Normal Serum IgG4 Research Articles

Treatment Response to Idiopathic Retroperitoneal Fibrosis-associated Hydronephrosis With a Focus on IgG4/IgG3 Serum Concentration Ratio.

Hydronephrosis, a common complication of idiopathic retroperitoneal fibrosis (iRPF), may lead to poor renal outcomes unless resolved in a timely manner IgG4-related diseases characterized by elevated serum IgG4 levels are responsible for a few iRPF cases However, the underlying immunologic features of most iRPF cases have not been clearly defined, and these cases exhibit varied responses to medical treatment Thus, we investigated the predictive factors for hydronephrosis-associated outcomes among iRPF patients. We retrospectively included 18 iRPF patients with hydronephrosis in a tertiary referral hospital from 2012 to 2019 Hydronephrosis improvement was assessed on images taken 6 months after diagnosis Categorical variables were compared using chi-square or Fisher's exact test Continuous variables were compared using Mann-Whitney U-test. On follow-up images, 8 patients (444%) showed an improvement in hydronephrosis Patients with improvement more frequently had reverse serum IgG4/IgG3 ratio (875% vs 30%, p=0025), abdominal aorta involvement (875% vs 30%, p=0025) and glucocorticoid treatment administration (875% vs 30%, p=0025) than those without improvement The proportion of elevated serum IgG4 level did not differ between the two groups Even in the 14 cases with normal serum IgG4 levels, reverse serum IgG4/IgG3 ratio was more frequently observed in patients with improvement than in those without improvement (833% vs 125%, p=0026). The reverse serum IgG4/IgG3 ratio was associated with hydronephrosis improvement in iRPF patients, suggesting it to be a suitable serologic marker for predicting favourable responses to glucocorticoid treatment.

S1477 A Spy Took a Bite to Get the Dx Right - A Case of Idiopathic Pancreatitis

INTRODUCTION: Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis that is infrequently recognized and is characterized clinically by frequent presentations with obstructive jaundice. Serum IgG4 testing as a means to “rule out” IgG4 related disease may not be as helpful as initially thought and may lead to inappropriate lack of diagnosis if suspicion is low. CASE DESCRIPTION/METHODS: A 40-year-old white male with GERD, chronic portal vein thrombosis, history of alcoholism, and chronic pancreatitis (since 2015) presents with nausea, vomiting, chills, and epigastric pain radiating to the back. He has had 8 episodes in the last year and required biliary stenting for multiple biliary strictures. He denied fever, dyspnea, chest pain, hematemesis, melena, alcohol use, scorpion sting, and trauma. Labs were significant for TRG 172, Ca 8.6, Lipase 239, AST 34, ALT 37. CT of the abdomen showed acute on chronic pancreatitis with a stable biliary stent. Previous workup for pancreatitis included normal TRG and calcium levels, lack of cholelithiasis, no inciting medications or infection, and serum IgG4 level of 7.3 (normal: 2-120). After admission, lipase increased to 1321 with worsening AST/ALT and bilirubin concerning for obstruction prompting Magnetic Resonance Cholangiopancreatography (MRCP). MRCP demonstrated extensive retroperitoneal inflammation and obstruction of the biliary stent. Endoscopic retrograde cholangiopancreatography (ERCP) with SpyGlass direct visualization revealed an occluded biliary stent, multiple strictures, and exophytic tissue in the lower common bile duct which was biopsied with SpyBite. The strictures were dilated, the stent was exchanged, and the biopsies were sent for pathology. Pathology returned negative for malignancy but stained positive for IgG4 and the patient was initiated on systemic steroid therapy. DISCUSSION: With recurrent pancreatitis, classic histological findings, biliary strictures, cholangitis, and improvement with steroids in the setting of normal serum IgG4 levels; this complex patient represents a challenging case of type 1 AIP. A 2016 meta-analysis found that serum IgG4 had 87% sensitivity 83% specificity for IgG4-RD (1). Other studies suggest that many (as much as 33%) patients with biopsy-proven IgG4-RD have normal serum IgG4 (2). With these findings, we believe it is imperative that others give further consideration to tissue sampling in similar patients with difficult to define pancreatitis.Figure 1.: MRI Abd w CBD stent mass and pneumobilia.Figure 2.: Mass in CBD.Figure 3.: IgG4 stain positive tissue from CBD mass.

S1782 IgG4 Colitis and Infliximab Therapy

INTRODUCTION: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition. It is characterized by increased serum levels of IgG4 and tissue infiltration by IgG4 cells. It can involve multiple organs and if untreated the disease can lead to fibrosis and irreversible organ damage. IgG4-RD has mostly been described in adults and it's exact prevalence in pediatrics is unknown. We report a pediatric case of IgG4-positive sclerosing colitis who had dramatic response to Infliximab therapy. CASE DESCRIPTION/METHODS: 6 year old adopted male who was previously healthy presented to ER with acute onset of severe abdominal pain and fever. He was febrile with severe RLQ tenderness, guarding and minimal bowel sounds. Labs showed elevated WBC and CRP. US abdomen study did not visualize appendix. Subsequent MRI abdomen showed descending colitis with no evidence of obstruction, abscess or acute appendicitis. He soon developed abdominal distension and multiple episodes of bilious emesis. AXR obtained showed dilated loops of small bowel concerning for partial SBO, requiring NGT decompression. Stool studies including C. Diff returned negative. As he developed a SIRS picture with worsening abdominal distension, stat CT abdomen obtained showed bowel dilation without an obvious transition zone or pneumatosis but thickening of terminal ileum and left colon. Due to patient's worsening clinical picture, there was concern for possible compromised bowel or distal bowel obstruction not diagnosed by imaging, hence he underwent diagnostic ex-laparoscopy which showed thickening and inflammation of the left colon leading to segmental left colon resection and descending colostomy. Biopsies were taken and immunostaining was concerning for an IgG4 sclerosis colitis. Serum IgG4 level was elevated at 202. Patient was started on steroids followed by Infliximab as maintenance therapy. Repeat EGD/Colonoscopy prior to colostomy reversal showed normal biopsies and immunostaining. He responded well to Infliximab therapy with subsequent normal serum IgG4 levels. DISCUSSION: The pathogenesis of IgG4-RD remains incompletely understood. Study shows that small subset of patients with IBD can be characterized by high levels of serum and mucosal IgG4. These patients are generally prone to more severe and extensive lesions suggesting that high level of IgG4 may be a biomarker for a new subtype of IBD. The current literature in this area is sparse. Our case showed positive response to Infliximab therapy in IgG4 positive colitis.

Identification of serum IFN-\u03b1 and IL-33 as novel biomarkers for type 1 autoimmune pancreatitis and IgG4-related disease

IgG4-related disease (IgG4-RD) is a multi-organ autoimmune disease characterized by elevated serum IgG4 concentration. Although serum IgG4 concentration is widely used as a biomarker for IgG4-RD and type 1 autoimmune pancreatitis (AIP), a pancreatic manifestation of IgG4-RD, a significant number of patients have normal serum IgG4 levels, even in the active phase of the disease. Recently, we reported that the development of experimental AIP and human type 1 AIP is associated with increased expression of IFN-α and IL-33 in the pancreas. In this study, we assessed the utility of serum IFN-α and IL-33 levels as biomarkers for type 1 AIP and IgG4-RD. Serum IFN-α and IL-33 concentrations in patients who met the diagnostic criteria for definite type 1 AIP and/or IgG4-RD were significantly higher than in those with chronic pancreatitis or in healthy controls. Strong correlations between serum IFN-α, IL-33, and IgG4 concentrations were observed. Diagnostic performance of serum IFN-α and IL-33 concentrations as markers of type 1 AIP and/or IgG4-RD was comparable to that of serum IgG4 concentration, as calculated by the receiver operating characteristic curve analysis. Induction of remission by prednisolone treatment markedly decreased the serum concentration of these cytokines. We conclude that serum IFN-α and IL-33 concentrations can be useful as biomarkers for type 1 AIP and IgG4-RD.

Experience from the first UK inter-regional specialist multidisciplinary meeting in the diagnosis and management of IgG4-related disease

Immunoglobulin G4-related disease (IgG4-RD) is a complex multisystem fibro-inflammatory disorder, requiring diagnostic differentiation from malignancy and other immune-mediated conditions, and careful management to minimise glucocorticoid-induced toxicity and prevent progressive organ dysfunction. We describe the experience of the first inter-regional specialist IgG4-RD multidisciplinary team meeting (MDM) incorporating a broad range of generalists and specialists, held 6-weekly via web-link between Oxford University Hospitals NHS Foundation Trust and University College London Hospitals NHS Foundation Trust. Over 3 years, there were 206 discussions on 156 patients. Of these, 97 (62%) were considered to have definite or possible IgG4-RD; 67% had multi-organ involvement and 23% had a normal serum IgG4. The average number of specialist opinions sought prior to MDM was four per patient. Management was changed in the majority of patients (74%) with the treatment escalation recommended in 61 cases, including 19 for rituximab. Challenges arose from delays and misdiagnosis, cross-specialty presentation and the management of sub-clinical disease. Our cross-discipline IgG4-RD MDM enabled important diagnostic and management decisions in this complex multisystem disorder, and can be used as a model for other centres in the UK.

P119 Characteristics and treatment of fibrosclerosing orbital inflammatory disease

Abstract Background Orbital inflammatory disease (OID) encompasses a group of disorders which affect the orbit and neighbouring areas. Several multi-system inflammatory diseases including small vessel vascuilitides, Sarcoidosis and IgG4 disease can manifest as an OID. Treatment generally includes steroid therapy in combination with conventional immunosuppressant’s, cyclophosphamide or rituximab. Herewith we describe a series of non-vasculitic, fibroinflammatory OID. Methods We retrospectively reviewed records of 5 patients referred to rheumatology with inflammatory OID after malignancy, infection and Graves’ ophthalmopathy were excluded. General demographics, histology, MRI and treatment responses were reviewed. Results Patients were generally female (4:1) and of a young age (range 33-54). Proptosis and diplopia were the key symptoms with occasional sino-nasal symptoms. Inflammatory markers on presentation were marginally raised (CRP mean 11, ESR mean 37). All patients were negative for autoantibodies and had normal serum IgG4 levels. MRI showed fibrotic mass lesions in all cases with bone erosion/ destruction in 2 cases. Biopsy showed fibrosclerosis mixed with chronic inflammatory cells. 3 cases stained positive for IgG4 cells but only one of them achieved diagnostic levels (case 3). All patients were initially treated with high dose steroids (prednisolone 1mg/kg or IV methylprednisolone (MP)) with either methotrexate or cyclophosphamide (1g EUVAS protocol). Highly resistant cases were treated with rituximab (total 2g). There was a good clinical response to treatment in all cases but in 4 patients residual fibrosis persisted on follow-up MRI (Table 1). Conclusion We describe a series of fibrosclerosing OID with histology like IgG4 disease, but with normal serum IgG4 levels and negative tissue immunofluorescence (IF) in some cases. Most cases will respond well to steroids and second-line therapy, but residual fibrosis may persist with mild clinical sequelae. Early recognition and intensive therapy may minimise fibrotic complications. Disclosures V. Thanopoulou None. A. Weller None. E. Nigar None. J. Marais None. V. Lee None. B. Marjanovic None. A. Ahmed None. I. Balasundaram None. S. Hamdulay None.

P1323 From a suspicion of pulmonary arterial hypertension to a rare form of Takayasu disease

Abstract A 27-year-old female with a history of glomerulonephritis,with diagnosed systemic lupus and retroperitoneal fibrosis was admitted due to fast worsening dyspnoea(NYHA class IV) over the prior four weeks with suspicion for PA hypertension. In 2015, retroperitoneal fibrosis was diagnosed based on MR examination. With the methylprednisolone treatment a regression of changes was obtained. The patient was chronically treated with prednisone 7.5mg/day and mycophenolate mofetil 2g/d. When admitted to the ward, the patient was in a severe condition, with symptoms of resting dyspnea and blood oxygen saturation up to 80%. A loud systolic murmur was audible over the entire chest. In laboratory tests, the NT-proBNP values (11,000 pg/ml) were significantly elevated, arterial blood gases showed tendency to alkalosis, hypoxemia (PO2 45mmHg)with hypocapnia. Parameters of inflammation were moderately elevated (CRP 25mg/l, WBC 12,000/ul), with normal serum IgG4 concentrations. In TTE, significant dilatation of the right ventricle with left chamber compression were observed. Tricuspid ring dilation with no leaflets coaptation and a severe tricuspid regurgitation (Vmax 5m/s, RVSP 100mmHg) were found. In addition, the critical proximal pulmonary artery (PA) stenosis was revealed (left PA Vmax 3.3m/s, Pmax 42mmHg, right PA Vmax 5.2 m/s, Pmax 110mmHg). Angio-CT confirmed critical proximal constriction of both PAs with a flow channelup to 4 mm. Based on angio-CT and cardiac MR study the inflammatory etiology of stenoses was suspected and an empiric diagnosis of the Takayahu disease of pulmonary arteries was made. The patient was qualified for conservative treatment using prednisone and cyclophosphamide. Over the course of two months,2.8 g of cyclophosphamide were administered intravenously in three cycles with good response to the treatment. It resulted in regression of dyspnea and a improvement in exercise tolerance - to the NYHA class II, normalization of saturation. Laboratory tests showed reduction of NT-proBNP (1300 pg/ml). Control TTE revealed reduction in the size of the right ventricle and regression of PAs stenoses (left PA 11mm, right PA 7mm), also reduction of systolic flow gradients (left PA Vmax 3.1 m / s, Pmax 39 mmHg, right PA 4.1 m/s, Pmax 68 mmHg). Because of the significant improvement in patient’s condition,it was decided to continue the treatment. Legend for the Fig.1 A angio-CT, critical proximal constriction of both PA B TTE, parasternal short axis view, imflammatory infiltration C TTE, continuous wave doppler, flow velocity pattern in the PA stenosis D TTE PLAX, dilatation of the right ventricle with left chamber compression fig. 1 Abstract P1323 Figure. Fig.1 artety pulmonary stenosis

Clinical Characteristics of 76 Patients with IgG4-Related Hypophysitis: A Systematic Literature Review

Background IgG4-related hypophysitis (IgG4-RH) is a rare disease, and its prevalence remains unclear. In recent years, an increasing number of cases have been reported because of the increasing recognition of this disease. We aimed to summarize case reports of IgG4-RH and outline the clinical features and outcomes. Methods We performed PubMed search of articles using the search terms “hypophysitis [AND] IgG4.” Consequently, only 54 English articles (76 cases) met Leporati's diagnostic criteria. Results Of the 76 cases, the ratio of men to women was 1.5 : 1, and the age at diagnosis was 54.1 ± 17.8 years. The median IgG4 concentration was 405.0 mg/dl. Anterior hypopituitarism, isolated central diabetes insipidus, and panhypopituitarism were observed in 14 (18.4%), 12 (15.8%), and 44 (57.9%) cases, respectively. The sequence of anterior hormone deficiency was as follows: gonadotropin (68.4%), ACTH (63.2%), TSH (59.2%), GH (48.7%), and prolactin (42.1%). The median number of involved organs was 1.5, and the lung (18.4%), retroperitoneum (17.1%), kidney (15.8%), submandibular glands (14.5%), and pancreas (13.2%) were the common involved organs. Elevated IgG4 concentration and normal IgG4 level were in 42 (76.4%) and 13 (23.6%) cases, respectively. Patients with elevated serum IgG4 concentration were older (60.9 ± 14.3 vs 45.6 ± 17.4, p=0.001) and male-prone (78.6% vs 40.4%, p=0.003) and had a susceptibility of multiple organ involvement (78.6% vs 35.0%, p=0.001) compared to those with normal serum IgG4 levels. Males were older at disease onset (61.5 ± 12.6 vs 42.9 ± 18.8, p < 0.001) and had a higher IgG4 concentration (425.0 vs 152.5, p=0.029) and a greater number of involved organs (2.0 vs 0.0, p=0.001), while isolated hypophysitis was more prominent in female (63.3% vs 26.1%, p=0.001). Conclusion In this review, we found that there were different characteristics between different genders. Patients with elevated serum IgG4 level in terms of some clinical features were also different from those with normal serum IgG4 level. However, the data in this review were limited by bias and confounding. Further clinical studies with larger sample sizes are warranted.

Native T1 mapping of autoimmune pancreatitis as a quantitative outcome surrogate

To investigate the ability of T1 mapping to visualize and quantify the short-term and mid-term response of autoimmune pancreatitis (AIP) to corticosteroid treatment (CST) and to correlate T1 relaxation time of the pancreas with clinical status and serum IgG4 level. The institutional review board approved this prospective study, and all patients provided written informed consent. Pancreatic MRI including native T1 mapping was performed in 39 AIP patients before and during CST, and 40 patients without pancreatic diseases served as control. T1 relaxation time of the pancreatic head, body, and tail was measured in each patient. Clinical symptoms and serum IgG4 level of the patients were recorded. The native T1 relaxation time of AIP was significantly elongated compared to normal pancreatic tissue (1124.5ms ± 95.7ms vs 784.3ms ± 41.8ms, p < 0.001). After short-term CST (4weeks), T1 relaxation time of AIP already shortened significantly (957.2ms ± 97.3ms, p < 0.001). After mid-term CST (12weeks), the T1 relaxation time further shortened towards normalization (844.2ms ± 71.6ms, p < 0.001). In 33 AIP patients with elevated serum IgG4 at baseline, T1 relaxation time demonstrated a significant positive correlation with serum IgG4 level (r = 0.329, p = 0.011). In six AIP patients with normal serum IgG4 level at baseline, T1 relaxation time shortening preceded or was in accordance with symptom relief. Native T1 mapping can be used to assess parenchymal inflammation of AIP and to quantify response to treatment. It provides a quantitative outcome surrogate for AIP. • Parenchymal inflammation in autoimmune pancreatitis results in T1 relaxation time elongation, which shortens after effective treatment. • T1 relaxation time of the pancreas correlates with serum IgG4 level, and in serum IgG4-negative AIP patients, T1 relaxation time shortening predicts clinical improvement. • T1 mapping provides a quantitative outcome surrogate for AIP.

Serum and histological IgG4-negative type 1 autoimmune pancreatitis

A 66-year-old man who was on oral medication for type 2 diabetes experienced a rapid decline in glycemic control (increase in glycosylated hemoglobin level from 7.7 to 10.2% over 3months). Abdominal ultrasonography revealed a 20-mm hypoechoic mass in the pancreatic tail. Serum tumor marker carbohydrate antigen 19-9 and DUPAN2 levels were within the respective normal ranges; serum IgG4 level was also normal at 21.8mg/dL. Abdominal contrast computed tomography revealed a 26-mm tumor in the pancreatic tail. Magnetic resonance cholangiopancreatography revealed disruption of the main pancreatic duct and dilation of the caudal pancreatic duct. Endoscopic ultrasonography revealed a near-round-shaped hypoechoic mass with interspersed hyperechoic areas. Endoscopic ultrasonography-guided fine needle aspiration was performed using a 22-G needle, but no malignant findings were observed. There were no signs of sialadenitis, retroperitoneal fibrosis, nephropathy, or other conditions associated with IgG4-related diseases. Distal pancreatectomy was performed; a 23-mm white mass was resected from the pancreatic tail. A histopathological examination showed advanced inflammatory cell infiltration mainly involving lymphocytes/plasma cells along with storiform fibrosis and obliterative phlebitis. No more than five IgG4-positive cells were observed per high-power field. These were level 1 pathological findings, and a definitive diagnosis of type 1 autoimmune pancreatitis (AIP) was made according to the International Consensus Diagnostic Criteria. Type 1 AIP associated with normal serum IgG4 levels and absence of IgG4-positive cells on histological examination is a rare clinical entity, which is very difficult to distinguish from pancreatic cancer. Here we report such a case and present a review of the relevant literature.

Does IgG4 level at the time of diagnosis correlate with disease outcome in IgG4-Related disease?

Background/Objectives: Serum IgG4 level is used as a diagnostic criterion for immunoglobulin G4-related disease (IgG4-RD) but whether it predicts disease progression is unclear. Aim of the study was to investigate if serum IgG4 level at the time of diagnosis correlates with disease outcome. MethodsPatients with a definitive diagnosis of IgG4-RD were included in this study. They were divided into two groups – Group 1: Elevated serum IgG4 at diagnosis and Group 2: Normal serum IgG4 at diagnosis. Outcome parameters including multiple organ involvement, exocrine and endocrine dysfunction, relapse and mortality were compared. Data was subanalysed for outcomes on 2 levels of serum IgG4 cut-off – A: The upper limit of normal (ULN) and B: Twice the ULN. ResultsOf 47 patients, 31 (66%) patients had elevated serum IgG4 at diagnosis. There was no statistically significant difference between the two groups in any of the outcome parameters. Data analysed with the serum IgG4 levels > ULN showed no difference between the 2 groups for any of the outcome parameters. However, when the serum IgG4 cut-off was set to twice the ULN, there was a significantly higher rate of disease relapse (42.9% vs 11.5%, p = 0.02) and pancreatic exocrine insufficiency (PEI) (76.2% vs 42.3%, p = 0.041). ConclusionRaised serum IgG4 greater than two times the ULN was significantly associated with disease relapse and PEI in patients with IgG4-RD. Larger multicentre studies with longer follow-up are required to corroborate these findings and define the role and cut-off value of serum IgG4 in outcomes of IgG4-RD.

A case series of atypical features of patients with biopsy-proven isolated IgG4-related hypophysitis and normal serum IgG4 levels

IgG4-related hypophysitis is a rare clinical entity that forms part of an emerging group of multi-organ IgG4-related fibrosclerotic systemic diseases. The rare prevalence of the disease, presenting features that overlap with other sellar pathologies, and variable imaging features can make preoperative identification challenging. We report three cases of isolated IgG4-related hypophysitis with atypical clinical and imaging features that mimicked those of pituitary apoplexy and other sellar lesions. Additionally, we review the literature of IgG4-related hypophysitis to provide context for individual patient data described herein. All patients presented with symptoms that mimicked those of pituitary apoplexy and visual disturbance, and MRI findings suggestive of pituitary macroadenoma, Rathke's cleft cyst and craniopharyngioma. The clinical presentation warranted surgical decompression, resulting in rapid symptomatic improvement. Preoperative high-dose followed by postoperative low-dose glucocorticoid replacement therapy was administered in all cases. Histopathology showed dense infiltrate of IgG4 cells. Post-operative follow-up monitoring for 12-26months revealed normal serum IgG4 levels with no other organ involvement, while endocrinological testing revealed persistent pituitary hormone deficiencies. Our cases highlight the importance of considering IgG4-related hypophysitis in the differential diagnosis of solid and cystic sellar lesions presenting acutely with pituitary apoplexy symptoms. Existing diagnostic criteria may not be sufficiently precise to permit rapid and reliable identification, or avoidance of surgery in the acute setting. In contrast to other reports of the natural history of this condition, despite the severity of presenting features, the disease in our cases was pituitary-restricted with normal serum IgG4 levels.

IgG4-related hepatobiliary disease: an overview.

IgG4-related hepatobiliary diseases are part of a multiorgan fibroinflammatory condition termed IgG4-related disease, and include IgG4-related sclerosing cholangitis (IgG4-SC) and IgG4-related hepatopathy. These diseases can present with biliary strictures and/or mass lesions, making them difficult to differentiate from primary sclerosing cholangitis (PSC) or other hepatobiliary malignancies. Diagnosis is based on a combination of clinical, biochemical, radiological and histological findings. However, a gold standard diagnostic test is lacking, warranting the identification of more specific disease markers. Novel assays - such as the serum IgG4:IgG1 ratio and IgG4:IgG RNA ratio (which distinguish IgG4-SC from PSC with high serum IgG4 levels), and plasmablast expansion to recognize IgG4-SC with normal serum IgG4 levels - require further validation. Steroids and other immunosuppressive therapies can lead to clinical and radiological improvement when given in the inflammatory phase of the disease, but evidence for the efficacy of treatment regimens is limited. Progressive fibrosclerotic disease, liver cirrhosis and an increased risk of malignancy are now recognized outcomes. Insights into the genetic and immunological features of the disease have increased over the past decade, with an emphasis on HLAs, T cells, circulating memory B cells and plasmablasts, chemokine-mediated trafficking, as well as the role of the innate immune system.

IgG4-Related Disease: Retrospective Analysis of One Hundred Sixty-Six Patients.

To investigate clinical and pathologic aspects of IgG4-related disease (IgG4-RD) in non-Asian populations. We conducted a retrospective review of the medical records of patients with IgG4-RD who presented to an academic medical center from January 1994 to September 2012. Among 166 patients identified, the median age at diagnosis was 61 years (interquartile range [IQR] 49-70 years), 75% were male, and 80% were white. The median number of organs involved was 2 (IQR 2-3). When organs were grouped according to anatomic system, the hepatopancreaticobiliary system was most commonly involved (77%). The median highest serum IgG4 level during the clinical course was 215 mg/dl (IQR 122-466). Forty-three patients (26%) had a normal serum IgG4 level. Seventy-nine pathology specimens were available for immunostaining. The median number of IgG4+ cells was 37 (IQR 25-82) per high-power field, with an IgG4+:IgG+ ratio of 0.50 (IQR 0.32-0.68). Among 151 patients who received medical therapy, 72 (48%) received steroid-sparing agents because of relapse, recurrence, or corticosteroid intolerance. Of the 66 patients who were newly diagnosed, started on corticosteroid monotherapy as the initial treatment, and followed up at our institution, 30 (45%) experienced relapse or recurrence despite an initial favorable response. The number of organs involved had a significant impact on time to relapse or recurrence, with a hazard ratio of 1.48 (95% confidence interval [95% CI] 1.12-1.93) (P < 0.01) in multivariate analysis. The standardized incidence ratio of malignancy was 4.5 (95% CI 1.5-7.5). IgG4-RD is a multisystem disorder that commonly affects older men and has a propensity for relapse, recurrence, and malignancy.

Role of IgG4 serology in identifying common orbital lymphoproliferative disorders.

To explore the role of IgG4 serology in identifying common orbital lymphoproliferative disorders. Eighty-one patients with orbital lymphoproliferative diseases were treated in the Department of Ocular Oncology, Beijing Tongren Hospital, Capital Medical University between September 2010 and December 2012. Serum IgG4 levels were measured in 46 cases of idiopathic orbital inflammatory pseudotumor (IOIP), 17 benign lymphoepithelial lesion (BLEL), 12 cases of orbital mucosa-associated lymphoid tissue (MALT), and 6 cases of diffuse large B-cell lymphoma (DLBL) using immuno-scatter turbidmetry (ISTM). The frequency of elevated IgG4 levels in patients with IOIP, BLEL, MALT, and DLBL was 30.43% (14/46), 76.47% (13/17), 8.33% (1/12), and 0.00 (0/6), respectively. Among the patients with elevated serum IgG4 levels, all IgG-IOIP patients were male, and 92.31% of the IgG4-BLEL patients were female (12/13). The mean serum IgG4 level of IgG4-IOIP patients was lower than that of individuals with IgG4-BLEL, but the variation in serum IgG4 levels was larger in IgG4-IOIP than IgG4-BLEL patients. Only one case of IgG4-MALT with elevated serum IgG4 levels had a medical history >10y, which was significantly longer than the MALT patients with normal serum IgG4 levels. There was no significant elevation of serum IgG4 levels in patients with DLBL. Detecting serum IgG4 levels plays an important role in the differential diagnosis of orbital lymphoproliferative diseases.

Biopsy-proven IgG4-related lung disease.

BackgroundImmunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory disorder that may involve single or multiple organs. Biopsy-proven lung involvement of this disease is occasionally reported, but not well understood.MethodsPatients with the diagnosis of biopsy-proven IgG4-related lung disease (IgG4-RLD) from Peking Union Medical College Hospital between January 2011 and July 2015 were retrospectively analyzed. Age, sex, clinical symptoms, laboratory findings, pulmonary function test results, chest CT tests, positron emission tomography (PET) examinations, treatments and prognoses were retrieved from medical records and analyzed.ResultsSeventeen patients were included in this study (mean age: 44.8 ± 15.0 years). Ten patients were diagnosed via surgery, and 7 patients were diagnosed via percutaneous transthoracic core-needle lung biopsy. Extrapulmonary involvement was observed in only one patient. The clinical symptoms included cough, fever, dyspnea, chest pain and hemoptysis. The serum IgG4 concentration was elevated in 7/13 patients (mean: 1955 ± 1968 mg/L). The chest CT findings included mainly nodules and masses with spiculated borders, alveolar consolidations with air bronchograms, and ground glass opacities with or without reticular opacities. PET scans indicated increased standardized uptake values, and 7/8 patients were correctly diagnosed with benign inflammation. Corticosteroids and immunosuppressants were administered to 14/17 patients and effectively alleviated the disease.ConclusionsIn biopsy-proven IgG4-RLD, a normal serum IgG4 concentration is commonly seen, while extrapulmonary involvement is infrequent. Alveolar consolidation with air bronchograms is an important imaging finding of IgG4-RLD, which has not been emphasized before.

What are the characteristics of asthma patients with elevated serum IgG4 levels?

IntroductionIgG4 has recently been a subject of great interest in human pathology. No data are available about the characteristics of asthma patients with elevated IgG4 levels. Population and methodsAn observational study was conducted from January 2006 to March 2015 in a difficult-to-treat population of asthma patients. Twenty-six difficult-to-treat asthma patients with elevated serum IgG4 levels (IgG4/IgG ratio up to 10%) were compared with a control population of 98 difficult-to-treat asthma patients with normal serum IgG4. Blood eosinophilia, total IgE and FeNO were compared between groups to better characterize asthma patients with elevated serum IgG4 levels. ResultsMedian IgG4 concentrations were 1.72 g/l [1.19–2.36] and 0.22 g/l [0.10–0.49] in the elevated IgG4 group and normal Ig4 group, respectively. Median blood eosinophilia was more than three times higher in patients with elevated serum IgG4 levels than in controls (0.75 109/L [IQR 0.54–1.78] vs 0.22 109/L [IQR 0.09–0.54] respectively, p < 0.0001). Total IgE was twice as high (264.5 kUI/l [IQR 166.3–779] vs 126 kUI/l [IQR 26–350] respectively; p < 0.05) and FeNO was nearly twice as high (61 [IQR 41–111] ppb vs 35 [IQR 23–51] ppb, p < 0.001). Allergic broncho-pulmonary aspergillosis (ABPA) and eosinophilic granulomatosis with polyangiitis (EGPA) were observed in the asthma patients with elevated serum IgG4. Ten patients had unexplained increased blood eosinophilia. ConclusionAsthma patients with elevated IgG4 levels have significantly higher blood eosinophilia, total IgE and FeNO. ABPA and EGPA are observed in patients with elevated serum IgG4.

IgG4-Related Disease: Clinical and Laboratory Features in One Hundred Twenty-Five Patients.

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition that can affect nearly any organ. Prior studies have focused on individual cases of IgG4-RD or small case series. This study was undertaken to report detailed clinical and laboratory findings in a larger group of patients with IgG4-RD whose diagnosis was established by strict clinicopathologic correlation. The baseline features of 125 patients with biopsy-proven IgG4-RD were reviewed. The diagnosis was confirmed by pathologists' review, based on consensus diagnostic criteria and correlation with clinicopathologic features. Disease activity and damage were assessed using the IgG4-RD Responder Index (RI). Flow cytometry was used to assess levels of circulating plasmablasts. Of the 125 patients, 107 had active disease and 86 were not receiving treatment for IgG4-RD. Only 51% of the patients with active disease had elevated serum IgG4 concentrations. However, patients with active disease and elevated serum IgG4 concentrations were older, had a higher IgG4-RD RI score, a greater number of organs involved, lower complement levels, higher absolute eosinophil counts, and higher IgE levels compared to those with active disease but normal serum IgG4 concentrations (P < 0.01 for all comparisons). The correlation between IgG4+ plasmablast levels and the IgG4-RD RI of disease activity (Spearman's ρ = 0.45, P = 0.003) was stronger than the correlation between total plasmablast levels and the IgG4-RD RI. Seventy-six (61%) of the patients were male, but no significant differences according to sex were observed with regard to disease severity, organ involvement, or serum IgG4 concentrations. Treatment with glucocorticoids failed to produce sustained remission in 77% of patients. Nearly 50% of this patient cohort with biopsy-proven, clinically active IgG4-RD had normal serum IgG4 concentrations. Elevations in the serum IgG4 concentration appeared to identify a subset of patients with a more severe disease phenotype. In addition, the levels of IgG4+ plasmablasts correlated well with the extent of disease activity.

Lymphoplasmacytic sclerosing pancreatitis without IgG4 tissue infiltration or serum IgG4 elevation: IgG4-related disease without IgG4

Type 1 autoimmune pancreatitis can be diagnosed by and is synonymous with its pathognomonic histopathologic appearance called lymphoplasmacytic sclerosing pancreatitis. Type 1 autoimmune pancreatitis, also called IgG4-related pancreatitis, is the pancreatic manifestation of IgG4-related disease. However, the role of IgG4 in the pathogenesis of IgG4-related disease is unclear. We describe patients with LPSP without serum or tissue IgG4 abnormalities. From the Mayo Clinic database of autoimmune pancreatitis patients, we identified three patients with histologically confirmed type 1 autoimmune pancreatitis (lymphoplasmacytic sclerosing pancreatitis) who had normal serum IgG4 and no increase in IgG4-positive plasma cells in tissue. We reviewed original clinical records and pathologic specimens, and describe the clinical and histologic features of these three patients. All patients (age/gender: 63/F, 70/M and 68/M) had normal serum IgG and IgG4 levels, and multiple sections of pancreatic histology did not show increased IgG4-positive plasma cells. Two patients were diagnosed retrospectively following pancreatic surgery, one relapsed in another organ and one has remained relapse free. Another patient was diagnosed by pancreatic core biopsy and has suffered multiple relapses that have been controlled by rituximab. These cases highlight the fact that although the currently agreed upon name for type 1 autoimmune pancreatitis is IgG4-related pancreatitis, serum and tissue IgG4 abnormalities are best considered characteristic, but not essential for the diagnosis of this enigmatic condition.

Pulmonary embolism and Takotsubo syndrome as comorbidities versus employing mere pulmonary embolism to model the Takotsubo syndrome pathophysiology

neoplasms, infections, or other inflammatory disorders. It often causes sub-acute tissue damage and can lead to organ failure [1]. IgG4-RD is a corticosteroid-responsive disorder and immunosuppressive agents have been used in corticosteroid-refractory disease, however, treatment data is limited. IgG4-RD epidemiological data is scarce, however 62 to 83% patients are men and older than 50 years of age. 40% of patients with IgG4-RD have a history of allergic diseases such as bronchial asthma, chronic sinusitis, or seasonal allergies as seen in the patient presented. The pathophysiologic mechanism of IgG4-RD remains unknown. Autoimmunity, infectious agents, and molecular mimicry are thought to be potential triggers for disease development. Type-2 helper T cell immune-mediated responses are pathogenic [2]. In the case presented, recent Mycoplasma and Coxsackie B infections as well as autoimmunity, as evidenced by anti-nuclear antibody seroconversion, may have initiated the development of IgG4-RD. IgG4-RD with effusive–constrictive pericarditis, tamponade, and hepatopathy with normal serum IgG4 concentrations is a novel presentation of IgG4-RD. Increased awareness of this disease entity could potentially mitigate morbidity and improve patient outcomes. The authors report no relationships that could be construed as a conflict of interest.