[Endocrine orbitopathy]. / Endokrine Orbitopathie.

Endocrine orbitopathy (EO), also known as Graves' orbitopathy or thyroid-associated orbitopathy, is a self-limiting, immunologically induced co-reaction of the retrobulbar tissue of the eye triggered by an autoimmune disease of the thyroid gland. It is particularly associated with Graves' disease and is its most common extrathyroidal manifestation. In addition to typical anamnestic data, characteristic local findings and laboratory changes in immunothyroidism, orbital imaging plays a central role in the diagnosis and management of this disease. This review article provides comprehensive insight into various imaging modalities used to assess morphologic changes associated with EO. A detailed presentation of imaging findings provides a better understanding of orbital physiology.

Understanding the clinical and molecular basis of thyroid orbitopathy: a review of recent evidence.

Thyroid eye disease (TED) is an autoimmune orbital inflammatory disease which ranges from mild to severe. Tissue remodeling, fibrosis and fat proliferation cause changes in the orbital tissues which can affect esthetics and visual function. In its severe form, it is sight threatening, debilitating, and disfiguring and may lead to social stigma, the embarrassment about which has an impact on the quality of life of those affected and the family members. The pathogenesis of TED, which is influenced by genetic, immunological, and environmental factors, is complex and not fully elucidated. However, it remains unknown what factors determine the severity of the disease. Recent research has revealed a number of diagnostic and prognostic biomarkers of this disease. In this overview of TED, we focus on new insights and perspectives regarding biological agents that may provide a basis for new treatment modalities.

Presentation of Graves' orbitopathy within European Group On Graves' Orbitopathy (EUGOGO) centres from 2012 to 2019 (PREGO III).

BACKGROUND: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time. METHODS: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012. RESULTS: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027). CONCLUSION: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment.

Thyroid eye disease in Eastern Province of Saudi Arabia: clinical profile and correlation with vitamin D deficiency.

PURPOSE: To obtain clinical data about disease activity and severity of thyroid eye disease (TED) in a tertiary eye hospital in the Eastern Province of Saudi Arabia and to correlate this data with vitamin D levels. METHODS: A clinical observational study was conducted in a specialized eye hospital in Saudi Arabia. It included prospective enrollment of Saudi patients with confirmed TED to evaluate activity and severity according to Clinical Activity Score (CAS) and European Group on Graves' Orbitopathy (EUGOGO), respectively, and also for blood investigation, including thyroid profile and vitamin D levels. In addition, some retrospective data collection included previous medical and surgical treatment and complications. RESULTS: A total of 74 TED patients were included, with a median age of 42 years and a female predominance of 64.9%. Smokers were 18.9%. A family history of thyroid disease was noted in 12.16% of patients. There were 10.8% of patients with active TED. A moderate to severe severity level was observed in 71% of the cases, mild in 15%, and sight-threatening in 6%. Smoking and older age were associated with the active form of TED. There was a 48.4% prevalence of vitamin D deficiency among TED patients and it was not associated with TED severity or activity. CONCLUSIONS: This is the first study demonstrating the clinical profile of TED among Saudi patients. Smoking and older age were associated with TED. Vitamin D deficiency among TED patients was not worse than that of the general Saudi population.

Dysthyroid Optic Neuropathy.

PURPOSE: Dysthyroid optic neuropathy (DON) is a sight-threatening complication of thyroid eye disease (TED). This review provides an overview of the epidemiology, pathogenesis, diagnosis, and current therapeutic options for DON. METHODS: A literature review. RESULTS: DON occurs in about 5% to 8% of TED patients. Compression of the optic nerve at the apex is the most widely accepted pathogenic mechanism. Excessive stretching of the nerve might play a role in a minority of cases. Increasing age, male gender, smoking, and diabetes mellitus have been identified as risk factors. Diagnosis of DON is based on a combination of ≥2 clinical findings, including decreased visual acuity, decreased color vision, relative afferent pupillary defect, visual field defects, or optic disc edema. Orbital imaging supports the diagnosis by confirming apical crowding or optic nerve stretching. DON should be promptly treated with high-dose intravenous glucocorticoids. Decompression surgery should be performed, but the response is incomplete. Radiotherapy might play a role in the prevention of DON development and may delay or avoid the need for surgery. The advent of new biologic-targeted agents provides an exciting new array of therapeutic options, though more research is needed to clarify the role of these medications in the management of DON. CONCLUSIONS: Even with appropriate management, DON can result in irreversible loss of visual function. Prompt diagnosis and management are pivotal and require a multidisciplinary approach. Methylprednisolone infusions still represent first-line therapy, and surgical decompression is performed in cases of treatment failure. Biologics may play a role in the future.

Computed tomography and magnetic resonance imaging of the orbit in the diagnosis and treatment of thyroid-associated orbitopathy - experience from practice. A Review.

The purpose is to acquaint readers with the contribution of imaging methods (IMs) of the orbit, specifically computed tomography (CT) and magnetic resonance imaging (MRI), in the diagnosis of thyroid-associated orbitopathy (TAO). Methods: IMs of the orbit are an indispensable accessory in the clinical and laboratory examination of TAO patients. The most frequently used and probably most accessible method is an ultrasound examination of the orbit (US), which, however, has a number of limitations. Other methods are CT and MRI. Based on the published knowledge implemented in our practice and several years of experience with the diagnosis and treatment of TAO patients, we would like to point out the benefits of CT and MRI in the given indications: visualisation of the extraocular muscles, assessment of disease activity, diagnosis of dysthyroid optic neuropathy and differential diagnosis of other pathologies in the orbit. Our recommendation for an ideal MRI protocol for disease activity evaluation is also included.  Conclusion: IMs play an irreplaceable role not only in the early diagnosis of TAO, but also in the monitoring of the disease and the response to the applied treatment. When choosing a suitable IM for this diagnosis, a number of factors must always be taken into account; not only availability, cost and burden for the patient, but especially the sensitivity and specificity of the given method for the diagnosis of TAO.

Orbitopatía tiroidea. Puntos clave para el diagnóstico y tratamiento / Thyroid orbitopathy. Tricks for diagnosis and treatment

La orbitopatía tiroidea (OT) es una patología autoinmune de etiología desconocida. Se trata de una enfermedad edematosa e inflamatoria crónica y a veces subaguda o aguda, cuyas características principales son edema palpebral, úlceras corneales, hipertensión ocular, exoftalmos generalmente bilateral, estrabismo restrictivo, diplopía y neuropatía óptica. El objetivo principal es realizar una revisión y actualización acerca del enfoque diagnóstico y terapéutico de la OT. Realizar una revisión y actualización acerca del enfoque diagnóstico, terapéuticos de la OT. Métodos: Revisión de la literatura publicada referente a la OT y manera actual de enfocar esta patología. Resultados: La OT es una enfermedad inflamatoria orbitaria con un posible origen autoinmune y que suele asociarse a trastornos metabólicos de la glándula tiroidea. Fisiopatológicamente su mecanismo no está claro. Afecta mayormente a mujeres y está negativamente influenciada por factores como el tabaquismo, la edad, el sexo y la raza. Es imprescindible clasificarla en cuanto a su severidad y su actividad para un correcto manejo. Conclusiones: El conocimiento clínico de OT es esencial para el diagnóstico precoz de la enfermedad. El tratamiento médico, en caso de OT activa, debe ser precoz, agresivo y acorde a la fase en que se presente el paciente con el fin de evitar las graves consecuencias de la OT. El tratamiento quirúrgico deberá ser lógico y ordenado, pero a su vez rápido, con el fin de devolver al paciente al entorno laboral, social y familiar. (AU)

Purpose: Thyroid orbitopathy (TO) is an autoimmune disease of unknown etiology. It is a chronic and sometimes subacute or acute edematous and inflammatory disease, the main characteristics of which are eyelid edema, corneal ulcers, ocular hypertension, generally bilateral exophthalmos, restrictive strabismus, diplopia and optic neuropathy. The main purpose of this work is to review and update the current diagnostic and therapeutic approaches. To propose a practical, basic and precocious approach based in the knowledge of the TO. Methods: Literature review and exposition of our experience in the management of TO. Results: TO is an inflammatory orbital disease that probably has an autoimmune origin and most of the time is related to systemic disorders of the thyroid gland. Pathogenesis of the disease is not yet fully understood. Women are more likely to develop TO, and the disease is clearly affected by several factors such as smoking, age, sex and race. It is crucial to determine TO severity and activity for a correct management. Conclusions: Clinical knowledge is essential for the early diagnosis of this disorder, and it is the most important factor for the proper management of the disease. The medical treatment must be initiated promptly and should be aggressive and based in the current phase of the disease, in order to avoid the severe damage that follows TO. The surgical approach must be logical and sequential, but, on the other hand, must be rapid and aggressive in order to return the patient to his/her labour, social and familiar environment. (AU)

Graves' Orbitopathy Models: Valuable Tools for Exploring Pathogenesis and Treatment.

Graves' orbitopathy (GO) is the most common extrathyroidal complication of Graves' disease (GD) and severely affects quality of life. However, its pathogenesis is still poorly understood, and therapeutic options are limited. Animal models are important tools for preclinical research. The animals in some previous models only exhibited symptoms of hyperthyroidism without ocular lesions. With the improvements achieved in modeling methods, some progressive animal models have been established. Immunization of mice with A subunit of the human thyroid stimulating hormone receptor (TSHR) by either adenovirus or plasmid (with electroporation) is widely used and convincing. These models are successful to identify that the gut microbiota influences the occurrence and severity of GD and GO, and sex-related risk factors may be key contributors to the female bias in the occurrence of GO rather than sex itself. Some data provide insight that macrophages and CD8+ T cells may play an important pathogenic role in the early stage of GO. Our team also replicated the time window from GD onset to GO onset and identified a group of CD4+ cytotoxic T cells. In therapeutic exploration, TSHR derived peptides, fingolimod, and rapamycin offer new potential options. Further clinical trials are needed to investigate these drugs. With the increasing use of these animal models and more in-depth studies of the new findings, scientists will gain a clearer understanding of the pathogenesis of GO and identify more treatments for patients.

Computer aided volumetric assessment of orbital structures in patients with Graves' orbitopathy: correlation with serum thyroid antiperoxidase antibodies and disease activity.

INTRODUCTION: Graves' disease is an autoimmune disorder. Goiter and Graves' orbitopathy are frequently seen clinically. It would be helpful for the diagnosis, grading, prognosis, and treatment of this condition if it was possible to find serum biomarkers to establish a connection between the plasma levels of these compounds and orbital changes. METHODS: A retrospective study was performed by revising the medical records of 44 patients with Graves' orbitopathy and 15 controls. The Osirix software (Pixmeo, Geneva, Switzerland) was used for manual orbital measurements. Plasma levels of Graves' orbitopathy substances were obtained in the analytical review of the patients. RESULTS: A greater muscle volume was observed in patients with Graves' orbitopathy in relation to the control group (p < 0.001). The clinical activity score (CAS) was associated to total muscle mass (p = 0.013) and retrorbital fat (p = 0.048). Our results indicated a direct relationship between serum concentrations of anti-thyroid peroxidase antibodies and inferior rectus thickening (p = 0.036); however, we did not observe a positive correlation between other muscle volumes and serum concentrations of various thyroid-related substances. CONCLUSIONS: This study is the first that uses Osirix measurement software to manually assess orbital features in patients with Graves' orbitopathy. These measurements were compared to the outcomes of tests performed in a laboratory. Among several serum biomarkers, anti-thyroid peroxidase appears to be a reliable biomarker that correlates positively with inferior rectus muscle thickness in patients with thyroid eye disease. This may help to improve the management of this disease.

Influence of biological sex, age and smoking on Graves' orbitopathy - a ten-year tertiary referral center analysis.

Purpose: Severity of Graves' orbitopathy (GO) shows wide individual differences. For optimal treatment, it is important to be able to predict the natural course of the disease as accurate as possible to counteract with anti-inflammatory and surgical treatment. Therefore, we aimed to further elucidate the impact of sex, age and smoking on GO. Methods: We collected the clinical and demographic data of all patients of our tertiary referral center from January 2008 till December 2018 and analyzed it with descriptive statistics. Only patients with a complete data set were included in the further analysis. Odds ratio's for moderate-to-severe and sight-threatening GO in relation to age, sex and smoking were calculated by means of multivariate logistic regression models. Results: We evaluated the data of 4260 patient with GO and complete data sets. Most of these were women (83%). There were no significant differences between male and female patients regarding smoking habits and thyroid treatment. Men were significantly older at initial manifestation of TED (51.8 vs. 49.9y, p<0.01) and showed significant more often severe stages (61% vs. 53%, p<0.0001). Therefore, they needed significantly more intense treatment with steroids, irradiation, orbital decompression and muscle surgery. In multivariate logistic regression analyses age (OR 0.97, 95% CI:0.97-0.98, p<0.0001), male sex (OR 1.64, 95% CI:1.38-1.9, p<0.0001), smoking (OR 1.19, 95% CI:1.04-1.36, p=0.01), Grave's disease (OR 1.55, 95% CI:1.26-1.90, p<0.0001) and history of radioiodine treatment (RAI) (OR 2.44, 95% CI:2.10-2.86, p<0.0001) showed an significant association with severe stages of GO. Discussion: Our retrospective analysis showed once more that women are more often afflicted by GO. In contrast, men seem to be more severely afflicted and in need of anti-inflammatory and surgical treatments. This might be due to a different approach to the health system and resilience to GO specific symptoms, as well as previously described worse thyroid control. Estrogen mediated effects might also play a role as in other autoimmune diseases and should be subject of further trials. Besides the biological sex, smoking could again be confirmed as serious risk factor for severe GO. Of note, RAI was associated with more severe stages of GO, which should be subject to further investigation.

Monoclonal Antibodies for the Treatment of Graves Orbitopathy: Precision Medicine?

PURPOSE: To summarize the development, nomenclature, and rationale of the reported use of monoclonal antibodies (Mabs) in Graves Orbitopathy (GO) and to undertake a systematic review of the management of GO with Mabs. METHODS: The Pubmed and Embase databases and the Federal Brazilian searching site (Periódicos-CAPES) were screened. The authors searched all the keywords "monoclonal antibodies," "adalimumab," "belimumab," "infliximab," "rituximab," "teprotumumab," and "tocilizumab" combined with the terms "Graves Orbitopathy," "Graves eye disease" and "thyroid eye disease." All the articles published in English, French, and Spanish from 2000 to May 2022 were screened. Only publications with quantitative data on the activity of orbitopathy, proptosis, or both were included. RESULTS: Seventy-six articles of the 954 screened records met the inclusion criteria. Seven Mabs were described for treating GO. The three most reported Mabs were Rituximab, Tocilizumab, and Teprotumumab. Only eight randomized clinical trials compared the effect of these three Mabs and Belimumab with the effect of steroids or placebos. Adalimumab, Infliximab, and K1-70 only appeared in a few case series and case reports. Frequent mild-to-moderate and few major side effects occurred with the three most used Mabs. Relapse rates ranged from 7.4% for Tocilizumab to at least 29.4% for Teprotumumab. No randomized clinical trials compared Mabs head-to-head. CONCLUSION: Considering the lack of head-to-head comparisons between Mabs, the relapse rate, the possibility of severe collateral effects, and the cost of Mabs, it is not clear which Mab is the safest and most useful to treat GO.

A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves' orbitopathy.

Graves' orbitopathy (GO) is an organ-specific autoimmune disease, but its pathogenesis remains unclear. There are few review articles on GO research from the perspective of target cells and target antigens. A systematic search of PubMed was performed, focusing mainly on studies published after 2015 that involve the role of target cells, orbital fibroblasts (OFs) and orbital adipocytes (OAs), target antigens, thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R), and their corresponding antibodies, TSHR antibodies (TRAbs) and IGF-1R antibodies (IGF-1R Abs), in GO pathogenesis and the potentially effective therapies that target TSHR and IGF-1R. Based on the results, OFs may be derived from bone marrow-derived CD34+ fibrocytes. In addition to CD34+ OFs, CD34- OFs are important in the pathogenesis of GO and may be involved in hyaluronan formation. CD34- OFs expressing Slit2 suppress the phenotype of CD34+ OFs. ß-arrestin 1 can be involved in TSHR/IGF-1R crosstalk as a scaffold. Research on TRAbs has gradually shifted to TSAbs, TBAbs and the titre of TRAbs. However, the existence and role of IGF-1R Abs are still unknown and deserve further study. Basic and clinical trials of TSHR-inhibiting therapies are increasing, and TSHR is an expected therapeutic target. Teprotumumab has become the latest second-line treatment for GO. This review aims to effectively describe the pathogenesis of GO from the perspective of target cells and target antigens and provide ideas for its fundamental treatment.

Teprotumumab-Related Hyperglycemia.

CONTEXT: Graves orbitopathy (GO) or thyroid eye disease is a potentially sight-threatening and disfiguring autoimmune disease. Teprotumumab is a monoclonal antibody against the insulin-like growth factor-I receptor that was recently approved for GO treatment. Hyperglycemia is a recognized adverse event of teprotumumab, occurring in 10% of patients in 2 recent randomized controlled trials. OBJECTIVE: Our study aimed to report the incidence, severity, management, and longitudinal glycemic changes in patients treated with teprotumumab in an academic practice cohort. METHODS: This longitudinal, observational study included all consecutive patients treated with teprotumumab between March 2020 and May 2022 at 1 institution. Hemoglobin A1c (HbA1c) was measured every 3 months. RESULTS: Forty-two patients with baseline normoglycemia (n = 22), prediabetes (n = 10), and diabetes (n = 10) were followed for a mean of 47.5 weeks. Overall, HbA1c increased by 0.5% at 3 months. Least-squares mean changes in HbA1c at 3 months were 1.3 (P < .001), 0.7 (P = .01), and 0.1 (P = .41) in patients with diabetes, prediabetes, and normoglycemia, respectively. Twenty-two patients (52%) had hyperglycemia, which was graded as mild, moderate, and life-threatening in 55% (12/22), 41% (9/22), and 5% (1/22) of cases, respectively. Age, pre-existing diabetes, and Hispanic and Asian race/ethnicity were significant risk factors for hyperglycemia. Among patients with hyperglycemia, 36.4% (8/22) returned to baseline glycemic status at last follow-up. CONCLUSION: While effective, teprotumumab carries a significant risk of hyperglycemia, especially in patients with diabetes. Hyperglycemia may persist after stopping teprotumumab. These findings underscore the importance of guidelines for screening and management of teprotumumab-related hyperglycemia.