Manifestation Of Graves Research Articles

Pancytopenia, Cholestatic Jaundice, and Pulmonary Hypertension: Rare Extrathyroidal Manifestations of Graves’ Disease

Pancytopenia, Cholestatic Jaundice, and Pulmonary Hypertension: Rare Extrathyroidal Manifestations of Graves’ Disease

Therapeutic role of histone deacetylase inhibition in an in vitro model of Graves' orbitopathy.

Graves' orbitopathy (GO), a manifestation of Graves' disease, is characterized by orbital fibroblast‑induced inflammation, leading to fibrosis or adipogenesis. Histone deacetylase (HDAC) serves a central role in autoimmune diseases and fibrosis. The present study investigated HDAC inhibition in orbital fibroblasts from patients with GO to evaluate its potential as a therapeutic agent. Primary cultured orbital fibroblasts were treated with an HDAC inhibitor, panobinostat, under the stimulation of IL‑1β, TGF‑β or adipogenic medium. Inflammatory cytokines, and fibrosis‑ and adipogenesis‑related proteins were analyzed using western blotting. The effects of panobinostat on HDAC mRNA expression were measured in GO orbital fibroblasts, and specific HDACs were inhibited using small interfering RNA transfection. Panobinostat significantly reduced the IL‑1β‑induced production of inflammatory cytokines and TGF‑β‑induced production of fibrosis‑related proteins. It also suppressed adipocyte differentiation and adipogenic transcription factor production. Furthermore, it significantly attenuated HDAC7 mRNA expression in GO orbital fibroblasts. In addition, the silencing of HDAC7 led to anti‑inflammatory and anti‑fibrotic effects. In conclusion, by inhibiting HDAC7 gene expression, panobinostat may suppress the production of inflammatory cytokines, profibrotic proteins and adipogenesis in GO orbital fibroblasts. The present in vitro study suggested that HDAC7 could be a potential therapeutic target for inhibiting the inflammatory, adipogenic and fibrotic mechanisms of GO.

HYPERTHYROIDISM AND GRAVES' DISEASE: OPHTHALMOLOGICAL MANIFESTATIONS AND SURGICAL TREATMENT.

Introduction: Hyperthyroidism, characterized by the excessive production of hormones by the thyroid gland, can lead to various systemic complications, including ophthalmological manifestations such as Graves' Orbitopathy (GO). Graves' Disease, one of the main causes of hyperthyroidism, is often associated with these ocular complications, which include ocular protrusion, diplopia, and periorbital swelling. Surgical treatment, including total or subtotal thyroidectomy, emerges as an option to control the progression of hyperthyroidism and improve associated ophthalmological symptoms. **Objective**: To analyze the ophthalmological manifestations of hyperthyroidism and Graves' Disease, as well as evaluate the effectiveness of surgical treatment in managing these complications. **Methodology**: The review followed the PRISMA checklist to ensure rigor and transparency. Searches were conducted in PubMed, Scielo, and Web of Science databases using five descriptors: "Hyperthyroidism," "Graves' Disease," "Graves' Orbitopathy," "Surgical Treatment," and "Ophthalmological Manifestations." Inclusion criteria encompassed articles published in the last 10 years, studies focused on surgical treatment for GO, and works explicitly addressing the ophthalmological manifestations of Graves' Disease. Exclusion criteria included studies that did not discuss surgical treatment, non-peer-reviewed articles, and publications older than a decade. **Results**: The analysis revealed that Graves' Orbitopathy frequently manifests with symptoms such as ocular protrusion, diplopia, and periorbital edema, significantly impacting patients' quality of life. Thyroidectomy proved effective in reducing hormone levels, resulting in symptomatic improvements for many patients. However, outcomes varied, and surgical intervention was not always associated with complete resolution of ophthalmological manifestations. **Conclusion**: Surgical treatment of hyperthyroidism and Graves' Disease can provide significant relief from ophthalmological manifestations, though it does not guarantee complete resolution of symptoms. Surgery should be considered within a multidisciplinary context, taking into account the severity of ocular symptoms and response to conservative treatment. The review highlighted the need for integrated treatment strategies to optimize outcomes for patients with ophthalmological complications associated with hyperthyroidism and Graves' Disease.

Correlation of Quality of Life (QoL) and Self-perception in Patient with Thyroid Eye Disease (TED)

Abstract Introduction Tyroid eye disease (TED) is an autoimmune disorder representing the commonest extrathyroidal manifestation of Graves’ disease (GD), with a prevalence of 10 per 10,000 persons in the European population. Although most frequently associated with hyperthyroidism secondary to GD, about 10% of patients with TED are euthyroid or hypothyroid. Patients with Graves orbitopathy (GO) have a significantly lower life quality, both regarding vision problems and worsened appearance, compared to a healthy person. It has been associated with increased rates of anxiety, depression, social isolation and decreased self-confidence. Materials and Methods The results of standard treatments in this disease are often unsatisfactory, but outcomes often do not correlate well with patient reports of how visible they feel their TED is, and the impact on their lives. The present study was designed to correlate QoL and self-perception of well-being with the different clinical and surgical approaches recommended by EUGOGO. The aim is to determine whether there were differences between treatment options in determining patient perception of well-being and satisfaction with treatment received, and whether they would recommend the treatment they had experienced to people with the same condition. Results Scheduled patients undergone medical or surgical treatments based on presence or not of inflammation signs. Evaluation of clinically relevant improvements in each clinical variable was carried out 6 months and one year after treatment. Later, patients were asked a set of general questions about improvement (or worsening) of symptoms, health condition before and after the treatment, degree of limitations of daily activities caused by the pathology, overall satisfaction. After one-year, visual acuity unchanged in all the cases, and exophthalmos’ absolute values improved. Daily activities limitations and heath conditions improved in most patients. In this study we demonstrate that although the majority of patients were satisfied with the treatment they received, patients presenting most severe disease at presentation and received most invasive procedures (such orbital decompression) were less satisfied due to an unrealistic expectation about the impact of surgery on their appearance, including expecting to return to a pre-morbid appearance. Conclusion This study highlights the importance of healthcare professionals eliciting and managing patients’ expectations, in order to optimize surgical outcomes.

A Review of Novel Medical Treatments for Thyroid Eye Disease.

Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves disease. There has been no effective medication to prevent proptosis in thyroid eye disease until 2020 when the anti-insulin-like growth factor 1 receptor (anti-IGF-1R) antibody, Teprotumumab, was approved by the US Food and Drug Administration, sparking increased interest in immune-based drug development. This study aims to review the newly developed drug therapy as well as conventional treatment for TED. Treatment of TED has traditionally been high-dose steroids and orbital radiotherapy, but recently there has been a paradigm shift in the treatment of TED in the United States with the introduction of the therapeutic agent teprotumumab, which dramatically reduces proptosis. However, concerns remain about the development of hearing impairment as a potentially fatal complication and long-term safety. Recently, several clinical trials are underway to assess the efficacy and safety of novel drugs targeting mammalian target of rapamycin complex 1, interleukin-6, fragment crystallizable receptor, and IGF-1R in treating TED. With the explosive increase in interest from academia and pharmaceutical companies in TED, there is anticipation for the development of drugs that are equivalent or superior to teprotumumab while being safer.

Teprotumumab for the treatment of Thyroid eye disease.

Thyroid eye disease (TED) is the most common extra thyroidal manifestation of Graves' disease (GD). It may also present in those who are hypothyroid or euthyroid. The characteristic clinical manifestations of TED: chemosis, lid swelling, proptosis and diplopia are driven by a combination of inflammation and extracellular matrix modification. It has recently emerged that one of the major drivers of this molecular signature is the over-expression of the insulin like growth factor-1 receptor (IGF-1R) on key effector cells in TED pathogenesis. The overexpression of the IGF-1R is coupled with a dysregulation of the IGF-1R axis, which links other pathways that modulate inflammation, such as fibrosis and extracellular matrix organization, in patients with TED. This overexpression is also found to persist from the acute stage into the chronic phase. Teprotumumab, a fully human immunoglobulin (Ig) G1 monoclonal antibody that inhibits the IGF-1R, recently gained approval in the US for the treatment of TED. In phase 2 and phase 3 clinical studies, teprotumumab showed efficacy in reducing inflammation, proptosis, diplopia and burden on quality of life, in patients who were treated. Post introduction studies have confirmed the results of the phase 2 and phase 3 studies. Since 2020, over 5, 800 patients have been treated with teprotumumab and it appears to be well tolerated. The American Thyroid Association and the European Thyroid Association have recommended it as first line therapy for patients with moderate to severe TED, who display features of proptosis and diplopia.

Immune checkpoints: new insights into the pathogenesis of thyroid eye disease.

Thyroid eye disease (TED) is a disfiguring autoimmune disease characterized by changes in the orbital tissues and is caused by abnormal thyroid function or thyroid-related antibodies. It is the ocular manifestation of Graves' disease. The expression of thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1 R) on the cell membrane of orbital fibroblasts (OFs) is responsible for TED pathology. Excessive inflammation is caused when these receptors in the orbit are stimulated by autoantibodies. CD34+ fibrocytes, found in the peripheral blood and orbital tissues of patients with TED, express immune checkpoints (ICs) like MHC II, B7, and PD-L1, indicating their potential role in presenting antigens and regulating the immune response in TED pathogenesis. Immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, it can also lead to the occurrence of TED in some instances, suggesting the abnormality of ICs in TED. This review will examine the overall pathogenic mechanism linked to the immune cells of TED and then discuss the latest research findings on the immunomodulatory role of ICs in the development and pathogenesis of TED. This will offer fresh perspectives on the study of pathogenesis and the identification of potential therapeutic targets.

Graves’ disease thyroid dermopathy: a case report

BackgroundGraves’ disease is the autoimmune activation of the thyroid gland causing diffuse enlargement and hyperfunction of the gland. Manifestations of Graves’ disease are multisystemic and include thyroid orbitopathy; pretibial myxedema, also referred to as thyroid dermopathy; and thyroid acropachy, described as a severe form of thyroid dermopathy. Our paper focuses on an atypical case of thyroid dermopathy.Case presentationAn 11-year-old Saudi male presented with a prominent diffuse goiter and exophthalmos. Investigations were consistent with a diagnosis of Graves’ disease. The physical exam showed diffuse, non-pitting swelling of the ankle and penis, mimicking a lymphatic malformation. Further, multiple nodules were found on the hands and feet. Treatment of the nodules with cautery resulted in more severe nodules.ConclusionThis report describes rare presentations of thyroid dermopathy mimicking lymphatic malformation. The Koebner phenomenon can explain this patient’s atypical presentations. Intralesional injections of triamcinolone and total thyroidectomy showed clear improvement.

Comparison of orbital fibroblasts from Graves’ ophthalmopathy and healthy control

Graves' ophthalmopathy (GO) is an extrathyroidal manifestation of Graves' disease, Orbital fibroblasts (OFs) are recognized as key players in GO pathogenesis, involved in orbital inflammation, tissue remodeling, and fibrosis. This study offers a primary exploration of cell behavior and characteristics on OFs from GO (GO-OFs), and compared to OFs from healthy control (HC-OFs). Results reveal that GO-OFs exhibit delayed migration from tissue fragments, while no significant difference in cell proliferation is observed between GO-OFs and HC-OFs. Aberrant expression pattern of surface proteins Thy-1, TSHR, and IGF-1R suggests shared autoantigens and pathways between GO and GD, contributing to inflammation and fibrosis. Investigations into cytokine responses unveil elevated secretion of hyaluronic acid (HA) and prostaglandin E2 (PGE2) in GO-OFs, emphasizing their role in tissue remodeling. These findings deepen our understanding of OFs in GO pathogenesis, offering potential therapeutic avenues.

Temporal trends in the clinical presentation of Graves’ orbitopathy: a single–center retrospective study

PurposeGraves’ ophthalmopathy (GO) is an autoimmune disease that affects orbital soft tissues and represents the most common extrathyroidal manifestation of Graves’ disease (GD). The European Group of Graves’ Ophthalmopathy (EUGOGO) has attempted to shed light on the European epidemiological picture of GO, suggesting that GO in newly diagnosed patients in recent years has a trend towards a less severe clinical presentation. There are no studies that focus this issue on the population of our area; we aimed to evaluate the trend of GO clinical presentation in our outpatient clinic through an observation period of 10 years.MethodsWe compared 55 consecutive patients, 11 males (F) and 44 females (M), who came to our observation from January 2005 to December 2006 [Group 1 (G1)], with 56 patients, 15 males, and 41 females, who were referred to us from 2015 to 2016 [Group 2 (G2)]. We studied the following putative predictors of GO presentation and severity: thyroid function, smoking, diabetes, hypercholesterolemia, time from GO diagnosis to referral to our thyroid centre (TGOD), sex and age.ResultsGO severity was significantly reduced in G2 vs. G1 (p = 0.04). TGOD ≥ 3 months was related to clinical characteristics of GO (severity and Clinical Activity Score ≥ 4) and was an independent predictor of GO severity (p = 0.01). The other variables evaluated had no independent effects.ConclusionsWe found that GO severity at presentation was significantly reduced over a ten-year observation period (2005–2006 vs. 2015–2016) in GO patients referred to our tertiary thyroid centre. TGOD ≥ 3 months was an independent predictor of GO severity.

The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves' Ophthalmopathy.

Graves' ophthalmopathy (GO), or thyroid eye disease (TED), is the most frequent extrathyroidal manifestation of Graves' disease (GD). Inflammation and subsequent aberrant tissue remodeling with fibrosis are important pathogenesis. There are many proposed mechanisms and molecular pathways contributing to tissue remodeling and fibrosis in GO, including adipogenesis, fibroblast proliferation and myofibroblasts differentiation, oxidative stress, endoplasmic reticulum (ER) stress, hyaluronan (HA) and glycosaminoglycans (GAGs) accumulation in the extracellular matrix (ECM) and new concepts of epigenetics modification, such as histone modification, DNA methylation, non-coding RNAs, and gut microbiome. This review summarizes the current understanding of ECM proteins and associated tissue remodeling in the pathogenesis and potential mediators for the treatment of GO.

THERMAL IMAGING ACCURACY ON CLINICAL ACTIVITY SCORE (CAS) THYROID EYE DISEASE PATIENTS

Abstract
 Introduction & Objectives : Thyroid Eye Disease (TED) also known as Graves' ophthalmopathy, thyroid-associated orbitopathy, and other terms is an autoimmune inflammatory disorder with the most common extra-thyroid manifestations of Graves' Disease (GD). The disease phase is usually assessed clinically, by assessing the presence or absence of cardinal signs and symptoms of inflammation which are assessed in the form of a clinical activity score (CAS). In addition, the use of Thermal Imaging (IT) as a passive measurement technique that does not require contact with the patient (non-invasive and non- contact) and does not use ionizing radiation or contrast agents is another option. The use of TI in patients with TED still has minimal data and does not have more specific results. This study aims to determine the accuracy of TI and CAS images in TED patients.
 Methods : This study design is accuracy test at the Ophthalmology Polyclinic of RSUP Dr. Mohamad Hoesin Palembang in July 2021 until the sample is filled with 24 people. Thermal Imaging (TI) accuracy test was performed to establish active and inactive TED compared to CAS (Clinical Activity Score) in TED patients. Analysis of research results with SPSS version 22.0.
 Results : The result shown that the proportion of research subjects who were female was 17 people (70.8%) and male research subjects were 7 people (29.2%). At 7 locations the Thermal Imaging examination was found to have varying sensitivity
 Conclusion : Thermal Imaging can be used to help diagnose active and inactive TED.

Safety of non-standard regimen of systemic steroid therapy in patients with Graves' orbitopathy: a single-centre experience.

Graves' orbitopathy (GO) is an autoimmune disorder of the orbit and retro-ocular tissues and the primary extrathyroidal manifestation of Graves' disease. In moderate-to-severe and active GO iv glucocorticoids (GCs) are recommended as first-line treatment. The aim was to assess the safety profile of methylprednisolone administered intravenously for three consecutive days at 1g in patients with active, moderate-to-severe or sight-threatening Graves' orbitopathy. We retrospectively evaluated 161 medical records of patients with GO treated with high-dose systemic GCs in the Department of Endocrinology, Metabolic Disorders, and Internal Medicine in Poznań between 2014 and 2021. Clinical data included age, gender, laboratory results, activity and severity of GO, smoking status, disease duration, and presented side effects. The presence of mild side effects was observed during 114 (71%) hospitalizations. The most common complications were hyperglycemia (n = 95) and elevated aminotransferases (n = 31). Increased levels of aminotransferases were more likely observed in smokers and GO duration above 12months. Based on the multivariate logistic regression, higher TRAb and CAS values were significantly associated with lower odds of hyperglycemia. In turn, the increased odds of elevated aminotransferases were significantly correlated with higher initial ALT levels, female gender, and GO duration above 12months. In addition, the multidimensional correspondence analysis (MPA) showed that GO patients who declared smoking and had not L-ornithine L-aspartate applied demonstrated a higher probability of elevated aminotransferases. Active GO treatment with high-dose systemic GCs is not associated with serious side effects. Hyperglycemia is the most common steroid-induced complication.

PREVALENCE OF THYROID EYE DISEASE IN PATIENTS WITH THYROID DYSFUNCTION IN A TERTIARY CARE HOSPITAL OF CENTRAL NEPAL

Background: Thyroid eye disease is the most common extra thyroidal manifestation of Graves’ disease. The pattern and prevalence of thyroid eye disease vary widely from a mild disorder characterized by dry eye symptoms and ocular irritation to a severe disfiguring form of orbitopathy. Thyroid eye disease is a frequently encountered Ophthalmological morbidity in Nepal and across the globe. The aim of this study was to ascertain the prevalence of thyroid eye disease in subjects with thyroid dysfunction in a tertiary care hospital in central Nepal.. Methods: This was a prospective cross-sectional study, conducted in Chitwan medical college Teaching hospital (CMCTH), department of Ophthalmology. Subjects presenting to Ophthalmology department or referred patients from different departments with thyroid dysfunction were enrolled in the study. The data thus collected was analyzed using SPSS version 26 and the data was presented as frequency and percentage. Results: Among 320 subjects screened for Thyroid eye disease prevalence, 106 (33.3%) were hyperthyroid, 207 (64.7%) were hypothyroid whereas, 7 (2.2%) were euthyroid. The prevalence of Thyroid eye disease was 40% and this was more prevalent among hypothyroid. Among the 320 patients with thyroid eye disease, 126 (39.4%), 95 (29.7%), 53 (16.6%), 24 (7.5%), 15 (4.7%), 5 (1.6%) and 2 (0.6%) had CAS score of 1,2,3,4,5,6 and 7 respectively. Similarly, NOSPECS score (American Thyroid Association) 243 (75.9%), 57 (17.8%), 1 (0.3%), 7 (2.2%), 8 (2.5%), 3(0.9%) and 1 (0.3%) were graded from 0-6 accordingly respectively. Conclusions: Thyroid eye disease was more prevalent in hypothyroid middle-aged females and the overall prevalence of Thyroid Eye disease was more in hypothyroid patients. Though sight threatening complications didn’t exist in our study, close workup by endocrinologist and ophthalmologist can decrease ocular morbidity.

Immunological Processes in the Orbit and Indications for Current and Potential Drug Targets.

Thyroid eye disease (TED) is an extrathyroidal manifestation of Graves' disease (GD). Similar to GD, TED is caused by an autoimmune response. TED is an autoimmune inflammatory disorder of the orbit and periorbital tissues, characterized by upper eyelid retraction, swelling, redness, conjunctivitis, and bulging eyes. The pathophysiology of TED is complex, with the infiltration of activated T lymphocytes and activation of orbital fibroblasts (OFs) and autoantibodies against the common autoantigen of thyroid and orbital tissues. Better understanding of the multifactorial pathogenesis of TED contributes to the development of more effective therapies. In this review, we present current and potential drug targets. The ideal treatment should slow progression of the disease with as little interference with patient immunity as possible. In the future, TED treatment will target the immune mechanism involved in the disease and will be based on a strategy of restoring tolerance to autoantigens.

Thyroid Eye Disease: Epidemiology, Natural History, and Risk Factors.

Thyroid eye disease (TED) is an autoimmune disorder of the orbit and the most frequent extrathyroidal manifestation of Graves' disease but it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. TED is a relatively infrequent disorder, particularly in its severe forms. Men tend to have more severe TED at an older age. The prevalence of TED is lower than in the past among patients with recent onset Graves' hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5% to 6% of all cases. After an initial inflammatory (active) phase and a plateau phase, TED stabilizes and eventually inactivates (inactive or burnt-out phase) after an estimated period of 18-24 months. Minimal-to-mild TED often remits spontaneously, but complete restitutio ad integrum almost never occurs when TED is more than mild. Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them, but thyroid dysfunction (both hyper- and hypothyroidism), radioactive iodine therapy (if not accompanied by low-dose steroid prophylaxis), elevated thyrotropin receptor antibodies, and, probably, hypercholesterolemia represent relevant modifiable risk factors. Early diagnosis, control and removal of modifiable risk factors, and early treatment of mild forms of GO (local treatment and selenium) may effectively limit the risk of progression to more severe forms.

FACTORS ASSOCIATED WITH THYROID ASSOCIATED ORBITOPATHY DUE TO GRAVES’ DISEASE

Background: Thyroid associated orbitopathy (TAO) is the principal extrathyroidal manifestation of Graves’ disease (GD). TAO is described as chronic inflammation of orbital and periorbital tissue. Environmental risk factors variably influence development of TAO and risk factors vary with ethnicity and geographical region. Aims: To evaluate the clinical factors for TAO in patients with GD. Setting and Design: This was a hospital-based cross-sectional study done on consecutive 76 newly diagnosed patients of GD documented by thyroid 99mTechnetium-pertechnetate scan. Materials and Methods: Patients were subjected to complete clinical workup and thyroid profile. The diagnosis of TAO was based on the criteria of Bartley and Gorman. Fifty two TAO patients were compared with twenty four non TAO patients (controls) for risk. Statistical Analysis Used: All analyses were performed with SPSS software (version 21.0). Results: TAO was present in 52 (68%) of patients with GD. TAO was bilateral in 50 (96%) of patients. Majority of patients had mild orbitopathy 34 (65.4%) and none of the patients showed any signs of sight-threatening disease. Clinical activity score (CAS) was active in 13.5% of the study group. There was significant female preponderance in TAO. Current smoking increased the risk of TAO (P = 0.023). Total triiodothyronine (T3) and mean intraocular pressure (IOP) in primary and upward gaze was significantly elevated at baseline in TAO patients. Braley’s sign was seen in 30.7% of patients with TAO and in 8.3% of patients in the control group (P = 0.033). Current smoking, total T3 > 4ng/dl and differential IOP > 6 mmHg were found to be associated with risk of TAO. Conclusion: TAO was clinically inactive and of mild severity in most cases. This study identified current smoking, total T3 > 4 ng/dl and differential IOP > 6 mmHg as risk factors for TAO.

Myxœdème prétibial pseudo-tumoral après une maladie de Basedow : un diagnostic différentiel du lymphœdème

IntroductionPretibial myxedema is a rare manifestation of Graves’ disease, and pseudotumoral forms may be confused with lower limb lymphedema. ObservationsWe reported 3 cases of pretibial myxedema in 2 women and 1 man, aged 72, 66, and 49 years, treated for Graves’ disease 3, 25 and 32 years previously. Two patients were active smokers. Lymphedema diagnosis of the lower limbs was suspected in the presence of bilateral pseudotumoral lesions of the feet, toes and ankles and the presence of a Stemmer's sign (skin thickening at the base of the 2nd toe, pathognomonic of lymphedema). Lymphoscintigraphy in one case was normal, not confirming lymphedema. ConclusionPretibial pseudotumoral myxedema is a differential diagnosis of lower limb lymphedema. This diagnosis is confirmed by questioning the patient about preexisting Graves’ disease, the underlying etiology, to decide the appropriate treatment and to encourage cessation of smoking, which is a risk factor for pretibial myxedema.

Potential involvement of the bone marrow in experimental Graves' disease and thyroid eye disease.

Graves' disease is an autoimmune disorder caused by auto-antibodies against the thyroid stimulating hormone receptor (TSHR). Overstimulation of the TSHR induces hyperthyroidism and thyroid eye disease (TED) as the most common extra thyroidal manifestation of Graves' disease. In TED, the TSHR cross talks with the insulin-like growth factor 1 receptor (IGF-1R) in orbital fibroblasts leading to inflammation, deposition of hyaluronan and adipogenesis. The bone marrow may play an important role in autoimmune diseases, but its role in Graves' disease and TED is unknown. Here, we investigated whether induction of experimental Graves' disease and accompanying TED involves bone marrow activation and whether interference with IGF-1R signaling prevents this activation. Immunization of mice with TSHR resulted in an increase the numbers of CD4-positive T-lymphocytes (p ≤0.0001), which was normalized by linsitinib (p = 0.0029), an increase of CD19-positive B-lymphocytes (p= 0.0018), which was unaffected by linsitinib and a decrease of GR1-positive cells (p= 0.0038), which was prevented by linsitinib (p= 0.0027). In addition, we observed an increase of Sca-1 positive hematopietic stem cells (p= 0.0007) and of stromal cell-derived factor 1 (SDF-1) (p ≤0.0001) after immunization with TSHR which was prevented by linsitinib (Sca-1: p= 0.0008, SDF-1: p ≤0.0001). TSHR-immunization also resulted in upregulation of CCL-5, IL-6 and osteopontin (all p ≤0.0001) and a concomitant decrease of the immune-inhibitory cytokines IL-10 (p= 0.0064) and PGE2 (p ≤0.0001) in the bone marrow (all p≤ 0.0001). Treatment with the IGF-1R antagonist linsitinib blocked these events (all p ≤0.0001). We further demonstrate a down-regulation of arginase-1 expression (p= 0.0005) in the bone marrow in TSHR immunized mice, with a concomitant increase of local arginine (p ≤0.0001). Linsitinib induces an upregulation of arginase-1 resulting in low arginase levels in the bone marrow. Reconstitution of arginine in bone marrow cells in vitro prevented immune-inhibition by linsitinib. Collectively, these data indicate that the bone marrow is activated in experimental Graves' disease and TED, which is prevented by linsitinib. Linsitinib-mediated immune-inhibition is mediated, at least in part, by arginase-1 up-regulation, consumption of arginine and thereby immune inhibition.

Роль ритуксимаба в терапии эндокринной офтальмопатии

Endocrine ophthalmopathy (EOP) is a vision-threatening and disfiguring extrathyroid manifestation of Graves' disease, which often impairs the quality of life of patients and causes severe social and psychological consequences. Currently, intravenous glucocorticosteroids are the first line treatment for EOP. However, their effectiveness in these patients is frequently unsatisfactory, whereas the recurrence rate of EOP is high. Rituximab (RТX) is a chimeric monoclonal antibody directed against CD20, a surface antigen present on B cells. Numerous clinical studies of RТX in patients with EOP have shown promising results. RТX is currently considered an acceptable second-line option in patients who do not respond to previous treatments or present with relapse of the disease. This review summarizes the available data on the efficacy and safety of RTX in EOP patients, including the results of two randomized controlled trials. The potential benefits as well as limitations of RТX therapy are discussed.