Median IgG4 Research Articles

IgG subclass levels in referred hemochromatosis probands with HFE p.C282Y/p.C282Y.

IgG subclass levels in hemochromatosis are incompletely characterized. We characterized IgG subclass levels of referred hemochromatosis probands with HFE p.C282Y/p.C282Y (rs1800562) and human leukocyte antigen (HLA)-A and -B typing/haplotyping and compared them with IgG subclass levels of eight published cohorts of adults unselected for hemochromatosis. There were 157 probands (82 men, 75 women; mean age 49±13 y). Median serum ferritin, mean body mass index (BMI), median IgG4, and median phlebotomy units to achieve iron depletion were significantly higher in men. Diabetes, cirrhosis, and HLA-A*03,-B*44, -A*03,B*07, and -A*01,B*08 prevalences and median absolute lymphocyte counts in men and women did not differ significantly. Mean IgG subclass levels [95% confidence interval] were: IgG1 5.31 g/L [3.04, 9.89]; IgG2 3.56 g/L [1.29, 5.75]; IgG3 0.61 g/L [0.17, 1.40]; and IgG4 0.26 g/L [<0.01, 1.25]. Relative IgG subclasses were 54.5%, 36.6%, 6.3%, and 2.7%, respectively. Median IgG4 was higher in men than women (0.34 g/L [0.01, 1.33] vs. 0.19 g/L [<0.01, 0.75], respectively; p = 0.0006). A correlation matrix with Bonferroni correction revealed the following positive correlations: IgG1 vs. IgG3 (p<0.01); IgG2 vs. IgG3 (p<0.05); and IgG2 vs. IgG4 (p<0.05). There was also a positive correlation of IgG4 vs. male sex (p<0.01). Mean IgG1 was lower and mean IgG2 was higher in probands than seven of eight published adult cohorts unselected for hemochromatosis diagnoses. Mean IgG subclass levels of hemochromatosis probands were 5.31, 3.56, 0.61, and 0.26 g/L, respectively. Median IgG4 was higher in men than women. There were positive associations of IgG subclass levels. Mean IgG1 may be lower and mean IgG2 may be higher in hemochromatosis probands than adults unselected for hemochromatosis.

Laboratory characteristics of IgG4-related disease: A retrospective study from a single tertiary medical center.

Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory condition with unique histopathological features that can affect most organs, making diagnosis challenging. This study characterized detailed laboratory characteristics of IgG4-RD. Baseline clinical and laboratory features of 33 patients with IgG4-RD were reviewed, including serum IgG4 concentrations, serum free light chains (sFLCs), IgGĸ- and IgGλ-heavy/light chains (HLCs), capillary serum protein electrophoresis (SPE), and immunofixation electrophoresis (IFE) of IgG4 subclass. The cohort of 33 patients showed male predominance (94%), with 8 (24%) exhibiting multiple organ involvement. Most patients (88%) had an elevated IgG4 concentration, and 67% had elevated erythrocyte sedimentation rate and IgE levels. Median IgG4 concentration at baseline was significantly higher in patients with >2 organs involved than those with ≤2. Furthermore, erythrocyte sedimentation rate was significantly correlated with serum IgG4 concentrations at baseline. SPE results demonstrated polyclonal gammopathy in most patients. Half of the patients had an increased κ/λ sFLC ratio, 42% had an increased IgGκ/IgGλ HLC ratio. Most patients exhibited hypergammaglobulinemia in the anodal end of the ɤ region on SPE. This study describes detailed laboratory features of IgG4-RD. Although none of these tests are considered diagnostically sufficient by itself, the provided laboratory characteristics can increase awareness of this disorder and help distinguish it from other IgG4-RD mimics.

Management, outcomes and survival of an Australian IgG4-SC cohort: The MOSAIC study.

IgG4 sclerosing cholangitis (IgG4-SC) is the biliary component of the multisystem IgG4-related disease. We aimed to investigate the clinical features, demographics, treatment response and outcomes of IgG4-SC in a large Australian cohort. We conducted nationwide retrospective cohort via the Australian Liver Association Clinical Trials Network (ALA-CRN). 39 sites were invited to participate. IgG4-SC was defined by the clinical diagnostic criteria established by the Japanese Biliary Association in 2012. Data were collected on patient demographic, clinical and laboratory information, presenting features, response to therapy and clinical outcomes. 67 patients meet inclusion criteria from 22 sites. 76% were male with mean age of 63.3±14.5years and a median IgG4 level of 3.6g/L [0.09-67.1]. The most frequent presenting symptom was jaundice (62%) and abdominal pain (42%) and Type 1 biliary stricturing (52%) at the distal common bile duct was the most frequent biliary tract finding. Prednisolone was used as a primary treatment in 61 (91%) and partial or complete response occurred in 95% of subjects. Relapse was common (42%) in those who ceased medical therapy. After a median follow up of 3.9years there was one hepatocellular carcinoma and no cholangiocarcinomas. Our study confirms the preponderance of IgG4-SC in males and highlights the steroid response nature of this condition although relapse is common after steroid cessation. Progression to malignancy was uncommon.

AB0125 CLINICAL CHARACTERISTICS OF RHEUMATOID ARTHRITIS PATIENTS WITH IGG4-RELATED SYNOVITIS

Background:Elevated serum IgG4 (sIgG4) and IgG4+ plasma cell tissue infiltration are outstanding features of IgG4-related disease (IgG4-RD). However, elevated IgG4 is not specific for IgG4-RD. Our previous study reported elevated sIgG4 in 46% of rheumatoid arthritis (RA) patients (Mediators Inflamm 2014). Whether synovium from RA patients show similar characteristics of IgG4-RD and how about the clinical characteristics of RA patients with IgG4-related synovitis have not been reported yet.Objectives:To explore the serum and synovial IgG4 level and their correlation with disease indicators in RA.Methods:Active RA patients who underwent needle synovial biopsy with qualified synovium tissue were recruited. Demographic and clinical data were collected simultaneously. Synovium tissue were stained with H&amp;E for Krenn synovitis score and immunohistochemistry for positive cell densities of CD20, CD38, IgG and IgG4. Serum IgG4 level was detected by immunonephelometry.Results:Among 96 RA patients recruited, 74 (77.1%) were female, the median age was 55.0 (46.0~61.0) years, disease duration was 42.0 (12.0~120.0) months and SDAI was 31.2 (22.1~42.8).The median sIgG4 was 1.38 (0.86~2.42) g/L and 49(51.0%) patients had elevated sIgG4. Compared with those with normal sIgG4, RA patients with elevated sIgG4 had significantly higher levels of PrGA [7 (5~8) vs. 6 (4~7)], ESR [90 (64~116) mm/h vs. 61 (38~75) mm/h], CRP [46.20 (17.20~74.20) mg/L vs. 18.90 (9.46~49.20) mg/L], DAS28-ESR [6.3 (5.6~7.4) vs. 5.7 (4.7~6.4)], SDAI [34.2 (25.3~48.8) vs. 27.8 (18.9~35.9)] and HAQ-DI [1.70 (0.61~2.28) vs. 0.88 (0.40~1.75), all P&lt;0.05]. Meanwhile, they also showed significantly higher synovial counts of CD38+ plasma cells [1240(559~2290) /mm2 vs. 1020(354~1777) /mm2], IgG4+ plasma cells [106 (39~249) /mm2 vs. 68 (3~123) /mm2], and higher ratio of IgG4+/IgG+ plasma cells [26.3 (15.5~38.0) % vs. 15.2 (0.9~24.7) %, all P&lt;0.05].The median IgG4+ plasma cells count was 83 (10~192) /mm2 and median ratio of IgG4+/IgG+ plasma cells was 19.1 (8.4~31.5)%. Both of them correlated positively with ESR, CRP and sIgG4 (r=0.216~0.394, all P&lt;0.05). There were 46 (47.9%) patients with IgG4+ plasma cells &gt;10/HPF, who had significant higher ESR [86 (50~109) mm/h vs. 65 (40~84) mm/h] and CRP [43.35 (16.93~77.85) mg/L vs. 26.15 (9.54~52.53) mg/L, both P&lt;0.05] than those with IgG4+ plasma cells ≤10/HPF. There were 13 (13.5%) patients with the ratio of IgG4+/IgG+ plasma cells &gt;40%, and 11 (11.5%) patients with both IgG4+ plasma cells &gt;10/HPF and IgG4+/IgG+ plasma cells ratio &gt;40% (IgG4-related synovitis). RA patients with IgG4-related synovitis had significant higher ESR than the others [106 (53~125) mm/h vs. 69 (41~91) mm/h, P&lt;0.05].There were 10 (10.4%) patients showing elevated sIgG4 and IgG4-related synovitis. Four patients completed 1-year follow-up and all of them achieved remission at 6th month (SDAI≤3.3, Figure 1). Only one patient had radiographic progression at 12th month.Figure 1.Dynamic disease activity of 4 RA patients with elevated sIgG4 and IgG4-related synovitis during 1-year follow-up.Conclusion:IgG4-related synovitis can be found in RA patients. Their clinical significance in disease characteristics and outcomes are worth further study.Acknowledgements:This work was supported by National Natural Science Foundation of China (no. 81971527, 81801606 and 81801605), Guangdong Natural Science Foundation (no. 2018A030313541 and 2018A030313690), Guangdong Medical Scientific Research Foundation (no. A2018062), Guangdong Basic and Applied Basic Research Foundation (no. 2019A1515011928 and 2020A1515110061), and Science and Technology Program of Guangzhou (no. 201904010088).Disclosure of Interests:None declared

Quantification, epitope mapping and genotype cross-reactivity of hepatitis B preS-specific antibodies in subjects vaccinated with different dosage regimens of BM32.

BackgroundChronic hepatitis B virus (HBV) infections are a global health problem. There is a need for therapeutic strategies blocking continuous infection of liver cells. The grass pollen allergy vaccine BM32 containing the preS domain of the large HBV surface protein (LHBs) as immunogenic carrier induced IgG antibodies in human subjects inhibiting HBV infection in vitro. Aim of this study was the quantification, epitope mapping and investigation of HBV genotype cross-reactivity of preS-specific antibodies in subjects treated with different dosage regimens of BM32MethodsHundred twenty eight grass pollen allergic patients received in a double-blind, placebo-controlled trial five monthly injections of placebo (aluminum hydroxide, n= 34) or different courses of BM32 (2 placebo + 3 BM32, n= 33; 1 placebo + 4 BM32, n= 30; 5 BM32, n= 31). Recombinant Escherichia coli-expressed preS was purified. Overlapping peptides spanning preS and the receptor-binding sites from consensus sequences of genotypes A–H were synthesized and purified. Isotype (IgM, IgG, IgA, IgE) and IgG subclass (IgG1-IgG4) responses to preS and peptides were determined by ELISA at baseline, one and four months after the last injection. IgG1 and IgG4 subclass concentrations specific for preS and the receptor-binding site were measured by quantitative ELISA.FindingsFive monthly injections induced the highest levels of preS-specific IgG consisting mainly of IgG1 and IgG4, with a sum of median preS-specific IgG1 and IgG4 concentrations of >135 μg/ml reaching up to 1.8 mg/ml. More than 20% of preS-specific IgG was directed against the receptor-binding site. BM32-induced IgG cross-reacted with the receptor-binding domains from all eight HBV genotypes A-H.InterpretationBM32 induces high levels of IgG1 and IgG4 antibodies against the receptor binding sites of all eight HBV genotypes and hence might be suitable for therapeutic HBV vaccination.FundingThis study was supported by the PhD program IAI (KPW01212FW), by Viravaxx AG and by the Danube-ARC funded by the Government of Lower Austria. Rudolf Valenta is a recipient of a Megagrant of the Government of the Russian Federation, grant No 14.W03.31.0024.

Definite IgG4-related disease had no overlap with eosinophilic granulomatosis with polyangiitis in Korean patients: a pilot study in one centre.

Serum IgG4 may often increases in allergic diseases. Eosinophilic granulomatosis with polyangiitis (EGPA) has an allergic phase. For this reason, it was questionable whether IgG4-RD and EGPA may share some clinical and laboratory features. In this study, we investigated whether definite IgG4-RD might share those features with EGPA. We retrospectively reviewed the medical records of 42 Korean immunosuppressive drug-naïve patients with definite IgG4-RD. The American College of Rheumatology 1990 criteria for classification (the 1990 ACR criteria) for Churg-Strauss syndrome (CSS, known as EGPA) were applied to patients who were previously diagnosed with definite IgG4-RD and had no antineutrophil cytoplasmic antibody (ANCA). Definite IgG4-RD was defined when 3 components of the comprehensive diagnostic criteria were met. The median age of 42 patients was 61.0years and 69% of them were men. The median serum IgG4 level was 379.0mg/dL and the median IgG4+/IgG+ cells ratio was 50.0%. The most common biopsy site was the salivary gland (14.3%). Antinuclear antibody was detected in 6 patients, and test results for ANCA were negative in all patients. Among 42 patients with definite IgG4-RD without ANCA, none of them met the 1990 ACR classification criteria for EGPA. Definite IgG4-RD found to have no overlap with EGPA when the 1990 ACR criteria for CCS were applied to Korean patients. Key Points • None of 42 Korean patients with definite IgG4-RD without ANCA met the 1990 ACR classification criteria for EGPA. • Definite IgG4-RD found to have no overlap with EGPA in Korean patients without ANCA.

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.

The diagnostic value of serum IgG4 for the diagnosis of IgG4-related disease: and is that so great?

IgG4-related disease (IgG4-RD) is a systemic immune mediated condition that is characterized by the formation of tumor-like fibroinflamma-tory foci in different organs and by the elevation of serum and tissue IgG4 levels in the majority of patients. The pathogenesis of the disease, including the role of IgG4, has not been established exactly. Serum and tissue IgG4 hypersecretion is a nonspecific sign and occurs in many rheumatic, infectious, and malignant diseases. Objective : to determine the range of nosological entities associated with the increase in serum IgG4 levels, as well as the frequency and nature of this increase in patients with IgG4-RD. Patients and methods . The results of all serum IgG4 measurements carried out in the Laboratory of Immunology and Molecular Biology of Rheumatic Diseases, V.A. Nasonova Research Institute of Rheumatology, in 2017—2018 were analyzed. Serum IgG4 parameters were separately estimated in 52 patients with verified IgG4-RD according to the universal diagnostic criteria proposed by H. Umehara et al (2011). Results and discussion . In 2017—2018, a total of247patients were tested for serum IgG4 levels. The latter were elevated in 76 (30.8%) patients, but only 28 (36.8%) were diagnosed as having IgG4-RD. Along with IgG4-RD, antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis, rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) were characterized by increased serum IgG4 levels. The highest median IgG4 level was found in patients with a verified diagnosis of IgG4-RD: 6.31 vs 3.2, 3.22, and 2.69 g/L in ANCA-associated vasculitis, RA, and SLE, respectively. In 52 patients with IgG4-RD, the IgG4 level >1.35 g/L was found in 88% of cases. The median serum IgG4 level was 3.45 g/L (2.1; 11.4). The highest level was observed in patients with generalized lymphadenopathy and in those with IgG4-related sialoadenitis and dacryoadenitis (Mikulicz disease). The serum IgG4 level was positively correlated with the number of affected organs (Spearman's correlation coefficient, 0.39; p=0.0056, Student's t-test). All the patients showed a tendency towards decreasing serum IgG4 levels during treatment regardless of its clinical response; however, the levels returned to normal only in 73% after 12 months of treatment. Conclusion . The increased serum and tissue IgG4 concentration is not specific, but at the moment it is the only disease marker available in clinical practice. To correctly interpret the diagnosis, it is necessary to assess the entire set of clinical manifestations, imaging data, and morpholopathological findings.

Clinical observation of isolated immunoglobulin G4-related sclerosing cholangitis and immunoglobulin G4 sclerosing cholangitis combined autoimmune pancreatitis

Objective: To compare and analyze patient's general condition, laboratory testing and therapeutic responses of isolated immunoglobulin G4- related sclerosing cholangitis (IgG4-SC) and immunoglobulin G4 sclerosing cholangitis combined autoimmune pancreatitis (IgG4-SC/AIP). Methods: A retrospective study was conducted on IgG4-SC patients who attended outpatient and inpatients department of our hospital from April 2014 to March 2018 and their demographic characteristics, laboratory testing, and therapeutic responses were statistically analyzed. Normal distribution of continuous variables was compared with t-test, non-normal distribution of continuous variables was compared using the Mann-Whitney U test, and the categorical variables were compared with χ (2) test. Results: 29 IgG4-SC patients were included, including 19-isolated IgG4-SC and 10 IgG4-SC combined AIP (IgG4-SC/AIP). The average age of onset in the isolated IgG4-SC group was (46.06±19.03) years which was lower than IgG4-SC/AIP group (62.60±15.11), t = -2.360, P < 0.05. The median IgG4 in IgG4-SC/AIP patients is higher than that in isolated IgG4-SC, respectively 10.87 (3.73 ~ 20.13) and 3.14 (2.37 ~ 4.78)g/L(U = 159.000, P < 0.05). IgG4/IgG ratio is higher in IgG4-SC/AIP, than that in isolated IgG4-SC, respectively 0.62(0.23 ~ 0.86) and 0.16(0.10 ~ 0.21), U = 130.000, P < 0.05. Liver cirrhosis was more common in isolated IgG4-SC group (47%) than the IgG4-SC/AIP group (0), χ (2) = 9.637, P < 0.05. The median biochemical response time of isolated IgG4-SC group was 3.00 (2.00 to 4.00) months, which was longer than 1.00 (1.00 to 1.25) months of IgG4-SC/AIP group, U = 30.000, P < 0.05. The biochemical recurrence rate of isolated IgG4-SC group was 32%, which was lower than that of IgG4-SC/AIP (χ (2) = 6.461, P < 0.05). Conclusion: Serum IgG4 level and IgG4/IgG ratio were higher in patients with IgG4-SC/AIP group, and therapeutic responses in isolated IgG4-SC patients were worse than that of IgG4-SC/AIP patients. The efficacy of glucocorticoid monotherapy and immunosuppressive agents combined with glucocorticoid therapy demonstrated no considerable difference in IgG4-SC patients.

Association of immunoglobulin G4 and free light chain with idiopathic pleural effusion.

The cause of pleural effusion remains uncertain in approximately 15% of patients despite exhaustive evaluation. As recently described immunoglobulin (Ig)G4-related disease is a fibroinflammatory disorder that can affect various organs, including the lungs, we investigate whether idiopathic pleural effusion includes IgG4-associated etiology. Between 2000 and 2012, we collected 830 pleural fluid samples and reviewed 35 patients with pleural effusions undiagnosed after pleural biopsy at Yamaguchi-Ube Medical Center. Importantly, IgG4 immunostaining revealed infiltration of IgG4-positive plasma cells in the pleura of 12 patients (34%, IgG4+ group). The median effusion IgG4 level was 41 mg/dl in the IgG4+ group and 27 mg/dl in the IgG4- group (P<0·01). The light and heavy chains of effusion IgG4 antibodies of patients in the IgG4+ group were heterogeneous by two-dimensional electrophoresis, indicating the absence of clonality of the IgG4 antibodies. Interestingly, the κ light chains were more heterogeneous than the λ light chains. The measurement of the κ and λ free light chain (FLC) levels in the pleural fluids showed significantly different κ FLC levels (median: 28·0 versus 9·1 mg/dl, P<0·01) and κ/λ ratios (median: 2·0 versus 1·2, P<0·001) between the IgG4+ and IgG4- groups. Furthermore, the κ/λ ratios were correlated with the IgG4+ /IgG+ plasma cell ratios in the pleura of the IgG4+ group. Taken together, these results demonstrate the involvement of IgG4 in certain idiopathic pleural effusions and provide insights into the diagnosis, pathogenesis and therapeutic opportunities of IgG4-associated pleural effusion.

IgG4-Related Lung Disease: Retrospective Review of 9 Cases

SESSION TITLE: Pulmonary Manifestation of Systemic Disease SESSION TYPE: Original Investigation Poster PRESENTED ON: Wednesday, October 26, 2016 at 01:30 PM - 02:30 PM PURPOSE: IgG4-related disease is a corticosteroid-responsive systemic fibroinflammatory disease that affects various organs. Although pancreatic involvement is the most common presentation, pulmonary manifestation, known as IgG4-related lung disease (IgG4-RLD) has been increasingly recognized. While many reports are from Asian populations, we aimed to clarify the clinical and pathologic aspects of IgG4-RLD in non-Asian populations. METHODS: A retrospective review was conducted of cases with biopsy-proven IgG4-RLD encountered from January 1994 till February 2016 at an academic medical center. IgG4-RLD was defined as meeting at least 2 out of 3 characteristic histopathological features (IgG4-positive lymphoplasmacytic infiltration, fibrosis, and obliterative phlebitis) with IgG4+ cell counts of more than 50 per high power field (HPF) in either surgical or nonsurgical specimens and IgG4+: IgG+ ratio of greater than 0.4 in combination with compatible clinicoradiologic features. We also included cases manifesting at least one histopathologic feature, IgG4+ cell counts per HPF of more than 50 in a surgical specimen or more than 20 in a nonsurgical specimen, with IgG4+: IgG ratio of greater than 0.4, if either elevated serum IgG4 level or initial favorable corticosteroid responsiveness (or complete surgical resection) was seen along with compatible clinicoradiologic features. RESULTS: A total of 9 patients with IgG4-RLD were identified, of which 8 were male and all were Caucasians. The median age at diagnosis was 64 years (interquartile range [IQR], 59-70). Serum IgG4 measurement was available in 8 patients, and the median peak serum IgG4 level was 234 mg/dL (IQR, 93-479). Five patients had respiratory symptoms on presentation, of which cough (N=4) and dyspnea (N=4) were most common, followed by nasal congestion (N=3). The main radiographic abnormality that led to biopsy was seen in the parenchyma (mass or nodule) in 7 patients, the central airway (stenosis) in 1 patient, and the pleura (pleural thickening and effusion) in 1 patient. The secondary radiographic abnormality was seen in 5 patients; 4 had mediastinal and/or hilar lymphadenopathy, and 1 had bronchial stenosis. The median count of IgG4+ cells was 65 (IQR, 49-117) per HPF, and the median IgG4+:IgG+ ratio was 0.56 (IQR, 0.47-0.74). No medical treatment was immediately necessary in 4 patients who underwent complete surgical resection of the pulmonary lesion. Among those patients; however, 3 had a recurrence of IgG4-RLD and received either corticosteroids or steroid-sparing agents during the clinical follow-up. The remaining 5 patients received corticosteroids immediately after the diagnosis of IgG4-RLD. All 5 patients subsequently developed either recurrence of IgG4-RLD or experienced the re-emergence of IgG4-related disease in the extra-pulmonary organs. CONCLUSIONS: IgG4-RLD is the pulmonary manifestation of IgG4-related disease, which commonly affects middle-aged or elderly men, with a high propensity for recurrence. Majority of patients present with mass or nodule with associated lymphadenopathy. CLINICAL IMPLICATIONS: IgG4-RLD mimics malignancy or other infectious or inflammatory conditions in its presentation. DISCLOSURE: The following authors have nothing to disclose: Reina Suzuki, Eunhee Yi, Jay Ryu, Hiroshi Sekiguchi No Product/Research Disclosure Information

A small subgroup of Hashimoto's thyroiditis is associated with IgG4-related disease.

IgG4-related disease is a newly identified syndrome characterized by high serum IgG4 levels and increased IgG4-positive plasma cells in involved organs. The incidence of IgG4-related thyroiditis in the Caucasian population of Europe is unknown. We investigated formalin-fixed thyroid gland samples of 216 patients (191 Hashimoto's thyroiditis, 5 Riedel's thyroiditis, and 20 goiters, as controls), morphologically, and immunohistochemically. Cases were divided into two groups: IgG4-related Hashimoto's thyroiditis (24 cases) together with Riedel thyroiditis (1 case) and 171 non-IgG4-related thyroiditis. Compared to the non-IgG4-related cases, IgG4-related thyroiditis showed a higher IgG4/IgG ratio (0.6 vs. 0.1, p < 0.0001), a higher median IgG4 count (45.2 vs. 6.2, p < 0.0001), an association with younger age (42.1 vs. 48.1 years, p = 0.036), and a lower female-to-male ratio (11:1 vs. 17.5:1). Fibrous variant of Hashimoto's thyroiditis was diagnosed in 23 of the 24 IgG4-related cases (96 %) and in 13 of 167 (18 %, p > 0.001) non-IgG4-related cases. The single case of IgG4-related Riedel's thyroiditis also showed a higher median IgG4 plasma cell count (56.3 vs. 14.3) and a higher IgG4/IgG ratio (0.5 vs. 0.2) than the four cases of non-IgG4-related Riedel's thyroiditis. Our data suggests the incidence of IgG4-related disease (IgG4-RD) of the thyroid gland in Europe is considerably lower than that observed in other studies. A significant elevation of IgG4-positive plasma cells was only found in a small group of Hashimoto's thyroiditis and then accompanied by intense fibrosis, indicating an association with IgG4-RD. Morphologically, IgG4-RD of the thyroid gland differs from that in other organ systems, exhibiting a dense fibrosis without intense eosinophilia or obliterative phlebitis.

OP0115 Igg4-Related Disease Spanish Register: Clinical and Epidemiological Features

BackgroundIgG4-related disease is a rare entity consisting of inflamation and fibrosis that has been described in many locations. Diagnosis may be challenging and concrete diagnostic criteria have been established recently.ObjectivesTo...

IgG4 Levels in Bile for Distinguishing IgG4-Associated Cholangiopathy from Other Biliary Disorders: A Single Blinded Pilot Study.

Background/AimsImmunoglobulin G4 (IgG4)-associated cholangiopathy (IAC) is an inflammatory disease and may mimic primary sclerosing cholangitis (PSC), cholangiocarcinoma (CCA), or pancreatic cancer on cholangiography. We investigated whether IgG4 levels in bile aspirated during endoscopic retrograde cholangiopancreatography (ERCP) can distinguish IAC from PSC, CCA, and pancreatic cancer.MethodsBile was aspirated directly from the common bile duct during ERCP in patients with IAC prior to steroid therapy. For control purposes, bile was obtained from patients with PSC, CCA, pancreatic cancer, and benign biliary conditions (sphincter of oddi dysfunction/choledocholithiasis).ResultsBiliary IgG4 levels were measured in 54 patients. The median bile IgG4 levels were markedly elevated in patients with IAC (5.5 mg/dL; interquartile range [IQR], 5.1 to 15.6) as compared to patients with benign biliary conditions (0 mg/dL; IQR, 0 to 0.1; p=0.003). The median biliary IgG4 levels in PSC, CCA, and pancreatic cancer were 1.2 (IQR, 0.2 to 3.8), 0.9 (IQR, 0.2 to 3.4), and 0.2 mg/dL (IQR, 0.1 to 0.8), respectively. A cutoff value of 3.8 mg/dL distinguished IAC from PSC and CCA patients with 100% and 76.9% sensitivity and specificity, respectively.ConclusionsThe results of this pilot study suggest that measurement of biliary IgG4 levels may have clinical value in distinguishing patients with IAC from biliary disorders that can mimic IAC.

Diagnosis of immunoglobulin g4-related sclerosing cholangitis.

See Levels in Bile for Distinguishing IgG4-Associated Cholangiopathy from Other Biliary Disorders: A Single Blinded Pilot Study) by Udayakumar Navaneethan, Norma G. Gutierrez, Ramprasad Jegadeesan, et al., on page 555-559 Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) is a characteristic type of SC with increased serum IgG4 levels and dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall.1 IgG4-SC is now recognized within the spectrum of systemic IgG4-related diseases. IgG4-SC is well resolved by steroid therapy, which is a characteristic feature of IgG4-related disease. IgG4-SC is frequently associated with type 1 autoimmune pancreatitis (AIP) and IgG4-related sialadenitis; retroperitoneal fibrosis can also occasionally be observed in IgG4-SC. However, some IgG4-SC cases do not involve any other organs. The cholangiographic abnormalities observed in IgG4-SC may resemble those of primary sclerosing cholangitis (PSC) and hilar cholangiocarcinoma. Since obstructive jaundice is frequently observed in IgG4-SC, and IgG4-SC is most common in elderly men, the differential diagnosis compared to that for hilar cholangiocarcinoma is sometimes very difficult. Secondary SC also should be ruled out. An elevated serum IgG4 level is a characteristic feature of IgG4-SC and can effectively detect patients with IgG4-SC.2 However, IgG4-SC patients without pancreatic involvement displayed no marked increase in serum IgG4 levels compared to patients with AIP-associated IgG4-SC. Even though an IgG4 cutoff level of 135 mg/dL is widely used as part of the diagnostic criteria for AIP, a few reports concerning the IgG4 cutoff level in the diagnosis of IgG4-SC have been published.3,4 Oseini et al.3 reported that among 126 patients with cholangiocarcinoma, 17 (13.5%) had elevated serum IgG4 levels (>140 mg/dL), while four (3.2%) had a >2-fold increase (>280 mg/dL) in serum IgG4 levels. They concluded that diagnosis using a 2-fold higher cutoff serum IgG4 level may not reliably distinguish IgG4-SC from cholangiocarcinoma, but a cutoff level 4-fold higher than the normal upper limit had 100% specificity for IgG4-SC. A recent Japanese study, which included 344 IgG4-SC patients, established a cutoff value of serum IgG4 to differentiate IgG4-SC from other diseases in nine high-volume centers in Japan.4 The cutoff obtained from receiver-operator characteristic curves displayed similar sensitivity and specificity to a cutoff of 135 mg/dL, when IgG4-SC cases were compared with controls. A cutoff of 182 mg/dL increased the specificity for distinguishing IgG4-SC from cholangiocarcinoma to 96.6%. A cutoff of 207 mg/dL might be more useful for unambiguously distinguishing IgG4-SC from all cholangiocarcinoma, but the sensitivity was only 68.4%. Only three diagnostic criteria for IgG4-SC have been proposed5,6,7 and no standard international diagnostic criteria have been defined until now. IgG4-SC should be discriminated from all three intractable diseases, namely, pancreatic cancer, PSC, and cholangiocarcinoma. The Japanese criteria were derived from a combination of characteristic clinical, serological, morphological, and histopathological features with cholangiographic classification.6,7 Recently, Navaneethan et al.8 performed a single center pilot study on the diagnostic role of biliary IgG4 in IgG4-SC. They enrolled 54 patients in total, and bile was directly aspirated from the common bile duct during endoscopic retrograde cholangiography. The median biliary IgG4 levels were markedly elevated in patients with IgG4-SC (5.5 mg/dL) compared to patients with other diseases such as PSC (1.2 mg/dL) and cholangiocarcinoma (0.9 mg/dL). A cutoff value of 3.8 mg/dL distinguished IgG4-SC from PSC and cholangiocarcinoma with a 100% and 76.9% sensitivity and specificity, respectively. However, the limitations of this study were the small number of patients enrolled (three patients with IgG4-SC and nine patients with cholangiocarcinoma) and a possibility of type II errors. Therefore, the number of patients is too small to derive a definite cutoff value at present. Another limitation was that serum IgG4 levels were not obtained from the enrolled patients. Despite these limitations, this study suggested a potential role for biliary IgG4 measurement as a diagnostic tool in patients with IgG4-SC. Thus, biliary IgG4 levels can be included in new diagnostic criteria for a prospective large multicenter study.

Autoimmune thyroiditis in children and adolescents with type 1 diabetes mellitus is associated with elevated IgG4 but not with low vitamin D.

To assess levels of vitamin D and of immunoglobulin G subclasses in children and adolescents with type 1 Diabetes Mellitus with or without autoimmune thyroiditis. Among 213 patients with type 1 diabetes, the cases with thyroid-specific autoantibodies formed Group 1 [n=19, M/F: 7/12, median age 13 years (10.1-14.7)]. Nineteen age-, gender-, and diabetes duration-matched cases with type 1 diabetes without any other systemic disease were designated as controls [Group 2, M/F: 7/12, median age 12.9 years (10.5-14.9)]. Levels of thyroid hormones, vitamin D, total IgG and IgG subclasses, as well as IgG subclasses/total IgG ratios were similar between the groups. Five cases (26%) in Group 1 had IgG4 levels > + 2 SDS, whereas there were no such cases in Group 2 (p=0.046). These five patients had similar clinical features but higher median IgG4 levels and IgG4/Total IgG ratios compared to the subjects with IgG4 levels < + 2 SDS in Group 1 and Group 2. There was no difference of vitamin D levels between the groups. Only a small percentage of patients with type 1 diabetes also having autoimmune thyroiditis had elevated serum IgG4 levels, revealing the heterogeneity of autoimmune thyroiditis and existence of IgG4 thyroiditis in the pediatric age group. Total IgG, the other IgG subclasses, and vitamin D levels did not differ in patients with autoimmune thyroiditis and type 1 diabetes compared to those suffering only from type 1 diabetes.

Diagnostic value of IgG4 Indices in IgG4-Related Hypertrophic Pachymeningitis

Diagnosis of IgG4-Related Hypertrophic Pachymeningitis (IgG4-HP) relies on meningeal biopsies, because cerebrospinal fluid (CSF) diagnostic biomarkers are lacking. Here, we determined whether IgG4 intrathecal production could distinguish IgG4-HP from other disorders presenting with HP (OHP). In patients with IgG4-HP, the median CSF IgG4 concentration, IgG4 Index and IgG4Loc were significantly higher than in both controls and OHP. CSF IgG4 levels higher than 2.27mg/dL identified 100% of IgG4-HP and 5% of OHP. An IgG4Loc cut-off of 0.47 identified 100% of IgG4-HP and no cases of OHP. Our results support CSF IgG4 quantification and IgG4 Indices as alternatives to meningeal biopsy for the diagnosis of IgG4-HP when this procedure is contraindicated or uninformative.

Fibrosing variant of Hashimoto thyroiditis is an IgG4 related disease

Hashimoto thyroiditis (HT) and the fibrosing variant of Hashimoto thyroiditis (FVHT) are immune-mediated tumefactive lesions of the thyroid. Immunoglobulin G4-related disease (IgG4-RD) is now a widely recognised multi-organ system disease...

Individualized IgE-based dosing of egg oral immunotherapy and the development of tolerance

Hen's egg allergy is among the most common food allergies in childhood and predicts later development of allergic disease. The optimal efficacy and mechanism(s) of egg allergen immunotherapy are poorly understood. To enhance immunologic and clinical outcomes of egg oral immunotherapy (OIT) using a conditionally increased dosing strategy. In an open-label clinical trial of egg OIT, egg-allergic children ingested daily doses of egg protein that were gradually increased based on the egg white (EW) IgE level. Skin prick test reactivity and EW- and ovomucoid-specific cellular and humoral responses were measured longitudinally. To confirm clinical tolerance, patients underwent double-blinded, placebo-controlled food challenges 1 month after completing the dosing protocol. Children aged 3 to 13 years with characteristics of clinical egg allergy were enrolled. All 6 patients who completed the entire protocol developed clinical tolerance to egg during the study. The median wheal diameter on EW skin prick testing decreased from 10 to 2.5 mm during OIT (P = .03). Both EW and ovomucoid IgE levels significantly decreased during the study (median EW IgE level: from 18.8 kU/L at baseline to 3.9 kU/L, P = .03), and corresponding IgG4 levels increased (median EW IgG4 level: from 0.65 mg/L at baseline to 86.15 mg/L, P = .03). Transient increases were seen in egg-induced interleukin 10 (P = .06) and transforming growth factor β (P = .18) levels, and the ratio of T(H)2:T(H)1 cytokine production was decreased (P = .25). Egg OIT is associated with tolerance acquisition in children with persistent egg allergy. Individualized dosing regimens may be necessary to achieve a full therapeutic effect in some patients.

Elevation of Serum IgG4 in Western Patients With Autoimmune Sclerosing Pancreatocholangitis: A Word of Caution

Autoimmune pancreatocholangitis is characterized by sclerosing inflammation of the biliary tree or pancreatic duct and can mimic pancreaticobiliary malignancy. Serum immunoglobin (Ig) G4 values seem to be helpful in distinguishing autoimmune pancreatocholangitis from pancreatic malignancy in the Japanese population; however, its significance in the Western population has not been well studied. We report a retrospective analysis of 7 consecutive patients with autoimmune pancreatocholangitis and compare them to 23 patients with pancreatic malignancy. Clinical presentation, diagnostic tests, and preoperative IgG4 levels were reviewed in all patients. Presence of autoimmune pancreatocholangitis or pancreatic malignancy was determined by pathologic analysis in all patients and reviewed by a single pathologist. In all patients, autoimmune pancreatocholangitis manifested in a similar fashion to pancreatic malignancy. Median IgG4 levels were far lower in pancreatic cancer patients with localized, resectable disease (24 mg/dL), locally advanced disease (24 mg/dL), and metastatic disease (28 mg/dL) as compared with patients with autoimmune pancreatocholangitis (142 mg/dL, P < .05). Only one patient with pancreatic cancer had an IgG4 level that was >100 mg/dL. In contrast, all patients with autoimmune pancreatitis or cholangitis had levels >100 mg/dL. However, in five of these seven patients, IgG4 levels were below the upper limits of normal. Autoimmune pancreatocholangitis mimics pancreatobiliary malignancy. Serum IgG4 values seem to be helpful in distinguishing autoimmune pancreatocholangitis from malignancy in the Western population. However, absolute values seem to be lower in the United States compared with Japan. The upper limit of normal as reported in laboratories in the United States may not be useful in identifying abnormally high IgG4 values. A new upper limit of normal may need to be defined because IgG subclass determinations are being used more frequently in Western patients with biliary obstruction.