Immunoglobulin G4-related autoimmune pancreatitis and sialadenitis: A case report

Immunoglobulin G4 (IgG4)-related disease is a rare systemic diseases. A 67-year-old male presented at our institution with mild upper abdominal pain and jaundice for 20 d. Laboratory results revealed high levels of IgG4 (15.4 g/L, range: 0.08-1.4 g/L). Computed tomography (CT) showed significant enlargement of the entire pancreas and a capsule-like low-density rim surrounding the whole pancreas. Positron emission tomography/CT revealed increased uneven metabolism of the entire pancreas. Both magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed stenosis of the distal common bile duct and proximal main pancreatic duct, and dilation of the proximal common bile duct and extra- and intra-hepatic bile ducts. He was diagnosed with IgG4-related autoimmune pancreatitis. The patient was treated with prednisone for 14 mo. The patient responded well to prednisone but upon cessation of the corticosteroid developed enlargement of the submandibular gland. The patient’s serum IgG4 was elevated at 23.9 g/L. It is important to maintain treatment, so the patient was again treated with prednisone and had a good response. Follow-up of IgG4-related disease is thus necessary.     

Immunoglobulin G4-related gastrointestinal diseases,are they immunoglobulin G4-related diseases?

In immunoglobulin G4(IgG4)-related disease(RD),organ enlargement or nodular lesions consisting of abundant infiltration of lymphocytes and IgG4-positive plasma cells and fibrosis are seen in various organs.Although infiltration of many IgG4-positive plasma cells is detected in the gastric and colonic mucosa and major duodenal papilla of patients with autoimmune pancreatitis,it cannot be diagnosed as a gastrointestinal lesion involved in IgG4-RD,because none of the following is observed in these lesions:a mass-like formation;dense fibrosis;or obliterative phlebitis.Based on our review of the literature,there appear to be two types of IgG4-related gastrointestinal disease.One is a gastrointestinal lesion showing marked thickening of the wall of the esophagus and stomach,consisting of dense fibrosis with abundant infiltration of IgG4-positive plasma cells,which usually show submucosal spreading.The other is an IgG4-related pseudotumor occurring in gastrointestinal regions such as the stomach,colon,and major duodenal papilla,showing polypoid or mass-like lesions.Most solitary IgG4-related gastrointestinal lesions that are not associated with other IgG4-RD appear to be difficult to diagnose.It is of utmost importance to rule out malignancy.However,these lesions may respond to steroid therapy.To avoid unnecessary resection,IgG4-related gastrointestinal diseases should be considered in the differential diagnosis.     

IgG4-related disease manifesting as an acute gastric-pericardial fistula

Ig G4-related disease is a recently recognized entity linked initially to autoimmune pancreatitis and has been subsequently described in nearly every organ system. Men over the age of 50 represent the most affected demographic group and a comprehensive set of diagnostic criteria has been developed to aid treating clinicians. Though elevated levels of Ig G4 in the serum are suggestive of the disease, definitive diagnosis is made on histopathology. Treatment is tailored to the clinical presentation with corticosteroid therapy known to have proven efficacy. Gastric manifestations of the Ig G4-related disease primarily come in two varieties, notably chronic ulceration or pseudotumor formation. Autoimmune pancreatitis conveys increased risk for Ig G4-related disease of the stomach, which is independent of Helicobacter pylori status. In this case report, we present an acute gastric-pericardial fistula secondary to Ig G4-related disease that required urgent operative management. To our knowledge, this is the first report in the medical literature describing this complication of Ig G4-related disease.     

IgG4-related sclerosing disease

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

Gastric Calcifying Fibrous Tumor: A Case of Suspected Immunoglobulin G4-related Gastric Disease

Gastrointestinal lesions resulting from immunoglobulin G4-related disease are classified into two types: One is a gastrointestinal lesion showing marked thickening of the wall, and the other is an IgG4-related pseudotumor. We report the case of a woman with gastric calcifying fibrous tumor undergoing endoscopic resection that contained 62 IgG4+ plasma cells per high-power field and an IgG4-to-IgG ratio of 41% in lesional plasma cells, which shared clinical and histopathological features associated with gastric IgG4-related pseudotumor. So, we postulate that calcifying fibrous tumor as part of the spectrum of IgG4-related disease might be the unifying concept with IgG4-related pseudotumor. Meanwhile, the patient had coexistent autoimmune diseases, including autoimmune atrophic gastritis, Hashimoto''s thyroiditis, and possible primary biliary cirrhosis. The clinical follow-up evaluation was uneventful.     

Significance of peripheral eosinophilia for diagnosis of IgG4-related disease in subjects with elevated serum IgG4 levels

ObjectivesIn this study, we aim to assess the diagnostic utility of elevated serum IgG4 (sIgG4) concentration alone and in combination with peripheral eosinophilia (PE) for IgG4-related disease (IgG4-RD).MethodsFrom the Mayo Clinic, Rochester electronic medical record database we identified 409 patients with above normal levels of sIgG4 (reference range 121–140 mg/dL) who had sIgG4 measured to differentiate IgG4-RD from another disease.ResultsAmong 409 patients with any elevation in sIgG4 levels, 129 (31.5%) had a definite diagnosis of IgG4-RD. The prevalence of PE increased with increasing sIgG4 levels and was more likely to be seen in subjects with IgG4-RD vs. non-IgG4-RD at ≥1X (n = 35/120, 29.2% vs. n = 23/258, 8.9%; p < 0.001), ≥2X (n = 23/64, 35.9% vs. n = 5/54,9.3%; p = 0.001) and ≥3X (n = 18/42, 42.9% vs. n = 0/9, 0%; p = 0.015) of sIgG4 upper limit of normal (ULN), respectively. After adjusting for gender and age, sIgG4 levels ≥ 2X ULN with PE as a predictor, had a higher positive predictive value in predicting IgG4-RD (72.2% vs. 65.9%) with an Area Under the Receiver Operatic Characteristic Curve (AUC) of 0.776, compared to sIgG4 ≥ 2X ULN without PE predictor (AUC = 0.74), p = 0.016. PE, sIgG4≥2X ULN, male gender, and age independently predicted the disease with odds ratio of 4.89 (95% CI:2.51–9.54), 3.78 (95% CI:2.27–6.28), 2.78 (95% CI:1.55–4.97), and 1.03 (95% CI:1.02–1.05), respectively.ConclusionEven in subjects in whom IgG4-RD is suspected, only a minority (∼30%) with elevated sIgG4 levels have IgG4-RD. sIgG4 by itself is more specific at higher levels, though never diagnostic. PE increases with increasing sIgG4 and adds diagnostic value at higher sIgG4 levels.     

Immunoglobulin G4 (IgG4)-related autoimmune hepatitis and IgG4-hepatopathy: A histopathological and clinical perspective

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic inflammatory disease that simultaneously or consecutively involves multiple organs of the body. It is characterized by elevated serum IgG4 levels and massive infiltration of IgG4⁺ plasma cells in the damaged tissues. IgG4-related autoimmune hepatitis (IgG4-AIH) and IgG4-hepatopathy are relatively new entities that have been proposed as a phenotype of IgG4-RD in the liver. Immunoglobulin G4-AIH is defined as a disorder with serological, histopathological, and clinical features of both IgG4-RD and AIH, simultaneously satisfying the diagnostic criteria of both classical AIH and IgG4-RD. Although there are several case reports and studies of IgG4-AIH among the published works, no consensus regarding the histopathological characteristics of IgG4-AIH has been established, and its clinical implications remain obscure. Immunoglobulin G4-hepatopathy is defined as a comorbidity of IgG4-RD in the liver, and patients not meeting the diagnostic criteria of classical AIH could be diagnosed with IgG4-hepatopathy. Numerous issues regarding these diseases, especially their epidemiology, histopathological and clinical characteristics, and treatment response to corticosteroids, remain unsolved, and need to be determined to establish the disease concepts of IgG4-AIH and IgG4-hepathopathy.     

Diagnóstico diferencial entre compromiso pancreático en enfermedad relacionada con IgG4 y cáncer de páncreas

IgG4-related disease is a systemic disorder characterised by diffuse or tumoural inflammatory lesions. It can mimic pancreatic cancer, leading to errors in diagnosis and treatment increasing rates of morbidity and mortality in patients. The aim of this review is to take a differential diagnostic approach to these two entities using epidemiology, clinical and laboratory findings, imaging and histopathology.     

Roles of plasmablasts in IgG4-related disease and various immune-based diseases

IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease with multiple organ disorders. Recently, in IgG4-RD, increased circulating plasmablasts have been found. The subsets of plasmablasts are negative for RP105 (CD180). A large population of B cells lacking RP105 (RP105-negative B cells) are found in patients with active with systemic lupus erythematosus and other systemic autoimmune diseases, including dermatomyositis, and Sjögren’s syndrome. In other conditions, such as neuromyelitis optica, Kawasaki’s disease, primary biliary cirrhosis and aging, RP105 expression on B cells and monocytes also alters. We review the basic science and clinical significance of RP105-negative B cells including plasmablasts in various immune-based diseases. RP105-negative B cells, especially plasmablasts, play crucial roles in both systemic and organ-specific autoimmune and inflammatory disorders.     

Immunoglobulin G4-related lung disease: A disease with many different faces

Immunoglobulin (Ig) G4-related lung disease is a fibroinflammatory entity that presents in protean ways. Diagnostically, IgG4-related lung disease requires a high clinical index of suspicion complemented by elevated serum IgG4 levels and/or biopsy that shows the characteristic pathological features. The disease is almost always responsive to systemic corticosteroids. However, relapse is common following their discontinuation. The authors present three cases to highlight the diverse clinical features, and to illustrate the diagnostic and therapeutic approaches to this disease.     

Efficacy and safety of rituximab for IgG4-related pancreato-biliary disease: A systematic review and meta-analysis

BackgroundType I autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC) belong to the IgG4-related disease (IgG4-RD) spectrum. Both entities respond to glucocorticoids, but iatrogenic toxicity associated with prolonged steroid therapy and relapse represent relevant clinical concerns in the long-term. Rituximab is increasingly used as an effective alternative strategy to induce remission but data regarding the safety and efficacy of B-cell depletion therapy for pancreato-biliary involvement of IgG4-RD are limited. We performed a systematic review and meta-analysis to estimate the rate of remission, flare, and adverse events (AEs) occurring in pancreato-biliary IgG4-RD following rituximab treatment.MethodsThe MEDLINE, SCOPUS, and EMBASE databases were searched from inception to December 2020 to identify studies reporting the outcomes of IgG4-related pancreato-biliary disease after treatment with rituximab. Studies involving ≥2 patients were selected. In case of duplicated studies, the most recent or the one with the biggest N were chosen. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled effects were calculated using a random-effect model and expressed in terms of pooled remission, relapse, and AEs rates.ResultsSeven cohort studies met inclusion criteria and 101 patients were included. Reasons for rituximab administration were new disease onset (18.5%), disease flare after glucocorticoids (63.5%), and glucocorticoids intolerance (17.9%). The median follow-up time was 19 months. The pooled rate of complete response at 6 months was 88.9% (95%CI 80.5–93.9) with no heterogeneity (I² = 0%). The pooled estimate of relapse rate was 21% (95%CI 10.5–40.3) with moderate heterogeneity (I² = 51%). A higher rate of relapse (35.9%, 95%CI 17.3–60.1) was reported in studies including patients with multiorgan involvement (OOI). The median time to relapse was 10 months. The pooled estimate of rituximab-related AEs was 25% (95%CI 8.8–53) with substantial heterogeneity (I² = 73.6%). No publication bias was observed.ConclusionTreatment of IgG4-related pancreato-biliary disease with rituximab is associated with high remission rate, a higher relapse rate in the presence of OOI, and limited AEs. Randomized controlled trials with adequate power are needed to confirm these findings.     

Immunoglobulin G4-related Pleuritis Complicated with Minimal Change Disease

A 70-year-old woman with bilateral pleural effusion and respiratory failure was admitted to our hospital. Nephrotic syndrome due to minimal change disease had been diagnosed four months before admission. Because blood tests and a pleural fluid analysis did not reveal the etiology of her condition, we performed a video-assisted thoracoscopic pleural biopsy. No specific thoracoscopic findings were noted. The pathological findings revealed an increase in immunoglobulin G4 (IgG4)-positive cells; IgG4-related pleuritis was diagnosed. Her pleuritis improved with oral corticosteroid therapy. A further investigation was performed on previous kidney samples; however, the etiology of the nephrotic syndrome was not IgG4-related disease but minimal change disease.     

Intraductal papillary mucinous neoplasm of the pancreas and IgG4-related disease: A coincidental association

Background/aimsCoexistence of autoimmune pancreatitis (AIP) and pancreatic cancer, elevation of serum IgG4 levels in pancreatic cancer patients, and infiltration of IgG4-positive plasma cells in peritumorous pancreatitis have been described in a few reports. This study examined the relationship between intraductal papillary mucinous neoplasm (IPMN) of the pancreas and peritumorous IgG4-positive lymphoplasmacytic infiltrates.MethodsSerum IgG4 levels were measured in 54 patients with IPMN (median 70 years, 26 males and 28 females; 13 main duct type and 41 branch duct type). Histological findings focusing on dense lymphoplasmacytic infiltration, storiform fibrosis, and obliterative phlebitis were reviewed, and immunostaining with IgG4 and IgG was performed in 23 surgically resected IPMN cases (18 main duct type and 5 branch duct type). The presence of IgG4-positive plasma cells >10/hpf and an IgG4-positive/IgG-positive plasma cell ratio >40% were considered significant.ResultsSerum IgG4 levels were elevated in 2 (4%) IPMN patients. Significant infiltration of IgG4-positive plasma cells was detected in 4 IPMN cases (17%). The IgG4-positive/IgG-positive plasma cell ratio was >40% in all 4 cases. In one case with a markedly elevated serum IgG4 level (624 mg/dL), typical lymphoplasmacytic sclerosing pancreatitis (AIP type 1) lesions surrounded the whole IPMN. In the 3 other cases, infiltration of IgG4-positive plasma cells with fibrosis was focally detected mainly in the periductal area around the IPMN.ConclusionsIn a few patients with IPMNs, IgG4-positive plasma cell infiltration can occur in the peritumorous area. The association of an IPMN with AIP type 1-like changes seems to be exceptional and coincidental.     

Autoimmune hepatitis and IgG4-related disease

IgG4-related disease(IgG4-RD) is a chronic-fibroinflammatory disorder affecting a wide range of organs. Elevation of serum IgG4 concentrations and abundant infiltration of IgG4-expressing plasma cells are key diagnostic features of this autoimmune disease. Although common organ involvement of IgG4-RD includes the salivary glands, pancreas, and bile duct, hepatic involvement is less well established. Recently, five studies identified a subtype of autoimmune hepatitis(AIH), called IgG4-associated AIH(IgG4-AIH). IgG4-AIH is diagnosed based on significant accumulation of IgG4-expressing plasmacytes in the liver in patients who met the diagnostic criteria for classical AIH. Although four of the five reports regarded IgG4-AIH based on hepatic accumulation of IgG4-positive cells alone, one report diagnosed IgG4-AIH based on both hepatic accumulation of IgG4-positive cells and elevated serum concentrations of IgG4. IgG4-AIH diagnosed based on the latter criteria may be a hepatic manifestation of IgG4-RD whereas IgG4-AIH diagnosed based on the former criteria may be a subtype of AIH. In this review article, we summarize and discuss clinicopathological features of IgG4-AIH.     

Isolated intrapancreatic Ig G4-related sclerosing cholangitis

Immunoglobulin G4-related sclerosing cholangitis(Ig G4-SC) is frequently associated with type 1 autoimmune pancreatitis(AIP). Association with AIP can be utilized in the diagnosis of Ig G4-SC. However, some cases of Ig G4-SC are isolated from AIP, which complicates the diagnosis. Most of the reported cases of isolated Ig G4-SC displayed hilar biliary strictures, whereas isolated Ig G4-SC with intrapancreatic biliary stricture is very rare. Recently, we have encountered 5 isolated intrapancreatic Ig G4-SC cases that were not associated with AIP, three of which were pathologically investigated after surgical operation. They all were males with a mean age of 74.2 years. The pancreas was not enlarged in any of these cases. No irregular narrowing of the main pancreatic duct was found. Bile duct wall thickening in lesions without luminal stenosis was detected by abdominal computed tomography in all five cases, by endoscopic ultrasonography in two out of four cases and by intraductal ultrasonography in all three cases. In three cases, serum Ig G4 levels were within the normal limits. The mean serum Ig G4 level measured before surgery was 202.1 mg/d L(4 cases). Isolated intrapancreatic Ig G4-SC is difficult to diagnose, especially if the Ig G4 level remains normal. Thus, this type of Ig G4-SC should be suspected in addition to cholangiocarcinoma and pancreatic cancer if stenosis of intrapancreatic bile duct is present.     

IgG4相关性疾病

IgG4相关性疾病是一种与IgG4淋巴细胞密切相关的慢性、系统性疾病,该类疾病以血清IgG4水平升高以及IgG4阳性细胞浸润多种器官和组织为特征,常见受累器官包括泪腺、胰腺和腹膜后间隙等,累及的器官或组织由于慢性炎症及纤维化进程可导致弥漫性肿大。该类疾病对皮质激素治疗反应良好。