Efficacy and safety of mirikizumab in paediatric participants with moderately-to-severely active ulcerative colitis (SHINE-1): a multicentre, open-label, non-randomised phase 2 trial.

Sarcoidosis is a systemic disease of unknown etiology, characterized by granulomatous inflammation in various organs. Elevated serum Immunoglobulin G4 (IgG4) levels are typically associated with IgG4-related disease (IgG4-RD), characterized by plasma cell infiltration and fibrosis, but their role in sarcoidosis remains unclear. Given the fibro-inflammatory nature of both conditions, this study aimed to describe a cohort of sarcoidosis patients with elevated IgG4 levels and explore the potential clinical relevance of this finding. We retrospectively analyzed biopsy-confirmed sarcoidosis cases with measured serum IgG4 levels. Clinical data were gathered, including demographics, organ involvement, pulmonary function tests (PFTs), sarcoidosis-associated pulmonary hypertension (SAPH), and markers of autoimmunity. The study cohort included ten patients with a mean age of 50 ± 15 years, comprising six males and seven Black individuals. Two patients reported a family history of sarcoidosis; the mean body mass index (BMI) was 28.5 ± 5.7. Five patients were never smokers, and four were former smokers. Eight patients had lung involvement, two with advanced Scadding stage 4, four with airflow obstruction, and two with restriction physiology on PFT. Out of seven patients with echocardiography, five had SAPH. Other organ manifestation included ocular disease in three patients, joint involvement in two, liver disease in two, and heart disease in one. Autoimmune markers were present in five patients. These findings suggest a potential overlap between IgG4-RD and sarcoidosis. Further research is needed to clarify IgG4's role in sarcoidosis and whether elevated serum IgG4 identifies a subset of patients who may benefit from B-cell depletion therapies.

The sole approved treatment for egg allergy is abstaining from consuming eggs. We assessed the effectiveness of oral immunotherapy (OIT) utilizing egg-white powder to treat egg allergy in children. This is a randomized clinical trial on patients with egg white allergy. A desensitization protocol for egg allergies involves a modify rush desensitization method with a build-up and maintenance phase. During the build-up phase, patients consume increasing doses of egg white powder mixed with mashed potatoes for 5-7 days until they can tolerate a whole egg white. During the maintenance phase, patients consume a daily intake of whole cooked egg whites for six months. After two weeks of abstinence, a food challenge test is administered to determine if the patient has developed tolerance. Thirty-two patients aged 4-7 years with egg white hypersensitivity were recruited. Sixteen participants were in the intervention group, and 16 were in the control group. The intervention group had the highest number of anaphylaxis reactions on day one. During the build-up phase, all patients in the intervention group experienced 60 responses, with skin reactions being the most common. In the maintenance phase, patients were prescribed medications to ensure the success of desensitization. After six months, the intervention group demonstrated a higher tolerance rate for egg whites compared to the control group. Before OIT, the levels of total immunoglobulin E (IgE), serum immunoglobulin G4 (IgG4), and Radioallergosorbent Test (ImmunoCAP RAST) were similar between the intervention and control groups. After OIT, the level of IgG4 increased in the intervention group and decreased in the control group. ImmunoCap RAST increased in both groups, but significantly more in the intervention group. Skin Prick Test (SPT) wheal decreased significantly in the intervention group but not in the control group. The size of the SPT flare significantly decreased in the intervention group but remained the same in the control group. OIT is adequate for most children with egg allergies. It is a promising intervention for food allergies, but the mechanism underlying its efficacy remains unclear. A better understanding of risks and effective dosing schedules is needed for it to become a recommended standard of care. Long-term immune tolerance strategies are also critical. (No. IRCT20190116038387N1).

Enhanced Detection of Dermal-Binding Autoantibodies in Pemphigoid Diseases with a Modified Indirect Immunofluorescence Cell-Based Mosaic Assay using Immunoglobulin G4 and Optimized Testing Conditions: A Single-Centre Retrospective Study.

ImmunoglobulinG4 (IgG4)-related diseases are aheterogenous group of chronic inflammatory systemic disorders characterized by fibrosing inflammation with infiltration of IgG4-positive plasma cells. They can affect nearly any organ system. Typical manifestations include autoimmune pancreatitis, sclerosing cholangitis, lymphadenopathy, retroperitoneal fibrosis, and inflammatory orbitopathy as well as involvement of the salivary and lacrimal glands. Each manifestation may present in isolation or in combination with others. Diagnosis requires careful exclusion of malignant or other inflammatory conditions, as IgG4-related diseases can mimic awide range of disease entities. Amultimodal approach combining laboratory findings, histopathological evaluation and radiological imaging is essential for establishing the diagnosis. Astructured diagnostic algorithm and close interdisciplinary collaboration are crucial to avoid misdiagnosis and enable appropriate treatment.

A 72-year-old male patient with jaundice and hilar bile duct stenosis, initially suspected to have cholangiocarcinoma, was referred to our hospital. Subsequent cholangiography revealed bile duct stenosis improvement, and intraductal ultrasonography demonstrated homogeneous bile duct wall thickening. The increased serum immunoglobulin G4 (IgG4) levels and the presence of other organ lesions possibly indicated to IgG4-related sclerosing cholangitis (IgG4-SC). After 2 months, the patient developed acute cholecystitis. Endoscopic ultrasonography revealed circumferential wall thickening that extended from the common bile duct to the cystic duct. Cholangiography demonstrated cholecystic duct stenosis. The cholecystitis might have originated from bile stasis caused by cystic duct stenosis associated with IgG4-SC. Consequently, both IgG4-SC and the cholecystitis improved with steroid treatment.

ABSTRACT Background: Papillary thyroid carcinoma represents the most common thyroid cancer. The co-existence of Hashimoto thyroiditis and papillary thyroid carcinoma has long been described in clinical research; however, the relationship is still debatable. This study aimed to estimate the coexistence of Hashimoto's thyroiditis and papillary thyroid carcinoma and to correlate these two conditions with the expression of immunological markers, including CD19 and IgG4, and with clinicopathological factors. Methods: The research conducted a retrospective investigation evaluating thyroid tissue obtained from papillary thyroid carcinoma patients with Hashimoto thyroiditis or tumor-associated lymphocytes coexistence. The examination determined B-cell and plasma cell infiltration using CD19 and immunoglobulin G4 markers to correlate them statistically with demographic and clinicopathological variables. Results: Showed coexistence of Hashimoto thyroiditis and tumor-associated lymphocytes with papillary thyroid carcinoma in 74%. A significant association between immunoglobulin G4-related disease and age was detected in patients below 45 years, particularly among those with Hashimoto thyroiditis (P=0.039), and with the histological subtypes in patients with classic variant (66.7% in Hashimoto thyroiditis and 20% in tumor-associated lymphocytes) (P=0.049). In contrast, other clinicopathological findings showed no correlation to Hashimoto thyroiditis and immunological markers. Conclusions: The high percentage of the coexistence of Hashimoto thyroiditis with papillary thyroid carcinoma, together with the predominance of immunoglobulin G4-related disease in young age patients, draws attention to immunobiological mechanisms behind this cancer, which might help in the development of modern-immune-based diagnostic and therapeutic approaches.

IntroductionCoronary involvement in immunoglobulin G4–related disease (IgG4-RD) has remained underexplored despite its risk posed in terms of major adverse cardiovascular events (MACEs). The study provides a comprehensive review, particularly focusing on multimodal imaging characteristics and clinical applicability.MethodsA systematic review was conducted on IgG4-related coronary involvement, supplemented by serial cases from our center included. We analyzed clinical features and multimodal imaging, focusing on the presence or absence of cardiovascular symptoms.ResultsA total of 134 IgG4-RD patients with coronary involvement were included and analyzed, including 118 from the literature and 16 from our center. Seven (5%) patients died from secondary myocardial ischemia/infarction. Coronary anomalies commonly affected the left anterior descending artery (LAD) (79%) and presented as diffuse wall thickening or periarterial soft tissue encasement (85%). Stenosis was frequent (47%) and often secondary. Symptoms, primarily induced by myocardial ischemia or infarction (84%), were largely due to stenosis (68%). Chest computed tomography (CT) and coronary computed tomography angiography (CTA) were the primary imaging modalities (81%), particularly in symptomatic cases (88%). Positron emission tomography-computed tomography (PET-CT) was applied in 55 patients (41%) and often in asymptomatic cases (51%). CMR, though less adopted (23%), demonstrated potential in detecting coronary lesions (77%). Glucocorticoid therapy is the most common (76%), with the best response of periarterial encasement (66%). Surgery was less common (32%), primarily being applied to aneurysms (63%).ConclusionCoronary involvement in IgG4-RD presents four phenotypes, sometimes with an insidious onset and as the sole affected site, poses a potential risk for MACEs. Multimodal imaging is essential for early diagnosis and effective monitoring, with coronary CMR showing promise for early detection without the risk of radiation-induced inflammation and fibrosis.

Esophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of all esophageal cancer cases and is associated with poor prognosis. However, recent advancements have transformed the treatment landscape. Tislelizumab, a humanized immunoglobulinG4 (IgG4) anti-programmed cell death protein1 (PD-1) monoclonal antibody, was developed to overcome resistance mechanisms by minimizing binding to FcγR on macrophages. The RATIONALE-302 clinical trial showed statistically significant survival benefits of tislelizumab over chemotherapy in second-line ESCC highlighting the necessity of evaluating comparative efficacy with existing treatments. This study aimed to identify trials evaluating anti-PD-1 therapies for second-line ESCC and indirectly estimate the relative efficacy of tislelizumab versus existing anti-PD-1 therapies. A systematic literature review (SLR) was originally conducted in 2021 then updated in 2022 and 2023. A feasibility assessment (FA) was undertaken to evaluate required assumptions for indirect treatment comparisons (ITCs) and determined that anchored simulated treatment comparisons (STCs) were the most appropriate methodology. Assessed outcomes included overall survival (OS), progression-free survival (PFS), and grade ≥ 3 treatment-related adverse events (TRAEs). Analyses were conducted in the hazard ratio scale for OS and PFS and in the odds ratio scale for TRAEs, whilst uncertainty was expressed in 95% confidence intervals. The SLR identified 13 studies, six of which evaluated immunotherapies and were included in the FA. All studies were deemed similar and considered in the ITC, except for RAMONA, which differed substantially in study design, inclusion criteria, and patient characteristics. Indirect estimates obtained from the STCs were not statistically significant, except for the comparison of TRAEs with tislelizumab versus camrelizumab, where tislelizumab was more favorable. Tislelizumab appears comparable to existing anti-PD-1 therapies (nivolumab, pembrolizumab, camrelizumab, and sintilimab) in OS, PFS, and TRAEs of grade ≥ 3 for patients receiving second-line treatment for ESCC with a potentially more favorable TRAE grade ≥ 3 profile than camrelizumab that requires confirmation. NCT03430843.

The aetiology of crescentic glomerulonephritis is multifactorial, with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and anti-glomerular basement membrane (GBM) antibody disease being well-documented causes. Monoclonal immunoglobulin and immunoglobulin G4 (IgG4)-related diseases can also exacerbate kidney damage through varying mechanisms. However, cases where both ANCA and anti-GBM antibodies are positive, in the presence of serum M protein and elevated IgG4 levels, have not yet been reported. We herein report the first patient with dual ANCA and anti-GBM antibody-positive crescentic glomerulonephritis, along with monoclonal gammopathy and elevated IgG4 levels.

BackgroundBepranemab is a recombinant, humanized, full‐length immunoglobulin G4 monoclonal antibody that targets a mid‐region epitope of human tau considered essential for aggregation. TOGETHER (NCT04867616), a Phase II participant‐ and investigator‐blind, randomized, placebo‐controlled study, assessed efficacy and safety of bepranemab in people with prodromal–mild Alzheimer’s disease (AD). The relationships between clinical measures and systemic bepranemab exposure, in conjunction with placebo response, were investigated through modeling and simulation, to support bepranemab dosing for further clinical development.MethodsPharmacokinetic, demographic, and efficacy data from a low tau burden or apolipoprotein ε4 (APOε4) genotype non‐carrier subpopulation (N=189; age range: 69.7–72 years), a “responder” population to bepranemab in the TOGETHER study (in which participants received 45 mg/kg bepranemab, 90 mg/kg bepranemab, or placebo every 4 weeks [Q4W] for <76 weeks), were modeled using non‐linear mixed‐effect models. Disease progression models, assessing Baseline scores and the influence of selected clinical covariates, were developed separately for Clinical Dementia Rating Sum of Boxes (CDR‐SB), Alzheimer's Disease Assessment Scale‐Cognitive subscale (ADAS‐Cog) 14, and tau‐positron emission tomography (PET; whole cortical gray and jack temporal meta), with each model characterizing the time‐course of placebo response and a change of response due to bepranemab exposure. Model‐based simulations were conducted to predict improvements in the 80‐week time course of each endpoint due to bepranemab dosing at 45, 60, and 90 mg/kg Q4W, versus placebo, in larger study participant cohorts with low and high tau burdens.ResultsThe time courses of CDR‐SB, ADAS‐Cog 14, and tau‐PET were best described by linear disease progression models. In each model, bepranemab exposure (concentrations) in all dose cohorts was found to reduce clinical markers of AD progression. For all models, simulations predicted that higher bepranemab doses (ie, >45 mg/kg) may result in improved clinical outcomes versus placebo in prodromal–mild AD.ConclusionsExposure‐response modeling and simulation of TOGETHER study data confirmed improvement in clinical outcomes with bepranemab in a prodromal–mild AD population with low tau burden or APOε4 non‐carriers. The modeling also predicted that higher bepranemab doses are likely to be therapeutically beneficial (vs placebo) in future clinical trials.

BackgroundBepranemab is a recombinant, humanized, full‐length immunoglobulin G4 monoclonal antibody that targets a mid‐region epitope of human tau. TOGETHER (NCT04867616), a Phase II participant‐ and investigator‐blinded, randomized, placebo‐controlled study, assessed efficacy and safety of bepranemab in people with prodromal–mild Alzheimer’s disease (AD). Previously presented data from TOGETHER indicate a clinical benefit with bepranemab. Here, we describe the effect of bepranemab on tau accumulation in the brain in study participants with prodromal or mild AD.MethodsParticipants (aged 50–80 years) received bepranemab (45 mg/kg or 90 mg/kg, intravenously every 4 weeks) or placebo over an 80‐week treatment period. Participants received [18F] Genentech tau probe 1 (GTP1) and underwent positron emission tomography (PET) imaging at Baseline, Week 56, and Week 80. Eligibility criteria included prodromal–mild AD (National Institute on Aging and the Alzheimer's Association 2018 Stage 3/4); cerebral amyloid beta presence (PET or cerebrospinal fluid); global Clinical Dementia Rating (CDR) score of 0.5; CDR‐Memory Box score ≥0.5. Secondary objectives included investigating the effect of bepranemab on tau‐PET imaging at Weeks 56 and 80. PET images were analyzed by a central imaging laboratory to determine the standardized uptake value ratio relative to cerebellum in multiple brain regions.ResultsIn total, 466 participants were randomized 1:1:1 across three arms (90 mg/kg bepranemab, 45 mg/kg bepranemab, placebo). Bepranemab slowed tau accumulation (by 33–58% vs placebo, across both bepranemab arms) in the whole cortical gray (n=scanned/total: 90 mg/kg bepranemab [n=113/152], 45 mg/kg bepranemab [n=104/152], and placebo [n=97/156]) and jack temporal meta regions (n=scanned/total: 90 mg/kg bepranemab [n=114/152], 45 mg/kg bepranemab [n=105/152], and placebo [n=97/156]) at Week 80 in the initial analysis of the full trial population (those who received at least a partial dose of study medication and had at least one valid post‐Baseline clinic visit and efficacy assessment). Data on tau accumulation in regions based on Braak staging will be presented.ConclusionTOGETHER provides the first clinical demonstration of slowing of tau accumulation with an antibody targeting the tau mid‐region, as evidenced by tau PET imaging, and marks the first time that any tau‐directed therapy has demonstrated a clinical benefit.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a systemic inflammatory disorder characterized by abundant infiltration of IgG4-positive lymphocytes and plasma cells with fibrosis in the involved organs. Periarterial lesions are relatively rare manifestations of IgG4-RD, and their clinical and imaging findings remain unclear. A 66-year-old man presented with persistent upper abdominal pain. Contrast-enhanced computed tomography (CECT) showed a gradually enhanced 47mm soft tissue mass lesion adjacent to the pancreatic uncinate and spreading around the superior mesenteric artery. Considering the imaging findings, pancreatic cancer could not be ruled out. We decided to perform an endoscopic ultrasound-guided fine-needle biopsy to confirm the histological diagnosis; however, we could not obtain a sufficient amount of tissue. Finally, the patient was diagnosed with IgG4-related periarteritis by performing a percutaneous biopsy of the lesion. The patient was treated with oral prednisolone (PSL) and approximately six months after PSL induction, CECT revealed marked shrinkage of the lesion. Although imaging findings are important for diagnosis, histopathological findings are essential for accurate clinical diagnosis. All possible means, including percutaneous targeted biopsy, should be attempted to acquire sufficient tissue to confirm the pathological diagnosis to enable appropriate treatment.

BackgroundXeligekimab is a novel immunoglobulin G4 (IgG4) monoclonal antibody targeting interleukin-17A (IL-17A). In a phase III trial in patients with plaque psoriasis, xeligekimab showed efficacy and safety consistent with other IL-17A inhibitors, supporting its potential application in the treatment of spondyloarthritis.ObjectiveThis phase III trial aimed to investigate the efficacy and safety of xeligekimab in patients with radiographic axial spondyloarthritis (r-axSpA).MethodsThis was a phase III study conducted at multiple centers in China. Eligible patients were randomly assigned (1:1:1) to receive xeligekimab 100 mg, xeligekimab 200 mg, or placebo. Randomization was stratified by medication history (biologic-experienced vs. biologic-naïve) and weight (≥ 70 kg vs. < 70 kg). The primary endpoint was the proportion of patients achieving an Assessment of SpondyloArthritis International Society 20 (ASAS20) response at week 16. A key secondary endpoint was the ASAS40 response rate at the same time point.ResultsA total of 465 patients were recruited. A significantly higher proportion of patients receiving xeligekimab 200 mg (n = 114 (74.0%); p < 0.001, 95% confidence interval (CI) 28.5–48.4) and xeligekimab 100 mg (n = 102 (65.8%); p < 0.001, 95% CI 19.4–41.0) achieved an ASAS20 response compared to the placebo group (n = 56 (35.9%)) at week 16. Similarly, a significantly higher ASAS40 response rate was observed in the xeligekimab 100 mg group (n = 62 (40.0%); p < 0.001) and the xeligekimab 200 mg group (n = 64 (41.6%); p < 0.001) compared to placebo. Adverse events were similar across all groups, with serious adverse events occurring in 1.6% of the treatment group during the core treatment period. No unexpected safety signals were reported through week 48.ConclusionXeligekimab demonstrated significant efficacy in improving the signs and symptoms of active r-axSpA in Chinese patients at week 16, with sustained effects observed through week 48 and no new safety signals identified.Trial RegistrationClinicalTrials.gov identifier: NCT05881785 (Date: 21 May 2023).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40259-025-00750-0.

Rationale:Immunoglobulin G4–related disease (IgG4-RD) is a chronic immune-mediated fibroinflammatory condition that can mimic infection or malignancy. Renal involvement may present as a perirenal mass suggestive of an abscess. This case highlights a diagnostic pitfall and a favorable response to therapy.Patient concerns:A 48-year-old man had a persistent fever for over 20 days. Imaging revealed a left renal mass. Empirical antibiotics were initiated without improvement, and he was transferred for further evaluation.Diagnoses:Laboratory tests showed elevated inflammatory markers, including C-reactive protein and interleukin-6, positive proteinase 3 antineutrophil cytoplasmic antibody, and markedly increased serum immunoglobulin G4 (IgG4). Computed tomography and magnetic resonance imaging demonstrated renal and pulmonary abnormalities. Renal biopsy confirmed dense infiltration of IgG4-positive plasma cells. The final diagnosis was IgG4-RD involving the kidneys and lungs, initially misdiagnosed as a perirenal abscess.Interventions:Systemic corticosteroid therapy was started.Outcomes:The patient experienced rapid resolution of fever and clinical improvement, with reductions in serum IgG4 and interleukin-6 levels.Lessons:IgG4-RD should be considered in patients with unexplained fever and space-occupying renal lesions unresponsive to antibiotics. Timely recognition and immunosuppressive therapy can lead to favorable outcomes and help prevent irreversible organ damage.

Immunoglobulin G4 (IgG4)-related pancreatobiliary disease typically manifests as obstructive jaundice, complicating therapeutic choices. Glucocorticoids (GCs) are the primary treatment with many challenges, including high recurrence rates and patient tolerance variability. Endoscopic biliary drainage (EBD) is used to alleviate obstruction, but its role during treatment in IgG4-related pancreatobiliary disease is still contested. There remains a paucity of research comparing the potential benefits of combination therapy with GCs and EBD versus GCs monotherapy. This retrospective study divided 55 IgG4-related pancreatobiliary disease patients into two groups: GCs and GCs + EBD groups. We collected clinical data at the 1st, 3rd, 6th, and 12th months post-treatment to compare treatment efficacy, complication rates, and recurrence. Furthermore, logistic regression was used to analyze independent risk factors for recurrence. The results demonstrated that both treatment regimens significantly reduced total bilirubin (TBIL) and IgG4 levels within one year. The common bile duct diameter significantly decreased at the 6th and 12th months post-treatment compared to baseline. Except for significantly greater TBIL improvement in the GCs+EBD group at the 12th month, no other statistically significant differences were observed between groups. No statistically significant difference was observed in the cumulative recurrence rate within one year after treatment between the GCs and GCs+EBD groups. Finally, we identified elevated baseline IgG4 levels as an independent risk factor for post-treatment recurrence. The combination therapy of GCs and EBD did not exhibit significant differences in immunologic remission, complication rates, or recurrence compared with GCs monotherapy for IgG4-related pancreatobiliary disease. Nonetheless, EBD showed certain benefits in alleviating biliary obstruction.

IMC-002 is a fully human cluster of differentiation 47-targeted immunoglobulin G4 monoclonal antibody, designed to minimize off-target effects. This study (NCT05276310) assessed its safety/tolerability and preliminary anti-tumor activity in patients with advanced solid tumors who were not eligible for or had progressed on standard treatment. Here we report results from the initial 3 + 3 design dose-escalation part of a two-part Phase 1, open-label, dose-escalation/expansion study. IMC-002 was administered intravenously every 2 weeks at four doses (5, 10, 20, and 30 mg/kg). The primary objective was to assess safety/tolerability, including maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary objectives included pharmacokinetics and clinical activity, including best overall response (BOR), disease control rate (DCR), and clinical benefit rate (CBR). Twelve patients were included in total, with three per dose level. Most patients (11/12) had stage IV disease; 7/12 had received three prior systemic therapies. No dose-limiting toxicities were observed and MTD was not reached. The most common treatment-related adverse events (TRAEs) were rash (9/12), vitreous floaters (8/12), and (hemolytic) anemia (5/12). There was no treatment-related thrombocytopenia, neutropenia, or infection. IMC-002 had dose-proportional pharmacokinetics, achieving steady state levels from Cycle 2. BOR was stable disease in six patients (DCR 50.0%). CBR was 33% (four patients maintaining disease control for ≥6 months). IMC-002 demonstrated favorable safety/tolerability at doses of 5-30 mg/kg every 2 weeks. RP2D was defined as 20 mg/kg every 3 weeks. Preliminary anti-tumor activity was observed, with a CBR of 33%.

A Phase 2/3, multicenter, randomized, open-label study evaluating the efficacy and safety of etentamig and daratumumab compared to daratumumab, lenalidomide, and dexamethasone in frailer transplant-ineligible patients with newly diagnosed multiple myeloma

A man in his 60s with a history of asbestos exposure had been followed for progressive right-sided pleural thickening over several years. Imaging findings on high-resolution CT and 18F-fluorodeoxyglucose positron emission tomography/CT strongly suggested malignant pleural mesothelioma. However, both CT-guided pleural biopsy and endobronchial ultrasound-guided transbronchial needle aspiration of the mediastinal lymph nodes showed no evidence of malignancy, and a definitive diagnosis could not be established. After a 2-year interruption in follow-up, pleural thickening had further progressed. Immunostaining of previously obtained tissue samples ultimately led to a diagnosis of immunoglobulin G4 (IgG4)-related pleurisy. Steroid therapy resulted in a reduction of pleural thickening. This case highlights the importance of considering IgG4-related pleurisy in the differential diagnosis of pleural disease mimicking malignant pleural mesothelioma, particularly in patients with a history of asbestos exposure.

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disorder of unknown aetiology, potentially linked to genetic factors. This study conducted the first genome-wide association study on IgG4-RD in the Chinese Han population to identify genetic susceptibility loci. The study analysed data from 1161 patients with IgG4-RD and 10,539 controls across 2 independent cohorts, with 1115 patients and 10,154 controls passing quality control criteria. Using the Han-MHC reference dataset of the Chinese Han population, IgG4-RD genotyping data were imputed for the human leukocyte antigen (HLA) locus. Additionally, the study assessed the association between genetic variants and clinical characteristics, including disease activity, subtype classification, and relapse. We identified 22 single nucleotide polymorphisms (SNPs) that surpassed genome-wide significance thresholds (P < 5E-08) and replicated consistently across both cohorts, defining 16 distinct genetic susceptibility loci. The strongest signal mapped to chromosome 6 in the extended major histocompatibility complex region. Notably, chromosome 1 harboured significant loci involving immune-related genes such as the FC-γ receptor gene family. Fine mapping identified 6 independent HLA alleles, 2 amino acid mutations, and SNP rs3888777 as independent significant signals. Genetic variants were significantly associated with clinical manifestations such as serum immunoglobulin G4 levels, extent and pattern of organ involvement, clinical subtypes, and relapse risk. Furthermore, meta-analysis integrating Japanese cohort data confirmed known loci and revealed novel susceptibility variants. This study identified multiple susceptibility loci for IgG4-RD, uncovering novel genetic variants closely linked to clinical features and disease prognosis. These findings provide valuable genomic insights, advancing the understanding of IgG4-RD pathogenesis.