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.

Graves' disease.

Graves' disease (GD) is an autoimmune disease that primarily affects the thyroid gland. It is the most common cause of hyperthyroidism and occurs at all ages but especially in women of reproductive age. Graves' hyperthyroidism is caused by autoantibodies to the thyroid-stimulating hormone receptor (TSHR) that act as agonists and induce excessive thyroid hormone secretion, releasing the thyroid gland from pituitary control. TSHR autoantibodies also underlie Graves' orbitopathy (GO) and pretibial myxoedema. Additionally, the pathophysiology of GO (and likely pretibial myxoedema) involves the synergism of insulin-like growth factor 1 receptor (IGF1R) with TSHR autoantibodies, causing retro-orbital tissue expansion and inflammation. Although the aetiology of GD remains unknown, evidence indicates a strong genetic component combined with random potential environmental insults in an immunologically susceptible individual. The treatment of GD has not changed substantially for many years and remains a choice between antithyroid drugs, radioiodine or surgery. However, antithyroid drug use can cause drug-induced embryopathy in pregnancy, radioiodine therapy can exacerbate GO and surgery can result in hypoparathyroidism or laryngeal nerve damage. Therefore, future studies should focus on improved drug management, and a number of important advances are on the horizon.

Noninflammatory Diffuse Follicular Hypertrophy/Hyperplasia of Graves Disease: Morphometric Evaluation in an Experimental Mouse Model.

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).

Tendon Elongation with Bovine Pericardium in Patients with Severe Esotropia after Decompression in Graves' Orbitopathy-efficacy and Long-term Stability.

BACKGROUND/AIMS: We performed a retrospective analysis to examine clinical results, establish a dose-effect coefficient and analyze the long-term efficacy of tendon elongation with bovine pericardium (Tutopatch®) for surgical correction of severe esotropia, occurring after three-wall orbital decompression for dysthyroid optic neuropathy in patients with Graves' orbitopathy (GO). METHODS: Tendon elongation of the medial rectus muscle (MR) was performed in our institution using an interponate of bovine pericardium in 60 patients (27 underwent unilateral and 33 bilateral surgery). Success-rate (total horizontal deviation of 10 prism-diopters (PD) or less and evidence of binocular single vision with or without prism glasses) and horizontal motility were examined 3 months, 1 and >4 years after surgery. A dose-effect coefficient for deviation reduction (PD) per recession distance (mm) was established. RESULTS: Horizontal deviations between 28-80Δ were corrected. Diplopia in primary-gaze disappeared in 65% of the patients after 3 months and in 83% after one year (including 12 patients who underwent subsequent surgery after 3-month follow-up). Patients with deviations ≤40Δ after unilateral and ≤50Δ after bilateral tendon elongation showed higher primary success-rates after 3 months (78% and 72%). Vertical deviations (≤10Δ) were corrected by the procedure in 28% without need of recession of the inferior rectus (IR). Only 3 patients showed overcorrection after one year. One of these underwent revision surgery, in which the interponate was no longer discernible from surrounding fibrotic scar tissue. At >4-year follow-up (4.3-15years) effects were stable and 95% of patients showed fusion in primary gaze. Median dose-effect coefficient was lower after tendon elongation (1.8Δ/mm) compared to conventional medial rectus recession in patients with GO. Horizontal motility was slightly decreased, but much more symmetric around primary gaze. CONCLUSION: Tendon elongation with a bovine pericardium implant is a safe surgical method, suitable to correct severe esotropia after decompression surgery. A lower dose-effect has to be taken into account. Patients with esotropia ≥42Δ should not be treated with unilateral, but bilateral tendon elongation, to avoid undercorrections. In patients with deviations ≥52Δ it has to be further investigated if the application of even higher elongation distances is viable or if another approach-the recession of more than one rectus muscle has to be performed simultaneously to handle the severe restriction. Generally, a step-by-step approach is advisable, since small vertical deviations could also be corrected in a third of patients with the procedure and the dose-effect was more variable as in medial recessions without tendon elongation.

A novel mechanism involved in the pathogenesis of Graves ophthalmopathy (GO): clathrin is a possible targeting molecule for inhibiting local immune response in the orbit.

INTRODUCTION: Excessive orbital fibroblast (OF) proliferation and extracellular matrix production, as well as inflammation resulting in the expansion and remodeling of orbital tissue, are characteristic of Graves ophthalmopathy (GO). Our aim was to analyze and inhibit signaling pathways in resident OF that are involved in GO. METHODS/MAIN OUTCOME MEASURES: Primary human OF were obtained from 12 patients with active, severe GO and from 12 healthy control subjects. The cells were characterized by immunofluorescence assay and flow cytometry. Tyrosine phosphorylation of cellular proteins was determined by Western blot techniques, immunoprecipitation, and protein identity with mass spectrometry. Cell proliferation was determined by 5-bromo-2-deoxyuridine incorporation, hyaluronan (HA) production was assessed by a HA-binding protein based assay, and intracellular reactive oxygen species (ROS) were determined by the dichlorofluorescein assay. Clathrin heavy-chain (CHC) expression was inhibited with small interfering RNA technology. RESULTS: Tyrosine phosphorylation of CHC is constitutively increased in vitro in GO-derived OF, independent of serum or other stimulating factors. The proliferative and biosynthetic capabilities (production of HA, ROS) of GO-derived OF are significantly higher than those of OF from healthy control subjects. Down-regulation of CHC expression leads to a normalization of pathologically increased proliferation and production of HA and ROS in GO-derived OFs in vitro. CONCLUSIONS: Our findings strongly suggest that clathrin and clathrin-mediated signaling pathways are involved in the inflammatory signal transduction of OF in GO. With the identification of clathrin, we report a new potential targeting molecule for specific pharmacological inhibition of the local inflammatory response characteristic of GO.

A retrospective study on the efficacy of total absorbed orbital doses of 12, 16 and 20 Gy combined with systemic steroid treatment in patients with Graves' orbitopathy.

BACKGROUND: Graves' disease (GD) is an autoimmune disease that typically affects the thyroid gland. Thirty to sixty percent of patients also suffer from orbital inflammation. Retrobulbar radiotherapy for Graves' orbitopathy (GO) has been used for decades, though there is no direct evidence for the influence of dose and fractionation schedules on various signs and symptoms. Indeed, optimal fractionation schedules and recommended total irradiation doses are still a matter of discussion. Our aim was to investigate treatment efficacy of retrobulbar irradiation for GO at different total absorbed doses and fractionation schedules. METHODS: A retrospective evaluation of 129 patients who were examined before, as well as 6-8 months after irradiation with different treatment schedules at eight radiotherapeutic departments. Total absorbed doses were 12, 16, or 20 Gy. All patients were additionally treated with systemic application of corticosteroids. Treatment efficacy was evaluated through assessment of proptosis, horizontal and vertical ocular motility and of clinical activity (CAS). Overall group and individual responses were evaluated. Treatment response was defined as inactivation of GO, reduction of proptosis by at least 2 mm, improvement of motility by > or = 8 degrees or unchanged normal parameters. RESULTS: Prior to irradiation, neither age, disease duration, gender distribution, smoking behavior or serologic parameters, nor clinical activity or severity stages varied significantly between groups. Neither did outcome measures, except proptosis, differ significantly. Retrobulbar irradiation led to inactivity of GO in approximately 80% of patients, with no significant group difference. After irradiation with 16 and 20 Gy, vertical motility improved in a significantly higher percentage of patients than after irradiation with 12 Gy. Median improvement of vertical motility in responding patients was excellent in all groups (15 degrees at 12 Gy, 10 degrees at 16 Gy, 10 degrees at 20 Gy). Horizontal motility did not change significantly. CONCLUSION: If the aim of retrobulbar irradiation is primarily to reduce soft-tissue signs, lower doses are sufficient. If a patient also suffers from dysmotility, doses exceeding 12 Gy may be more effective.

Patients with severe Graves' ophthalmopathy have a higher risk of relapsing hyperthyroidism and are unlikely to remain in remission.

OBJECTIVE: To evaluate the relationship between severity of Graves' ophthalmopathy (GO) and relapse/remission rate of associated thyroid disease. PATIENTS AND METHODS: One hundred and fifty-eight patients with Graves' disease (GD) were seen within the first 6-12 months after the onset of GO and were followed for at least 18 months. During treatment, GO was classified as mild (n = 65) or severe course (n = 93) by severity and activity scores. All patients received standard anti-thyroid drug (ATD) treatment for 1 year, and in cases of relapse another cycle of ATD, thyroidectomy or radioiodine therapy. RESULTS: Following ATD treatment, 27 patients (42%) with a mild course of GO went into thyroid disease remission, while only seven (8%) patients with a severe course of GO achieved remission (P < 0.0001). Eventually, 32 patients (49%) with a mild course needed definitive thyroid therapy and the remaining 9% preferred another cycle of ATD. However, among patients with a severe GO course, 84% needed definitive therapy (P < 0.0001) and 8% opted for another course of ATD treatment. The probability of relapse could also be predicted by TBII levels 12 months after initiation of ATD therapy, as 96.8% of patients with TBII levels above 7.5 IU/l relapsed (odds ratio 24.3). CONCLUSION: Patients with severe GO and high TBII are unlikely to go into remission. This allows early decision-making regarding definitive treatment of the thyroid in GD patients with severe GO or very high TBII levels.

Thyrotropin receptor autoantibodies are independent risk factors for Graves' ophthalmopathy and help to predict severity and outcome of the disease.

OBJECTIVE: The objective of this study was to examine whether TSH-receptor antibody [TSH binding inhibitory antibodies (TBII)] levels are associated with the severity of Graves' ophthalmopathy (GO) over the entire course of the disease. METHODS AND PATIENTS: A total of 159 patients with GO were followed for 12-24 months. One year after the first symptoms of GO, all patients were classified into mild or severe GO according to their clinical manifestations. TBII were measured every 3 months after onset of GO. Receiver operating characteristic plot analysis was performed to assess the power to discriminate both patient groups by TBII (specificity >90%). RESULTS: TBII levels and prevalence at each time point during follow-up were significantly higher in patients with a severe course of GO compared with patients with a mild course of GO. Prognostic statements on the course of the disease were possible for about half of the GO patients at all time points (except the first). If at first presentation and at consecutive time points TBII levels were less than 5.7, 2.6, 1.5, 1.5, 1.5, and 1.5 IU/liter, the patients had a 2.3- to 15.6-fold higher chance of a mild course. If 5-8 months after GO onset and at consecutive time points TBII levels were above 8.8, 5.1, 4.8, 2.8, and 2.8 IU/liter, the patients had a 8.7- to 31.1-fold higher risk of a severe course. This relationship of TBII to the severity was independent from age and smoking. CONCLUSION: Follow-up measurements of TBII allow, in half of the patients, assessment of the prognosis of GO and, therefore, could be of additional help for the disease management.

Clinical results of anti-inflammatory therapy in Graves' ophthalmopathy and association with thyroidal autoantibodies.

OBJECTIVE: Graves' ophthalmopathy (GO) is clinically associated with autoimmune thyroid disease, and autoantibodies to thyroidal antigens, especially to the TSH-receptor (TRAb), might be involved in the disease process. While there is mounting evidence that TRAb are associated with GO at the onset of the disease, so far no studies have looked at the association between thyroidal autoantibodies and the clinical outcome of GO therapy. The aim of this retrospective study was to evaluate whether TSH binding inhibitory immunoglobulins (TBII) and thyroid stimulating antibodies (TSAb) are still associated with the clinical activity and severity of GO after the completion of anti-inflammatory therapy. In addition, we wanted to elucidate whether thyroid peroxidase (TPO) or thyroglobulin (TG) autoantibodies (TPOAb and TGAb) are in any way related to GO. DESIGN PATIENTS AND MEASUREMENTS: Clinical activity score (CAS) and the severity of GO (modified NOSPECS score) were assessed in 108 patients with GO after steroid therapy and, if indicated, orbital irradiation. Patients were grouped according to their clinical presentation and autoantibody levels (TBII, TSAb, TPOAb and TGAb) were measured. After therapy for hyperthyroidism, all patients were clinically euthyroid but showed clear heterogeneity for GO 4-12 months after the end of anti-inflammatory therapy. Fifty-two patients had inactive GO, 41 had moderately active and 15 still had very active (non-responsive) GO. Concerning severity, 27 patients had mild GO, 64 moderately severe and 17 severe GO. RESULTS: TBII titres were still positive in 14 (93%) of 15 patients in the non-responsive group (CAS > 6) compared to 22 (42%) of 52 patients (P < 0.001) with post-therapeutic inactive GO (CAS

Dry eye syndrome in thyroid-associated ophthalmopathy: lacrimal expression of TSH receptor suggests involvement of TSHR-specific autoantibodies.

PURPOSE: We evaluated the relationship between ocular surface damage, elevated lid aperture/impaired Bell's phenomenon and reduced tear production in thyroid-associated ophthalmopathy (TAO). Suspecting a possible role of autoantibodies specific for TSH receptor (TSHR), we further investigated TSHR expression in the healthy lacrimal gland (LG). METHODS: A total of 48 patients with active TAO and 26 controls were examined for basal tear secretion, Rose Bengal and fluorescein staining, impression cytology (IPC), break-up time (BUT), and blinking (lid width, lid closure, ocular surface, upward excursion). Healthy LGs were investigated immunohistochemically for expression of TSHR. RESULTS: Thyroid-associated ophthalmopathy patients showed significant ocular surface damage (Rose Bengal staining score: TAO: 2.0 [0-5] versus controls: 0 [0-0.4]; IPC score: TAO 3.0 [0-8] versus controls: 0 [0-1], and BUT: TAO: 3.0 seconds [0-9 seconds] versus controls: 19.5 seconds [13-35.4 seconds]), and significantly reduced tear secretion (TAO: 10 mm [3-20 mm] versus controls: 17 mm [10-27 mm]). Ocular surface damage correlated significantly with tear secretion (r = - 0.35) but not significantly with mechanical alterations (impaired upgaze [r = - 0.34] and ocular surface increase [r = 0.32]). We firstly demonstrate that lacrimal acinar cells physiologically express TSHR. CONCLUSIONS: As ocular surface damage in TAO significantly correlates with reduced tear production, LG impairment appears to be a major cause of ocular surface drying. Intriguingly, physiological expression of TSHR by LG suggests that, in thyroid disease, autoantibodies may bind to lacrimal TSHR and, perhaps via aberrant signal transduction, contribute to LG impairment and, hence, dry eye syndrome.