Increased risk of Graves´ophthalmopathy in patients with increasing TRAb after radioiodine treatment and the impact of CTLA4 on TRAb titres

Introduction Treatment of Graves´ disease (GD) with radioiodine increases the risk of developing Graves´ ophthalmopathy (GO), and the link between thyroid and orbital tissue may be the presence of TSH-receptors. Radioiodine increases the titers of TRAb and the aim was to investigate the relationship between GO and TRAb titers after treatment with radioiodine and to define the impact of risk genes. Methods GD patients without ophthalmopathy or previous treatment with radioiodine were prospectively included at treatment with radioiodine for hyperthyroidism. A follow-up was performed 1 year later for the registration of GO development. The study was performed at a University Hospital Clinic; a referral center of all patients treated with radioiodine in the south of Sweden. The main outcome measures were the development of TRAb, anti-TPO, and anti-TG after 3 months and GO after 12 months and relationship to the genetic background (HLA, CTLA-4, and CYR61). Results Three months of radioiodine TRAb titers increased in two thirds of patients (p < 0.0005) but not in the other third. Anti-TPO titers were associated with TRAb (R = 0.362, p < 0.0001) but not anti-TG. At follow-up 1 year later (n = 204) 32 patients developed GO with a proportion of 70% in the group increasing in TRAb titers and 30% in the group with unchanged or lower TRAb titers (p-value < 0.0005). Patients with GO had higher titers of TRAb than patients without GO. CTLA-4 (rs231775 SNP) was significantly (p < 0.005) associated with TRAb titers above the median three months after radioiodine. Conclusions The increase in TRAb titers after treatment with radioiodine is associated with GO and a genetic variation in CTLA-4 is associated with higher titers of TRAb.

Orbital Signaling in Graves’ Orbitopathy

Graves’ orbitopathy (GO) is a complex and poorly understood disease in which extensive remodeling of orbital tissue is dominated by adipogenesis and hyaluronan production. The resulting proptosis is disfiguring and underpins the majority of GO signs and symptoms. While there is strong evidence for the thyrotropin receptor (TSHR) being a thyroid/orbit shared autoantigen, the insulin-like growth factor 1 receptor (IGF1R) is also likely to play a key role in the disease. The pathogenesis of GO has been investigated extensively in the last decade with further understanding of some aspects of the disease. This is mainly derived by using in vitro and ex vivo analysis of the orbital tissues. Here, we have summarized the features of GO pathogenesis involving target autoantigens and their signaling pathways.

IgG4-related disease in patients with idiopathic orbital inflammation

Background To identify the prevalence of positive IgG4 immunostaining in orbital tissue among patients previously diagnosed with nongranulomatous idiopathic orbital inflammation (IOI) and to compare the clinical characteristics of patients with and without IgG4-positive cells. Methods A retrospective review of all patients with a histopathologic diagnosis of IOI was performed. Immunohistochemical staining was performed to identify IgG-positive cells and IgG4-positive cells. Multivariate analysis was performed using likelihood ratio-test logistic regression on the differences between IgG4-related disease (IgG4-RD) and non-IgG4-RD. Results Of the 45 patients included, 21 patients (46.7%) had IgG4-positive cells, with 52.4% being male and a mean age of 55.9 ± 13.4 years. Bilateral ocular adnexal involvement (adjusted odds ratio [aOR] = 9.45; P = 0.016) and infraorbital nerve enlargement (aOR = 12.11; P = 0.008) were frequently found in IgG4-RD patients. Complete remission occurred in 23.8% of IgG4-RD patients and 41.7% of non-IgG4-RD patients. IgG4-RD patients had more frequent recurrent disease than non-IgG4-RD patients. Conclusions Nearly 50% of IgG4-RD patients were previously diagnosed with biopsy-proven IOI. IgG4-RD was more frequent in patients with bilateral disease and infraorbital nerve enlargement, showing the importance of tissue biopsy in these patients. Immunohistochemistry studies of all histopathology slides showing nongranulomatous IOI are highly recommended to evaluate for IgG4-RD.

Increased Risk of Graves´ophthalmopathy in Patients With Increasing TRAb After Radioiodine Treatment and the Impact of CTLA4 on TRAb Titres

Introduction. Treatment of Graves´ disease (GD) with radioiodine increases the risk of developing Graves´ ophthalmopathy (GO) but the link between thyroid and orbital tissue remains undefined.The aim was to investigate the relationship between GO and TRAb after treatment with radioiodine and to define the impact of risk genes.Methods. GD patients without ophthalmopathy or previous treatment with radioiodine were prospectively included at treatment with radioiodine for hyperthyroidism. A follow-up was performed one year later for registration of GO development. The study was performed at a University Hospital Clinic; referral center of all patients treated with radioiodine in the south of Sweden. The main outcome measures were development of TRAb, anti-TPO, anti-TG after three months and GO after 12 months and relationship to the genetic background (HLA, CTLA-4, CYR61).Results. Three months of radioiodine TRAb increased in two thirds of patients (p<0.0005) but not in the other third. Anti-TPO was associated with TRAb (R=0.362, p <0.0001) but not anti-TG. At follow-up one year later (n=204) 32 patients developed GO with a proportion of 70% in the group increasing in TRAb and 30 % in the group with unchanged or lower TRAb (p-value <0.0005). Patients with GO had higher levels of TRAb than patients without GO. CTLA-4 (rs231775 SNP) was significantly (p<0.005) associated with TRAb levels above the median three months after radioiodine.Conclusions. The increase in TRAb after treatment with radioiodine is associated with GO and a genetic variation in CTLA-4 is associated with higher levels of TRAb.

The Diagnostic Value of the Leukocyte Shift Index in Purulent-Septic Rhinosinusogenic Complications in Children

The aim of this study was to investigate the diagnostic value of the leukocyte shift index (LSI) in inflammatory pathology of the paranasal sinuses (PNS) with the rhinosinusogenic orbital complications (RSOC) in pediatric patients. Methods and Results: The study involved 50 patients (26 boys and 24 girls) with diseases of the PNS and RSOC (reactive edema of the eyelids, orbital tissue, and purulent-septic complications of the eyelids and orbit) aged from 1 to 17 years (mean age of 6.66±0.63 years). Group 1 included 29 patients (16 boys and 13 girls) with reactive edema of the eyelids and orbital tissue. Group 2 included 21 patients (10 boys and 11 girls) with purulent-septic RSOC. As a marker for determining the activity of the inflammatory process and the disorders of the immunological reactivity of the body, LSI (leukocyte shift index) was calculated. In general, the LSI value was 1.61±0.21 in Group 1 and 3.45±0.49 in Group 2 (P=0.001). Among patients aged between 3 and 12 years, the LSI was 1.66±0.30 in Group 1 and 3.93±0.79 in Group 2 (P=0.012). The results obtained indicate that LSI can be used to predict purulent-septic RSOC in inflammatory diseases of PNS in patients aged between 3 and 12 years. LSI values from 1.36 to 1.96 may predict the development of reactive edema of the eyelids and orbital tissue; from 3.14 to 4.72 - the development of purulent-septic complications of the eyelids and orbit. Conclusion: The results obtained can be useful in predicting the clinical course of the RSOC in inflammatory pathology of PNS in patients in the age group of 3-12 years.

Adipose/Connective Tissue From Thyroid-Associated Ophthalmopathy Uncovers Interdependence Between Methylation and Disease Pathogenesis: A Genome-Wide Methylation Analysis

In response to pathological stimulation, methylation status conversion of the genome drives changes of cell feature and is able to promote disease development. Yet the role of methylation in the development of thyroid-associated ophthalmopathy (TAO) remains to be evaluated. Overexpansion of orbital tissue is the key feature of TAO. In this study, the methylation profile of orbital adipose/connective tissue from TAO patients and normal individuals were compared. After screening 3,739 differentially methylated probes, the distribution and properties of these probes were analyzed. Furthermore, enriched biological functions of these genes associated with differential methylation and the relationship between their methylation status and expression profile were also identified, including PTPRU and VCAM-1. According to our results, methylation was involved in disregulated immune response and inflammation in TAO and might contribute to activation of fibroblast and adipogenesis, leading to the expansion of orbital tissue. Neuropathy and neurobehavioral symptoms were also potentially associated with methylation. These results may help to extend the understanding of methylation in TAO and provide more insights into diagnosis and treatment of patients.

Association of fibroblast growth factor 10 with the fibrotic and inflammatory pathogenesis of Graves’ orbitopathy

Purpose The role of fibroblast growth factor (FGF) in orbital fibroblasts (OFs) is rarely known. In this study, we investigated the effect of FGF10 on fibrosis and the inflammation mechanism of Graves′ orbitopathy (GO). Methods Orbital tissue from GO (n = 15) and non-GO (n = 15) was obtained for this study. The mRNA and protein expression levels of FGF10 and FGF receptor 2b (FGFR2b) in orbital tissue were determined by real-time polymerase chain reaction, western blot analysis, and confocal microscopy. The effects of FGF10 on transforming growth factor (TGF)-β1 induced fibrotic proteins and interleukin (IL)-1β- or tumor necrosis factor (TNF)-α- induced inflammatory proteins were investigated using recombinant human (rh) FGF10 and small interfering (si) RNA transfection against FGF10. Results FGF10 and FGFR2b mRNA expression levels were significantly lower in GO orbital tissues than in non-GO orbital tissues (p = 0.009 and 0.005, respectively). Immunostaining of FGF10 in orbital adipose tissues showed differences in FGF10 expression between GO and control samples. Immunostaining of FGF10 was very weak in the orbital tissues of GO patients. TGF-β1-induced fibronectin, collagen Iα, α-smooth muscle actin protein expression in GO OFs was attenuated by rhFGF10 treatment and increased by knockdown of FGF10 via siFGF10 transfection. Similarly, IL-1β- or TNF-α-induced IL-6, IL-8, and cyclooxygenase-2 protein production in GO OFs was either blocked by rhFGF10 treatment or further upregulated by inhibition of FGF10 via siFGF10 transfection. Conclusions Our data demonstrate that FGF10 has beneficial effects on the inflammatory and fibrotic mechanisms of GO in primary cultured OFs, providing new insights into GO pathology and the discovery of FGF10 as a promising novel therapeutic application for the treatment of GO.

The role of oxidative stress in the pathogenesis of Graves’ orbitopathy

Graves’ disease (GD) is a chronic autoimmune condition in which the anti-thyroid stimulating hormone receptor antibodies (TRAb) activate the thyrotropin receptor (TSHR) located on thyrocytes, leading to excessive thyroid hormone production. TSHR is also expressed in extrathyroidal tissues, in particular, within the orbit. The serum levels of TRAb correlate with the severity and activity of thyroid orbitopathy (TO). TO is the most common extrathyroidal manifestation of GD. It is an autoimmune inflammation of orbital tissues, that is, extraocular muscles, orbital adipose tissue or a lacrimal gland. Increased orbital fibroblast and adipocyte proliferation, overproduction of glycosaminoglycans, as well as extraocular muscle oedema, result in increased orbital tissue volume and trigger the onset of TO symptoms. The pathophysiology of TO is complex and has not been fully unexplained to date. Orbital fibroblasts show expression of the TSHR, which is the main target of autoimmunity. It has been hypothesised that T-cell activation induced by orbital receptor stimulation by the target antibody results in orbital tissue infiltration, triggering a cascade of events which leads to the production of cytokines, growth factors and reactive oxygen species (ROS). ROS cause damage to many components of the cell: the cell membrane through the peroxidation of lipids and proteins leading to a loss of their function and enzymatic activity. Oxidative stress leads to the activation of the antioxidant system, which operates through two mechanisms: enzymatic and non-enzymatic. Assessment of the concentration of oxidative stress markers and the concentration or activity of anti-oxidative system parameters enables the evaluation of oxidative stress severity, which in the future may be utilized to assess treatment efficacy and prognosis in patients with active OT.

Case report of isolated gastric IgG4-related lesion and series of literature review

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disease that responds to glucocorticoids, which is gradually well known in recent years. It can involve multiple organs of patients, including pancreas, bile duct, gallbladder, salivary gland, orbital tissue, lung, liver, lacrimal gland, kidney, retroperitoneal, aorta, thyroid and lymph node, [1] in which gastrointestinal involvement is relatively rare [2]. Most of the known reports of isolated gastric IgG4-related lesions were accidental found (in physical examination or other site examination), and often treated as Gastrointestinal Stromal Tumors (GIST) lead to surgically resection. In addition, Calcified Fibrous Tumor (CFT) in gastrointestinal tract often occurs with submucosa [3] is histologically similar to IgG4-RD, [4] whether it belongs to IgG4-RD is still controversial.