Immunoglobulin G4 Concentrations Research Articles

The spectrum of B cells in the pathogenesis, diagnosis and therapeutic applications of immunoglobulin G4-related disease.

Immunoglobulin G4 (IgG4)-related disease is a chronic fibroinflammatory disease mediated by immune disorders. Given the challenging clinical diagnosis and treatment, knowledge of the pathogenesis of IgG4-related disease is important. The typical elevation of serum IgG4 concentrations and infiltration of IgG4-positive plasma cells in the involved tissues indicate the involvement of B lymphocytes in the pathogenesis of IgG4-related disease. Mass production of autoantibodies reflects abnormal activation of B cells, which causes tissue damage. Circulating plasmablasts are recently discovered markers that correlate with serum IgG4 concentration, the extent of organ involvement and disease activity. B-cell depletion therapy is an emerging curative strategy that can significantly alleviate clinical manifestations and achieve remission in patients with IgG4-related disease. These findings highlight the potential role of B cells in IgG4-related disease. In this review, we discuss the pathogenic impact of B lymphocytes on IgG4-related disease and describe novel therapies targeting B cells.

A 41-Year-Old Man With an Abdominal Mass and Hepatomegaly

A 41-Year-Old Man With an Abdominal Mass and Hepatomegaly

The differential diagnosis of IgG4-related disease based on machine learning

IntroductionTo eliminate the disparity and maldistribution of physicians and medical specialty services, the development of diagnostic support for rare diseases using artificial intelligence is being promoted. Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a rare disorder often requiring special knowledge and experience to diagnose. In this study, we investigated the possibility of differential diagnosis of IgG4-RD based on basic patient characteristics and blood test findings using machine learning.MethodsSix hundred and two patients with IgG4-RD and 204 patients with non-IgG4-RD that needed to be differentiated who visited the participating institutions were included in the study. Ten percent of the subjects were randomly excluded as a validation sample. Among the remaining cases, 80% were used as training samples, and the remaining 20% were used as test samples. Finally, validation was performed on the validation sample. The analysis was performed using a decision tree and a random forest model. Furthermore, a comparison was made between conditions with and without the serum IgG4 concentration. Accuracy was evaluated using the area under the receiver-operating characteristic (AUROC) curve.ResultsIn diagnosing IgG4-RD, the AUROC curve values of the decision tree and the random forest method were 0.906 and 0.974, respectively, when serum IgG4 levels were included in the analysis. Excluding serum IgG4 levels, the AUROC curve value of the analysis by the random forest method was 0.925.ConclusionBased on machine learning in a multicenter collaboration, with or without serum IgG4 data, basic patient characteristics and blood test findings alone were sufficient to differentiate IgG4-RD from non-IgG4-RD.

Blood biomarkers recommended for diagnosing and monitoring IgG4-related disease. Considerations from the ERN ReCONNET and collaborating partners.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic, clinically heterogenous fibroinflammatory condition, characterised by an accumulation of IgG4 secreting plasma cells in affected tissues and associated with increased serum IgG4 concentrations. Despite a growing recognition of the disease among clinicians from different specialties worldwide, its indolent nature, lack of a single diagnostic test and ability to mimic other malignant, infective and inflammatory conditions, makes the diagnosis challenging. As treatment options evolve, biomarkers correlating with disease activity, predicting prognosis and response to treatment are deemed required. A multidisciplinary panel of experts from the European Reference Network for Rare and Complex Connective tissue diseases (ERN ReCONNET) and affiliated international partners have performed a narrative literature search and reviewed the current evidence of biomarkers in IgG4-RD, including immunoglobulins, cytokines, chemokines and other soluble immune mediators, and cellular components of the immune system. The aim of this paper is to provide useful information for clinicians as to the utility of biomarkers for diagnosing and monitoring IgG4-RD in clinical routine and sets out recommendations for clinical decision making.

Time-related variation in IgG subclass concentrations in a group of healthy Danish adults.

IntroductionImmunoglobulin G subclass measurements are important for the diagnostic work‐up of immunodeficiencies and immunoglobulin G4 (IgG4) related diseases. It is currently unknown whether a single sampling is truly representative for an individual's IgG subclass concentrations. This study aimed to investigate whether IgG and IgG subclass concentrations in healthy individuals are stable over time.MethodWith a span of median 42 weeks, four samples from each of 54 (34M, 20F) healthy adult volunteers (24–66 years) were analyzed for IgG and IgG1–4 using turbidimetry. Concentrations were compared within and between individuals.ResultsIgG and IgG subclass concentrations followed either a normal (IgG, IgG1, and IgG3) or log normal (IgG2 and IgG4) distribution. Immunoglobulin 4 demonstrated by far the widest range of concentrations between individuals (670‐fold: 0.004–2.68 g/L). Immunoglobulin G subclass variations within individuals were expressed as pooled standard deviations (PSD). These ranged from 0.056 (IgG4) to 0.955 g/L (IgG) and correlated with mean concentration of IgG or the particular IgG subclass. As a consequence, the relative PSDs (i.e., PSD divided by mean IgG or IgG subclass concentration) fell within a narrow range: 5.82%–10.1%. Based on these numbers, the 95%‐upper one‐sided confidence limits for intraindividual IgG and IgG subclass variation was calculated to range from 9.82% (IgG2) to 16.9% (IgG4).ConclusionThe study documents that IgG or IgG subclass concentrations within healthy individuals are very stable over at least 42 weeks. The expected variation for IgG4 concentrations at a 95% confidence level does not exceed ±16.9%.

IDIOPATHIC RETROPERITONEAL FIBROSIS: A RARE CAUSE OF ABDOMINAL PAIN AND OBSTRUCTIVE UROPATHY

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Retroperitoneal fibrosis (RPF) is a rare disorder that presents with subtle symptoms. It may be idiopathic or secondary to other causes; with the idiopathic form being either immunoglobulin G4 (IgG4) or non-IgG4 related. The incidence of idiopathic RPF has been reported to be 0.1 per 100,000 person-years with a male-to-female ratio of 1.9:1. Our case aims at highlighting this rare disorder as a cause of abdominal pain in a middle-aged man. CASE PRESENTATION: A 48-year-old man presented with persistent lower abdominal pain, decreased appetite and weight loss for three months. Physical exam was remarkable for mild abdominal tenderness. Laboratory results were remarkable for creatinine 1.6 mg/dL, BUN 56 mg/dL, CRP 35.7 mg/L and ESR 95 mm/hr. CBC, infectious workup, autoimmune panel, serum protein electrophoresis and tumor markers were unremarkable. Serum IgG and immunoglobulin G4 (IgG4) were normal. CT abdomen and pelvis revealed a soft tissue mass surrounding the distal abdominal aorta and inferior mesenteric artery; entrapping the left ureter accounting for left-sided hydroureteronephrosis. The patient underwent left uterolysis and DJ stent placement. Histopathology (H/P) of the mass showed an abundance of fibro-adipose tissue and lympho-plasmacytic infiltration with rare IgG4 positive plasma cells; negative for infection or malignancy. The patient was started on high dose prednisone leading to resolution of clinical symptoms. Serum creatinine level, ESR and CRP also returned to normal. A follow up CT scan showed regression of the mass. DISCUSSION: RPF is a rare fibro-inflammatory disease with poorly understood pathogenesis. Idiopathic RPF accounts for more than 70% of cases, with secondary causes related to retroperitoneal injury, malignancy, infection, drug therapy or genetic factors. Interestingly, a recent study (Zen et al) found a positive correlation between immunoglobin G4 (IgG4) on H/P and idiopathic RPF in 10 cases out of 17 patients. These cases were hallmarked by a unique H/P pattern and elevated serum IgG4 concentration. Our case, however, was the non-IgG4 related type. Patients with IRF most frequently present with abdominal pain, weight loss and features of obstructive uropathy. Elevated inflammatory markers and imaging studies aid in the diagnosis but biopsy is the gold standard. Goals of treatment for RPF is relief of ureteral obstruction and disease regression with glucocorticoids with or without other immunosuppressants. Tamoxifen has been used with success in patients who cannot tolerate glucocorticoids. Biologic therapies such as rituximab and tocilizumab have shown promise in select patients with refractory disease but further research is warranted. CONCLUSIONS: Idiopathic retroperitoneal fibrosis should be kept in the differential diagnosis of a patient presenting with abdominal or flank pain, obstructive uropathy and elevated markers of inflammation. Reference #1: Idiopathic retroperitoneal fibrosis: clinicopathologic features and outcome analysis. Yachoui R, Sehgal R, Carmichael B. Clin Rheumatol. 2016 Feb;35(2):401-7. https://doi.org/10.1007/s10067-015-3022-y. Epub 2015 Jul 25. Reference #2: Idiopathic and secondary forms of retroperitoneal fibrosis: a diagnostic approach. Urban ML, Palmisano A, Nicastro M, Corradi D, Buzio C, Vaglio A. Rev Med Interne. 2015 Jan;36(1):15-21. https://doi.org/10.1016/j.revmed.2014.10.008. Epub 2014 Nov 18. Reference #3: Idiopathic retroperitoneal fibrosis and its overlap with IgG4-related disease. Rossi GM, Rocco R, Accorsi Buttini E, Marvisi C, Vaglio A. Intern Emerg Med. 2017 Apr;12(3):287-299. https://doi.org/10.1007/s11739-016-1599-z. Epub 2017 Jan 9. DISCLOSURES: No relevant relationships by Moses Bachan, source=Web Response No relevant relationships by Muneer Khan, source=Web Response No relevant relationships by Zinobia Khan, source=Web Response No relevant relationships by Mariam Saeed, source=Web Response

Distribution characteristics of elevated serum immunoglobulin G4 (IgG4) and its relationship with IgG4-related disease

Objective: To elucidate the distribution characteristics of elevated serum immunoglobulin G4 (IgG4) and its relationship with immunoglobulin G4-related disease (IgG4-RD).Methods: In total, 14 522 unique patients who were tested for serum IgG4 over a 4.5 year period were enrolled. Demographic and serological characteristics of all patients, and the range of diseases and serological characteristics of patients with elevated serum IgG4, were retrospectively analysed. Organ involvement in IgG4-RD patients and the utility of serum immunoglobulin for distinguishing IgG4-RD from non-IgG4-RD were also investigated.Results: Elevated serum IgG4 (> 1.4 g/L) was observed in 1793/14 522 patients (12.3%) and primarily appeared in middle-aged and elderly men. Only 7.3% of patients with elevated serum IgG4 met the diagnostic criteria for IgG4-RD. Elevated serum IgG4 was also found in over 30 types of non-IgG4-RD. Serum IgG4 levels were higher in IgG4-RD patients with multiple-organ involvement and were positively correlated with the number of affected organs. The diagnostic utility of serum IgG4 for IgG4-RD was higher than that of the IgG4/IgG ratio and serum IgG. The optimal serum IgG4 cut-off value for diagnosing IgG4-RD was 2.06 g/L, with a sensitivity of 95.6% and specificity of 94.7%.Conclusions: Elevated serum IgG4 may be present in multiple non-IgG4-RD conditions. However, a high serum IgG4 concentration is of great value for IgG4-RD diagnosis, and there appears to be a positive relationship between serum IgG4 levels and organ involvement in patients with IgG4-RD. Examining the IgG4/IgG ratio and serum IgG does not improve the ability of IgG4-RD diagnosis.

IgG4 subclass and gamma-glutamyl transferase in children with ulcerative colitis with primary sclerosing cholangitis and without sclerosing cholangitis.

Aim of the studyPrimary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease which could be associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC). The aim of this study was to compare GGT and IgG4 levels among children with UC with PSC and without PSC.Material and methodsIn this cross sectional study children with UC with PSC and UC without PSC were included. Serum immunoglobulin G4 (IgG4) and gamma-glutamyl transpeptidase (GGT) levels of the 90 UC patients with and without concomitant PSC were measured. Children with serum IgG4 concentration > 175 mg/dl were considered to have elevated IgG4.ResultsElevated serum IgG4 was found in 8 of 30 (26.6%) patients with PSC vs. 3 of 60 (5.0%) patients without PSC. Compared with the group without symptoms of PSC, the group with PSC showed significantly higher levels of aspartate aminotransferases (AST; 22.5 U/l vs. 70.0 U/l, p < 0.001), alkaline phosphatase (ALP; 359.0 U/l vs. 602.0 U/l, p < 0.001), and IgG4 (56.0 vs. 73.0, p = 0.02). The odd ratio of the elevated IgG4 and GGT in predicting PSC was 6.9 (95% CI: 1.6-28.4) and 18 (95% CI: 5.7-55.9), respectively.ConclusionsAST, alanine aminotransferase (ALT), GGT, ALP, and serum IgG4 were significantly higher in UC patients with sclerosing cholangitis (SC) compared to UC patients without SC. GGT and IgG-4 measurements are recommended for evaluation of UC.

Idiopathic retroperitoneal fibrosis: a cross-sectional study of 142 Chinese patients

Objective: To investigate the epidemiological, clinicolaboratory, imaging, and therapeutic characteristics of idiopathic retroperitoneal fibrosis (iRPF) in China.Method: All patients presenting to the Chinese People’s Liberation Army General Hospital from October 1996 to July 2016 diagnosed with iRPF were included. Data were collected from medical records and the smoking index was calculated. Scheel radiological classification was used to assess the extent of soft-tissue density.Results: The study included 142 patients (120 men, 22 women). The mean age was 54.3 years. Disease duration ranged from 0.23 to 109.5 months (median 2.7). Current smoking rate was 53.5%. Flank pain was more common in males (p = 0.041) and in the high smoking index group (p = 0.03). C-reactive protein level ranged from 0.08 to 8.9 mg/dL (median 1.9). Serum immunoglobulin G4 (IgG4) was elevated in 31/63 patients (49.2%), and males had higher IgG4 concentrations (p = 0.017) at presentation. Respectively, 44.4%, 5.6%, and 22.5% of cases were classified into Scheel classes I, II, and III. Eight patients (5.6%) had atypical RPF localization and 103 (72.5%) presented with hydronephrosis, which was more common in class III patients (p = 0.04). Nine patients (6.3%) received no treatment; the others received medical (34.5%) or surgical treatment (14.8%), or both (44.4%).Conclusions: There was a higher rate in males and younger age at disease onset in these Chinese iRPF patients than in other populations. Acute-phase reactants and serum IgG4 were elevated in some patients. Tobacco use may be a risk factor for iRPF in Chinese populations.

Value of Serum IgG4 in the Diagnosis of Autoimmune Pancreatitis and in Distinguishing it from Acute and Chronic Pancreatitis of Other Etiology

Immunoglobulin G4 (IgG4)-related autoimmune pancreatitis (AIP) is one of the most common clinical presentations of the IgG4-related disease and distinct from acute pancreatitis and chronic pancreatitis derived from other etiology. Elevated serum IgG4 concentration has been established as one of the diagnostic criteria for AIP. However, a subset of patients of AIP have normal serum IgG4. It is essential to establish the value of serum IgG4 level in identifying AIP patients in clinical setting, and its association with the severity of the disease and the pathology diagnosis. We performed a retrospective study involving 67 patients who were identified to have elevated serum IgG4 measurements (>86 mg/dL) from a pool of 833 patients in our institute from 2012 to 2015. The concentration of serum IgG4 was significantly higher in AIP compared to acute pancreatitis and chronic pancreatitis of other etiology (p<0.01). The sensitivity of distinguishing AIP from acute and chronic pancreatitis of other etiology increased from 61% to 100% as the cutoff value for serum IgG4 was set from 135 mg/dL to 86 mg/dL. On the other hand, the specificity was decreased from 98% to 91%. A cutoff value of 120 mg/dL gave rise to the highest specificity without sacrificing the sensitivity. The level of serum IgG4 exhibited a trend to associate with the severity of IgG4-related AIP determined clinically based on the endoscopic ultrasound findings, although it did not reach statistical significance (p value = 0.05). All the pathology-proven cases of IgG4-related AIP exhibited elevated serum IgG4 concentration. Only one of eight cases of non-AIP cases confirmed by pathology showed elevated serum IgG4. [N A J Med Sci. 2017;10(3):94-99. DOI: 10.7156/najms.2017.1003094]

From Pathogenesis, Clinical Manifestation, and Diagnosis to Treatment: An Overview on Autoimmune Pancreatitis.

Autoimmune pancreatitis (AIP) is a special type of chronic pancreatitis which is autoimmune mediated. The international consensus diagnostic criteria (ICDC) 2011 proposed two types of AIP: type I is associated with histological pattern of lymphoplasmacytic sclerosing pancreatitis (LPSP), characterized by serum IgG4 elevation, whereas type 2 is named idiopathic duct-centric pancreatitis (IDCP), with granulocytic epithelial lesion (GEL) and immunoglobulin G4 (IgG4) negative. The pathogenic mechanism is unclear now; based on genetic factors, disease specific or related antigens, innate and adaptive immunity may be involved. The most common clinical manifestations of AIP are obstructive jaundice and upper abdominal pain. The diagnosis can be made by a combination of parenchymal and ductal imaging, serum IgG4 concentrations, pancreatic histology, extrapancreatic disease, and glucocorticoid responsiveness according to ICDC 2011. Because of the clinical and imaging similarities with pancreatic cancer, general work-up should be done carefully to exclude pancreatic malignant tumor before empirical trial of glucocorticoid treatment. Glucocorticoid is the most common drug for AIP to induce remission, while there still exists controversy on steroid maintenance and treatment for relapse. Further studies should be done to identify more specific serum biomarkers for AIP, the pathogenic mechanisms, and the treatment for relapse.

IgG4-related Disease from Head to Toe.

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.

Overview of the Immunoglobulin G4-related Disease Spectrum

Immunoglobulin G4 (IgG4)-related disease is a newly named fibroinflammatory condition characterized by tumefactive lesions that contain dense lymphoplasmacytic infiltrates rich in IgG4-positive cells. Elevated serum IgG4 concentrations also often accompany IgG4-related disease. Many medical conditions that were long viewed as diseases confined to single organs (e.g., Mikulicz disease, type 1 autoimmune pancreatitis, Riedel’s thyroiditis, multifocal fibrosclerosis, inflammatory pseudotumor, mediastinal fibrosis, retroperitoneal fibrosis, and etc.) are now designated as part of the spectrum of IgG4-related disease. The preferred nomenclature suggested by a committee of international experts uses the prefix “IgG4-related-” for individual organ involvement, regardless of the organ system affected. One exception is type 1 autoimmune pancreatitis (IgG4-related pancreatitis). Comprehensive diagnostic criteria for IgG4-related disease and organ-specific diagnostic criteria (e.g., IgG4-related dacryoadenitis and sialadenitis, type 1 autoimmune pancreatitis, IgG4-related kidney disease and IgG4-related sclerosing cholangitis) can aid clinicians in the diagnosis of this erratic condition. Keywords: Immunoglobulin G4-related disease, Autoimmune pancreatitis, Autoimmune diseases Keywords: 면역글로불린 G4 연관질환, 자가면역췌장염, 자가면역질환

The degree of mucosal damage to the small intestine and serum immunoglobulin G4 levels correlate with celiac disease.

Celiac disease (CD) is an immune-mediated and chronic inflammatory enteropathy, triggered by the ingestion of gluten in genetically susceptible individuals. Immunoglobulin G4 (IgG4)-related diseases are a recently defined emerging clinical condition, characterized by increased serum IgG4 concentrations. The aim of this study was to investigate whether IgG4 levels correlate with the titers of intestinal antibodies and the degree of mucosal damage in CD patients. A total of 41 CD patients and 28 healthy controls were included in the study. All patients underwent a duodenal biopsy and were then diagnosed with the modified Marsh classification. Blood samples were obtained for IgG4 measurements. Serums were kept at -80 °C until the analysis was carried out and plasma IgG4 levels were determined using an enzyme-linked immune sorbent assay method with a diagnostic cutoff value of 135 mg/dl. The mean age of the CD and the control group was 26.8 ± 8.3 and 26.9 ± 6.2 years, respectively. The mean IgG4 levels were significantly higher in CD patients (283.21 ± 39.02 mg/dl) compared with the healthy control group (68.97 ± 15.89 mg/dl, P<0.0001). In the CD group, 27/41 patients and in the control group, 4/28 patients had high IgG4 levels (>135 mg/dl, P < 0.0001). A close correlation was found between the grade of mucosal damage, IgG4 levels, and antigliadin-IgA; the higher the grade Marsh score, the higher the measured IgG4 (P < 0.05). In our study, IgG4 levels of CD patients were higher than normal ranges whereas the results of the control group were within physiologic limits. We also showed for the first time that there was a correlation between IgG4 levels, autoantibody, and severity of mucosal damage. To the best of our knowledge, this is the first study to evaluate IgG4 levels and mucosal damage in CD patients.

Cutaneous plasmacytosis: a clinicopathologic study of 12 cases in Taiwan revealing heterogeneous underlying causes.

Cutaneous plasmacytosis is clinically characterized by multiple pigmented papules and plaques that occur mainly on the trunk and many plasma cells in the lesional skin. Most of the cases reported have occurred in Japan. Whether cutaneous plasmacytosis is a unique reactive disease or a neoplastic condition has not been established. We collected 12 cases fulfilling the criteria for a diagnosis of cutaneous plasmacytosis at our institution from 2001 to 2013. We analyzed clinicopathologic features and performed immunohistochemical and immunoglobulin gene rearrangement studies. All 12 patients presented with characteristic cutaneous lesions mainly on the trunk and proximal extremities. Many plasma cells were observed in the lesional skin, and the basal layer was hyperpigmented. Four patients had numerous plasma cells in lymph nodes, and one patient also had increased plasma cells in bone marrow. One patient fulfilled the criteria for immunoglobulin G4 (IgG4)-related lymphadenopathy. Elevated serum IgG and IgG4 concentrations were found in seven patients. Monoclonal immunoglobulin gene rearrangements were detected in four patients. The median duration of follow-up was four years. One patient was lost from follow-up. Partial remission of the cutaneous lesions was observed in five patients, and progressive disease was noted in five patients. One patient died of respiratory failure. Our study suggests that the so-called "cutaneous plasmacytosis" has heterogeneous underlying causes with or without systemic involvement and may be associated with clonal immunoglobulin gene rearrangements and IgG4-related lymphadenopathy. No effective treatment is available for this condition.

Clinical research on benign lymphoepithelial lesions of lacrimal gland in 20 Chinese patients.

Background:Benign lymphoepithelial lesion (BLEL) is characterized by symmetric bilateral swelling of the lacrimal and salivary glands and considered a subtype of immunoglobulin G4 (IgG4)-related sclerosing disease, the etiology and pathogenesis of which has not been determined. The purpose of the present study was to analyze the clinical features of BLEL in the lacrimal gland and the relationship between the serum level of IgG4 and BLEL.Methods:Twenty consecutive patients with BLEL diagnosed in Department of Ophthalmology at Beijing Tongren Hospital, Capital Medical University between January 2012 and December 2013 were observed. The clinical features, imaging findings, laboratory tests, treatments and follow-up status of these 20 consecutive patients were analyzed.Results:In all 20 patients, the ratio of male to female was 1:4, the ages ranged from 28 to 57 years, the ratio of unilateral to bilateral eyes involvement was 1:4, and painless uncongested symmetrical swelling of the upper eyelid was the main clinical manifestation. Orbital magnetic resonance imaging (MRI) showed that all patients involved lacrimal gland, which were obviously enlarged with equal signals in T1W images and T2W images and obvious enhancement on contrast MRI. Extraocular muscles were involved in 5 patients, salivary gland in 8 patients, and frontal nerve in 3 patients. Serum IgG4 concentration was elevated in 18 patients. The treatment strategy mainly included surgery and steroid administration. Three patients were lost to follow-up, 17 patients reached complete response, and no recurrence was observed.Conclusions:Eyelid swelling is the typical symptom of BLEL. Most of the patients involved bilateral lacrimal glands. High serum IgG4 level and abundant IgG4-positive plasma cell infiltration are the important features, which can be found in most of BLEL patients. Surgery combined with glucocorticoids is an efficient treatment strategy.

Diagnostic and Therapeutic Challenges in IgG4-Related Disease in the Sphenoid Sinus

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.

Diagnostic criteria for IgG4-related ophthalmic disease.

Immunoglobulin G4 (IgG4)-related disease is a novel clinical entity characterized by infiltration of IgG4-immunopositive plasmacytes and elevated serum IgG4 concentration accompanied by enlargement of and masses in various organs, including the lacrimal gland, salivary gland, and pancreas. Recent studies have clarified that conditions previously diagnosed as Mikulicz disease as well as various types of lymphoplasmacytic infiltrative disorders of the ocular adnexa are consistent with a diagnosis of IgG4-related disease. Against this background, the diagnostic criteria for IgG4-related ophthalmic disease have recently been established, based on both the clinical and the histopathologic features of the ocular lesions. This article reviews these new criteria with reference to the comprehensive diagnostic criteria for IgG4-related disease for all systemic conditions reported in 2012.

Use of Serum Level of Immunoglobulin G4 in the Differential Diagnosis of Autoimmune Pancreatitis 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.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.

IgG4-related disease.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is an immune-mediated condition that can affect almost any organ and is now being recognized with increasing frequency. IgG4-RD is characterized by a lymphoplasmacytic infiltrate composed of IgG4(+) plasma cells, storiform fibrosis, obliterative phlebitis, and mild to moderate eosinophilia. The diagnosis of IgG4-RD unifies many eponymous fibroinflammatory conditions that had previously been thought to be confined to single organs. IgG4-RD lesions are infiltrated by T helper cells, which likely cause progressive fibrosis and organ damage. IgG4 antibodies are generally regarded as noninflammatory. Although autoreactive IgG4 antibodies are observed in IgG4-RD, there is no evidence that they are directly pathogenic. Rituximab-induced B cell depletion in IgG4-RD leads to rapid clinical and histological improvement accompanied by swift declines in serum IgG4 concentrations. Although IgG autoantibodies against various exocrine gland antigens have been described in IgG4-RD, whether they are members of the IgG4 subclass is unknown. The contribution of autoantibodies to IgG4-RD remains unclear.