New-onset Thyroid Eye Disease after COVID-19 Vaccination in a Radioactive Iodine-Treated Graves' Disease Patient: A Case Report and Literature Review.

Autoimmunity associated with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been well-described as the mechanism of development of thyroid dysfunction following Coronavirus Disease 19 (COVID-19) infection and SARS-CoV-2 vaccination. However, the occurrence of thyroid eye disease (TED) after SARS-CoV-2 vaccination is scarcely described. The postulated mechanisms include immune reactivation, molecular mimicry and the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). We report a case of new-onset TED after receiving the SARS-CoV-2 vaccine.

Nonsurgical treatment for upper eyelid retraction in patients with inactive Graves' orbitopathy.

PURPOSE: To evaluate the effectiveness of incobotulinumtoxinA (Xeomin®) in treating upper eyelid retraction in patients with Graves orbitopathy (GO) initially scheduled for surgery via two different application sites. METHODS: This is a comparative, prospective study, conducted at the Department of Ophthalmology, Medical School, University Hospital Centre Zagreb, EUGOGO site (EUropean Group On Graves' Orbitopathy) in Croatia from January 2020 till January of 2021 in accordance with national health headquarter recommendations. All patients were classified as inactive with marked eyelid retraction and randomly divided into groups according to application sites. Group A underwent transconjunctival application (18 eyes) and group B transcutaneous application (20 eyes) of incobotulinumtoxinA. The primary end point of this study was lowering the eyelid, to alleviate anterior eye segment symptoms and achieve acceptable aesthetic appearance until surgery becomes available. RESULTS: There were no nonresponders and we found no statistically significant difference in the degree of lowering the eyelid between the two application sites. Following rules for avoiding spread of SARS-CoV-19, none of the patients included in this study were infected. Moreover, participants reported diminishing of anterior eye segment irritation and improved aesthetics. CONCLUSION: Treatment of inactive GO patients with incobotulinumtoxinA for upper eyelid retraction is efficient and safe and can be used as an adjuvant treatment while patients wait for surgery, by alleviating symptoms and improving the level of aesthetic satisfaction without causing a threat to anterior eye segment and visual function. The study showed that effect of treatment was the same, whether we applied the toxin transconjunctivaly or transcutaneously.

Changes of Volume Parameters in the Treatment of Graves Ophthalmopathy by Endoscopic Transethmoidal Decompression of the Orbital Inner Wall Combined with Fat Decompression.

Objective: To observe the orbital volume changes and the analysis of surgical effect of Graves orbitopathy (GO) after endoscopic medial wall decompression combined with muscle cone fat. Methods: Twenty-two patients (30 eyes) with Graves orbital disease who visited the Department of Ophthalmology of Ningbo Medical Center from December 2019 to September 2021 were retrospectively collected. All patients were diagnosed as nonorganic active stage before operation, and all of them received endoscopic transethmoidal decompression of the medial orbital wall combined with intramuscular orbital fat decompression due to decreased vision, visual field defect or color vision disorder, and concomitant proptosis. Regular follow-up after operation. The curative effect is judged according to the degree of improvement of visual acuity, color vision, degree of correction of exophthalmos, diplopia, and other complications at 9 months after operation. Orbital CT combined with computer aided measurement software (Mimics 21) was used to measure the changes of orbital volume before and after exophthalmos surgery. The relationship between the value and eyeball regression is analyzed. Results: Preoperative exophthalmos ranged from 17.4 mm to 27.6 mm, with an average of (22.08 ± 2.86) mm. The postoperative exophthalmos was 14-25 mm, with an average of (19.52 ± 3.10) mm. Among them, 7 eyes (23.3%) had exophthalmos regression less than 1 mm, 6 eyes (20%) had a regression of 1-2 mm, 7 eyes (23.3%) had a regression of 2-3 mm, 5 eyes (16.7%) had a regression of 3-4 mm, and 5 eyes (16.7%) had a regression of 4-5.3 mm. The exophthalmos after operation was significantly lower than that before operation, and the difference was statistically significant (t = 9.909, P < 0.05). The preoperative orbital volume was 18.6 cm3-25.3 cm3 with an average of (22.39 ± 1.91) cm3. The postoperative orbital volume was 19.8 cm3-26.6 cm3, with an average of (23.89 ± 1.90) cm3.The orbital volume change range is 0.1 cm3-3.8 cm3, and the average orbital volume change is (1.51 ± 1.00) cm3. Compared with preoperative orbital volume, the difference was statistically significant (t = -8.074, P < 0.05). Conclusion: Endoscopic decompression of the medial orbital wall through the ethmoid approach combined with decompression of the orbital fat within the muscle cone can effectively correct the exophthalmos while decompressing the orbital apex, and it is minimally invasive and has no facial scars. It has the advantages of extremely low incidence of postoperative diplopia and eye shift. There is a significant correlation between orbital volume changes and the regression of exophthalmos, which can provide reference for clinical guidance of surgical methods and prediction of surgical results.

Disulfiram Exerts Antifibrotic and Anti-Inflammatory Therapeutic Effects on Perimysial Orbital Fibroblasts in Graves' Orbitopathy.

Fibrosis of extraocular muscles (EOMs) is a marker of end-stage in Graves' orbitopathy (GO). To determine the antifibrotic and anti-inflammatory therapeutic effects and the underlying molecular mechanisms of disulfiram (DSF) on perimysial orbital fibroblasts (pOFs) in a GO model in vitro, primary cultures of pOFs from eight patients with GO and six subjects without GO (NG) were established. CCK-8 and EdU assays, IF, qPCR, WB, three-dimensional collagen gel contraction assays, cell scratch experiments, and ELISAs were performed. After TGF-ß1 stimulation of pOFs, the proliferation rate of the GO group but not the NG group increased significantly. DSF dose-dependently inhibited the proliferation, contraction, and migration of pOFs in the GO group. Additionally, DSF dose-dependently inhibited fibrosis and extracellular matrix production markers (FN1, COL1A1, α-SMA, CTGF) at the mRNA and protein levels. Furthermore, DSF mediates antifibrotic effects on GO pOFs partially through the ERK-Snail signaling pathway. In addition, DSF attenuated HA production and suppressed inflammatory chemokine molecule expression induced by TGF-ß1 in GO pOFs. In this in vitro study, we demonstrate the inhibitory effect of DSF on pOFs fibrosis in GO, HA production, and inflammation. DSF may be a potential drug candidate for preventing and treating tissue fibrosis in GO.

Worsening of Graves' ophthalmopathy after SARS-CoV-2 mRNA vaccination.

More reports are documenting how vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could represent new external triggers for autoimmune endocrine diseases (AIED) in patients with individual predisposition. We report two cases of Graves' Ophthalmopathy (GO) recrudescence few days after the administration of BNT162B2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Even if causality relationship cannot be excluded, the development of these events could be explained through immune mediated mechanism such as the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). While further investigations are necessary to improve our knowledge of the underlying pathogenesis of these phenomena, caution may be warranted when vaccinating individuals with known autoimmune diseases.

Thyroid Eye Disease Following COVID-19 Vaccine in a Patient With a History Graves' Disease: A Case Report.

A 50-year-old woman with a history of controlled Graves' disease without clinical ophthalmopathy presents with 2 months of left more than right periorbital swelling and proptosis. Her eye symptoms and signs began 3 days following her second vaccination against the COVID-19 virus. Orbital imaging, elevated thyroid stimulating immunoglobulin, and negative systemic work up for other diseases were consistent with a diagnosis of active thyroid eye disease. The temporal relationship to her vaccination was likely consistent with autoimmune/inflammatory syndrome associated with adjuvants. Clinicians should remind patients of the symptoms and signs of thyroid eye disease and to seek appropriate medical and ophthalmic advice if they occur after the COVID-19 vaccine.

Rapidly progressive cognitive decline associated with teprotumumab in thyroid eye disease.

Teprotumumab (Tepezza), an insulin-like growth factor type 1 receptor antagonist, was approved for treatment of thyroid eye disease in 2020. Teprotumumab is administered intravenously every 3 weeks for a total of eight doses. Common side effects include nausea, diarrhoea, muscle spasms, hearing impairment, dysgeusia, headaches, dry skin, infusion reactions and hyperglycaemia. We report here a 76-year-old man with Graves-related thyroid eye disease who developed a rapidly progressive cognitive decline after receiving four out of eight doses of teprotumumab (cumulative dose 4620 mg). He was admitted for workup and teprotumumab infusions were discontinued. Intravenous glucocorticoids and immunoglobulin were given which showed no improvement in clinical symptoms. He subsequently underwent plasmapheresis with resolution of his symptoms, suggesting a teprotumumab-induced encephalopathy. Further studies involving larger populations and longer durations are needed.

Management of thyroid disorders during the COVID-19 outbreak: a position statement from the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM).

This position statement was prepared to guide endocrinologists on the best approach to managing thyroid disorders during the coronavirus disease (COVID-19) pandemic. The most frequent thyroid hormonal findings in patients with COVID-19, particularly in individuals with severe disease, are similar to those present in the non-thyroidal illness syndrome and require no intervention. Subacute thyroiditis has also been reported during COVID-19 infection. Diagnosis and treatment of hypothyroidism during the COVID-19 pandemic may follow usual practice; however, should avoid frequent laboratory tests in patients with previous controlled disease. Well-controlled hypo and hyperthyroidism are not associated with an increased risk of COVID-19 infection or severity. Newly diagnosed hyperthyroidism during the pandemic should be preferably treated with antithyroid drugs (ATDs), bearing in mind the possibility of rare side effects with these medications, particularly agranulocytosis, which requires immediate intervention. Definitive treatment of hyperthyroidism (radioiodine therapy or surgery) may be considered in those cases that protective protocols can be followed to avoid COVID-19 contamination or once the pandemic is over. In patients with moderate Graves' ophthalmopathy (GO) not at risk of visual loss, glucocorticoids at immunosuppressive doses should be avoided, while in those with severe GO without COVID-19 and at risk of vision loss, intravenous glucocorticoid is the therapeutic choice. Considering that most of the thyroid cancer cases are low risk and associated with an excellent prognosis, surgical procedures could and should be postponed safely during the pandemic period. Additionally, when indicated, radioiodine therapy could also be safely postponed as long as it is possible.

From SARS-CoV-2 hematogenous spreading to endothelial dysfunction: clinical-histopathological study of cutaneous signs of COVID-19. (preprint)

Background: To date, very few studies on clinical-histopathological correlations of cutaneous disorders associated with COVID-19 have been conducted. Case presentation: The Case 1 was a 90-year-old man, who tested positive for SARS-CoV-2 from a nasopharyngeal swab. Two days later, he was hospitalized and after eleven days transferred to Intensive Care Unit. A chest CT showed bilateral ground-glass opacities. Just that day, an erythematous maculo-papular rash appeared on trunk, shoulders and neck, becoming purpuric after few days. Histological evaluations revealed a chronic superficial dermatitis with purpuric aspects. The superficial and papillary dermis appeared edematous, with a perivascular lympho-granulocytic infiltrate and erythrocytic extravasation. At intraepithelial level, spongiosis and a granulocyte infiltrate were detected. Arterioles, capillaries and post-capillary venules showed endothelial swelling and appeared ectatic. The patient was treated with hydroxychloroquine, azithromycin, lopinavir-ritonavir and tocilizumab. Regrettably, due to severe lung impairment, he died.The Case 2 was a 85-year-old man, admitted to Intensive Care Unit, where he was intubated. He had tested positive for SARS-CoV-2 from a nasopharyngeal swab two days before. A chest RX showed bilateral atypical pneumonia. After seven days, a cutaneous reddening involving trunk, upper limbs, neck and face developed, configuring a sub-erythroderma. Histological evaluations displayed edema in the papillary and superficial reticular dermis, and a perivascular lymphocytic infiltrate in the superficial dermis. The patient was treated with hydroxychloroquine, azithromycin, lopinavir-ritonavir and tocilizumab. Sub-erythroderma as well as respiratory symptoms gradually improved until healing. Conclusions: : The endothelial swelling detected in the Case 1 could be a morphological expression of SARS-CoV-2-induced endothelial dysfunction. We hypothesize that cutaneous damage could be initiated by endothelial dysfunction, caused by SARS-CoV-2 infection of endothelial cells or induced by immune system activation. The disruption of endothelial integrity could enhance microvascular permeability, extravasation of inflammatory cells and cytokines, with cutaneous injury. The Case 2 developed a sub-erythroderma associated with COVID-19, and a non-specific chronic dermatitis was detected at histological level. We speculate that a purpuric rash could represent the cutaneous sign of a more severe coagulopathy, as highlighted histologically by vascular abnormalities, while a sub-erythroderma could be expression of viral hematogenous spreading, inducing a non-specific chronic dermatitis.

Thyroid disorders and SARS-CoV-2 infection: From pathophysiological mechanism to patient management.

The World Health Organization (WHO) declared the COVID-19 epidemic to be a global pandemic in March 2020. COVID-19 is an infection caused by SARS-CoV-2, a coronavirus that utilizes the angiotensin-2 converting enzyme to penetrate thyroid and pituitary cells, and may result in a "cytokine storm". Based on the pathophysiological involvement of the pituitary-thyroid axis, the current review discusses the diagnosis of abnormal thyroid function test, and the management of patients presenting with thyrotoxicosis, thyroid-associated orbitopathy and hypothyroidism in the context of SARS-CoV-2 infection.