Vascular changes of the peripapillary choroidal area in the thyroid orbitopathy.

PURPOSE: The aim of this study was to investigate the peripapillary choroidal vascular changes in thyroid orbitopathy (TO). METHODS: The study included 20 eyes of 10 patients with active TO (aTO), 30 eyes of 15 patients with inactive TO (inaTO) and 30 eyes of 30 healthy subjects. The peripapillary choroidal vascular change was assessed with peripapillary choroidal vascular index (pCVI), peripapillary choroidal luminal area (pLA), peripapillary choroidal stromal area (pSA), peripapillary total choroidal area (pTCA). RESULTS: Compared to the control group, there was a reduction in the nasal and temporal areas of pCVI in both the aTO and inaTO groups (aTO vs control: nasal p = 0.001 and temporal p = 0.004; inaTO vs control: nasal p = 0.007 and temporal p < 0.001), while the inferior area was lower only in the inaTO group (p = 0.001). Compared to the other groups, the inaTO group exhibited a decrease pSA (vs aTO: total p = 0.004, inferior p = 0.02 and vs control: total p = 0.01, inferior p = 0.03), pLA (vs aTO: total p = 0.02, inferior p = 0.02, temporal p < 0.001 and vs control: total p = 0.002, inferior p < 0.001, temporal p < 0.001) and pTCA (vs aTO: total p = 0.009, inferior p = 0.01, temporal p < 0.001 and vs control: total p = 0.003, inferior p = 0.001, temporal p < 0.001). CONCLUSION: The horizontal area (nasal and temporal area) of the peripapillary choroidal vascular structure may be more sensitive than the vertical area in TO patients. The first affected quadrant of RPC-VD in the active TO may be the inferior quadrant. Structural or vascular choroidal changes may occur during the chronic or post-active phase of the disease.

[Graves' orbitopathy as the cause of diplopia in old age-Differences between young and old]. / Endokrine Orbitopathie als Ursache einer Diplopie im Senium ­ Unterschiede zwischen Jung und Alt.

BACKGROUND: Endocrine orbitopathy (EO) is an autoimmune disease mostly associated with a disease of the thyroid gland, which leads to inflammation, adipogenesis and fibrosis. The severity of EO can vary greatly between individuals, which makes it difficult to exactly predict the natural course of the disease; however, this is important to be able to individually adapt the treatment. The aim of this study was to compare the clinical features, course, treatment and prognosis for patients with EO under 50 years old with older patients. The results of the study with a focus on motility are presented in this special issue. PATIENTS AND METHODS: The hospital records of a randomly selected sample of 1000 patients from the EO databank in Essen (GODE), which includes 4260 patients, were analyzed. The patients were divided into two groups: group 1 ≤50 years and group 2 >50 years. Only patients with complete data sets were included in the statistical analyses. RESULTS: Younger patients (n = 484) presented significantly more frequently with milder EO (53% vs. 33%, p < 0.0001), whereas older patients (n = 448) more frequently suffered from moderate or severe forms (44% vs. 64%, p < 0.0001). Older patients showed more severe strabismus, motility and clinical activity scores (5.9 vs. 2.3 prism diopters, PD/310° vs. 330°, both p < 0.0001, CAS 2.1 vs. 1.7, p = 0.001). Proptosis and the occurrence of optic nerve compression showed no significant differences between the groups (3% each). Multiple logistic regression showed that the necessity for a second eye muscle surgery was most strongly associated with a previous decompression (OR = 0.12, 95 % CI 0.1-0.2, p < 0.0001), followed by orbital irradiation and age. CONCLUSION: In summary, younger patients with EO presented with milder clinical features, such as a lower rate of restrictive motility disorders and weaker expression of signs of inflammation. Therefore, older patients needed steroids, irradiation, eyelid and eye muscle surgery more frequently; however, the risk of dysthyroid optic neuropathy and the necessity of a second eye surgery were not or only slightly associated with age.

Role of Inositol-Requiring Enzyme 1 and Autophagy in the Pro-Fibrotic Mechanism Underlying Graves' Orbitopathy.

PURPOSE: Orbital fibroblasts play key roles in the pathogenesis of Graves' orbitopathy (GO), and previous findings have shown that endoplasmic reticulum (ER) stress and autophagy also contribute to GO. In this study, we investigated the presently unclear roles of inositol-requiring enzyme 1 (IRE1) and related autophagy processes in the pro-fibrotic mechanism of GO. MATERIALS AND METHODS: Orbital adipose/connective tissues were obtained from eight GO patients and six normal individuals during surgery. GO fibroblasts were transfected with IRE1 small-interfering RNA and treated with bafilomycin A1 (Baf-A1) to evaluate the inhibitory effects of ER stress and autophagy, and protein-expression levels were analyzed through western blotting after stimulation with transforming growth factor (TGF)-ß. RESULTS: TGF-ß stimulation upregulated IRE1 in GO orbital fibroblasts, whereas silencing IRE1 suppressed fibrosis and autophagy responses. Similarly, Baf-A1, an inhibitor of late-phase autophagy, decreased the expression of pro-fibrotic proteins. CONCLUSION: IRE1 mediates autophagy and the pro-fibrotic mechanism of GO, which provides a more comprehensive interpretation of GO pathogenesis and suggests potential therapeutic targets.

Plasma exosomes from patients with active thyroid-associated orbitopathy induce inflammation and fibrosis in orbital fibroblasts.

BACKGROUND: The pathogenesis of thyroid-associated orbitopathy (TAO) remains incompletely understand. The interaction between immunocytes and orbital fibroblasts (OFs) play a critical role in orbital inflammatory and fibrosis. Accumulating reports indicate that a significant portion of plasma exosomes (Pla-Exos) are derived from immune cells; however, their impact upon OFs function is unclear. METHODS: OFs were primary cultured from inactive TAO patients. Exosomes isolated from plasma samples of patients with active TAO and healthy controls (HCs) were utilized for functional and RNA cargo analysis. Functional analysis in thymocyte differentiation antigen-1+ (Thy-1+) OFs measured expression of inflammatory and fibrotic markers (mRNAs and proteins) and cell activity in response to Pla-Exos. RNA cargo analysis was performed by RNA sequencing and RT-qPCR. Thy-1+ OFs were transfected with miR-144-3p mimics/inhibitors to evaluate its regulation of inflammation, fibrosis, and proliferation. RESULTS: Pla-Exos derived from active TAO patients (Pla-ExosTAO-A) induced stronger production of inflammatory cytokines and hyaluronic acid (HA) in Thy-1+ OFs while inhibiting their proliferation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and single sample gene set enrichment analysis (ssGSEA) suggested that the difference in mRNA expression levels between Pla-ExosTAO-A and Pla-ExosHC was closely related to immune cells. Differential expression analysis revealed that 62 upregulated and 45 downregulated miRNAs in Pla-ExosTAO-A, with the elevation of miR-144-3p in both Pla-Exos and PBMCs in active TAO group. KEGG analysis revealed that the target genes of differentially expressed miRNA and miR-144-3p enriched in immune-related signaling pathways. Overexpression of the miR-144-3p mimic significantly upregulated the secretion of inflammatory cytokines and HA in Thy-1+ OFs while inhibiting their proliferation. CONCLUSION: Pla-Exos derived from patients with active TAO were immune-active, which may be a long-term stimulus casual for inflammatory and fibrotic progression of TAO. Our finding suggests that Pla-Exos could be used as biomarkers or treatment targets in TAO patients.

Efficacy of rituximab in treating steroid-resistant Graves' orbitopathy in active moderate-to-severe and sight-threatening forms: A retrospective observation from China.

Background and objectives: The efficacy of rituximab (RTX) in treating steroid-resistant Graves' orbitopathy (GO) has been limitedly studied in Asians. Moreover, RTX has been considered even less for patients with steroid-resistant dysthyroid optic neuropathy (DON) who failed to undergo orbital decompression surgery for physical or financial reasons, or who responded poorly to the procedure. This study aimed to investigate the efficacy of RTX in treating steroid-resistant active moderate-to-severe and sight-threatening GO in a Chinese population. Methods: Data from 28 patients with steroid-resistant GO prescribed a single dose of 500 mg RTX were retrospectively retrieved. Treatment responses and contributing factors were analyzed. Results: The median follow-up time was 22 (8-34) weeks. 23 (82.1 %) patients had a positive objective outcome recommended by the European Group on Graves' Orbitopathy (EUGOGO), while 25 (92.6 %) had a decrease in 7-item clinical activity score (CAS) by at least 2. Diplopia, visual dysfunction, and MRI-detected T2 relaxation time of the involved extraocular muscles improved significantly at the last follow-up compared to baseline (81.0 % vs. 47.6 %, 38.9 % vs. 16.7 %, and 87.8 (8.64) vs. 75.8 (10.9) ms, respectively; all p values < 0.05). No significant improvement was seen in terms of proptosis and eye muscle duction. Notably, a higher baseline IgG4 to IgG ratio was a predictor for RTX-induced positive EUGOGO outcomes. After RTX treatment, all 8 patients with DON demonstrated inactivation, and 4 improved in visual acuity by ≥ 1 line. No patient with DON experienced obvious deterioration. Conclusion: A single dose of 500 mg RTX seemed to be an effective and tolerable treatment for steroid-resistant GO. However, larger-scale studies with a control group are required for a more solid conclusion. The role of RTX in steroid-resistant DON management where surgery is unavailable or ineffective should be further explored.

Therapeutic effect of selective interleukin-2-inducible tyrosine kinase inhibitor in orbital fibroblasts from patients with Graves' orbitopathy.

Interleukin-2-inducible tyrosine kinase (ITK) is a crucial cytoplasmic protein in the T-cell signaling pathway. Here, we aimed to demonstrate the anti-inflammatory effect of the selective IL-2-induced tyrosine kinase inhibitor BMS-509744 (BMS) on Graves' orbitopathy (GO) in an in vitro model. ITK mRNA expression in orbital tissues from GO and normal controls was compared using real-time polymerase chain reaction (RT-PCR) and immunohistochemistry. Primary cultured orbital fibroblasts from each group were pretreated with BMS and stimulated with interleukin (IL)-1ß to induce inflammatory reaction. ITK mRNA expression was evaluated using western blotting, and inflammatory cytokine production and downstream transcription factor expression were analyzed after pretreatment with BMS. ITK mRNA expression in GO tissues was significantly higher than that in normal control tissues. After stimulation with IL-1ß, ITK phosphorylation significantly increased in both GO orbital and normal control tissues. BMS inhibited IL-1ß-induced IL-8 expression in the GO orbital fibroblasts. BMS pretreatment significantly suppressed NF-κB phosphorylation in both GO and normal controls. The selective ITK inhibitor attenuates proinflammatory cytokine production and proinflammatory transcription factor phosphorylation in in vitro model of GO.

A Preliminary Evaluation of the Diagnostic Performance of a Smartphone-Based Machine Learning-Assisted System for Evaluation of Clinical Activity Score in Digital Images of Thyroid-Associated Orbitopathy.

Background: We previously developed a machine learning (ML)-assisted system for predicting the clinical activity score (CAS) in thyroid-associated orbitopathy (TAO) using digital facial images taken by a digital single-lens reflex camera in a studio setting. In this study, we aimed to apply this system to smartphones and detect active TAO (CAS ≥3) using facial images captured by smartphone cameras. We evaluated the performance of our system on various smartphone models and compared it with the performance of ophthalmologists with varying clinical experience. Methods: We applied the preexisting ML architecture to classify photos taken with smartphones (Galaxy S21 Ultra, iPhone 12 pro, iPhone 11, iPhone SE 2020, Galaxy M20, and Galaxy A21S). The performance was evaluated with smartphone-captured images from 100 patients with TAO. Three ophthalmology residents, three general ophthalmologists with <5 years of clinical experience, and three oculoplastic specialists independently interpreted the same set of images taken under a studio environment and compared their results with those generated by the smartphone-based ML-assisted system. Reference CAS was determined by a consensus of three oculoplastic specialists. Results: Active TAO (CAS ≥3) was identified in 28 patients. Smartphone model used in capturing facial images influenced active TAO detection performance (F1 score 0.59-0.72). The smartphone-based system showed 74.5% sensitivity, 84.8% specificity, and F1 score 0.70 on top three smartphones. On images from all six smartphones, average sensitivity, specificity, and F1 score were 71.4%, 81.6%, and 0.66, respectively. Ophthalmology residents' values were 69.1%, 55.1%, and 0.46. General ophthalmologists' values were 61.9%, 79.6%, and 0.55. Oculoplastic specialists' values were 73.8%, 90.7%, and 0.75. This smartphone-based ML-assisted system predicted CAS within 1 point of reference CAS in 90.7% using facial images from smartphones. Conclusions: Our smartphone-based ML-assisted system shows reasonable accuracy in detecting active TAO, comparable with oculoplastic specialists and outperforming residents and general ophthalmologists. It may enable reliable self-monitoring for disease activity, but confirmatory research is needed for clinical application.

Balanced medial-lateral wall vs selective 3-wall orbital decompression for sight-threatening Graves's orbitopathy: a clinical retrospective cohort study from 2016 to 2022.

PURPOSE: Although urgent orbital decompression surgery for sight-threatening Graves' orbitopathy unresponsive to available medical treatments continues to evolve, post-operative new-onset or worsened pre-operative strabismus or diplopia remains a significant complication. At present, the optimal surgical technique remains debatable. Here, we sought to compare long-term outcomes after balanced medial-lateral wall versus selective 3-wall decompression as an urgent treatment for unresponsive sight-threatening GO. METHODS: This retrospective study examined the post-operative outcome of 102 eyes (57 patients) that underwent urgent orbital decompression for sight-threatening GO. Treatment effectiveness was measured by visual acuity, proptosis, perimetry, and strabismus/diplopia, while fundus findings were detected by fundus color photography and optical coherence tomography and followed up for more than 12 months. RESULTS: Fifty-seven patients (102 orbits) with an average age of 52.7 ± 10.2 years were evaluated. Balanced medial-lateral wall (BMLW-OD) or selective 3-wall decompression(S3W-OD) were performed in 54 and 48 eyes, respectively. Twelve months after orbital decompression, all parameters significantly improved in both groups, including best-corrected visual acuity (BCVA), mean defect of visual field (VF-MD), pattern standard deviation of visual field (VF-PSD), and proptosis (all P < 0.01). However, new-onset esotropia occurred in 25.8% and 3.8% of patients who underwent BMLW-OD surgery or S3W-OD, respectively. Moreover, 6.5% and 38.5% of patients improved after decompression in the medial-lateral wall decompression group and the selective 3-wall decompression group, respectively. CONCLUSIONS: We demonstrated that S3W-OD provides a lower rate of new-onset strabismus/diplopia as compared with BMLW-OD surgery, while still allowing for satisfactory visual outcomes. TRIAL REGISTRATION NUMBER:  : NCT05627401. Date of registration: November 25, 2022.

Teprotumumab in thyroid eye disease.

Thyroid eye disease (TED) is an inflammatory condition involving the periocular and orbital soft tissues, affecting most commonly patients with hyperthyroid disorders. Traditional treatments used for the active phase of the disease range from conservative lubrication for mild symptoms to systemic immunomodulating drugs for moderate-to-severe symptoms. Teprotumumab (Tepezza) is a monoclonal antibody with an inhibitory effect on insulin-like growth factor 1 and is the first Food and Drug Administration (FDA) approved targeted medical therapy for reducing the inflammatory signs and symptoms associated with TED. Two large multicenter, randomized, double-masked, placebo-controlled trials have confirmed the efficacy and safety of teprotumumab in patients with active, moderate-to-severe TED. Recent reports and publications have also demonstrated the efficacy of teprotumumab in a wider range of patients. In this review, we summarize the clinical features and pathophysiology of TED, disease course, and traditional management methods. We further detail the development of teprotumumab, the founding studies that brought it to its FDA approval, adverse events profile, and ongoing as well as future investigations.

Once upon a time in Anatolia: the kings with bulging eyes.

The Hittite Empire, formed by the Hittites who settled in central Anatolia at the beginning of the second millennium BC, has left behind rich archeological remains. In this historical review, statues of the Hittite priest-kings, King Idrimi, King Suppiluliuma, and King Tarhunza, who ruled in these lands in ancient times, are analyzed. Graves' disease (GD) is the most common cause of hyperthyroidism. Patients with GD are also at risk of developing Graves' orbitopathy (GO). Upper eyelid retraction and exophthalmos (bulging eyes) are common in patients diagnosed with GO. Could the kings who lived in Anatolia at different times in the distant past have suffered from the same disease?

Mouse model of Graves' orbitopathy induced by the immunization with TSHR A and IGF-1R α subunit gene.

PURPOSE: The study aimed to establish a mouse model of Graves' disease (GD) with Graves' orbitopathy (GO; GD + GO) that can represent the clinical disease characteristics. METHODS: A eukaryotic expression plasmid of insulin-like growth factor 1 receptor (IGF-1R) α subunit (pcDNA3.1/IGF-1Rα) and a thyrotropin receptor (TSHR) A subunit plasmid (pcDNA3.1/TSHR-289) were injected in female BALB/c mice followed by immediate electroporation to induce a GD + GO model. Grouping was performed according to the frequency of injection (2- to 4-week intervals) and type of injected plasmids: T: pcDNA3.1/TSHR-289( +), I: pcDNA3.1/IGF-1Rα( +), or co-injection T + I: pcDNA3.1/TSHR-289( +) and pcDNA3.1/IGF-1Rα( +). Serum TSH, T4, TSAb, TSBAb, body weight, and blood glucose levels were evaluated. Thyroid 99mTcO4- imaging and retrobulbar magnetic resonance imaging (MRI) were performed, and bilateral eye muscle volumes were measured. Immunohistochemistry and hematoxylin-eosin staining were performed on the relevant tissues, and semi-quantitative analysis was performed. RESULTS: A total of 60% of mice (3/5, one mouse died) in the T group developed GD + GO. In the T + I group, 83.3% of mice (5/6) developed GD + GO. Mice in the I group did not develop GD. Compared with the control group, serum T4, TSAb, and TSBAb of the mice in the GD + GO model groups were increased to varying degrees (P < 0.05), and serum TSH and body weight were significantly lower compared to the control group (P < 0.05). The thyroid uptake capacity of 99mTcO4- and the volume of eye muscle of mice in the GD + GO group were significantly higher compared to the control group (P < 0.05). The thyroid and retrobulbar muscles of these mice showed varying inflammatory infiltration and interstitial muscle edema. The severity of GD + GO in the co-injection group was not related to injection frequency; however, GD and ocular signs in co-injection mice were more severe compared to the T group. CONCLUSIONS: We successfully induced a GD + GO mouse model by a repeated co-injection of pcDNA3.1/IGF-1Rα and pcDNA3.1/TSHR-289 plasmids. Injection of pcDNA3.1/IGF-1Rα alone failed to induce GD. Co-injection of two plasmids induced more severe GD + GO than pcDNA3.1/TSHR-289( +) alone.

Thyroid stimulating immunoglobulin concentration is associated with disease activity and predicts response to treatment with intravenous methylprednisolone in patients with Graves' orbitopathy.

Background: Thyroid stimulating immunoglobulins (TSI) play a central role in the pathogenesis of Graves' orbitopathy (GO), while soluble interleukin-2 receptor (sIL-2R) is a marker for T-cell activity. We investigated TSI and sIL-2R levels in relation to thyroid function, disease activity and severity and response to treatment with intravenous methylprednisolone (IVMP) in patients with GO. Methods: TSI (bridge-based TSI binding assay), sIL-2R, TSH and fT4 levels were measured in biobank serum samples from 111 GO patients (37 male, 74 female; mean age 49.2 years old) and 25 healthy controls (5 male, 20 female; mean age 39.8 years old). Clinical characteristics and response to treatment were retrospectively retrieved from patient files. Results: Higher sIL-2R levels were observed in GO patients compared to controls (p < 0.001). sIL-2R correlated with fT4 (r = 0.26), TSH (r = -0.40) and TSI (r = 0.21). TSI and sIL-2R concentrations were higher in patients with active compared to inactive GO (p < 0.001 and p < 0.05, respectively). Both TSI and sIL-2R correlated with total clinical activity score (CAS; r = 0.33 and r = 0.28, respectively) and with several individual CAS items. Cut-off levels for predicting active GO were 2.62 IU/L for TSI (AUC = 0.71, sensitivity 69%, specificity 69%) and 428 IU/mL for sIL-2R (AUC = 0.64, sensitivity 62%, specificity 62%). In multivariate testing higher TSI (p < 0.01), higher age (p < 0.001) and longer disease duration (p < 0.01) were associated with disease activity. TSI levels were higher in patients with a poor IVMP response (p = 0.048), while sIL-2R levels did not differ between responders and non-responders. TSI cut-off for predicting IVMP response was 19.4 IU/L (AUC = 0.69, sensitivity 50%, specificity 91%). In multivariate analysis TSI was the only independent predictor of response to IVMP (p < 0.05). Conclusions: High TSI levels are associated with active disease (cut-off 2.62 IU/L) and predict poor response to IVMP treatment (cut-off 19.4 IU/L) in GO. While sIL-2R correlates with disease activity, it is also related to thyroid function, making it less useful as an additional biomarker in GO.

Comparison of macular and optic disc vessel density in thyroid orbitopathy: a comparative octa study.

PURPOSE: To determine the microvascular and structural changes in the peripapillary and macular areas observed in patients with active thyroid orbitopathy(TO) before and after steroid treatment and compare with inactive TO and the control group by optical coherence tomography angiography (OCTA). MATERIAL AND METHOD: This cross-sectional study included 34 eyes of 17 active TO patients, 108 eyes of 54 inactive TO patients, and 60 eyes of 30 healthy controls. Central macular thickness (CMT), ganglion cell layer-inner plexiform layer (GCL-IPL) thickness, central choroidal thickness (CCT), retinal nerve fiber layer (RNFL) thickness, choroidal thickness in the peripapillary region, superficial capillary plexus (SCP), deep capillary plexus (DCP) and choriocapillaris vessel densities were determined by OCTA in before and after 12-week steroid treatment of active TO cases, inactive TO and control groups. RESULTS: Between the three groups in macula OCTA, a statistically significant difference was observed in the inferior and nasal quadrants in SCP (all p = 0.01) and only in the temporal quadrant choriocapillaris (p = 0.005). In peripapillary OCTA, a statistically significant difference was found only in the central choriocapillaris (p = 0.03). In the comparison of the active group before and after treatment, there was a statistically significant decrease in CMT and CCT; a statistically significant increase was observed in GCL-IPL (all p < 0.01). There was a statistically significant decrease in SCP and DCP only in the central (all p < 0.01). There was a statistically significant increase was found in the lower quadrant macular SCP vessel density and mean macular DCP in post-treatment measurements (p = 0.01 and p = 0.03, respectively). Peripapillary SCP and DCP vessel density was increased after treatment (p < 0.01). CONCLUSION: Active TO group had lower vessel density than inactive group and after treatment, vessel density was increased. Non-invasive quantitative analysis of retinal and optic disc perfusion using OCTA could be useful in early treatment before complications occur and monitoring patients with TO.

An Appraisal of the Preventive Effect of Statins on the Development of Graves' Ophthalmopathy: A Hospital-Based Cohort Study.

INTRODUCTION: Graves' ophthalmopathy (GO) is an autoimmune inflammatory disorder observed in a substantial proportion of patients with Graves' disease (GD), with debilitating symptoms of disfiguring, periorbital pain, dry eyes, diplopia, and even visual disturbances. Previous studies involving Western populations have noted discrepancies in risk factors for GO. Therefore, this study aimed to determine the risk factors for GO development and the protective effect of statins in newly diagnosed patients with GD in Taiwan. METHODS: This retrospective case-control study was based on a tertiary center cohort involving patients with GD diagnosed between 2010 and 2019 at the National Taiwan University Hospital (n = 11,035). Patients who were diagnosed or treated elsewhere, had been followed up for less than 6 months or were with a diagnosis of orbital tumor were excluded. Overall, 3578 patients with GD met the inclusion criteria. Univariate and multivariate logistic regression analyses were used to ascertain the odds ratio (OR) of developing GO, with adjustment for sociodemographic factors, interventions for managing GD and thyroid hormone levels, to determine protective and risk factors for GO. RESULTS: In our multivariate model, the use of statins reduced the risk of GO development (OR 0.2; 95% confidence interval [CI] 0.08-0.50; p < 0.001). Thyroid dysfunction including hyperthyroidism (OR 4.2; 95% CI 2.97-5.88; p < 0.001) and hypothyroidism (OR 4.7; 95% CI 3.02-7.19; p < 0.001) was associated with an increased risk of developing GO. Smoking status and lipid profile were not risk factors in our cohort. CONCLUSION: In newly diagnosed patients with GD, the use of statins decreased the risk of developing GO by 80%, whereas serum lipid levels were not considered risk factors. Further nationwide population-based studies may help clarify the differences in risk factors between various ethnic groups. TRAIL REGISTRATION: This trial was approved by the Research Ethics Committee of National Taiwan University Hospital (202202066RINC), retrospectively registered from January 1, 2010 to December 31, 2019.

Differential diagnosis of thyroid orbitopathy - diseases mimicking the presentation or activity of thyroid orbitopathy.

Thyroid orbitopathy (TO) is the most common cause of orbital tissue inflammation, accounting for about 60% of all orbital inflammations. The inflammatory activity and severity of TO should be diagnosed based on personal experience and according to standard diagnostic criteria. Magnetic resonance imaging (MRI) of the orbit is used not only to identify swelling and to differentiate inflammatory active from non-active TO, but also to exclude other pathologies, such as orbital tumours or vascular lesions. However, a group of diseases can mimic the clinical manifestations of TO, leading to serious diagnostic difficulties, especially when the patient has previously been diagnosed with a thyroid disorder. Diagnostic problems can be presented by cases of unilateral TO, unilateral or bilateral TO in patients with no previous or concomitant symptoms of thyroid disorders, lack of symptoms of eyelid retraction, divergent strabismus, diplopia as the only symptom of the disease, and history of increasing diplopia at the end of the day. The lack of visible efficacy of ongoing immunosuppressive treatment should also raise caution and lead to a differential diagnosis of TO. Differential diagnosis of TO and evaluation of its activity includes conditions leading to redness and/or swelling of the conjunctiva and/or eyelids, and other causes of ocular motility disorders and eye-setting disorders. In this paper, the authors review the most common diseases that can mimic TO or falsify the assessment of inflammatory activity of TO.

Long-term remission of corticosteroid-resistant Graves' orbitopathy after therapy with tocilizumab.

Not required for Clinical Vignettes.

Late orbital radiotherapy combined with intravenous methylprednisolone in the management of long-lasting active graves' orbitopathy: a case report and literature review.

PURPOSE: To present a case and review the literature on Orbital Radiotherapy (OR) combined with intravenous methylprednisolone, focusing on its late application in patients with long-lasting active Graves' Orbitopathy (GO). Additionally, we suggest emerging perspective for future research in this context. METHOD: Relevant literature (randomized controlled studies, retrospective studies and reviews) was explored on PubMed from January 1973 to January 2024, searching "orbital radiotherapy" & "Graves disease". RESULTS: OR is a well-established second-line treatment for moderate-to-severe active GO, providing response rates comparable to glucocorticoids. Its anti-inflammatory effect makes OR particularly suitable for early active GO, and when combined with glucocorticoids, outcomes are synergistically improved. The emergence of the new Volumetric Modulated Arc Image-Guided Radiation Therapy (VMAT-IGRT) technique enables precise radiation delivery to the target, significantly reducing associated toxicity. This technological advancement enhances the feasibility of radiotherapy in benign diseases like GO. A retrospective study indicated that late OR in patients with long-lasting active GO may improve diplopia and visual acuity, decreasing disease activity. Our case report supports this conclusion. CONCLUSIONS: This report and literature review underscores the importance of considering late OR combined with intravenous methylprednisolone as a viable treatment option for GO patients with prolonged disease activity, emphasizing the crucial role of personalized therapy in managing GO. However, further investigations are warranted to validate this approach in cases of long-lasting active GO.

Correlation between Structural and Functional Changes in Patients with Raised Intraocular Pressure Due to Graves' Orbitopathy.

This study explores the complication of secondary intraocular pressure (IOP) elevation and consequent glaucoma development in Graves' orbitopathy (GO), an autoimmune disorder associated with hyperthyroidism. Utilizing Octopus 900 visual field testing and optical coherence tomography (OCT), the research established correlations between functional and structural changes in optic nerve regions in patients with GO and patients with GO with elevated IOP (GO IOP) groups. A comparison with primary open-angle glaucoma (POAG) was conducted in a cohort of 182 subjects. The study identifies optic nerve head parameters that effectively differentiate changes in GO and GO IOP groups. In the GO group, the strongest correlation between structural and functional changes was observed in sector 7, while in the GO IOP group, it was in sectors 1 and 7. For POAG, correlation was found in six sectors. Elevated IOP in GO correlates with structural and functional impairments similarly to early glaucoma. Risk factors for GO-related elevated IOP included older age, longer duration of thyroid disease, and higher anti-thyroglobulin values. The study highlights the significance of regular IOP measurements, visual field assessments, and OCT examinations in GO patients. Early antiglaucoma intervention is warranted when characteristic structural and functional changes and/or risk factors are identified.

Alemtuzumab-induced thyroid eye disease successfully treated with a single low dose of rituximab.

Introduction: Secondary thyroid autoimmunity, especially Graves' disease (GD), frequently develops in patients with multiple sclerosis (MS) following alemtuzumab treatment (ALTZ; anti-CD52). Thyroid eye disease (TED) can also develop, and rituximab (RTX; anti-CD20) is a suitable treatment. Case presentation: A 37-year-old woman with MS developed steroid-resistant active moderate-to-severe TED 3 years after ALTZ, that successfully responded to a single 500 mg dose of i.v. RTX. Before RTX peripheral B-cells were low, and were totally depleted immediately after therapy. Follow-up analysis 4 years post ALTZ and 1 year post RTX showed persistent depletion of B cells, and reduction of T regulatory cells in both peripheral blood and thyroid tissue obtained at thyroidectomy. Conclusion: RTX therapy successfully inactivated TED in a patient with low B-cell count derived from previous ALTZ treatment. B-cell depletion in both thyroid and peripheral blood was still present 1 year after RTX, indicating a likely cumulative effect of both treatments.