Pericardial Involvement in IgG4-related Disease.

To investigate the clinical and imaging features predicting the histopathological diagnosis of immunoglobulin G4 (IgG4)-related disease (IgG4RD) in patients with suspected IgG4RD on computed tomography (CT). We retrospectively reviewed the medical records of 178 patients with CT findings suspicious of IgG4RD from January 2015 to December 2017. Patients who underwent tissue biopsy were included to evaluate the association between patient characteristics and histopathological diagnosis of IgG4RD. The histopathological diagnosis was classified into IgG4RD and non-IgG4RD. Clinical, laboratory, and imaging features were compared between patients with IgG4RD and non-IgG4RD, and logistic regression analysis was performed to identify the predictors for histopathologically confirmed IgG4RD. Of the 103 patients with histopathologically proven diseases, 46 and 57 patients were classified as IgG4RD and non-IgG4RD, respectively. The median age was 64 years; 65% of patients were male. There were significant differences in sex (P = 0.035), fever (P = 0.039), serum IgG4 level (P < 0.001), renal involvement (P = 0.036), lacrimal or salivary glands involvement (P = 0.050), swelling pattern on CT (P = 0.001), and positron emission tomography (PET)-CT findings (P < 0.001) between patients with IgG4RD and non-IgG4RD. Multivariate analysis revealed elevated IgG4 level > 135 mg/dL (odds ratio [OR] = 5.418, P < 0.001), kidney involvement (OR = 6.170, P = 0.044), and the swelling feature on CT (OR = 4.301, P = 0.012) to be independent factors for histopathological diagnosis of IgG4RD. This study suggests that elevated IgG4 level, renal involvement, and swelling pattern on CT are associated with histopathological diagnosis of IgG4RD. The clinical and imaging features might help to decide further evaluation in patients with clinically suspected IgG4RD. Key Points • Computed tomography (CT) is not sufficient to discriminate between IgG4-related disease (IgG4RD) and non-IgG4RD conditions. • Histopathological diagnosis of IgG4RD is associated with elevated IgG4 level, renal involvement, and swelling pattern on CT. • Positron emission tomography-CT may be a useful diagnostic tool in patients with clinically suspected IgG4RD. >.

Background: To determine the diagnostic performance of elevated serum Immunoglobulin G4 (IgG4) in the diagnosis of autoimmune pancreatitis (AIP) and its ability to distinguish AIP from pancreatic cancer. Methods: We retrospectively analyzed serum IgG4 levels in 865 patients with suspected AIP. There were 57 patients with confirmed AIP, 146 with pancreatic cancer, 9 with idiopathic pancreatitis, 104 with acute pancreatitis, 106 with chronic pancreatic disease, and 443 with other pancreatic conditions, including benign enlargement of pancreas, abdominal pain, or obstructive jaundice. Results: The median serum IgG4 level was significantly greater in AIP patients than in patients with other pancreatic diseases (442.0 vs. 73.8 mg/dL, p＜0.001). Based on an IgG4 cutoff value of 132 mg/dL (determined by receiver operating curve analysis), the sensitivity, specificity, and positive predictive values in the differential diagnosis of AIP and pancreatic cancer were 94.7%, 78.8%, and 63.5% respectively. Use of an IgG4 cutoff of 132 mg/dL meant that 31 of 146 patients (21.2%) with pancreatic cancer had elevated serum IgG4, 3 of 57 patients with AIP (5.2%) did not have elevated serum IgG4, and the positive and negative predictive values for diagnosis of AIP were 63.5% and 97.5% respectively. Conclusion: Serum IgG4 concentrations were significantly greater in AIP patients than in patients with other pancreatic diseases. A serum concentration of IgG4 that is more than 2 times the upper limit of normal is highly suggestive of AIP, but does not totally rule out pancreatic cancer. Mild (＜2-fold) elevations in serum IgG4 were present in many subjects without AIP, including 16.4% of subjects with pancreatic cancer. IgG4 elevation in a patient with a low pretest probability of having AIP is likely to represent a false positive. However, the high predictive value and high positive likelihood ratio confirm the good performance of 2-fold cutoff value in the differential diagnosis of AIP and pancreatic cancer.Background: To determine the diagnostic performance of elevated serum Immunoglobulin G4 (IgG4) in the diagnosis of autoimmune pancreatitis (AIP) and its ability to distinguish AIP from pancreatic cancer. Methods: We retrospectively analyzed serum IgG4 levels in 865 patients with suspected AIP. There were 57 patients with confirmed AIP, 146 with pancreatic cancer, 9 with idiopathic pancreatitis, 104 with acute pancreatitis, 106 with chronic pancreatic disease, and 443 with other pancreatic conditions, including benign enlargement of pancreas, abdominal pain, or obstructive jaundice. Results: The median serum IgG4 level was significantly greater in AIP patients than in patients with other pancreatic diseases (442.0 vs. 73.8 mg/dL, p＜0.001). Based on an IgG4 cutoff value of 132 mg/dL (determined by receiver operating curve analysis), the sensitivity, specificity, and positive predictive values in the differential diagnosis of AIP and pancreatic cancer were 94.7%, 78.8%, and 63.5% respectively. Use of an IgG4 cutoff of 132 mg/dL meant that 31 of 146 patients (21.2%) with pancreatic cancer had elevated serum IgG4, 3 of 57 patients with AIP (5.2%) did not have elevated serum IgG4, and the positive and negative predictive values for diagnosis of AIP were 63.5% and 97.5% respectively. Conclusion: Serum IgG4 concentrations were significantly greater in AIP patients than in patients with other pancreatic diseases. A serum concentration of IgG4 that is more than 2 times the upper limit of normal is highly suggestive of AIP, but does not totally rule out pancreatic cancer. Mild (＜2-fold) elevations in serum IgG4 were present in many subjects without AIP, including 16.4% of subjects with pancreatic cancer. IgG4 elevation in a patient with a low pretest probability of having AIP is likely to represent a false positive. However, the high predictive value and high positive likelihood ratio confirm the good performance of 2-fold cutoff value in the differential diagnosis of AIP and pancreatic cancer.

Immunoglobulin G4 (IgG4) related disease is a newly recognized fibro inflammatory condition characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis and often but not always, elevated serum IgG4 concentrations. We present a 38 years old female complaining of headache which was progressive and unilateral resistant to analgesics. Diagnosed as a case of migraine started anti migraine treatment with no benefit, it was further complicated by 3rd, 4th and 6th Cranial Palsy. Radiological finding of opacification of left sphenoid sinus with extension to the left cavernous sinus along with bone erosion was noted. The biopsy from the sphenoid sinus mass showed a moderately dense lymphoplasmacytic infiltration accompanied with fibrosis. Immunostaining for IgG4 show significant increase in IgG4-positive plasma cells with IgG4-IgG ratio > 40% and >100 IgG4 positive plasma cells per High Field Focus (HPF), giving the diagnosis of IgG4 sinusitis. This is a rare case of IgG4 related disease in the sphenoid sinus. Clinical, radiological and therapeutic challenges are discussed.

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.

BACKGROUND Immunoglobulin G4 (IgG4)-related diseases (IgG4-RD) are systemic fibroinflammatory diseases that can develop asynchronously in multiple organs. IgG4-related kidney disease (IgG4-RKD) is generally characterized by tubulointerstitial nephritis but can also manifest as membranous nephropathy without tubulointerstitial nephritis. IgG4-related membranous nephropathy can present as a phenotype of systemic disorders, including autoimmune pancreatitis-associated diabetes mellitus; however, its clinical features remain unclear. CASE REPORT A 56-year-old Japanese man presented to our university hospital with bilateral edema of his lower legs. He had received a diagnosis of type 1 autoimmune pancreatitis and associated diabetes mellitus 16 months prior. He was successfully treated with oral glucocorticoids 25 mg/day of prednisolone as an initial dose, followed by titration down to a maintenance dose (5 mg/day), without recurrence of autoimmune pancreatitis. The pancreas showed atrophy and required basal-bolus insulin therapy owing to insulin insufficiency. Massive proteinuria and hypoalbuminemia with nephrotic syndrome on examination led to a renal biopsy to investigate the etiology and diagnosis of IgG4-RKD. Methylprednisolone and cyclosporine A were successfully administered to ameliorate the proteinuria and control systemic IgG4-RD with IgG4-related membranous nephropathy. CONCLUSIONS Ig4-RKD occurred despite maintenance treatment with prednisolone monotherapy and was controlled with methylprednisolone and cyclosporine A. Measurement of clinical parameters, including proteinuria, was important, and a renal biopsy finally established the diagnosis of IgG4-RKD. IgG4-RKD can present with progressive glomerular lesions and can be latent in cases diagnosed with diabetic kidney disease, particularly in patients with insulin insufficiency.

Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder that has been recognized to involve virtually any organ in the body and typically manifests mass-like lesions (tumefactive). Although initial reports of this disease (autoimmune pancreatitis [AIP]) were described in the Japanese population, it has since been reported worldwide. It is most commonly seen in adults of middle age or older, more often men than women. The pathogenesis of IgG4-RD is largely unknown, but genetic factors, microorganisms, and autoimmunity are thought to play important roles. Serum IgG4 concentration is elevated in the majority of patients with IgG4-RD but is a nonspecific finding. Characteristic histopathologic features include dense lymphoplasmacytic infiltrate, fibrosis (often in storiform pattern), and obliterative phlebitis. Lung involvement in IgG4-RD was first reported in 2004 in two patients with AIP and coexisting interstitial lung disease. Since then, a wide spectrum of intrathoracic involvement has been reported and includes not only parenchymal lung diseases but also pleural, airway, vascular, and mediastinal lesions. Thoracic involvement in IgG4-RD is often found incidentally during the workup of extrathoracic lesions but can sometimes be the presenting abnormality. The diagnosis of IgG4-RD requires correlation of clinical, laboratory, imaging, and histopathologic features. Glucocorticoids are the first-line therapy but other options including B cell depletion are being investigated. IgG4-RD is generally associated with an indolent clinical course and most patients improve with glucocorticoid therapy.

The number of patients with autoimmune pancreatitis who visited hospitals in Japan in 2007 was approximately 2709 (95% confidence interval; range 2540–3040). Because IgG4-related disease is a new clinical entity, there are no data with regard to its prevalence. To estimate the number of patients with IgG4-related disease in Japan, we randomly selected hospitals using stratification and asked them how many patients they had with IgG4-related disease in 2009. The number of patients with Mikulicz's disease, IgG4-related retroperitoneal fibrosis, IgG4-related renal disease, IgG4-related pulmonary disease, and IgG4-related lymphadenopathy who visited hospitals in Japan in 2009 was approximately 4304 (95% confidence interval; range 3360–5048), 272 (95% confidence interval; range 264–306), 57 (95% confidence interval; range 47–66), 354 (95% confidence interval; range 283–424), and 203 (95% confidence interval; range 187–240), respectively. The total number of patients with IgG4-related disease without autoimmune pancreatitis in Japan was approximately 5190 (95% confidence interval; range 4141–6084). The male : female ratio was 1 : 0.77, and the average of age of disease onset was 58.8 years. The total number of patients with IgG4-related disease in Japan in 2009, including autoimmune pancreatitis, was approximately 8000.

BACKGROUNDImmune checkpoint inhibitors have significantly improved survivals for an increasing range of malignancies but at the cost of several immune-related adverse events, the management of which can be challenging due to its mimicry of other autoimmune related disorders such as immunoglobulin G4 (IgG4) related disease when the pancreaticobiliary system is affected. Nivolumab, an IgG4 monoclonal antibody, has been associated with cholangitis and pancreatitis, however its association with IgG4 related disease has not been reported to date.CASE SUMMARYWe present a case of immune-related pancreatitis and cholangiopathy in a patient who completed treatment with nivolumab for anal squamous cell carcinoma. Patients IgG4 levels was normal on presentation. She responded to steroids but due to concerns for malignant biliary stricture, she opted for surgery, the pathology of which suggested IgG4 related disease.CONCLUSIONWe hypothesize this case of IgG4 related cholangitis and pancreatitis was likely triggered by nivolumab.

Background: Autoimmune pancreatitis (AIP) and IgG4-related cholangitis (IRC) are newly-recognized diseases. Reports in Thailand are scarce. Objective: To evaluate clinical presentations, other organ involvement (OOI), serology, radiologic, endoscopic features and treatment of AIP and IRC in one institute. Materials and Methods: Patients with AIP and IRC, who were diagnosed and followed-up at Siriraj Hospital during 2005 to 2016 were retrospectively reviewed. Results: There were 15 patients (75%) with AIP, 7 patients (37%) with IRC (4 isolated IRC and 3 IRC with AIP) and 1 (5%) with IgG4-related disease without AIP or IRC (sialadenitis and retroperitoneal fibrosis). Male to female ratio was 1.9: 1. Median age of onset was 64 years. Among the 15 AIP, all were type 1. Initial presentations were jaundice (60%), abdominal pain (40%), OOI (20%; sialadenitis, orbital pseudotumor), and weight loss (7%). Clinical manifestations during the course were jaundice (80%), abdominal pain (67%), weight loss (47%), OOI (47%; retroperitoneal fibrosis, IRC, sialadenitis, orbital pseudotumor, periurethral mass, lung nodules) and steatorrhea (7%). Serum IgG4 was elevated in all patients. Radiography showed diffuse type in 8 cases (53%), focal type in 5 (33%), and unknown in 2 (13%). More than half were suspicious of AIP before diagnosis. Corticosteroid was required in 10 patients (67%). Maintenance therapy was offered in 5 patients (33%) with steroid and azathioprine. Surgery was performed before diagnosis in 7 patients (47%). Spontaneous remission occurred in 4 patients (27%). Among the 7 IRC, initial presentations were jaundice (57%), weight loss (29%), abdominal pain (14%), prolonged fever (14%), and cholangitis (14%). Clinical manifestations during the course were jaundice (57%), abdominal pain (57%), weight loss (29%), recurrent cholangitis (14%) and retroperitoneal fibrosis (14%). Serum IgG4 was elevated in 5 patients (71%). Prednisolone was prescribed in 6 cases (86%). Five patients (71%) required azathioprine. Surgery was performed before diagnosis in 4 patients (57%). Conclusion: AIP and IRC were uncommon. The most common presentation was jaundice. All AIP were type 1 and more than half were diffuse type. OOI were common. Half of IRC had AIP. Approximately half of AIP/IRC patients underwent surgery before diagnosis. Corticosteroid was mainstay treatment. Keywords: Autoimmune pancreatitis, IgG4, Immunoglobulin G4, Sclerosing cholangitis, Thailand &nbsp;

Splanchnic vascular involvement and autoimmune pancreatitis

Constrictive Pericarditis Caused by IgG4-Related Disease Requiring Pericardiectomy After Partial Response to Corticosteroids

Objective By reporting rare immunoglobulin G4 (IgG4) related and reviewing the literature, the clinical manifestation and prognosis of this disease were studied. Methods One case of IgG4-associated was reported and and pericarditis were searched in PubMed, the corresponding literature related were retrospectively analyzed. Results Pericarditis caused by IgG4-related disease is not easy to diagnosis after the clinical physical examination and imaging examination, the diagnosis of the disease can be mostly confirmed by surgery and pathology or its good response to the hormone therapy. Conclusions Pericarditis caused by IgG4-related disease is a rare clinical disease. When encountered the patients with clinical features of pericardial inflammation, the possibility of this disease should be considered. Screening serum IgG4 level and other related diseases such as autoimmune pancreatitis should be helpful. As soon as the diagnosis of the IgG4 associated pericarditis, early treatment with corticosteroids may avoid surgery. Key words: Pericarditis; Immunoglobulin G4-related disease

Membranous nephropathy (MN) with tubulointerstitial nephritis (TIN) is an established manifestation of immunoglobulin G4 (IgG4)-related disease (IgG4-RD). A pathological feature aiming to distinguish between primary and secondary MN is the presence or absence of glomerular staining for phospholipase A2 receptor (PLA2R), respectively. Isolated MN without TIN has been rarely reported in the context of IgG4-RD. This case report describes a patient with a history of MN successfully treated with steroids and cyclophosphamide, who, 3 years later, presented with unexplained exacerbation of diabetes mellitus due to IgG4-related autoimmune pancreatitis. Pancreatitis was treated, and diabetes improved after treatment with steroids. Based on the presence of isolated IgG4 glomerular capillary deposits along with negative staining for PLA2R and the metachronous appearance of autoimmune pancreatitis, MN was retrospectively classified as secondary to IgG4-RD. Isolated IgG4-positive/PLA2R-negative MN without TIN can be a prodrome of IgG4-RD, reminiscent of MN secondary to neoplasms.

Immunoglobulin G4 (IgG4)-related disease is a relatively recently proposed clinical-pathologic entity that is characterized by fibro-inflammatory lesions rich in IgG4-positive plasma cells and, often but not always, elevated serum IgG4 concentrations. IgG4-related disease was recognized as a systemic disease in 2003, when extrapancreatic manifestations were identified in patients with autoimmune pancreatitis. Since then, the disease has been reported as affecting virtually every organ system and has been identified in the biliary tree, salivary and lacrimal glands, periorbital tissues, lungs, lymph nodes, thyroid gland, kidneys, prostate gland, testicles, breasts, and pituitary gland. Its pathogenesis is poorly understood, but findings are consistent with both an autoimmune and an allergic disorder. Although definitive diagnosis requires histopathologic analysis, imaging plays an important role in demonstrating infiltration and enlargement of involved organs. Because of the systemic nature of the disease, imaging workup of IgG4-related disease should always include whole-body examinations to detect multiorgan involvement. Patients often present with subacute development of a mass in or diffuse enlargement of the affected organ, sometimes mimicking a neoplastic process. In every anatomic location, several inflammatory and neoplastic entities must be considered in the differential diagnosis. Because IgG4-related disease usually shows a marked response to corticosteroid therapy, radiologists should be familiar with its clinical and imaging manifestations to avoid a delay in diagnosis and unnecessary surgical interventions.

We read with interest the recently published case report by Patel et al1 describing a patient who died suddenly and for whom immunohistochemistry of the autopsy sample demonstrated marked immunoglobulin G4 (IgG4)–positive lymphocytic infiltration in the coronary artery wall and other organs, including the kidney, pancreas, and lymph nodes.Coronary artery involvement of IgG4-related disease has been demonstrated in several previous case reports: coronary artery luminal narrowing, presumably of an atherosclerotic nature, may occur at the site of a coronary artery surrounded by thickened or tumefactive adventitia with IgG4-positve lymphocytic infiltration,2 as in the case described by Patel et al.1 On the other hand, several case reports have demonstrated only mild coronary artery luminal narrowing, regardless of the marked adventitial IgG4-positive cell infiltration.3,4The condition that was documented by Patel et al might be termed IgG4-related coronary artery disease; on the other hand, it should be noted that there have been no specific criteria for diagnosing IgG4-related coronary artery disease or IgG4-related cardiac disease until now. Histologic findings are an important and indispensable requirement for the diagnosis of IgG4-related diseases; however, there are several organs, such as the pancreas, in which IgG4-related disease does exist but for which the acquisition of antemortem tissue is difficult and/or impractical. Diagnostic criteria for IgG4-related disease in such organs are advocated; however, diagnostic criteria for IgG4-related cardiovascular disease have not been defined as yet.According to a previous report by Tanigawa et al2 and the report by Patel et al,1 there is no doubt that the cardiovascular system is a target of the multiorgan involvement of IgG4-related disease, and IgG4-related coronary artery disease may lead to a fatal outcome. On the other hand, considering that IgG4 may counteract the overactivated inflammatory process and that the severe IgG4-related pericoronary phenomenon is not necessarily accompanied by coronary artery stenosis or occlusion, we may need to further assess whether IgG4-related pathological conditions enhanced or, in reverse, ameliorated the coronary artery luminal stenosis and occlusion observed in their case. It is possible that the IgG4-positive cell infiltrate in the pericoronary artery may have, conversely, reduced the severity of the coronary artery disease. Nevertheless, whether IgG4-positive lymphocytic infiltrates promote or suppress coronary artery disease, such a histology, or elevated serum IgG4, may indicate a higher possibility of the presence of coronary artery lesions.In terms of the role of IgG4-positive lymphocytes in coronary atherogenesis, it would be of relevance to determine whether the thickened intima was positive for infiltration of such cells in the case of Patel et al.1 In general, B and T cells may reside in adventitial regions, but T cells (but not B cells), as well as monocytes/macrophages, infiltrate the inflamed intimal lesions.5 Although Patel et al1 demonstrated immunostaining of the wall of a coronary artery, we would be interested in IgG4 staining in specific parts of the coronary artery wall, including the adventitia, media, and intima, and would welcome comment on this point from the authors.We think that the case report by Patel et al1 has two important messages: first, coronary artery involvement can occur as a component of multiorgan IgG4-related disease; and second, IgG4-related coronary artery disease may be associated with a sudden fatal outcome, although whether IgG4-positive lymphocytes promote the coronary artery atherogenic process remains unclear.