IgG4-positive plasma cells in inflammatory abdominal aortic aneurysm: the possibility of an aortic manifestation of IgG4-related sclerosing disease

Inflammatory abdominal aortic aneurysm (IAA) is associated with autoimmune disease. However, the precise mechanism of IAA remains unclear. There is increasing evidence that IgG4 is involved in the autoimmune mechanism of various idiopathic sclerosing lesions, including sclerosing pancreatitis and retroperitoneal fibrosis. The present study investigated the hypothesis that the IgG4-related autoimmune reaction is involved in the formation of IAA. The study group consisted of 11 cases of IAA (69.2 +/- 8.59y) and 12 age-matched cases of atherosclerotic abdominal aortic aneurysm (AAA, 69.6 +/- 5.94y), which were used in the previous report. A clinicopathologic examination of these lesions was performed, including histology and immunohistochemistry, in relation to the involvement of IgG4-positive plasma cells in the formation of IAA. No difference in the incidence of risk factors for atherosclerosis was observed between the patients with IAA and AAA. Autoimmune diseases were diagnosed in 2 patients with IAA, including rheumatoid arthritis and polyarteritis nodosa. A patient with IAA had pulmonary fibrosis. In contrast, autoimmune diseases were absent in patients with AAA. However, there was no significant difference in the incidence of autoimmune diseases between the patients with IAA and AAA. Lymphocyte and plasma cell infiltration and fibrosis were significantly more intense and extensive in IAA than in AAA. In addition, lymph follicle formation and vasculitis of small veins and arteries were frequently found in the affected lesions of IAA. Immunohistochemically, IAA showed a significant increase in the number of infiltrating IgG4-positive plasma cells and the incidence of a disrupted follicular dendritic cell network in lymph follicles, in comparison with AAA. These findings suggest that IAA may be an aortic lesion reflecting the presence of IgG4-related sclerosing disease, and not a simple inflammatory aneurysm of the aorta.     

Chronic periaortitis associated with membranous nephropathy: clues to common pathogenetic mechanisms

Chronic periaortitis (CP) is a rare disease hallmarked by the presence of a periaortic retroperitoneal fibro-inflammatory tissue which can often cause obstructive uropathy. CP is isolated in most cases but it may also be associated with other sclerosing inflammatory and immune-mediated diseases. We here present the case of a patient who was initially diagnosed as having CP and subsequently developed membranous nephropathy and chronic sclerosing sialoadenitis of the right parotid gland. As these conditions were all characterized by either pronounced infiltration of IgG4-positive plasma cells or marked IgG4 tissue deposition, we hypothesize that they are part of the same disease spectrum, and discuss the immune-mediated pathogenetic mechanisms potentially shared by these conditions. In particular, we consider the role of Th2-mediated immune reactions and of immunogenetic factors such as HLA genotype as common determinants of these disorders.     

Les atteintes uro-néphrologiques au cours de la maladie associée aux IgG4

Hyper-IgG4 syndrome, or IgG4-related disease, is an emerging disorder, involving one or more organ(s), and characterized by “storiform” fibrosis and inflammatory lesions with a predominance of IgG4+ plasma cells and increased IgG4 serum levels. Since the first report of auto-immune pancreatitis, numerous organ lesions have been reported and have been found to occur in a same patient including: sialadenitis, dacryoadenitis, lymphadenopathy, liver and biliary tract involvement, and renal and retroperitoneal lesions. Renal involvement was first described in 2004 and usually presents as functional and/or morphological abnormalities. In most cases, renal pathological analysis reveals tubulointerstitial nephritis that is rarely associated with glomerular lesions. Retroperitoneal fibrosis is also a typical feature that may be associated with periaortitis or inflammatory abdominal aortic aneurysm. First line treatment is based on corticosteroid therapy. Short-term outcome is usually favorable. However, patients should be carefully monitored for relapses and long-term complications. Although the multiple organ lesions share common clinical, biological, radiological and pathological features, no consensus diagnostic criteria have yet been validated for IgG4-related disease. Ruling out differential diagnoses is thus mandatory. Our literature review provides nephrologists, urologists and pathologists with key elements that will help in the early diagnosis and proper management of this new and emerging disorder.     

Endocapillary proliferative glomerulonephritis with crescent formation and concurrent tubulointerstitial nephritis complicating retroperitoneal fibrosis with a high serum level of IgG4

Renal lesions of IgG4-related disease have been reported recently. Most of them are tubulointerstitial nephritis, and a definite glomerulonephritis complicating IgG4-related disease is very rare. We report here a case of definite glomerulonephritis and concurrent tubulointerstitial nephritis complicating retroperitoneal fibrosis with a high serum level of IgG4. A 68-year-old Japanese woman was referred to our hospital for investigation of anasarca. We diagnosed her disease as a nephrotic syndrome and left hydroureteronephrosis due to retroperitoneal fibrosis. Her laboratory data revealed a high serum level of IgG4, renal injury, hypoproteinemia, hypocomplementemia, a positive finding of circulating immunocomplex (CIC), and negative findings ofautologous antibodies suggesting systemic lupus erythematosus (SLE) or Sj?gren's syndrome (SS). A diagnosis of SLE or SS could not be made clinically. Right renal biopsy revealed endocapillary proliferative glomerulonephritis with crescent formation and concurrent tubulointerstitial nephritis. Infiltration of plasma cells in interstitium was more conspicuous than seen with ordinary tubulointerstitial nephritis, and in most of them IgG4 was positive. We placed a percutaneous nephrostomy catheter in her left kidney, and prescribed prednisolone and cyclosporine. The responses to prednisolone and cyclosporine therapies were very good. Further studies are needed to clarify the relationship between glomerulonephritis and IgG4-related disease. However, when considering renal lesions of IgG4-related disease, we think that hypocomplementemia, a positive finding of CIC, negative findings of autologous antibodies suggesting SLE or SS, conspicuous interstitial infiltration of IgG4-positive plasma cells, and a good response to steroid or immunosuppressant therapy are key points.     

特发性腹膜后纤维化16例临床分析

目的 探讨特发性腹膜后纤维化(iRPF)临床特点、诊疗及转归,以提高临床诊断率,减少漏诊和误诊.方法 回顾分析在青岛大学附属医院住院确诊的16例iRPF患者,其中包括9例IgG4相关腹膜后纤维化患者.结果 iRPF多见于中老年男性,肾功能衰竭合并腰腹疼痛、体重减轻是最常见的临床表现.IgG4-RPF患者与非IgG4-RPF患者Hb、SCr、ESR、CRP组间比较差异无统计学意义.所有患者均存在CT或MRI下腹膜后软组织密度影;IgG4-RPF患者同时还可发现颌下腺、深部淋巴结、胰腺、胆管、胸腺、肾间质、甲状腺等多器官受累.病理学检查发现全部IgG4-RD患者不同受累器官均显示相同特点的改变,且其IgG4阳性的浆细胞计数、IgG4 +/IgG阳性浆细胞计数比例、席纹状纤维化例数较非IgG4-RPF患者有显著的统计学差异.8例行皮质类固醇和免疫抑制剂治疗;6例行药物及手术联合治疗;2例单纯手术治疗.所有接受皮质类固醇治疗的患者病情均缓解,其中2例停药后复发;但单纯外科治疗患者反复发作.结论 特发性腹膜后纤维化与IgG4-RD疾病谱有交集,但临床特点及普通影像学检查无法做出鉴别,需要进一步病理学检查.激素及免疫抑制剂对两者治疗均有效并可减少复发.     

Idiopathic retroperitoneal fibrosis associated with IgG4-positive-plasmacyte infiltrations and idiopathic chronic pancreatitis

Idiopathic retroperitoneal fibrosis (IRPF) is an inflammatory fibrosclerosing condition, leading to renal failure by obstruction of the ureters. Idiopathic chronic pancreatitis associated with marked inflammatory infiltrates has recently been referred to as autoimmune pancreatitis (AIP), and infiltrating plasmacytes carrying immunoglobulin-gamma type 4 (IgG4) are relevant to its pathogenesis. The case is described herein of IRPF associated with subclinical pancreatitis that was most probably AIP in a 70-year-old man. Biopsy specimens of the retroperitoneal pseudotumor revealed a marked lymphoplasmacytic infiltration with dense fibrosis. Infiltrating plasma cells were immunoreactive for anti-IgG4 antibodies. Subsequent systemic examinations showed an extremely elevated serum IgG4 level and pancreatitis concordant with AIP. Following oral steroid administration, the serum IgG4 level normalized, although the appearance of the pseudotumor did not alter. Some AIP cases have been associated with idiopathic fibrosclerosing disorders including IRPF, but histological evidence of IgG4-related IRPF has rarely been provided.     

IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis?

Sclerosing cholangitis (SC) is a heterogeneous disease entity. Different etiologies such as choledocholithiasis, biliary tumor, or pericholangitis can manifest as SC. Hepatic inflammatory pseudotumor (IP) is rarely associated with SC (sclerosing cholangitis associated with hepatic inflammatory pseudotumor; SC-hepatic IP), but sclerosing pancreatitis (SP) is not infrequently associated with bile duct lesions (sclerosing pancreatitis-associated sclerosing cholangitis; SP-SC). In this study, we compared the histologic changes of hepatic hilar and extrahepatic bile duct lesions of SC (7 cases), SC-hepatic IP (5 cases), SP-SC (5 cases), and typical primary sclerosing cholangitis (PSC) (5 cases). Histologically, all SP-SC cases showed extensive and dense fibrosis with marked lymphoplasmacytic infiltration, many eosinophils, and obliterative phlebitis. Four cases of SC showed bile duct lesions similar to those of SP-SC, whereas other three cases of SC showed milder lymphoplasmacytic infiltration, scant eosinophilic cell infiltration, and no obliterative phlebitis. All SC-hepatic IP cases showed bile duct lesions identical to those of SP-SC. Immunohistochemically, many IgG4-positive plasma cells were found in the bile duct lesions of all SP-SC cases, 4 SC cases with marked lymphoplasmacytic infiltration, and all SC-hepatic IP cases. By contrast, IgG4-positive plasma cells were scarce or hardly found in the remaining 3 SC cases and all PSC cases. In conclusion, 4 SC cases and all SC-hepatic IP cases showed bile duct lesions identical to those of SP-SC, suggesting that these three conditions may be a single disease entity. Their pathogenesis may be similar or closely related to that of SP, and in that respect they may represent an IgG4-related biliary disease. They may respond to steroid therapy as SP does.     

Recurrent Mastoiditis Mimics IgG4 Related Disease: A Potential Diagnostic Pitfall

IgG4-related disease (IgG4-RD) is a recently recognized entity that causes progressive fibrosis and formation of mass lesions. IgG4-RD can be diagnosed histologically by its hallmarks of storiform fibrosis, prominent lymphoplasmacytic infiltrate, and obliterative phlebitis, accompanied by the infiltration of excessive numbers of IgG4-positive plasma cells as well as elevations in serum IgG4 concentrations. A recent publication reported a case of IgG4-RD in the mastoid sinus, representing a new anatomic location for this disease. We report two additional cases of IgG4-RD occurring in the mastoid and causing clinical mastoiditis. The presenting symptoms were varied—tinnitus, hearing loss, and cranial nerve palsies. All three cases showed a dense lymphoplasmacytic infiltrate, storiform type fibrosis as well as elevated numbers of IgG4 positive plasma cells. The three patients responded to immunosuppressive therapy that included steroids and Rituximab. We further investigated 162 consecutive mastoiditis cases at our institution in order to determine the frequency of IgG4-RD as a previously unrecognized cause of mastoiditis. Within this latter cohort we identified nine cases of mastoiditis that had two of the histologic features of IgG4-RD, specifically storiform fibrosis and a dense lymphoplasmacytic infiltrate. Two of these cases showed >50 IgG4-positive plasma cells per high-power field with IgG4–IgG ratio of >40 %, thus fulfilling histological criteria for IgG4-RD. However, both were due to severe acute or chronic infection. In conclusion, we reaffirm IgG4 related mastoiditis as a distinct but uncommon cause of recurrent mastoiditis. The diagnosis of IgG4-related mastoiditis should be rendered with caution, and only after the exclusion of potential mimickers, particularly infection.     

Pathological characteristics and diagnosis of IgG4-related disease

IgG4-related disease (IgG4-RD) has been accepted as a distinct entity in various fields. It is being increasingly diagnosed and treated in routine practice. However, difficulties are still associated with the diagnostic process. Serum IgG4 elevations and imaging studies are useful, but not entirely diagnostic for this condition. Therefore, a pathological examination still plays an important role. Three characteristic microscopic changes are dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis. IgG4 immunostaining reveals many IgG4-positive plasma cells and an IgG4/IgG-positive cell ratio of more than 40%. In addition to the number and ratio of IgG4-positive plasma cells, the diffuse distribution of positive plasma cells needs to be confirmed because IgG4-positive plasma cells may focally aggregate in many other conditions. In small biopsy samples, it is important to recognize not only characteristic findings, but also microscopic changes that are unlikely to occur in IgG4-RD because the identification of the latter findings leads to the exclusion of this condition. Another challenging field regards the diagnosis of long-standing disease. Along with disease progression, inflammatory infiltrate decreases, while storiform fibrosis and obliterative phlebitis are suspected to persistently exist. Therefore, the recognition of the latter two findings will be a diagnostic clue. Given the general suspicion that IgG4-RD has recently been over-diagnosed, precise tissue examinations based on the proposed standards and close clinicopathological correlations are crucial.     

Proposal for diagnostic criteria for IgG4-related kidney disease

Background

IgG4-related disease has attracted wide attention recently. It is characterized by a high level of serum IgG4 and dense infiltration of IgG4-positive plasma cells into multiple organs, with the kidney being one representative target. Although several sets of diagnostic criteria for autoimmune pancreatitis (AIP) are available and renal lesion is recognized as an extra-pancreatic manifestation of AIP, it is difficult to differentiate IgG4-related tubulointerstitial nephritis (TIN) without AIP from other types of TIN. To clarify the entity of IgG4-related kidney disease (IgG4-RKD) and support in-depth studies, the Japanese Society of Nephrology has established a working group to prepare diagnostic criteria for IgG4-RKD.

Method

The working group analyzed 41 patients with IgG4-RKD, and collected the following data to devise a diagnostic algorithm and diagnostic criteria for IgG4-RKD: clinical features including extra-renal organ involvement, urinalysis and serological features including serum IgG4 levels, imaging findings demonstrated by computed tomography (CT), renal histology with IgG4 immunostaining, and response to steroid therapy.

Results

The conditions for criteria are as follows. (1) Presence of some kidney damage, as manifested by abnormal urinalysis or urine marker(s) and/or decreased kidney function with either elevated serum IgG level, hypocomplementemia, or elevated serum IgE level. (2) Kidney imaging studies showing abnormal renal imaging findings, i.e., multiple low density lesions on enhanced CT, diffuse kidney enlargement, hypovascular solitary mass in the kidney, and hypertrophic lesion of the renal pelvic wall without irregularity of the renal pelvic surface. (3) Serum IgG4 level exceeding 135?mg/dl. (4) Renal histology showing two abnormal findings: (a) dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells >10/high power field (HPF) and/or ratio of IgG4-positive plasma cells/IgG positive plasma cells >40%. (b) Characteristic ??storiform?? fibrosis surrounding nests of lymphocytes and/or plasma cells. (5) Extra-renal histology showing dense lymphoplasmacytic infiltration with infiltrating IgG4-positive plasma cells >10/HPF and/or ratio of IgG4-positive plasma cells/IgG-positive plasma cells >40%. The diagnosis is classified into 3 stages of definite, probable and possible according to the combinations of the above conditions. Thirty-nine cases (95.1%) were diagnosed with IgG4-RKD according to the criteria.

Conclusion

The provisional criteria and algorithm appear to be useful for clarifying the entity of IgG4-RKD and seeking underlying IgG4-RKD cases; however, further experience is needed to confirm the validity of these criteria.     

Lung involvement in IgG4-related lymphoplasmacytic vasculitis and interstitial fibrosis: report of 3 cases and review of the literature

There have been a few reports on lung diseases associated with an increased number of infiltrating IgG4-positive plasma cells or lung involvement of IgG4-related sclerosing disease, although their characteristic histologic features have not been well described. Herein, we present 3 cases of interstitial lung disease with common histology and abundant IgG4-positive cell infiltration. Patient 1, a 65-year-old man, was incidentally noted to have a nodular lesion in the left hilar region. In patient 2, a 78-year-old man with dyspnea on effort, computed tomography revealed multifocal consolidation adjacent to the pleura in both lower lobes. Patient 3, a 74-year-old man, underwent lung biopsy for right-sided pleural effusion of unknown etiology. The histologic findings of the 3 individuals were characterized by expansion of the interstitium by dense lymphoplasmacytic infiltrate with prominent vascular involvement, which was indistinguishable from grade 1 lesion of lymphomatoid granulomatosis (LYG-G1). In situ hybridization for Epstein-Barr virus-encoded small RNA (EBER) revealed few or no EBER-positive lymphocytes. Vascular involvement showed subendothelial lymphoplasmacytic infiltrate, including numerous IgG4-positive plasma cells. The percentages of IgG4-positive to IgG-positive plasma cells were 85%, 47%, 46%, respectively. Similar vascular lesions have been described in previous reports of lung complications in IgG4-related sclerosing diseases. Some of these lesions were diagnosed as LYG-G1 without EBER-positive cells. In conclusion, LYG-G1-like lesion characterized by lymphoplasmacytic vasculitis might be a characteristic feature of IgG4-related lung disease.     

Clinicopathological findings of immunoglobulin G4-related kidney disease

Immunoglobulin (Ig) G4-related kidney disease characterizing tubulointerstitial nephritis (TIN) is an organ complication recognized in IgG4-related systemic diseases that has some unique aspects compared to other types of TIN. TIN lesions in the kidney can be tumor-like, focal or diffuse. Abnormal urinalysis is usually mild or absent even in the cases with deteriorated renal dysfunction. Some cases are accidentally diagnosed from radiological findings without renal dysfunction and/or abnormal urinalysis. The typical pathological findings of TIN are unique fibrosis and infiltration of massive lymphocytes and IgG4-positive plasma cells. Glomerular lesions are rare but the complication of mesangial proliferative glomerulonephritis and membranous nephropathy is occasionally reported. Pathogenic mechanisms are unclear until now; however, auto-immune and allergic mechanisms have been suspected from laboratory data. The initial response to steroid agents is generally favorable; however, recurrence is possible after the discontinuation of steroid treatment. Long-term follow-up is necessary with continuous systemic checks for organ disorders due to IgG4-related systemic diseases.     

Autoimmune pancreatitis—a new evolving pancreatic disease?

Introduction  

Recent advances support the concept of autoimmune pancreatitis as a unique systemic disease because occasional extrapancreatic lesions such as sclerosing cholangitis, sclerosing sialoadenitis, and retroperitoneal fibrosis show similar pathological features with fibrosis and abundant infiltration of IgG4-positive plasma cells, and are steroid responsive. Based on these findings, several diagnostic criteria have been proposed.     

IgG4-related sclerosing disease of the small bowel presenting as necrotizing mesenteric arteritis and a solitary jejunal ulcer

Since first described in the mid 1990s, there has been burgeoning literature on IgG4-related sclerosing disease. The number of sites that may be involved is ever increasing, with the pancreas, salivary glands, and lymph nodes being the most commonly affected organs. There are no well-documented cases arising in the gastrointestinal tract. In this report, we present the first case to our knowledge of IgG4-related sclerosing disease involving the small bowel with a distinctly unusual clinicopathologic presentation. A previously well 46-year-old woman presented with a 2-year history of intermittent abdominal pain with recent worsening due to small bowel obstruction. Following imaging, which showed jejunitis with surrounding mesenteric inflammatory changes, she proceeded to a segmental small bowel resection. The resected jejunum revealed an isolated, stenosing chronic ulcer associated with a necrotizing mesenteric arteritis. A transmural inflammatory infiltrate rich in IgG4 plasma cells was seen in the wall of the bowel and mesenteric artery. Abundant IgG4 interfollicular plasma cells were also identified in a mesenteric lymph node. The serum IgG4 level was elevated at >800 mg/dL (reference range 8 to 140 mg/dL). Although phlebitis is an almost constant feature of this disease, arteritis is not described other than in the lung and aorta. In this report, we also discuss the diagnostic pitfalls and the differential diagnoses that should be considered when this condition arises in the gastrointestinal tract.     

Research Progress on IgG4-Related Hashimoto's Thyroiditis

IgG4-related disease is a systemic autoimmune disease with unknown cause and involves multiple organs and tissues. This disease became one of research hotspots in the last ten years. IgG4-related Hashimoto's thyroiditis(HT) exhibits unique clinical pathological characteristics: serum-free thyroxine reduction and increases in thyroid peroxidase antibody and IgG4; massive IgG4-positive plasmocyte infiltration in tissues; significant matrix fibrosis; and severe degeneration of thyroid follicular epithelium. IgG4-related HT is a subtype of HT; it presents relatively good therapeutic effect after thyroxine treatment.Cortical hormones can be used for IgG4 HT patients who may suffer from hypothyroidism with significant thyroid injury during early stage to constrain immune injury. This thesis summarizes clinical and pathological histology of IgG4-related HT based on its characteristics.     

IgG4-Related Lung Disease Exhibiting the Invasion into the Diaphragm: A Case Report

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition which involves various organs. This is a very rare case of IgG4-related lung disease (IgG4-RLD) with the invasion into diaphragm. The patient was a 71-year-old man with a long-term exposure to asbestos who had a mass shadow in the left lower lung lobe, which was suspected to invade the left diaphragm on computed tomography (CT). Positron emission tomography (PET)/CT also presented an avid intake of fluorodeoxyglucose in the mass, which suspected lung cancer. Although bronchoscopic biopsy could not lead to the definite diagnosis, we performed left lower lobectomy combined with the resection of left diaphragm. The specimen showed the features of IgG4-RLD on pathology: the vein stenosis and fibrosis around the vein, the infiltration of IgG4-positive cells, and IgG cells to IgG4 cells ratio of 40%. Furthermore, there were inflammatory cells infiltrating to the diaphragm.     

Immunoglobulin G4-related periaortitis mimicking an intramural hematoma

Immunoglobulin G4 (IgG4)-related sclerosing disease in the cardiovascular system is a recently proposed disease entity, which is still unfamiliar to most clinicians. We present a case of IgG4-related periaortitis of the ascending aorta mimicking an intramural hematoma in the computed tomography (CT) scan, which led to an unnecessary surgery. IgG4-related periaortitis needs to be considered in the differential diagnosis in a patient with thickened aortic wall because the disease should be treated medically in light of its good response to steroid therapy.     

Abundant IgG4-positive plasma cell infiltration characterizes chronic sclerosing sialadenitis (Küttner's tumor)

Chronic sclerosing sialadenitis (CSS) is a cryptogenic tumor-like condition of the salivary gland(s). While immune-mediated processes are suspected in its pathogenesis, and CSS is occasionally reported to be associated with sclerosing pancreatitis, an IgG4-related disease, the exact immunopathologic processes of CSS remain speculative. In this study, we examined the clinicopathologic findings of CSS (12 cases) in comparison with sialolithiasis (8 cases) and Sjogren's syndrome (13 cases), and tried to clarify whether CSS is an IgG4-related disease or not. Submandibular gland(s) were affected in all cases of CSS. CSS cases could be divided into two types: 5 cases were associated with sclerosing lesions in extrasalivary glandular tissue (systemic type), while only salivary gland(s) were affected in the remaining 7 cases (localized type). In the former type, which showed male predominance, bilateral salivary glands were frequently affected, and eosinophilia and elevations of gamma-globulin and IgG in serum were frequently found. Histologically, all cases of CSS showed marked lymphoplasmacytic infiltration admixed with fibrosis and the destruction of glandular lobules. Obliterative phlebitis was found in the affected salivary glands in all cases of CSS. Immunohistochemically, the proportion of IgG4/IgG-positive plasma cells was more than 45% in CSS, while it was less than 5% in controls. The resemblance of the clinicopathologic features of CSS with those of sclerosing pancreatitis suggests the participation of a similar immunopathologic process with IgG4 disturbance in CSS. The abundance of IgG4-positive plasma cells in the lesions would be useful for distinguishing CSS from other forms of sialadenitis.