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Gerd Krause Structural Biology, Leibniz-Forschungsinstitut für molekulare Pharmakologie (FMP), Berlin, Germany

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Anja Eckstein Department of Ophthalmology, University Hospital Essen, Essen, Germany

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Ralf Schülein Protein Trafficking, Leibniz-Forschungsinstitut für molekulare Pharmakologie (FMP), Berlin, Germany

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Autoimmune thyroid-stimulating antibodies are activating the thyrotropin receptor (TSHR) in both the thyroid and the eye, but different molecular mechanisms are induced in both organs, leading to Graves’ disease (GD) and Graves’ orbitopathy (GO), respectively. Therapy with anti-thyroid drugs to reduce hyperthyroidism (GD) by suppressing the biosynthesis of thyroid hormones has only an indirect effect on GO, since it does not causally address pathogenic TSHR activation itself. GO is thus very difficult to treat. The activated TSHR but also the cross-interacting insulin-like growth factor 1 receptor (IGF-1R) contribute to this issue. The TSHR is a heptahelical G-protein-coupled receptor, whereas the IGF-1R is a receptor tyrosine kinase. Despite these fundamental structural differences, both receptors are phosphorylated by G-protein receptor kinases, which enables β-arrestin binding. Arrestins mediate receptor internalization and also activate the mitogen-activated protein kinase pathway. Moreover, emerging results suggest that arrestin plays a critical role in the cross-interaction of the TSHR and the IGF-1R either in their common signaling pathway and/or during an indirect or potential TSHR/IGF-1R interaction. In this review, novel pharmacological strategies with allosteric small-molecule modulators to treat GO and GD on the level of the TSHR and/or the TSHR/IGF-1R cross-interaction will be discussed. Moreover, monoclonal antibody approaches targeting the TSHR or the IGF-1R and thereby preventing activation of either receptor will be presented. Another chapter addresses the immunomodulation to treat GO using TSHR-derived peptides targeting the human leukocyte antigen DR isotope (HLA-DR), which is a feasible approach to tackle GO, since HLA-DR and TSHR are overexpressed in orbital tissues of GO patients.

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Nora Dehina Institute for Experimental Endocrinology, Charité - Universitätsmedizin Berlin, Berlin
Department of Ophthalmology, University Hospital Essen, Essen, Germany

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Peter Josef Hofmann Institute for Experimental Endocrinology, Charité - Universitätsmedizin Berlin, Berlin

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Thomas Behrends Institute for Experimental Endocrinology, Charité - Universitätsmedizin Berlin, Berlin

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Anja Eckstein Department of Ophthalmology, University Hospital Essen, Essen, Germany

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Lutz Schomburg Institute for Experimental Endocrinology, Charité - Universitätsmedizin Berlin, Berlin

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Background: Selenium (Se) is of importance for regular functioning of the immune system and thyroid gland, and may have a health effect in mild Graves' ophthalmopathy (GO). Objective: As the Se status declines in inflammation, we analyzed whether GO activity or severity affects the Se status of patients. Methods: Serum Se and selenoprotein P (SePP) concentrations were retrospectively determined in 84 consecutive GO patients before treatment and compared to their clinical activity score (CAS) and severity of eye changes (NOSPECS) status, and to the concentrations of autoantibodies targeting the TSH receptor (TRAK) or the IGF1 receptor (IGF1R-aAB). Results: Serum Se and SePP were linearly associated, indicating a suboptimal Se status of our patients. In comparison to data from other European cohorts, the majority of GO patients had a relatively poor Se status ([Se] ± SD; 70.0 ± 23.8 µg/l), below the threshold needed for full expression of selenoproteins. TRAK were inversely associated with Se concentrations, while IGF1R-aAB titers were not associated with Se. Neither Se nor SePP concentrations differed between GO patients with severe versus mild or active versus inactive disease, or showed significant associations with the CAS or NOSPECS values. Conclusion: GO patients are at risk of a low Se status, yet disease severity or activity does not seem to affect Se or SePP concentrations directly. However, as the retrospective nature of the analysis does not allow conclusions on a potential causative role of Se on Graves' disease or GO risk, these results neither support nor discourage adjuvant Se supplementation attempts.

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Luigi Bartalena Department of Clinical and Experimental Medicine, University of Insubria, Endocrine Unit, Ospedale di Circolo, Varese, Italy

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Lelio Baldeschi Department of Ophthalmology, Hospital Saint Luc, Catholic University of Louvain, Brussels, Belgium

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Kostas Boboridis Ophthalmology Department, Aristotle University of Thessaloniki, Thessaloniki, Greece

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Anja Eckstein Zentrum für Augenheilkunde, Universitätsklinikum Essen, Essen

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George J. Kahaly Department of Medicine I, Johannes Gutenberg University (JGU) Medical Center, Mainz, Germany

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Claudio Marcocci Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy

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Petros Perros Department of Endocrinology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

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Mario Salvi Graves' Orbitopathy Center, Endocrinology, Fondazione Ca' Granda IRCCS, University of Milan, Milan, Italy

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Wilmar M. Wiersinga Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

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Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease, though severe forms are rare. Management of GO is often suboptimal, largely because available treatments do not target pathogenic mechanisms of the disease. Treatment should rely on a thorough assessment of the activity and severity of GO and its impact on the patient's quality of life. Local measures (artificial tears, ointments and dark glasses) and control of risk factors for progression (smoking and thyroid dysfunction) are recommended for all patients. In mild GO, a watchful strategy is usually sufficient, but a 6-month course of selenium supplementation is effective in improving mild manifestations and preventing progression to more severe forms. High-dose glucocorticoids (GCs), preferably via the intravenous route, are the first line of treatment for moderate-to-severe and active GO. The optimal cumulative dose appears to be 4.5-5 g of methylprednisolone, but higher doses (up to 8 g) can be used for more severe forms. Shared decision-making is recommended for selecting second-line treatments, including a second course of intravenous GCs, oral GCs combined with orbital radiotherapy or cyclosporine, rituximab or watchful waiting. Rehabilitative treatment (orbital decompression surgery, squint surgery or eyelid surgery) is needed in the majority of patients when GO has been conservatively managed and inactivated by immunosuppressive treatment.

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Anke Schlüter Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, Essen, Germany
Department of Oto-Rhino-Laryngology – Head and Neck Surgery, University Hospital Essen, Essen, Germany

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Anja K. Eckstein Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, Essen, Germany
Department of Ophthalmology, University Hospital Essen, Essen, Germany

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Alexandra Brenzel Imaging Center Essen (IMCES), Institute for Experimental Immunology and Imaging, University Hospital Essen, Essen, Germany

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Mareike Horstmann Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, Essen, Germany

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Stephan Lang Department of Oto-Rhino-Laryngology – Head and Neck Surgery, University Hospital Essen, Essen, Germany

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Utta Berchner-Pfannschmidt Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, Essen, Germany

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J. Paul Banga Molecular Ophthalmology, Department of Ophthalmology, University Hospital Essen, Essen, Germany

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Salvador Diaz-Cano Department of Histopathology, King’s College Hospital NHS, London, United Kingdom

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Objectives: Experimental models of Graves hyperthyroid disease accompanied by Graves orbitopathy (GO) can be efficiently induced in susceptible inbred strains of mice by immunization by electroporation of heterologous human TSH receptor (TSHR) A-subunit plasmid. The interrelated pathological findings in the thyroid glands of Graves disease (GD) that explain the core changes classically include diffuse follicular hyperplasia and multifocal mild lymphocytic infiltrate. However, the relative contributions of different thyroid tissue components (colloid, follicular cells, and stroma) have not been previously evaluated. In this study, we characterize the thyroid gland of an experimental mouse model of autoimmune GD. Our objective was to define the relative contribution of the different thyroid tissue components to the pathology of glands in the experimental model. Methods: Mice were immunized with human TSHR A-subunit plasmid. Antibodies induced to human TSHR were pathogenic in vivo due to their cross-reactivity to mouse TSHR. Results: Autoimmune thyroid disease in the model was characterized by histopathology of hyperplastic glands with large follicular cells. Further examination of thyroid glands of immunized animals revealed a significantly increased follicular area and follicle/stroma ratio, morphometrically correlated with a noninflammatory follicular hyperplasia/hypertrophy. The increased follicle/stroma ratio was the most relevant morphometrically variable summarizing the pathological changes for screening purposes. Conclusion: GD thyroid glands are enlarged and characterized by a noninflammatory diffuse follicular cell hyperplasia/hypertrophy and a significant increase in the follicles with an increased follicle/stroma ratio. Overall, this mouse model is a faithful model of an early hyperthyroid status of GD (diffuse glandular involvement and follicular expansion).

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Christiaan F Mooij Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

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Timothy D Cheetham Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK
Department of Pediatric Endocrinology, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK

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Frederik A Verburg Department of Radiology and Nuclear Medicine, Erasmus MC, Rotterdam, the Netherlands

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Anja Eckstein Department of Ophthalmology, University Duisburg Essen, Essen, Germany

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Simon H Pearce Translational and Clinical Research Institute, Newcastle University, Newcastle-upon-Tyne, UK
Endocrine Unit, Royal Victoria Infirmary, Newcastle-upon-Tyne, UK

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Juliane Léger Department of Pediatric Endocrinology and Diabetes, Reference Center for Rare Endocrine Growth and Development Diseases, Endo-ERN HCP, Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, University of Paris, NeuroDiderot Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France

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A S Paul van Trotsenburg Department of Pediatric Endocrinology, Emma Children’s Hospital, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands

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Hyperthyroidism caused by Graves’ disease (GD) is a relatively rare disease in children. Treatment options are the same as in adults – antithyroid drugs (ATD), radioactive iodine (RAI) or thyroid surgery, but the risks and benefits of each modality are different. The European Thyroid Association guideline provides new recommendations for the management of pediatric GD with and without orbitopathy. Clinicians should be alert that GD may present with behavioral changes or declining academic performance in children. Measurement of serum TSH receptor antibodies is recommended for all pediatric patients with hyperthyroidism. Management recommendations include the first-line use of a prolonged course of methimazole/carbimazole ATD treatment (3 years or more), a preference for dose titration instead of block and replace ATD, and to avoid propylthiouracil use. Where definitive treatment is required either total thyroidectomy or RAI is recommended, aiming for complete thyroid ablation with a personalized RAI activity. We recommend avoiding RAI in children under 10 years of age but favor surgery in patients with large goiter. Pediatric endocrinologists should be involved in all cases.

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