Current concepts regarding Graves' orbitopathy.

Graves' orbitopathy (GO) is an orbital autoimmune disorder and the main extrathyroidal manifestation of Graves' disease, the most common cause of hyperthyroidism. GO affects about 30% of Graves' patients, although fewer than 10% have severe forms requiring immunosuppressive treatments. Management of GO requires a multidisciplinary approach. Medical therapies for active moderate-to-severe forms of GO (traditionally, high-dose glucocorticoids) often provide unsatisfactory results, and subsequently surgeries are often needed to cure residual manifestations. The aim of this review is to provide an updated overview of current concepts regarding the epidemiology, pathogenesis, assessment, and treatment of GO, and to present emerging targeted therapies and therapeutic perspectives. Original articles, clinical trials, systematic reviews, and meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, Graves' orbitopathy, thyroid eye disease, glucocorticoids, orbital radiotherapy, rituximab, cyclosporine, azathioprine, teprotumumab, TSH-receptor antibody, smoking, hyperthyroidism, hypothyroidism, thyroidectomy, radioactive iodine, and antithyroid drugs. Recent studies suggest a secular trend toward a milder phenotype of GO. Standardized assessment at a thyroid eye clinic allows for a better general management plan. Treatment of active moderate-to-severe forms of GO still relies in most cases on high-dose systemic-mainly intravenous-glucocorticoids as monotherapy or in combination with other therapies-such as mycophenolate, cyclosporine, azathioprine, or orbital radiotherapy-but novel biological agents-including teprotumumab, rituximab, and tocilizumab-have achieved encouraging results.

[LIFESTYLE ADJUSTMENT AS THERAPEUTIC TOOL IN THYROID EYE DISEASE].

OBJECTIVES: Thyroid Eye Disease (TED), also known as Graves' ophthalmopathy, is the most frequent extrathyroidal manifestation of autoimmune dysthyroidism. The most common ocular signs are eyelid retraction, proptosis, and strabismus, alongside specific dermatopathies. This article aims to review the options to improve TED manifestation by lifestyle adjustment. RESULTS: Tobacco smoking is the strongest risk factor for the development of TED and is associated with increased incidence and severity of TED and reduction in response to treatment. Smoking cessation decreases the incidence of TED and compares the risk level of ex-smokers to the risk level of the general population. Selenium is a chemical element with anti-oxidative properties. Selenium levels were significantly lower in Graves' disease patients with TED compared with those without TED. A double-blinded, randomized-control trial demonstrated that supplementation of selenium was associated with improved quality of life, decreased ocular involvement, and slowed TED progression while taken for a limited period. Statins administration to thyroid patients is associated with a reduced risk of TED. Recently, a few studies have shown an increased risk of developing TED and increased severity depending on the level of lipids in the blood, which suggests that balancing blood lipid levels by statins or by low-fat diet can help prevent TED. CONCLUSIONS: Lifestyle adjustment might be critical for a significant portion of patients. By supporting smoking cessation, the recommendation of selenium supplementation for a limited period and reducing serum cholesterol levels can prevent the development of TED, reduce its severity, and improve the patient's quality of life.

The risk factors for Graves' ophthalmopathy.

PURPOSE: This review aimed to provide an overview of current research into the risk factors for Graves' ophthalmopathy (GO). METHODS: To find information about the risk factors for GO, the research database PubMed was searched and relevant articles were obtained to extract information about risk factors. RESULTS: Smoking has been widely accepted as an important risk factor and cigarette smoking cessation has been shown to improve the outcome and decrease the onset of GO. Radioactive iodine on the thyroid may induce hyperthyroidism and increase the occurrence of GO. Selenium deficiency is a risk factor for GO and the supplementation of selenium has been an adjuvant therapy. Decreasing stressful life events (SLE) may help improve GO. Imbalance in intestinal flora is essential to GO, with Yersinia enterocolitica and Escherichia coli both increased in the digestive tract of the individual with GO. In addition, controlling serum cholesterol may help improve GO since adipogenesis is an important pathological change in its pathogenesis. Considering the correlation between Graves' disease and GO, maintaining normal thyroid function hormone level is the first-line therapeutic strategy to prevent progression of GO. An increase in antibodies such as TSHR and IGF-1R is the main predictor of GO. Besides, gender and gene polymorphism are also risk factors towards GO. CONCLUSIONS: Risk factors for GO arise from five sources: physical and chemical environment, social-psychological environment, biological environment, the human organism, and genetic codes. Risk factors within these categories may interact with each other and their mechanisms in promoting the development of GO are complex. Research into risk factors for GO may promote emerging fields related to GO such as control of autoantibodies and intestinal microbiota.

Clinical Management and Therapeutic Strategies for the Thyroid-Associated Ophthalmopathy: Current and Future Perspectives.

PURPOSE: TAO is an organ specific autoimmune disease associated with thyroid, and inflammation of the orbit and periorbital tissues, which is different from systemic autoimmune diseases such as SLE. However, Grave's disease is a kind of systemic autoimmune syndrome which might involve the thyroid, the eye ball and the anterior tibial tissue. Considering the inexplicable understanding of TAO pathogenesis, the disease worsens for the patients. Therefore, this manuscript provides insights into the recent advancements of clinical features, epidemiology, pathogenesis with gene-interactions, diagnosis, including available and novel treatment options for TAO, based on available data including RCTs, meta-analyses, and systematic reviews. METHODS: Articles with clinical features, epidemiology, pathogenesis, diagnosis, and treatment of the disease were thoroughly studied. To perform the gene expression and pathway analysis, articles were searched on PubMed, MEDLINE Cochrane Library and ClinicalTrial.gov from 1982 to 2020. To predict novel TAO-specific therapeutic molecule, structure-based drug design (SBDD) was performed. RESULTS: We observed gene expression and pathway analysis and SBDD approaches might bring new insights in the field of TAO pathogenesis, diagnosis, and treatment. A genome-wide map of human genetic interactions revealed involvement of crucial cell-signalling pathways, such as TNF-mediated signalling pathway, type-I interferon signalling pathway, toll-like receptor signalling pathway, transforming growth factor-beta receptor signalling pathway etc. Recently, FDA-approved teprotumumab a breakthrough, first drug for the treatment of active thyroid eye disease, which reduces proptosis and the need for orbital decompression surgery. Furthermore, our SBDD results revealed that cost-effective Curcumin, Withaferin A, Resveratrol, Scopolamine, Quercetin, and Berberine may have significant binding affinity for hyaluronan protein and may be exploited for therapeutic purposes in TAO. CONCLUSIONS: Considering the increasing risk and nature of disease, novel drug therapies and markers for prognosis need to be investigated. Moreover, evidence-based non-invasive/minimal surgical therapies should be developed for the better management of the disease. ABBREVIATIONS: ADIPOQ: Adiponectin; CAS: Clinical Activity Score; CCL5: C-C Motif Chemokine Ligand 5; CT: Computed Tomography; DON: Dysthyroid Optic Neuropathy; EUGOGO: European Group of Graves' Orbitopathy; FDA: U.S. Food and Drug Administration; FOS: Fos Proto-Oncogene, AP-1 Transcription Factor Subunit; HLA: Human Leukocyte Antigen; HLA-DRA: Major Histocompatibility Complex, Class II, DR Alpha; ICAM1: Intercellular Adhesion Molecule 1; IFNG: Interferon Gamma; IGF-1: Insulin-like Growth Factor 1; IGF-1R: Insulin-like Growth Factor-1 Receptor; IL12B: Interleukin 12B; IL23R: Interleukin 23 Receptor; IL6: Interleukin 6; IOP: Intraocular Pressure; IRF1: Interferon Regulatory Factor 1; IRF5: Interferon Regulatory Factor 5; IRF7: Interferon Regulatory Factor 7; IRF9: Interferon Regulatory Factor 9; JUN: Jun Proto-Oncogene, AP-1 Transcription Factor Subunit; JUNB: JunB Proto-Oncogene, AP-1 Transcription Factor Subunit; MHC: Major Histocompatibility Complex; MRI: Magnetic Resonance Imaging; NFKB1: Nuclear Factor Kappa B Subunit 1; NFKBIA: Nuclear Factor Kappa B Inhibitor Alpha; OADSCs: Orbital Adipose Derived Stromal Cells; PDGFB: Platelet Derived Growth Factor Subunit B; PPARG: Peroxisome Proliferator Activated Receptor Gamma; RANTES: Regulated on Activation Normal T cell Expressed and Secreted; RARA: Retinoic Acid Receptor Alpha; RCTs (Randomized Controlled Trials; SLE: Systemic lupus erythematosus; SOCS3: Suppressor of Cytokine Signaling 3; STAT1: Signal Transducer and Activator of Transcription 1; TAO: Thyroid-Associated Ophthalmopathy; TED: Thyroid eye disease; TGFB1: Transforming Growth Factor Beta 1; TGFB2: Transforming Growth Factor Beta 2; TGF-ß: Transforming Growth Factor-beta; TLR7: Toll like Receptor 7; TLR9: Toll like Receptor 9; TNFRSF18: Tumor Necrosis Factor Receptor Superfamily Member 18; TNFSF11: Tumor Necrosis Factor Receptor Superfamily Member 11; TNF-α: Tumor Necrosis Factor-alpha; TSHR: Thyroid Stimulating Hormone Receptor; TSIs: Thyroid Stimulating Immunoglobulin; WNT5A: Wingless-Type MMTV Integration Site Family, Member 5A.

Serum Vitamin D Deficiency Is an Independent Risk Factor for Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) is an inflammatory orbitopathy with significant impact on visual function and quality of life. Although studies have shown that patients who are deficient in vitamin D are more likely to develop autoimmune conditions, there are no studies demonstrating a definitive correlation between serum 25-hydroxyvitamin D (25(OH)D) deficiency and an increased risk of TED. METHODS: This retrospective case-control study compared serum 25(OH)D levels among 4 groups: 1) Graves disease (GD) patients with TED (n = 89); 2) GD patients without TED (n = 89); and healthy control patients matched to 3) the TED group (n = 356); and 4) the GD group (n = 356). The authors compared 25(OH)D level in the TED group measured within 1 year of TED diagnosis to the most recently measured 25(OH)D level in the GD group using Student t test of the log transformation of serum levels. Linear regression was used to control for other risk factors. Thyroid eye disease patients and GD patients were compared separately to their matched healthy control patients with linear mixed models. RESULTS: Thyroid eye disease patients displayed significantly lower serum 25(OH)D levels than GD patients (24.8 ± 13.2 ng/ml vs. 29.4 ± 13.3 ng/ml; p = 0.006). Controlling for smoking status and previous radioactive iodine treatment did not affect this statistically significant difference. CONCLUSIONS: Low serum vitamin D is associated with TED diagnosis. Assessing and supplementing vitamin D levels may be an important addition to the early management of GD patients. Future research should include longitudinal studies and prospective clinical trials to further explore the mechanism responsible for the observed association.Thyroid eye disease is an inflammatory orbitopathy associated with Graves disease. Vitamin D is a known immune system regulator. The authors show that vitamin D deficiency is associated with the development of thyroid eye disease.

Severe unilateral orbitopathy in a patient with Hashimoto's thyroiditis - a case report.

BACKGROUND: Thyroid-associated orbitopathy (TAO) constitutes an immune-mediated inflammation of the orbital tissues of unclear etiopathogenesis. TAO is most prevalent in hyperthyroid patients with Graves' disease (GD); however, severe cases of orbitopathy associated with Hashimoto's thyroiditis (HT) have rarely been described. CASE PRESENTATION: Herewith we report an unusual case of a middle-aged clinically and biochemically euthyroid woman with a stable HT, who developed a severe unilateral left-sided TAO. Thyrotropin receptor antibodies (TRAb) concentration was negative. Intraocular pressure in the left eye was mildly elevated (24 mmHg), while vision acuity was not compromised. Abnormal positioning of the eyeball suggested the extraocular muscles involvement. Unilaterally, von Graefe's, Stellwag's, Kocher's and Moebius' signs were positive. Conjunctival erythema, redness and edema of the eyelid and an enlarged, swollen lacrimal caruncle were visible. She received 4/7 points in the Clinical Activity Scale (CAS) and class IV in the NO SPECS severity scale for the left eye (I-0, II-a, III-0, IV-b, V-0, VI-0). Magnetic resonance imaging (MRI) revealed thickening of the left medial rectus muscle with an increase in T2 signal intensity and prolonged T2 relaxation indicating an active form of TAO. The patient received therapy with glucocorticosteroids intravenously, followed by intramuscular injections with a cumulative dose of 3.24 g of methylprednisolone during a 9-week period with good tolerance. The applied therapy, combined with adequate L-thyroxine substitution, as well as vitamin D and selenium supplementation, resulted in a complete remission of ophthalmic symptoms. CONCLUSIONS: Unilateral exophthalmos in TRAb-negative patients with HT is not a typical manifestation of the disease, and requires a wider differential diagnosis with MRI of the orbits. Scheme of three iv. pulses of methylprednisolone intravenously and the continuation of treatment with im. injections seems to be an effective and safe method of treatment in this group of patients. What is more, adequate vitamin D supplementation and the maintenance of biochemical euthyroidism may help to achieve an ultimate therapeutic effect. Patients with TAO in the course of HT need a careful and continued interdisciplinary approach both ophthalmological and endocrinological. Further studies are needed to elucidate the etiopathogenesis of TAO in TRAb-negative patients.

Post-radioiodine De Novo Onset Graves' Ophthalmopathy: Case Reports and a Review of the Literature.

New-onset Graves' ophthalmopathy (GO) following radioiodine treatment (RAI) and worsening of existing GO are well-described in the endocrinology literature. These phenomena are recognized by ophthalmologists, yet poorly documented in the ophthalmology literature. Two male patients, aged 43 and 62 years, respectively, with Graves' disease without GO, received RAI. Four months later, one patient developed acute GO with unilateral reduction in visual acuity, conjunctival chemosis, lagophthalmos, bilateral severely restricted ocular motility, and lid retraction. High-dose intravenous steroids, followed by oral steroids, led to a dramatic clinical improvement. The second patient received a second dose of RAI for persistent hyperthyroidism and subsequently developed acute GO-comprising restricted ocular motility, peri-orbital swelling, and conjunctival chemosis. Symptoms gradually resolved on continued carbimazole treatment. Neither patient received pre-RAI prophylactic glucocorticoids, as currently they are only recommended for patients with pre-existing GO or multiple risk factors. We discuss the limitations of using this risk-based approach in preventing new-onset GO following RAI therapy.

Euthyroid Graves' orbitopathy and incidental papillary thyroid microcarcinoma.

UNLABELLED: Euthyroid Graves' orbitopathy (GO) combined with incidental papillary thyroid microcarcinoma has rarely been reported. CASE REPORT: A 61-year-old Caucasian woman initially presented with progressive fatigue, exophthalmos, and thyroid function tests within normal limits. She underwent thyroidectomy, was found to have two incidental papillary thyroid microcarcinomas, and received radioactive iodine ablation to eliminate thyroid antigen. In addition to following her eye disease, TSH-receptor antibodies, thyroid stimulating immunoglobulins, and serum thyroglobulin measurements were recorded, demonstrating no evidence of thyroid cancer at four-year follow-up. At first, she had mild GO, developing into moderate-to-severe GO, and at 4 years she had Hertel measurements of 20 mm in both eyes. CONCLUSION: This report underscores the difficulty of managing GO even when thyroid function is normal(ized) and thyroid antigen exposure has been minimized. In addition, it illustrates why antithyroidal antibodies should be considered in cases of concomitant papillary thyroid cancer, as thyroid cells can be stimulated not only by TSH but also by TSH-receptor stimulating antibodies.

Radiotherapy-associated euthyroid Graves ophthalmopathy following floor-of-mouth surgery: a case report.

The thyroid gland is commonly included in the radiation field during treatment of nonthyroidal neoplastic disease of the head and neck. As a result, thyroid abnormalities sometimes occur following external irradiation. We report an unusual case of radiotherapy-associated Graves ophthalmopathy 5 months after adjuvant external irradiation of the head and neck in a euthyroid patient who had undergone wide local excision of squamous cell carcinoma from the floor of the mouth.

[Graves' orbitopathy]. / Endokrin orbitopathia.

Graves' orbitopathy or thyroid associated orbitopathy is the most frequent extrathyroidal manifestation of Graves' disease with autoimmune mechanism which is still incompletely understood. The epidemiologic data provided evidence that severe, infiltrative orbitopathy is present in 3-5% of patients, and the quality of life is impaired even in individuals with mild form of this disease. The anti-TSH receptor and anti-eye muscle autoantibodies have been proved to be involved into pathomechanism of orbitopathy. The accumulation of glucose-aminoglycan and proinflammatory cytokines in retro-orbital fibroblasts are responsible for enlargement of eye muscle and the retro-orbital tissues resulting in inflammation of periorbital tissues and proptosis. Management of orbitopathy can be either medical and surgical. The medical therapy relies on the use of high dose systemic glucocorticoids or retro-orbital irradiation, either alone or in combination. Recent randomized clinical trials have confirmed that glucocorticoids are more effective in intravenous than oral use. Retro-orbital radiotherapy is an effective and safe therapy for orbitopathy and the side effects are avoidable. Somatostatin analogs are not so effective as it has been waited in previous studies. The high dose intravenous immunoglobulins and pentoxifylline therapy are favorable, however, prospective randomized trials have been not yet made. The manifestation of orbitopathy includes both unavoidable (genetic background) and avoidable (smoking, cytokine therapy, iodine exposure, radioiodine therapy) risk factors. Cigarette smoking must be given up by all patients with Graves' disease. Pentoxifylline therapy is advisable for all patients with Graves'diseases, especially for those who have genetic susceptibility to autoimmune disorders and not able to give up cigarette smoking.