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Thyroid-associated ophthalmopathy(TAO)is a rare organ-specific autoimmune disease with an unclear pathogenesis. At present, the treatment still relies mainly on glucocorticoids and traditional immunosuppressants. However, some patients respond poorly to these drugs and experience treatment-related adverse reactions, highlighting the urgent need for novel drugs for TAO treatment. In recent years, with the deepening of research on the pathogenesis of TAO, a multitude of biologics targeting specific targets have emerged. Among them, teprotumumab, which targets the insulin-like growth factor-I receptor(IGF-IR), has been approved by the Food and Drug Administration for the treatment of TAO, and several other biologics are currently in clinical trials. This review provides the latest reference for the clinical prevention, treatment, and research of TAO by summarizing the current clinical research status of biologics targeting IGF-IR, neonatal Fc receptor(FcRn), thyroid-stimulating hormone receptor(TSHR), B cells, cytokines, and other biological agents in TAO and analyzing their impact on clinical treatment and future research trends.
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OBJECTIVES@#Dysthyroid optic neuropathy (DON) is a class of diseases that makes seriously endanger to the vision of patients with thyroid-associated ophthalmopathy. This study aims to observe the visual function changes in patients with DON, and to evaluate the diagnostic value of indicators diagnosing DON.@*METHODS@#A retrospective study was conducted on 98 eyes of 49 patients with dysthyroid optic neuropathy (DON) who were treated in Xiangya Hospital of Central South University from January 2017 to December 2019. All patients were received the examination of best corrected visual acuity (BCVA), Humphrey visual field, visual evoked potential (VEP), and contrast sensitivity. Ninety-eight eyes were divided into a DON group (45 eyes) and a non-DON group (53 eyes). T-test was used to compare the related indicators between the 2 groups. The sensitivity and specificity of each indicator were analyzed by receiver operating characteristic (ROC) curve.@*RESULTS@#The BCVA and visual field index (VFI) of the DON group were significantly lower than those of the non-DON group (all P<0.05). The mean deviation (MD) and pattern standard deviation (PSD) of the DON group were significantly higher than those of the non-DON group (all P<0.05). The low frequency contrast sensitivity (CSL), medium frequency contrast sensitivity (CSM), and high frequency contrast sensitivity (CSH) of the DON group were significantly lower than those of the non-DON group (all P<0.05), with CSH being particularly prominent. Compared with the non-DON group, at spatial frequencies of 15°, 30°, and 60°, the amplitude of N135 wave was significantly reduced, and the latency of N75 wave, P100 wave, and N135 wave was significantly prolonged in the DON group (all P<0.05); at spatial frequencies of 15° and 30°, the amplitude of P100 wave was significantly reduced in the DON group (P<0.05). The ROC curve analysis results showed that the area under the curve (AUC) of VFI, CSL, CSM, CSH and 15° P100 amplitude diagnosing DON were 0.812, 0.841, 0.880, 0.784, and 0.791, respectively, with CSM possessing the highest sensitivity and specificity.@*CONCLUSIONS@#The visual function of patients with DON is decreased. VFI, contrast sensitivity of low, medium, and high frequency, and 15° P100 wave amplitude might be effective indicators for early diagnosis of DON.
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Humans , ROC Curve , Optic Nerve Diseases/complications , Retrospective Studies , Evoked Potentials, Visual , Graves OphthalmopathyABSTRACT
AIM: To evaluate the lacrimal gland parameters and their correlation with clinical examination in patients with thyroid-associated ophthalmopathy(TAO)using orbital magnetic resonance imaging(MRI).METHODS: A total of 38 patients(76 eyes)with TAO were selected as case group, and 26 patients(52 eyes)who matched the gender and age with case group and volunteered to accept examination were selected as normal control group. Patients in case group were categorized into active TAO group and inactive TAO group according to the modified clinical activity score(CAS). The exophthalmos was evaluated on T1WI after obtaining the MRI images, the longest lacrimal gland length, width, and the biggest area in axial and coronal images were evaluated on T2WI, and the maximum T2 value and mean T2 value of the lacrimal gland were recorded.RESULTS: There were no significant differences in age, gender and exophthalmos between active TAO and inactive TAO(P&#x003E;0.05). The area of lacrimal gland was higher in active TAO than that in inactive TAO, and was higher in inactive TAO than that in control group in coronal and axial section(all P&#x003C;0.01). The length of lacrimal gland in coronal and axial section was higher in the active TAO than that in the inactive TAO and the control group(all P&#x003C;0.05). The width of lacrimal gland in coronal and axial section was higher in active TAO and inactive TAO than that in the control group(all P&#x003C;0.05). The maximum T2 value in the active TAO was higher than that in the inactive TAO and control group, and the inactive TAO was higher than that in the control group(all P&#x003C;0.05). The average T2 value in the active TAO was higher than that in the inactive TAO and control group(all P&#x003C;0.05). CAS was positively correlated with lacrimal gland area in axial, coronal section and maximum T2 value(all P&#x003C;0.01).CONCLUSION: The lacrimal gland is significantly enlarged in patients with TAO, especially in active TAO. The lacrimal gland area in axial, coronal section and maximum T2 value could be potentially utilized as valuable radiographic biomarkers for the activity of TAO.
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Teprotumumab-trbw,a monoclonal antibody that acts on the insulin growth factor-Ⅰ receptor, was approved in 2020 for the treatment of thyroid-associated ophthalmopathy, but little is known about it in China. It is hoped to provide guidance for clinical use through the review of its molecular structure, pharmacokinetics, therapeutic mechanism, clinical research and safety. It inhibits immune inflammation by blocking thyroid-stimulating hormone receptor /insulin growth factor-Ⅰ receptor crosstalk signaling, so as to reduce the production of hyaluronic acid and inflammatory factors in response. It can also promote the apoptosis of retro-orbital fibroblasts/adipocytes and inhibit the expression of genes related to the synthesis of thyroid hormones, thereby significantly improving the clinical symptoms such as exophthalmos and diplopia. The common adverse reactions of Teprotumumab-trbw are muscle spasm, hyperglycemia, hearing loss and so on. Teprotumumab-trbw is effective and durable in the treatment of thyroid-associated ophthalmopathy, and patients with secondary treatment can also benefit from it, which provides a new way and hope for the treatment of thyroid-associated ophthalmopathy.
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Thyroid-associated ophthalmopathy(TAO)is an autoimmune inflammatory disease involving multiple orbital tissues with a variety of clinical manifestations, which has serious effects on the life quality of patients.Interventions of TAO mainly include medical treatment to stabilize thyroid function, reduce inflammation and regulate immune function, as well as surgical treatment to relieve ocular symptoms. Botulinum toxin type A can paralyze muscles by blocking nerve impulse conduction at the neuromuscular junction, which is of certain therapeutic value for restrictive strabismus due to extraocular muscle involvement and upper eyelid retraction due to involvements of levator palpebrae superioris and Müller's muscle in TAO patients, especially when they have surgical contraindications, lack surgical opportunity, or refuse surgery. This paper reviews the application of botulinum toxin type A in the treatment of TAO, focusing on its pharmacological mechanism, dosage, effectiveness, and possible complications when treating restrictive strabismus and upper eyelid retraction, and discussing potential therapeutic values of botulinum toxin type A for intraocular pressure elevation, glabellar frown lines and dry eye caused by extraocular muscle compression in TAO patients, in order to provide a reference for clinical intervention.
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AIM: To investigate the effect of orbital decompression on the central macular choroidal thickness(CMCT)in patients with thyroid-associated ophthalmopathy(TAO).METHOD: Prospective clinical studies. A total of 29 TAO patients(42 eyes)treated in our department from January 2021 to January 2022 were analyzed, and they were divided into 20 cases(30 eyes)in the moderate and severe group and 9 cases(12 eyes)in the extremely severe group. Both groups of patients received orbital decompression, and the changes of CMCT, visual acuity, intraocular pressure, exophthalmos, and clinical activity score(CAS)at 3 and 6mo before and after surgery were compared between the two groups.RESULTS: All patients completed follow-up. The CMCT, exophthalmos, intraocular pressure, and CAS of the extremely severe group at 3 and 6mo were 355.13±15.59 and 339.61±13.17μm, 19.33±2.23 and 17.83±1.70mm, 18.86±3.05 and 18.09±1.37mmHg, 3.75±0.87 and 2.42±1.00 points, respectively. The moderate and severe group was 325.00±10.48 and 321.04±11.34μm, 16.07±1.74 and 15.6±1.98mm, 16.65±2.04 and 16.03±2.3mmHg, 1.50±0.51 and 1.43±0.50 points, and there was differences with those before operation(extremely severe group: 396.46±17.61μm, 22.00±2.3mm, 21.85±2.82mmHg, 5.33±1.44 points; moderate and severe group: 335.77±11.60μm, 19.07±1.84mm, 18.89±3.06mmHg, 1.63±0.49 points; all P<0.001). The best corrected visual acuity(LogMAR)before surgery was 0.64±0.22 in the extremely severe group, and 0.43±0.20 and 0.34±0.15 at 3 and 6mo after operation, respectively, which were different from those before surgery(all P<0.001)CONCLUSION: Orbital decompression can effectively reduce CMCT, intraocular pressure and exophthalmos in TAO patients, relieve orbital vein stasis, and effectively improve vision and reduce mobility in patients with extremely severe disease.
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Interleukin-6(IL-6)is a pleiotropic cytokine produced by monocytes, macrophages, T lymphocytes and other cell types. It is significantly up-regulated in the process of infection and inflammation, and is the core cytokine of the host's defense against environmental stresses(such as injury and infection). Abnormal and persistent IL-6 production is closely associated with the development of various autoimmune and inflammatory diseases. A growing number of studies have shown that IL-6 plays a critical role in ocular inflammation and angiogenesis in the conjunctiva, cornea, uvea and retina. Blockade of IL-6 ameliorates chronic and refractory intraocular inflammation. This article aims to review the role as well as the mechanism of IL-6 in ocular inflammatory diseases, attempting to have a deep and systematic understanding of the role of IL-6 in ocular inflammatory diseases.
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Thyroid-associated ophthalmopathy(TAO)is an autoimmune disease associated with thyroid dysfunction that can significantly impact quality of life, result in visual impairment and facial disfigurement. Traditional treatments are often unsatisfactory. Studies have shown that teprotumumab, a human monoclonal antibody that can inhibit insulin-like growth factor 1 receptor(IGF-1R), has become an emerging targeted drug for TAO. Although the drug has proven to be effective and relatively safe in the treatment of TAO, adverse reactions are worthy of attention of ophthalmologists with the continuous promotion of clinical application, including hearing impairment, hyperglycemia, diarrhea, muscle spasms, infusion reactions, cognitive decline, thyroid suppression, alopecia, nausea and fatigue. Teprotumumab was generally well tolerated, with most adverse events being mild or moderate in severity. This paper aims to review the adverse reactions and precautions of teprotumumab in the treatment of TAO.
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Thyroid-associated ophthalmopathy (TAO) is a common orbital disease in the adults, which leads to a series of ocular symptoms and signs, seriously affecting the visual function and life quality of patients.Grasping the disease progression accurately and evaluating the severity and activity of TAO objectively play a crucial role in improving the management and prognosis of TAO patients.Grading and staging methods of TAO have been constantly improved.In the descriptive evaluation of subjective symptoms and signs of TAO, four international grading and staging systems with similarities and different focuses, namely, NOSPECS, CAS, VISA and EUGOGO, have been proposed successively.In recent years, with the rapid development of science and technology, objective evaluation methods such as imaging technology and laboratory examination have played an important role in the grading and staging of TAO.Among them, the application of orbital CT and MRI has made a great breakthrough in quantitative analysis of the disease.Continuous summary of grading and staging methods of TAO can contribute to the guidance for improving diagnosis, treatment and prognosis of TAO.
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Objective:To identify the proteins differentially expressed in extraocular muscles between restrictive strabismus patients with thyroid-associated ophthalmopathy (TAO) and concomitant esotropia patients by proteomic analysis using tandem mass tag (TMT).Methods:Extraocular muscles samples from 5 restrictive strabismus patients with TAO and 5 concomitant esotropia patients were collected at Peking University People's Hospital from August 2019 to December 2020.All the patients received strabismus surgery.Differentially expressed proteins (DEPs) in extraocular muscles samples were identified by quantitative proteomic analysis and bioinformatic analysis based on TMT.Fold change≥1.2 or≤0.83 and P value<0.05 was regarded as the threshold to screen DEPs.GO annotation, KEGG pathways enrichment analysis and protein-protein interaction (PPI) network of DEPs were conducted through UniProtGOA and STRING.This study protocol was approved by the Ethics Committee of Peking University People's Hospital (No.2021PHB058-001). Results:A total of 53 DEPs were identified, 34 of which were up-regulated and 19 were down-regulated.The biological processes DEPs mainly participated included response to stimulation, multicellular organismal process, metabolism, developmental process, intracellular signal transduction, and positive regulation of biological process.DEPs were involved in pathways including focal adhesion, tight junction, regulation of action cytoskeleton, and apoptosis.Six key proteins identified using PPI network were myosin heavy chain 2, myosin heavy chain 7, myosin regulatory light chain, α-actinin-2, fibrinogen alpha chain and fibrinogen beta chain.Conclusions:There are DEPs in extraocular muscles between restrictive strabismus patients with TAO and concomitant esotropia patients.Myosin, actinin and filamin may be involved in the pathogenesis of TAO through regulation of actin cytoskeleton and focal adhesion.
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Thyroid-associated ophthalmopathy(TAO)is an autoimmune disease that is closely related to thyroid dysfunction. It is one of the most common orbital diseases in adults with complex clinical manifestations. As the disease progresses, it may manifest as proptosis, diplopia, exposure keratitis, corneal ulceration and compressive optic neuropathy, leading to irreversible visual impairment or even blindness. The treatment is lack of specificity and only focuses on clinical symptomatic treatment, the efficacy is uncertain. It is currently a problematic area of ophthalmology. Clinical first-line drug treatment is based on glucocorticoids. Second-line treatments, such as immunosuppressants and radiotherapy, all them have certain limitations. With the in-depth and comprehensive understanding of the disease, a variety of new targeted drugs represented by teprotumumab and rituximab have been developed for the pathogenesis of TAO. Their excellent roles in relieving inflammation and controlling the disease are the future research direction. In this paper, the current status and research progress of conservative treatment of TAO will be reviewed.
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Thyroid-associated ophthalmopathy(TAO)is the most common orbital disease in adults, and its incidence is increasing year by year. The clinical manifestations include proptosis, eyelid retraction, ocular motility disturbance and visual impairment, which seriously damage the physical and mental health of patients. Treatment options for TAO mainly include glucocorticoids, radiotherapy and orbital decompression. Among them, the glucocorticoids are the mainstay of treatment for moderate-to-severe and active disease; Orbital decompression is mainly for patients with severe proptosis and increased orbital pressure leading to optic nerve compression injury; And radiotherapy is used for TAO patients who are intolerant of glucocorticoids and who refuse orbital decompression. Radiation therapy can effectively improve the clinical symptoms of patients by exerting a non-specific anti-inflammatory effect, and it is an important means of treating TAO. With the continuous update of computer technology and medical imaging, radiotherapy techniques have developed rapidly. The emergence of three-dimensional conformal radiotherapy technology and intensity-modulated radiotherapy technology has made it possible to locate the lesions accurately. Recently, a large number of clinical results show that radiotherapy for TAO has good curative effects and manageable adverse reactions. This article reviews the mechanism of action, technical characteristic, clinical protocol, radiation dose parameter selection and complications of radiotherapy for TAO, in order to provide clinical reference for peers and formulate personalized TAO treatment plans.
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Thyroid-associated ophthalmopathy(TAO)is an organ-specific autoimmune disease, which will cause a series of symptoms to significantly reduce the health level and life quality of patients. The pathogenesis of TAO has not been fully clarified. At present, there is a lack of unified and mature treatment scheme of it. Indeed, T-helper 17 lymphocyte(Th17)cells, regulatory T(Treg)cells and their imbalance are closely related to the immunological pathogenesis of TAO. It is currently believed that the cytokines secreted by Th17 cells can not only promote the inflammatory response of TAO and the fibrosis of orbital connective tissue, but also inhibit the adipogenic differentiation of TAO orbital connective tissue. In addition, Treg cells mainly exert immunosuppressive effect on TAO and delay the disease progression. At the same time, there is a dynamic balance relationship between Th17 and Treg cells, the imbalance of Th17/Treg cells can trigger the occurrence and development of TAO. This paper mainly expounds the influence mechanism of Th17, Treg cells and their balance on TAO, and analyzes the reasons for the differences between different research results, so as to provide some reference for the study of the pathogenesis and clinical treatment of TAO.
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Objective:To evaluate the efficacy and safety of mycophenolate mofetil(MMF) in patients with active moderate to severe thyroid associated ophthalmopathy(TAO) refractory to multiple intravenous glucocorticoid(GC).Methods:Fifty-two patients with active moderate to severe TAO that was refractory to multiple intravenous GC were treated with MMF 0.5g orally, 2/d. To evaluate the overall response rate of TAO patients, the improvement of more than 3 items including clinical disease activity score(CAS), soft tissue involvement, proptosis, diplopia, decrease of eye movements, visual acuity and other improvements were defined as response.Results:After 12 weeks of MMF treatment, the overall response rate of TAO patients was 75.0%, and then increased to 88.5% significantly at the 24th weeks. At the 12th weeks, CAS decreased from(5.06±1.21) to(2.52±1.13), and then continued to decrease to(2.02±0.92) at the 24th week( P<0.05), the response rates were 82.7% and 90.4%, respectively. In addition, after 12 weeks of treatment, 58.1% of patients with diplopia improved significantly, and the response rate was 74.2% at the 24th weeks. Similarly, the degree of proptosis decreased significantly at the 12th and 24th weeks, and the response rates were 53.8% and 69.2%, respectively. No serious adverse events occurred during the treatment. Conclusion:The MMF therapy is efficient and safe for patients with active moderate to severe corticosteroid-resistant TAO.
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In adult orbital diseases, thyroid associated ophthalmopathy (TAO) is of very high incidence rate, and it can seriously affect patients' appearance, eyesight and binocular visual function and so on, and significantly reduce the patients' quality of life.In addition to the common manifestations such as eyelid retraction, exophthalmos and strabismus, some TAO patients may suffer from obviously increased ocular pressure and even visual field damage, which are often ignored or missed in diagnosis and should be paid more attention to.The pathogenesis of elevated intraocular pressure in TAO is mainly related to the elevated episcleral venous pressure and the extraocular muscles.Because the elevated intraocular pressure resulted from TAO is secondary and its pathogenesis is complex, personalized treatment different from primary glaucoma therapy is needed.In this article, the epidemiology, pathogenesis and therapy of elevated intraocular pressure in TAO including medication, surgery, and radiotherapy were reviewed to provide reference for the clinical diagnosis and treatment for TAO.
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@#AIM: To explore the clinical effect and safety of deep lateral wall combined with medial wall orbital decompression in the treatment of thyroid associated ophthalmopathy(TAO).<p>METHODS: Totally 17 patients with TAO in our department from January 2019 to May 2020 were included. All patients underwent deep lateral wall combined with medial wall orbital decompression under general anesthesia, the visual acuity, recovery of exposure keratitis, exophthalmos, intraocular pressure and complications were compared before and after operation.<p>RESULTS: Eight patients(9 eyes)with TAO and dysthyroid optic neuropathy(DON)were included in the study. The best corrected visual acuity averaged 0.78±0.15 preoperatively and 0.36±0.12 1mo postoperatively, which was statistically significant(<i>P</i><0.01)compared with the preoperative visual acuity, 0.38±0.12 at 6mo after surgery, which was not statistically different from that at 1mo after surgery(<i>P</i>=0.594). The mean preoperative proptosis was 23.75±2.55mm and the mean postoperative proptosis was 14.85±1.53mm at 1mo, which was statistically significant compared with the preoperative proptosis(<i>P</i><0.01), proptosis was on average 14.60±1.64mm at 6mo after surgery and remained generally stable(<i>P</i>=0.658)from 1mo before surgery. The intraocular pressure of the patients was 25.56±3.23mmHg preoperatively and 18.42±2.35mmHg 1mo postoperatively, which was statistically significant compared with the preoperative value(<i>P</i><0.01), and the intraocular pressure of the patients was reduced to 15.82±2.57mmHg at the 6mo postoperative follow-up, which was statistically significant compared with the intraocular pressure of the patients 1mo postoperatively(<i>P</i><0.01). There were 6 eyes of 6 patients with exposure keratitis preoperatively, 4 eyes improved and 2 eyes were cured in the 1mo postoperative, and all 6 eyes were cured 6mo postoperatively. Postoperatively, the diplopia of the patients all decreased to various degrees, and there were some patients whose diplopia symptoms continued to improve 6mo thereafter without other serious complications.<p>CONCLUSION: Deep lateral wall combined with medial wall orbital decompression can effectively improve the proptosis and also have a good effect on severe complications such as DON and exposure keratitis with few complications, so deep lateral wall combined with medial wall orbital decompression is an effective surgical procedure in the treatment of severe TAO.
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@#Thyroid associated ophthalmopathy(TAO)is an autoimmune orbital inflammatory disease. Imaging methods play an important role in evaluating the change of orbital structures and differential diagnosis of orbital disease. In addition, imaging studies can also contribute to analyze the activity and severity of TAO and estimate compressive optic neuropathy(CON).
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@#AIM:To investigate the efficacy of 99Tcm-octreotide orbital imaging combined with magnetic resonance imaging(MRI)in stage diagnosis of thyroid associated ophthalmopathy(TAO). <p>METHODS: Retrospective analysis of clinical data of 35 surgically treated TAO patients admitted to hospital from June 2017 to June 2018. 99Tcm-octreotide orbital imaging and MRI were performed, and the pathological observation and stages were performed. The result of pathological staging was statistically analyzed. The imaging findings and results of 99Tcm-octreotide orbital imaging combined with MRI were observed. The efficacy of 99Tcm-octreotide orbital imaging, MRI, 99Tcm-octreotide orbital imaging combined with MRI in the stage diagnosis of TAO was analyzed. <p>RESULTS: Totally 58 eyes with TAO in 35 patients with pathological stages were 49 eyes in the active phases and 9 eyes and inactive phases. 99Tcm-octreotide orbital imaging and MRI diagnosis of TAO severity staging have typical imaging findings, and the sensitivity, specificity, accuracy of 99Tcm-octreotide orbital imaging combined with MRI in the diagnosis of active TAO was higher than that of 99Tcm-octreotide orbital imaging and MRI alone. The ROC results showed that the AUC of the active phase of 99Tcm-octreotide orbital imaging combined with MRI diagnosis was 0.893, which was higher than that of 99Tcm-octreotide orbital imaging or MRI alone. <p>CONCLUSION:It is recommended to use 99Tcm-octreotide orbital imaging and MRI imaging in combination with TAO stage diagnosis. The imaging findings are typical, and the combined application has higher diagnostic efficiency.
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@#Immune-mediated eye diseases(IMED)represent a kind of autoimmune eye diseases, such as thyroid-associated ophthalmopathy, autoimmune uveitis and Sjögren syndromes. Owning to its complicated pathophysiological mechanisms, the efficacies of current therapeutic strategies for IMED are unsatisfactory, which may ultimately result in severe visual impairment. Exosomes are lipid bilayer vesicles secreted by cells that play an important role in cell-to-cell communication and immune regulation. Recent studies have shown that exosomes secreted by cells under pathological conditions are closely associated with the development and progression of IMED, and the exosomes derived from certain cells(such as mesenchymal stem cells)are deemed as promising therapy for IMED. Hence, we review the recent advances of exosomes in IMED.
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@#Thyroid associated ophthalmopathy(TAO)is a type of orbital disease, it is caused by a specific autoimmune reaction, and is closely related to thyroid disease. Furthermore, TAO significantly affects the appearance and visual functionality of patients. Moreover, those with severe symptoms are at a risk of blindness, which makes it difficult for them to lead normal lives. However, its pathogenesis has not been fully established yet. Autophagy, is a process of phagocytosis and degradation of its own cytoplasmic proteins or organelles, this realizes the metabolic needs of cells and the renewal of some organelles. Previous studies have shown that, compared to normal people, the level of orbital autophagy in TAO patients is higher, and it plays an important role in the occurrence and development of the disease. This paper briefly describes the role of autophagy in the occurrence and development of TAO from three aspects, namely, inflammation, fat formation, and glycosaminoglycan(GAG)accumulation.