Broad screening of inflammation-associated proteins identifies serum CCL19 as a novel biomarker of disease activity in IgG4-related disease.

SAT0342 Features of Orbital Inflammatory Disease and Response To Immunosuppressive Therapy

Clinicopathologic analysis of IgG4-related skin disease

Diagnosis of IgG4-related systemic disease by cytology of large pericardial effusion with fine needle aspiration

The birthday of a new syndrome: IgG4-related diseases constitute a clinical entity

Objective To evaluate the clinical applications of serum IgG4 for the diagnosis of IgG4-related disease (IgG4-RD). Methods In this retrospective study, 160 adult patients with IgG4-RD who in their first time visit in Peiking Union Medical College Hospital between 2011 to 2013 were reviewed. All patients had detailed clinical reference and final clear diagnosis. Meantime we selected 126 patients with other non- IgG4-related immune disease and 125 healthy subjects as controls from Peiking Union Medical College Hospital physical checkup center, IgG4 was detected by nephelometry, takeing the first testing result for analysis. Statistical analysis was performed using SPSS13.0 software. Results Serum IgG4 levels higher than 1 350 mg/L were seen in 82.5% of the patients (132/160) with IgG4-RD and 20.6% of the patients（26/126）with other diseases respectively. The serum concentrations of IgG4 in IgG4-RD group were significantly higher than other disease group and healthy control group(χ2 =110.8，158.6, P 0.05). The optimal diagnostic cut-off values for IgG4-RD was 1575mg / L . Conclusion The best diagnostic cut valuse of serum IgG4 for Chinese IgG4-RD is different from the current international standard, and realize that to establish reference vange of Chinese for diagnosis of IgG4-RD has very important significance.（Chin J Lab Med,2014,37:593-596） Key words: Autoimmune diseases; Immunoglobulin G; Reference values; Nephelometry and turbidimetry

Solitary organ autoimmune disorders, formerly known as autoimmune pancreatitis (AIP), autoimmune sialadenitis, and autoimmune sclerosing cholangitis, are now considered organ-specific manifestations of systemic immunoglobulin G4-related disease (IgG4-RD). AIP and IgG4-RD are characterized by elevated serum concentration of IgG4 antibody (Ab), accumulation of IgG4-expressing plasmacytes in the affected organs, and involvement of multiple organs. It is well established that enhanced IgG4 Ab responses are a hallmark of AIP and IgG4-RD for diagnosis and monitoring disease activity. However, a significant fraction of patients with AIP and IgG4-RD who develop chronic fibroinflammatory responses have normal serum concentrations of this IgG subtype. In addition, disease flare-up is sometimes seen even in the presence of normalized serum concentrations of IgG4 Ab after successful induction of remission by prednisolone. Therefore, it is necessary to identify new biomarkers based on the understanding of the pathophysiology of AIP and IgG4-RD. Recently, we found that activation of plasmacytoid dendritic cells producing both interferon-α (IFN-α) and interleukin-33 (IL-33) mediate murine AIP and human IgG4-RD. More importantly, we provided evidence that serum concentrations of IFN-α and IL-33 could be useful biomarkers for the diagnosis and monitoring of AIP and IgG4-RD activity after induction of remission in these autoimmune disorders. In this Frontier article, we have summarized and discussed biomarkers of AIP and IgG4-RD, including Igs, autoAbs, and cytokines to provide useful information not only for clinicians but also for researchers.

FRI0590 Soluble interleukin-2 receptor levels reflect disease activity in IGG4-related disease and primary sjÖgren's syndrome

Transsphenoidal adenomectomy is the primary treatment for acromegaly. However, assessment of the therapeutical outcome remains problematic since the existing biomarkers of disease activity frequently show discordant results. To discover novel serum biomarkers of disease activity in acromegalic patients before and after surgery. Serum samples of eight newly diagnosed acromegaly patients before and after transsphenoidal surgery were analyzed for proteomic changes by two-dimensional gel electrophoresis. Protein spots displaying statistically significant changes, pre- versus post-surgery, were identified by mass spectrometry (MS), tandem MS (MS/MS), and western blot analysis. Six protein spots displaying decreased intensities after surgery were identified as transthyretin (two isoforms), haptoglobin α2, β-hemoglobin, and apolipoprotein A-1 (two isoforms). One protein spot, identified as complement C4B precursor, was increased after the surgery. Seven serum protein spots were differentially expressed following surgery in acromegalic patients. The identified proteins represent potential novel biomarkers to assess the effectiveness of surgical treatment in acromegalic individuals. Future studies will validate the use of the identified proteins as biomarkers of disease activity after medical treatment of acromegaly.

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.

Immunoglobulin G4 (IgG4)‐related disease (IgG4‐RD) of the biliary tree and pancreas is difficult to distinguish from sclerosing cholangitis and biliary/pancreatic malignancies (CA). An accurate noninvasive test for diagnosis and monitoring of disease activity is lacking. We demonstrate that dominant IgG4+ B‐cell receptor (BCR) clones determined by next‐generation sequencing accurately distinguish patients with IgG4‐associated cholangitis/autoimmune pancreatitis (n = 34) from those with primary sclerosing cholangitis (n = 17) and CA (n = 17). A novel, more affordable, and widely applicable quantitative polymerase chain reaction (qPCR) protocol analyzing the IgG4/IgG RNA ratio in blood also achieves excellent diagnostic accuracy (n = 125). Moreover, this qPCR test performed better than serum IgG4 levels in sensitivity (94% vs. 86%) and specificity (99% vs. 73%) and correlates with treatment response (n = 20). Conclusions: IgG4+ BCR clones and IgG4/IgG RNA ratio markedly improve delineation, early diagnosis, and monitoring of IgG4‐RD of the biliary tree and pancreas. (Hepatology 2016;64:501‐507)

Background and Objectives: IgG4-related disease is a chronic fibro-inflammatory condition. Despite the development of classification and responder indexes, reliable biomarkers for disease activity and therapeutic monitoring remain limited. We evaluate the performance of a panel of biomarkers, including cytokine profiles, plasmablasts and conventional markers. Materials and Methods: We conducted a cross-sectional, single-center study, involving 35 patients diagnosed with IgG4-RD. Disease activity was evaluated using the IgG4-RD Responder Index (RI), Damage Index (DI) and clinical assessment. Laboratory evaluation included serum IgG4, total IgG, CRP, ESR, eosinophils, IgE, complement levels, and cytokine profiling via multiplex immunoassay. B cell subpopulations were analyzed by flow cytometry. Statistical analyses were performed using STATA/BE 17.0. Results: Patients with active disease (RI > 4 or clinical judgment) exhibited significantly higher levels of total IgG (p = 0.02), IgG4 (p = 0.01), and IL-5 (p = 0.03). PET-positive patients showed a Th1-skewed immune profile, with elevated IFN-γ/IL-4 (p < 0.001), reduced IL-21/IFN-γ (p = 0.03), and increased eosinophils (p = 0.03). Clinician-assessed active disease was associated with higher total IgG levels (p = 0.01). Treatment-specific effects were observed: prednisone was associated with lower IgG4 and C3 levels. Notably, plasmablasts did not consistently correlate with clinical or imaging activity scores, possibly reflecting treatment status or B cell dynamics. Conclusions: This study demonstrates that cytokine ratios, particularly those involving IL-5, IL-13, IL-21, and IFN-γ, offer complementary information to traditional serological markers for IgG4-RD activity. While PET/CT-defined activity was best reflected by biomarkers of an IFN-γ-mediated pathway, the IgG4-RD RI demonstrated a stronger association with conventional humoral markers like serum IgG4 and total IgG. None of these biomarkers correlated with organ damage.

Biochemical diagnostic approach for acromegaly relies heavily on the 2 biomarkers, growth hormone (GH) and insulin like growth factor 1 (IGF1), known to be dynamically affected, and influencing diagnostic accuracy. We sought to identify disease-specific biomarkers to improve diagnostic and disease activity monitoring and add insight into systemic effects of chronic GH/IGF1 excess. Thirty-seven patients diagnosed with acromegaly were enrolled. A sub-cohort (n = 14) of these received primary somatostatin receptor ligand (SRL) treatment before surgery. Plasma samples collected at baseline, preoperative medical treatment and postoperative visits, were used to perform proteomic analysis of 184 proteins, with Olink Target 96 Cardiovascular III and Inflammation panels. Eight proteins were validated Enzyme Immunoassay (EIA). Dual-energy X-ray absorptiometry and biochemical measurements were performed at all visits. A total of 37 proteins were significantly differentially expressed (P-adjusted < .05) before and after disease control by surgery. Several proteins correlated with GH and IGF1. Interestingly, a strong correlation between some proteins and lean body mass, but not total adipose tissue, was observed. Strong correlation was observed between Olink and EIA measured protein levels. Enrichment analyses revealed 5 clusters, with extracellular matrix (ECM) remodeling and inflammation being most prominent. In addition, 5 proteins showed a temporal change with SRL treatment. Acromegaly is associated with changes in ECM remodeling and inflammation. Several proteins were linked to disease activity, with glial cell derived neurotrophic factor and insulin like growth factor binding protein 2 serving as promising plasma biomarkers with potential to further optimize management of disease.

IgG4-related disease (IgG4-RD) is a recently described autoimmune disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4+ plasma cells in multiple organ systems. Recent advancements have significantly enhanced our understanding of the pathological mechanism underlying this immune-mediated disease. T cell immunity plays a crucial role in the pathogenesis of IgG4-RD, and follicular helper T cells (Tfh) are particularly important in germinal center (GC) formation, plasmablast differentiation, and IgG4 class-switching. Apart from serum IgG4 concentrations, the expansion of circulating Tfh2 cells and plasmablasts may also serve as novel biomarkers for disease diagnosis and activity monitoring in IgG4-RD. Further exploration into the pathogenic roles of Tfh in IgG4-RD could potentially lead to identifying new therapeutic targets that offer more effective alternatives for treating this condition. In this review, we will focus on the current knowledge regarding the pathogenic roles Tfh cells play in IgG4-RD and outline potential therapeutic targets for future clinical intervention.

IgG4-related disease (IgG4-RD) is a systemic disorder characterised by elevated serum IgG4 levels, tissue infiltration by IgG4+ plasma cells and severe fibrosis.1 2 However, biomarkers for IgG4-RD disease activity are...

Fatal Dieulafoy lesion with IgG4-related disease: An autopsy case report