclerosing disease – an emerging and under-diagnosed condition

Autoimmune pancreatitis was first described in 1961, although it was not more widely recognized as an autoimmune condition until 1995. It has now become apparent that this form of pancreatitis is part of a clinical syndrome that is commonly multisystem in nature. One of the most common histopathological features is the presence of IgG4+ plasma cells within involved tissues. Many terms have been proposed to describe the condition, but 'IgG4-related systemic sclerosing disease' appears most appropriate. Commonly affected extrapancreatic tissues include the biliary tract, liver, kidneys and lung, but a wide range of other sites may be involved. Histological examination reveals features that are not entirely disease-specific, but that are often sufficiently characteristic to provide useful support to a clinicopathological diagnosis. The disease often responds well to systemic steroid therapy, unlike some of the conditions that it may simulate clinically. The emergence of this disease as a specific and treatable entity has favourably altered the clinical outlook for patients in whom steroid therapy might not previously have been considered appropriate.     

Immunology of IgG4-related disease

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that derives its name from the characteristic finding of abundant IgG4⁺ plasma cells in affected tissues, as well as the presence of elevated serum IgG4 concentrations in many patients. In contrast to fibrotic disorders, such as systemic sclerosis or idiopathic pulmonary fibrosis in which the tissues fibrosis has remained largely intractable to treatment, many IgG4-RD patients appear to have a condition in which the collagen deposition is reversible. The mechanisms underlying this peculiar feature remain unknown, but the remarkable efficacy of B cell depletion in these patients supports an important pathogenic role of B cell/T cell collaboration. In particular, aberrant T helper type 2 (Th2)/regulatory T cells sustained by putative autoreactive B cells have been proposed to drive collagen deposition through the production of profibrotic cytokines, but definitive demonstrations of this hypothesis are lacking. Indeed, a number of unsolved questions need to be addressed in order to fully understand the pathogenesis of IgG4-RD. These include the identification of an antigenic trigger(s), the implications (if any) of IgG4 antibodies for pathophysiology and the precise immunological mechanisms leading to fibrosis. Recent investigations have also raised the possibility that innate immunity might precede adaptive immunity, thus further complicating the pathological scenario. Here, we aim to review the most recent insights on the immunology of IgG4-RD, focusing on the relative contribution of innate and adaptive immune responses to the full pathological phenotype of this fibrotic condition. Clinical, histological and therapeutic features are also addressed.     

IgG4-related renal disease: clinical and pathological characteristics

IgG4-related disease is a recently established systemic condition. Tubulointerstitial nephritis is the most common renal manifestation. Glomerular lesions, particularly membranous glomerulonephritis, can develop simultaneously. Some patients present with serological renal dysfunction associated with elevated IgG or IgE levels and hypocomplementemia, while others are incidentally found to have abnormalities in kidneys on imaging. A majority of patients with IgG4-related kidney disease have similar lesions at other anatomical sites, which help us to suspect this condition. Serum IgG4 elevation (>135 mg/dL) is the most, although not entirely, specific marker for the diagnosis. Imaging findings varies from small nodules to bilateral diffuse abnormalities. In addition to the renal parenchyma, the renal pelvis and perirenal adipose tissue can be affected. Histological features include dense lymphoplasmacytic infiltration, storiform or “bird’s eye” fibrosis (highlighted by PAM stain), and IgG4-positive plasma cell infiltration (>10 cells/high-power field and IgG4/IgG-positive cell ratio >40%). Immune complex deposition is detectable in the tubular basement membrane by immunofluorescence and/or electron microscopy. Patients usually respond well to corticosteroids, but highly active diseases may require other immunosuppressive therapies. Further investigations will be required to fully understand pathophysiology underlying this emerging condition.     

IgG4相关性疾病临床病理学特征分析

目的：探讨IgG4相关性疾病的病理学形态、免疫表型特征。方法观察12例IgG4相关性疾病的镜下特点,结合免疫组化EnVision两步法染色检测IgG、IgG4、CD138、CD34的表达,分析IgG4相关性疾病的病理学形态特征。结果 IgG4相关性疾病主要表现为组织弥漫性纤维化;伴大量淋巴细胞、浆细胞浸润,围绕血管神经分布;闭塞性静脉炎形成,免疫组化EnVision两步法染色IgG4阳性浆细胞与IgG阳性浆细胞比例>40%。结论 IgG4相关性疾病临床特点和影像学无特异性,易误诊为肿瘤,术前血清IgG4检测可作为疑似病例的首选方法。     

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.     

Hypophysitis presented as inflammatory pseudotumor in immunoglobulin G4-related systemic disease

Immunoglobulin (Ig) G4-related systemic disease is a recently characterized entity. The best-known manifestation is pancreatitis. Other systemic involvements are also described. Three cases of this disease with hypophyseal involvement have been reported in the literature, all diagnosed clinically. We herein present the first case of IgG4-related hypophysitis diagnosed histopathologically. The patient is a 77-year-old Chinese man with a pituitary tumor. Histologic examination of the resected tumor showed hypophysitis with features of inflammatory pseudotumor. Clinical review showed history of pancreatitis and cholecystitis 4 years ago. The pancreatic biopsy and gall bladder specimens obtained previously had the same pathologic features of inflammatory pseudotumor. Immunohistochemistry highlighted abundant IgG4-positive plasma cells in all 3 specimens. Serum IgG4 level was also elevated. A diagnosis of IgG4-related systemic disease was confirmed. This is the first case of intracranial inflammatory pseudotumor shown to be associated with IgG4-related systemic disease.     

New insights into the pathophysiology of IgG4-related disease and markers of disease activity

Introduction: Recently, IgG4-related disease (IgG4-RD) has become a well-recognized clinical entity, although its causes are still not well understood. The pathophysiology of IgG4-RD has been reported from a variety of aspects.

Areas covered: In this review, we outline a number of recent advances in our understanding of the pathogenesis of IgG4-RD, divided according to acquired immunology and innate immunology and other topics. Furthermore, we also focus on some proposed markers of disease activity of IgG4-RD.

Expert commentary: One striking advance made recently is the identification of novel autoantigens of IgG4-RD. At the onset of IgG4-RD, various T cell side factors such as Tfh, Th2 cells are at work, in addition to B cell side factors like plasmablasts and plasma cells, and innate immunology via TLR and M2 macrophages. The efficacy of B cell depletion therapy using rituximab has been reported, with the establishment of steroid-sparing therapies targeting other molecules also anticipated.