Clinical Heterogeneity and Outcomes of IgG4-Related Disease: Insights from a Tertiary Rheumatology Unit in Hong Kong

ObjectivesTo characterize a single centre retrospective case series of patients with infra-orbital inflammatory masses with autoimmune disease including granulomatosis with polyangiitis (GPA) (formerly Wegener's granulomatosis), eGPA (eosinophillic granulomatosis with polyangiitis)...

This study aimed to explore the clinical characteristics, treatment, and prognosis of IgG4-related disease (IgG4-RD) patients with comorbid autoimmune diseases (AIDs). A total of 879 IgG4-RD patients treatment-naïve at baseline from Peking Union Medical College Hospital were retrospectively included in this study. IgG4-RD patients with comorbid AIDs were classified into the AID-positive (AID-Pos) group, while those without AIDs were classified into the AID-negative (AID-Neg) group. Additionally, AIDs were classified as systemic or organ-specific subgroups. The clinical features, laboratory findings, treatment regimens, and long-term prognosis were compared among the AID-Pos and AID-Neg groups, and the characteristics of AIDs were also explored. AID prevalence in IgG4-RD was 9.67% (85/879), with systemic (n = 47; 55.3%) and organ-specific (n = 38; 44.7%) subtypes. Common AIDs included vitiligo (n = 15; 17.6%), systemic vasculitis (n = 12; 14.1%), psoriasis (n = 12; 14.1%), Hashimoto's thyroiditis (n = 11; 12.9%), and rheumatoid arthritis (n = 10; 11.8%). Most preceded/synchronized with IgG4-RD; 88.2% had a single AID. All groups showed a median of 3 involved organs, but AID-Neg had more multi-organ involvement. AID-Pos had lower IgG4 levels, while systemic AIDs showed higher ESR and IgG1. Treatment and prognosis did not differ between groups. IgG4-RD patients can complicate with other AIDs. Compared with the AID-Neg group, IgG4-RD patients with comorbid AIDs contained a lower proportion of patients with multi-organ involvement, and their patients have lower serum IgG4 levels. The treatment and prognosis were similar between the two groups. Key Points • IgG4-related disease (IgG4-RD) can complicate with autoimmune diseases (AIDs). The relationship between IgG4-RD and AID is yet to be fully elucidated. • 9.67% of IgG4-RD patients (85/879) had comorbid AIDs. AID-positive patients showed lower IgG4, and patients with systemic AIDs showed higher ESR and IgG1. • IgG4-RD and AIDs are not entirely contrary in the diagnosis of IgG4-RD.

To investigate clinical and radiological features of IgG4-related disease (IgG4-RD) patients with intrathoracic involvement.A prospective cohort study was performed and IgG4-RD patients were enrolled from January 2011 to March 2015 in Peking Union Medical College Hospital, in which the clinical and radiological characteristics of IgG4-RD patients with intrathoracic involvement were summarized.Out of total 248 cases with IgG4-RD, 87 cases had intrathoracic lesions, including 58 male cases and 29 female cases, with average age of 54.19 ± 13.80 years. Hilar and mediastinal lymphadenopathy were the most common manifestations of IgG4-related intrathoracic disease, accounting for 52.9% (46/87). Other imaging findings of pulmonary disease included: solid nodular (25.3%), round-shaped ground-glass opacities (9.2%), alveolar-interstitial type (20.7%), bronchovascular type (23.0%), pleural effusion (4.6%), and pleural nodules or thickening (16.1%). Only 27 patients presented with respiratory symptoms, including cough, breathless, chest pain, and asthma. Compared with patients without intrathoracic disease, IgG4-related intrathoracic disease had higher IgG4 and C-reactive protein level, and higher incidence of allergy, fever, and multi-organ involvement. Most of lung interstitial disease, mediastinal mass, and bronchial thickening were sensitive to corticosteroid and immunosuppressant therapy, while 36.3% (8/22) of solitary nodular lesions were unresponsive to treatment. Eight patients were on no treatment, with 5 cases remained stable, 2 patients improved spontaneously, and 1 patient was lost follow-up.Intrathoracic lesions are not rare in patients with IgG4-RD, involving bronchial thickening, nodules, ground glass opacity, pleural thickening/effusion, lymphadenopathy, etc. Efficacy of corticosteroid and immunosuppressant therapy were noted in most of patients with lung interstitial disease, mediastinal mass, and bronchial thickening.

BackgroundThis study was undertaken in an attempt to characterize the frequency and clinical features of lung nodules in IgG4 related disease (IgG4-RD) patients as an insight for help with the diagnosis of lung nodules.MethodsA retrospective study was carried out in West China Hospital, Sichuan University from January 2012 to December 2018, 89 patients with definite IgG4-RD were enrolled.ResultsFifty of 89 patients with definite IgG4-RD had radiologically confirmed lung nodules, 6 of whom were diagnosed with definite IgG4 related lung disease. Lung nodules detected in more than 40 patients were small and solid, always with regular margins. Multiple (41/50) and bilateral (34/50) distributions was also a major characteristic of these lung nodules. Lobulation and speculation were simultaneously detected in 3 patients, including 2 patients combined with pleural indentation. Calcification of nodules was detected in only one patient. Thirty-seven patients also had additional radiological abnormalities of lungs, including ground-glass opacity (21/50), thickening of pleura (9/50), thickening of interlobular septa (4/50), thickening of bronchial wall (3/50), pleural effusion (4/50), mass (3/50), interstitial changes (5/50), and mediastinal or hilar lymphadenopathy (32/50). Most patients (44/50) were treated with glucocorticoids alone or combined with immunosuppressive agents. Sixteen patients received a re-examination by chest computed tomography (CT) scan after treatment, 10 of whom showed a decrease in the size and/or the number of nodules.ConclusionsThe incidence of lung nodules in IgG4-RD patients can be high. For an IgG4-RD patient with lung nodules, the possibility that the lung nodules related to IgG4-RLD is high. It is hard to differentiate IgG4 related lung nodules from other lung diseases, in particular, lung cancer. Radiological characteristics and positive responses to glucocorticoids and immunosuppressive agents can help with the differential diagnosis. For these patients, regular follow-up is also important.

In clinical practice, we found that IgG4-related disease (IgG4-RD) patients complicated with allergic rhinitis (AR)/chronic rhinosinusitis (CRS) seemed to have unique characteristics different from patients with IgG4-RD alone. In this study, demographic, clinical and laboratory characteristics of IgG4-RD patients complicated with AR/CRS were investigated. We retrospectively analyzed 756 IgG4-RD patients who were recruited in four medical centers from 2009 to 2021. We divided 756 IgG4-RD patients into 2 groups: the case group included IgG4-RD patients complicated with AR/CRS, and the control group included IgG4-RD patients without AR/CRS. 411 patients were complicated with AR/CRS among 756 IgG4-RD patients. Multiple organs involvement (≥ 3, p < 0.0001, OR 3.585 (95% CI 2.655–4.839)) and other types of allergic disease (p < 0.0001, OR 2.007 (95% CI 1.490–2.693)) were more common in the case group. Patients in the case group had a higher level of serum IgG4 (650 mg/dL vs 385 mg/dL, p < 0.0001), IgE (347 mg/dL vs 98 mg/dL, p < 0.0001) and ESR (14 mm/h vs 12 mm/h, p < 0.05). High IgE level (p < 0.01, OR 1.003 (95% CI 1.001–1.005)) and other types of allergic disease (p < 0.05, OR 3.196 (95% CI 1.146–8.908)) were risk factors for patients in the case group, in which most patients had nasal manifestations before the diagnosis of IgG4-RD. The median time interval from nasal symptoms appearance to IgG4-RD diagnosis was − 120 and − 90 months for patients complicated with AR and CRS, respectively. IgG4-RD patients are often complicated with AR/CRS and have distinct characteristics, which appear to be a subgroup of IgG4-RD. The data suggests a pathogenic association of IgG4-RD and AR/CRS.

We aimed to compare the demographic, clinical and laboratory characteristics between IgG4-related kidney disease (IgG4-RKD+) and extrarenal IgG4-related disease (IgG4-RKD−) in a large Chinese cohort, as well as describing the radiological and pathological features of IgG4-RKD+. We retrospectively analyzed the medical records of 470 IgG4-related disease (IgG4-RD) patients at Peking University People’s Hospital from January 2004 to January 2020. The demographic, clinical, laboratory, radiological and pathological characteristics between IgG4-RKD+ and IgG4-RKD− were compared. Twenty IgG4-RD patients who had definite etiology of renal impairment including diabetes, hypertension and etc. were excluded. Among the remained 450 IgG4-RD patients, 53 were diagnosed with IgG4-RKD+ . IgG4-RKD+ patients had older age at onset and at diagnosis. Male to female ratio of IgG4-RKD+ patients is significantly higher. In the IgG4-RKD+ group, the most commonly involved organs were salivary gland, lymph nodes and pancreas. It was found that renal function was impaired in approximately 40% of IgG4-RKD+ patients. The most common imaging finding is multiple, often bilateral, hypodense lesions. Male sex, more than three organs involved, and low serum C3 level were risk factors for IgG4-RKD+ in IgG4-RD patients. These findings indicate potential differences in pathogenesis of these two phenotypes.

Dedicated studies evaluating the impact of COVID-19 on outcomes of pancreatobiliary IgG4 related disease (IgG4-RD) patients are scarce. Whether COVID-19 infection or vaccination would trigger IgG4-RD exacerbation remains unknown. Pancreatobiliary IgG4-RD patients ≥18years old with active follow-up since January 2020 from nine referral centers in Asia, Europe, and North America were included in this multicenter retrospective study. Outcome measures include incidence and severity of COVID-19 infection, IgG4-RD disease activity and treatment status, interruption of indicated IgG4-RD treatment. Prospective data on COVID-19 vaccination status and new COVID-19 infection during the Omicron outbreak were also retrieved in the Hong Kong cohort. Of the 124 pancreatobiliary IgG4-RD patients, 25.0% had active IgG4-RD, 71.0% were on immunosuppressive therapies and 80.6% had ≥1 risk factor for severe COVID. In 2020 (pre-vaccination period), two patients (1.6%) had COVID-19 infection (one requiring ICU admission), and 7.2% of patients had interruptions in indicated immunosuppressive treatment for IgG4-RD. Despite a high vaccination rate (85.0%), COVID-19 infection rate has increased to 20.0% during Omicron outbreak in the Hong Kong cohort. A trend towards higher COVID-19 infection rate was noted in the non-fully vaccinated/unvaccinated group (17.6% vs 33.3%, P=0.376). No IgG4-RD exacerbation following COVID-19 vaccination or infection was observed. While a low COVID-19 infection rate with no mortality was observed in pancreatobiliary IgG4-RD patients in the pre-vaccination period of COVID-19, infection rate has increased during the Omicron outbreak despite a high vaccination rate. No IgG4-RD exacerbation after COVID-19 infection or vaccination was observed.

Proteomic analyses of plasma-derived exosomes in immunoglobulin (Ig) G4-related disease and their potential roles in B cell differentiation and tissue damage

The innate immune system participates in immunoglobulin G4-related disease (IgG4-RD). While the role of innate lymphoid cells (ILCs) in IgG4-RD remains to be elucidated, we aimed to evaluate the phenotype, function and clinical significance of ILCs in IgG4-RD patients. Sixty-seven untreated IgG4-RD patients and 44 age- and sex-matched healthy controls (HCs) were enrolled. Circulating and tissue infiltration of ILCs were detected by flow cytometry. Serum suppression of tumorigenicity 2 (sST2) was detected by ELISA and membrane-bound ST2 (ST2L) was detected by flow cytometry. Tissue infiltration of IL-33 was measured by immunohistochemistry staining. Real-time quantitative PCR was performed to analyse the expression pattern of ILC2-associated genes between HCs and IgG4-RD patients. In addition, correlation analysis was performed in order to evaluate the clinical significance of ILCs in IgG4-RD. The frequency of circulating pan ILCs in IgG4-RD patients was lower than in HCs. ILC2s were higher in IgG4-RD compared with HCs, whereas ILC1s were lower in IgG4-RD. sST2 and ST2L were higher in IgG4-RD than in HCs. Infiltration of ILC1s in the submandibular glands of IgG4-RD patients was more prominent than ILC2s. Intracellular secretion of IL-9 was increased in ILC2s of IgG4-RD patients than in HCs. Circulating ILC2s correlated positively with Treg cells and the surface expression of CD154, PD-1 and CXCR5 in ILC2s correlated positively with CD19+ B cells, serum IgG4 levels and serum IgE, respectively. ILCs and their subsets were significantly altered in IgG4-RD. We demonstrated the dysfunction of ILC2s in IgG4-RD by phenotype, correlation analysis and function investigation, revealing ILC2s participated in the pathogenesis of IgG4-RD.

BackgroundIgG4-related disease (IgG4-RD) is not rare and clinically important disease. It is very difficult to confirm the diagnosis because IgG4 positive lymphocyte infiltrates various organs such as pancreas, salivary glands,...

Background:IgG4-related ophthalmic disease (IgG4-ROD) is one of the phenotypes of IgG4-related disease (IgG4-RD), and its lesions are mainly located in the ocular. Currently, there are few studies on IgG4-ROD and...

The clinical utility of serum immunoglobulin free light chains (sFLC) in IgG4-related disease (IgG4-RD) is unknown. Herein we evaluated their association with clinical phenotypes, serology and activity in patients with IgG4-RD. Cross-sectional study that included 45 patients with IgG4-RD, and as controls 25 with Sjögren’s syndrome (SS) and 15 with sarcoidosis. IgG4-RD patients were classified in clinical phenotypes: pancreato-hepato-biliary, retroperitoneum/aorta, head/neck-limited and Mikulicz/systemic; as well as proliferative vs. fibrotic phenotypes. We assessed the IgG4-RD Responder Index (IgG4-RD RI) at recruitment and measured IgG1, IgG4, κ and λ sFLC serum levels by turbidometry. sFLC levels were similar among IgG4-RD, SS and sarcoidosis groups. Regarding the IgG4-RD patients, the mean age was 49 years, 24 (53.3%) were men and 55.5% had activity. Eight (17.7%) belonged to pancreato-hepato-biliary, 6 (13.3%) to retroperitoneum/aorta, 14 (31.1%) to head/neck-limited, 16 (35.5%) to Mikulicz/systemic phenotypes, whereas 36 (80%) to proliferative and 9 (20%) to fibrotic phenotypes. High κ sFLC, λ sFLC and κ/λ ratio were present in 29 (64.4%), 13 (28.9%) and 13 (28.9%) of IgG4-RD patients, respectively. There were no differences in sFLC among IgG4-RD phenotypes. κ sFLC and κ/λ ratio correlated positively with the number of involved organs and IgG4-RD RI. Patients with renal involvement had higher κ sFLC and λ sFLC. The AUC for κ sFLC and λ sFLC, for renal involvement was 0.78 and 0.72, respectively. Active IgG4-RD had higher levels of κ sFLC and more frequently a high κ/λ ratio. The AUC for κ sFLC and κ/λ ratio for predicting active IgG4-RD was 0.67 and 0.70, respectively. sFLC correlated positively with IgG1 and IgG4 levels. sFLC may be useful as a biomarker of disease activity as well as multiorgan and renal involvement. In particular, a high κ/λ ratio may identify patients with active disease.

Background:Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized systemic disease that can involve multiple organs and various clinical phenotypes. The purpose of this study was to analyze different types of organ involvement in IgG4-RD patients in China.Methods:We conducted a prospective cohort study on IgG4-RD patients to analyze the clinical manifestations and rare features of IgG4-RD. Patients were grouped into different types according to organ involvement regarding organ number and organ site. The constituent ratio in different types was also analyzed.Results:A total of 200 IgG4-RD patients, with a male:female ratio of 2.08:1, were grouped into different types. Cases having involvement of two or three organs were the most common whereas the fewest number of patients had multi-organ (≥4) involvement. Serum IgG4 and IgE levels, IgG4/IgG ratio, and percentage of eosinophils increased as the number of involved organs increased. In addition, constituent ratio analysis revealed that patients with salivary gland/lacrimal gland swelling, who also constituted the largest number of IgG4-RD patients, had higher serum IgG4 concentrations and IgG4/IgG values, had higher percentage of Eos, and were more likely to have had a history of allergies relative to patients with internal organ involvement.Conclusions:The characteristic feature of IgG4-RD is multiple organ involvement with various clinical manifestations and different types. Although serum IgG4 levels increased with the number of involved organs, serum IgG4 levels were higher for those patients with salivary gland/lacrimal gland swelling compared with those with internal organ involvement. Thus, valuable clues to the differential diagnosis of IgG4-RD could be obtained by examining the clinical patterns of organ involvement.

Background:IgG4-related disease (IgG4RD) is a chronic and systemic disease that is characterised by multiple organ inflammation, elevated serum IgG4, and storiform fibrosis. IgG4RD often presents with organ enlargement and can...

Immunoglobulin G4-related disease (IgG4-RD) share clinical features with primary Sjögren's syndrome (pSS). This study aimed to identify altered serological parameters and potential biomarkers of IgG4-RD and pSS. Forty IgG4-RD patients, 40 pSS patients, and 40healthy controls (HC) were enrolled in this study. Routine serological parameters and clinical manifestations were assessed. IgG subclasses (IgGSc) were detected using a Siemens BN P, and lymphocyte subsets were analyzed using flow cytometry. Cytokines assays were performed using cytometric bead array. Compared to pSS, IgG4-RD patients had higher IgG4 (p <0.001) and lower IgG1 (p =0.014). The natural killer (NK) cells (p = 0.004), CD4+ T cells (p = 0.028), and TBNK cells (p = 0.040) were increased in IgG4-RD compared to pSS. IgG4 used to differentiate IgG4-RD from pSS produced an area under the curve (AUC) of up to 0.952. In addition, we compared serum parameters, immune cells, and cytokines of IgG4-RDwith mouth dryness or eye dryness with those of pSS with the same symptoms, and similar serological changes were observed. IgG4-RD patients with mouth dryness had higher IgG4 (p <0.001) and Th cells (p = 0.016) but lower IgG1 (p = 0.009) compared to pSS with dry mouth. IgG4-RD patients with eye dryness had higher levels of IgG4 (p <0.001), Treg cells (p = 0.037), and NK cells (p = 0.017) than pSS patients with eye dryness. Moreover, IgG4-RD patients with mouth and eye dryness had higher levels of B (p = 0.006), Th (p = 0.026), Th2 (p = 0.007), and Treg cells (p = 0.028) than IgG4-RD patients without mouth and eye dryness. Immune system disorder is an outstanding feature of IgG4-RD, and its feature differ from pSS. Assessment of immune status is important in the diagnosis and differential diagnosis of IgG4-RD.