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Background: Fc receptor-like (FCRL) genes play a role in the immune system by encoding proteins that function as receptors on the surface of immune cells. The clinical significance of FCRL gene expression in Graves' Disease (GD) and Graves' Orbitopathy (GO) remains unclear. We evaluated the expression of FCRL 2, 3, 4 mRNA in patients with GD and GO and its role in the development and activity of these diseases. Methods: Peripheral blood samples from patients with GD (n = 24) or GO (n = 49) hospitalized in the Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, were collected. Expressions of FCRL2, FCRL3 and FCRL4 were measured by real-time PCR. Results: FCRL3 expression was higher in patients with GD compared to GO (1.375 vs. 0.673, p = 0.004) and, specifically, active GO (1.375 vs. 0.639, p = 0.005). Regarding FCRL4, mRNA expression was higher in GD compared to Control (3.078 vs. 0.916, p = 0.003), GO (3.078 vs. 1.178, p < 0.001), active GO (3.078 vs. 1.186, p = 0.002) and inactive GO (3.078 vs. 1.171, p = 0.008). In turn, FCRL4 mRNA expression was higher in patients with hyperthyroidism (subclinical + overt) than in euthyroid patients (2.509 vs. 0.995, p = 0.001 when the whole group of individuals was considered; 2.509 vs. 1.073, p = 0.004 when GO + GD was considered). Conclusions: The increased FCRL mRNA expression in patients with GD is associated with hyperthyroidism (but not with positive TSHRAbs), and our study is the first one to confirm this relationship.

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Introduction: Bruton's tyrosine kinase (BTK) and interleukin (IL)-2 Inducible T-cell Kinase (ITK) inhibitors have anti-inflammatory properties. We investigated the therapeutic effect of ibrutinib, an orally bioavailable BTK/ITK inhibitor, in a mouse model of Graves' orbitopathy (GO). Methods: Genetic immunization was performed through intramuscular administration of the recombinant plasmid, pCMV6-hTSHR cDNA, to 8-week-old female BALB/c mice. Serum levels of T3, T4, and thyroid-stimulating hormone receptor (TSHR) antibodies (TRAbs) were quantified using enzyme-linked immunosorbent assay. Histopathological changes in orbital tissues were examined using immunohistochemistry (IHC) staining for TSHR and various inflammatory markers. Following successful genetic immunization, ibrutinib was orally administered daily for 2 weeks in the GO model mice. After treatment, the mRNA and protein expression levels of BTK, ITK, IL-1ß, and IL-6 in orbital tissues were evaluated using real-time PCR and Western blotting. Results: In total, 20 mice were sacrificed to confirm successful genetic immunization. The GO mouse group exhibited significantly increased serum T3, T4, and TRAb levels. IHC revealed increased expression of TSHR, IL-1ß, IL-6, transforming growth factor-ß1, interferon-γ, CD40, CD4, BTK, and ITK in the GO mouse model. The orbital inflammation was significantly attenuated in ibrutinib-treated mice. The mRNA and protein expression levels of BTK, ITK, IL-1ß, and IL-6 in orbital tissue were lower in ibrutinib-treated GO mouse group compared to the phosphate-buffered saline-treated GO mouse group. Conclusion: The GO mouse model demonstrated enhanced BTK and ITK expression. Ibrutinib, a BTK/ITK inhibitor, suppressed the inflammatory cytokine production. These findings highlight the potential involvement of BTK/ITK in the inflammatory pathogenesis of GO, suggesting its role as a novel therapeutic target.

Asunto(s)

Adenina , Agammaglobulinemia Tirosina Quinasa , Modelos Animales de Enfermedad , Oftalmopatía de Graves , Inflamación , Ratones Endogámicos BALB C , Piperidinas , Pirimidinas , Animales , Oftalmopatía de Graves/tratamiento farmacológico , Oftalmopatía de Graves/metabolismo , Oftalmopatía de Graves/patología , Adenina/análogos & derivados , Piperidinas/uso terapéutico , Ratones , Femenino , Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Agammaglobulinemia Tirosina Quinasa/metabolismo , Inflamación/tratamiento farmacológico , Inflamación/patología , Pirimidinas/uso terapéutico , Pirazoles/uso terapéutico , Pirazoles/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Receptores de Tirotropina/metabolismo , Receptores de Tirotropina/genética , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico

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Composed of over 1200 species of anaerobes and aerobes bacteria along with bacteriophages, viruses, and fungal species, the human gut microbiota (GM) is vital to health, including digestive equilibrium, immunologic, hormonal, and metabolic homeostasis. Micronutrients, usually refer to trace elements (copper, iodine, iron, selenium, zinc) and vitamins (A, C, D, E), interact with the GM to influence host immune metabolism. So far, microbiome studies have revealed an association between disturbances in the microbiota and various pathological disorders, such as anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, anxiety, depression, early-onset cancers, type 1 diabetes (T1D) and type 2 diabetes (T2D). As common conditions, thyroid diseases, encompassing Graves' disease (GD), Graves' orbitopathy (GO), Hashimoto's thyroiditis (HT), benign nodules, and papillary thyroid cancer (TC), have negative impacts on the health of all populations. Following recent studies, GM might play an integral role in triggering diseases of the thyroid gland. Not only do environmental triggers and genetic predisposing background lead to auto-aggressive damage, involving cellular and humoral networks of the immune system, but the intestinal microbiota interacts with distant organs by signals that may be part of the bacteria themselves or their metabolites. The review aims to describe the current knowledge about the GM in the metabolism of thyroid hormones and the pathogenesis of thyroid diseases and its involvement in the appearance of benign nodules and papillary TC. We further focused on the reciprocal interaction between GM composition and the most used treatment drugs for thyroid disorders. However, the exact etiology has not yet been known. To elucidate more precisely the mechanism for GM involvement in the development of thyroid diseases, future work is needed.

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PURPOSE: The primary objective of this study was to identify predictive factors linked to the normalization of thyroid-stimulating immunoglobulin (TSI) levels in patients diagnosed with active, moderate-to-severe Graves' orbitopathy (GO). The study also tracked the longitudinal changes in TSI levels over a 36-month period following treatment. METHODS: The study population consisted of individuals who were recently diagnosed with active, moderate-to-severe GO and received a 12-week course of intravenous methylprednisolone (IVMP) treatment. A subgroup of patients who did not respond to the initial treatment received an additional 20 Gy of radiation therapy (RTx). TSI levels were monitored at the time of diagnosis, after treatment, and subsequently every 6 months for 36 months. Normalization was defined as a TSI level below 140%. Patients were divdied into two groups with success and failure group depending on whether TSI became normal or not. RESULTS: Out of 83 patients, 36 (43.4%) achieved normalized TSI levels within two years post-IVMP treatment. Lower initial TSI levels (< 425%), absence of additional RTx, and early treatment initiation were associated with a higher likelihood of TSI normalization (P = 0.035, P = 0.028, P < 0.001, respectively). Notably, significant differences in TSI level reduction were observed from 18 months post-treatment between the two groups (P = 0.031). A TSI cutoff value of 413% was identified as predictive for normalization at 24 months (P = 0.002). CONCLUSION: This study is the first to identify key factors that influence normalization of TSI levels in moderate-to-severe Graves' Orbitopathy. It highlights the importance of early treatment decisions, particularly for patients with initial TSI levels above 425%. Despite the treatment, less than half of the patients achieved TSI normalization within 24 months, underscoring the need for additional research to explore the relationship between TSI levels and the clinical manifestations of chronic GO.

Asunto(s)

Glucocorticoides , Oftalmopatía de Graves , Inmunoglobulinas Estimulantes de la Tiroides , Metilprednisolona , Humanos , Oftalmopatía de Graves/tratamiento farmacológico , Oftalmopatía de Graves/diagnóstico , Oftalmopatía de Graves/sangre , Femenino , Masculino , Persona de Mediana Edad , Pronóstico , Adulto , Metilprednisolona/uso terapéutico , Metilprednisolona/administración & dosificación , Glucocorticoides/uso terapéutico , Inmunoglobulinas Estimulantes de la Tiroides/sangre , Estudios Longitudinales , Estudios de Seguimiento , Anciano , Índice de Severidad de la Enfermedad , Estudios Retrospectivos

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BACKGROUND: Selenium is a trace element crucial for thyroid function, and has potential therapeutic benefits in Graves' orbitopathy (GO). Therefore, we aim to evaluate its efficacy and safety in GO patients to provide valuable insights into its role as a therapeutic option for this condition. DESIGN: Systematic review and meta-analysis. PATIENTS: GO Patients treated with selenium compared to placebo. MEASUREMENTS: Clinical activity score (CAS), Graves' orbitopathy quality of life (GO-QOL), eye symptoms and signs, and adverse events. RESULTS: Out of 1684 records screened, four randomised controlled trials were included. Selenium was superior at 6 months in lowering the CAS (MD = -1.27, 95% confidence interval [CI] [-1.68, -0.85], p < .0001]), improving total GO-QOL (RR = 2.54, 95% CI [1.69-3.81], p < .00001), and improving the visual and the psychological functioning scores (MD = 10.84, 95% CI [4.94-16.73], p = .003), (MD = 12.76, 95% CI [8.51-17.00], p < .00001) respectively. Similarly, it significantly improved these outcomes at 12 months. It also showed a significant decrease in the palpebral aperture at 6 months (MD = -1.49, 95% CI [-2.90, -0.08], p = .04). However, no significant differences were observed in proptosis, soft tissue involvement, ocular motility, and adverse effects. CONCLUSIONS: Selenium is effective in reducing CAS and improving the palpebral aperture and GO-QOL in patients with GO. Additionally, it is safe and has promising therapeutic implications. However, further research is needed to validate its long-term efficacy and safety.

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This study aimed to investigate the presence of structural and functional changes in extraocular muscles (EMs) among patients with inactive Graves' orbitopathy (GO) classified according to the Clinical Activity Score (CAS). Sixty-seven patients with Graves' disease (GD) and inactive GO were included. The data collected included clinical parameters, thyroid function, autoantibody levels, EOM morphology via orbital ultrasound (US), and ocular motility. Patients were stratified into Red Filter Test (RFT)-positive or RFT-negative groups based on the presence or absence of latent diplopia during the RFT examination. Thirty-three patients (49.25%) exhibited latent diplopia on the RFT, despite not reporting double vision during standard ocular motility tests. Significant differences were observed between the two groups in terms of age, disease duration, intraocular pressure (IOP) elevation in up-gaze, and medial rectus muscle thickness (p < 0.05). No significant differences were found in thyroid status, TRAb and ATA levels, CASs, exophthalmos, or lateral rectus thickness between the two groups. This study revealed that in inactive GO, subclinical EM dysfunction and morphological changes may be present, which might not be apparent through routine ocular examinations. The RFT is effective in detecting latent diplopia, highlighting its utility in identifying subtle ocular motility issues and subclinical muscle involvement. Comprehensive evaluations combining functional tests like the RFT and imaging are essential for early detection of GO-related abnormalities, enabling tailored and prompt management and improving patient outcomes.

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The authors describe a case of bilateral diffuse paraneoplastic orbital myositis induced by a stage IA left testicular pure seminoma. The patient presented with findings typical of thyroid-associated orbitopathy (TAO) and was thought to have TAO until discovery of the malignancy. Treatment included an urgent orchiectomy, as well as 7 weeks of therapeutic plasma exchange. This is the fifth reported case of seminoma-associated orbitopathy, and the second to occur while cancer was in the occult phase. Although seminoma-associated orbitopathy is exceedingly rare, it can masquerade as TAO and should be considered in the differential diagnosis of any young male with atypical TAO findings.

Asunto(s)

Oftalmopatía de Graves , Orquiectomía , Seminoma , Neoplasias Testiculares , Humanos , Masculino , Seminoma/diagnóstico , Seminoma/cirugía , Diagnóstico Diferencial , Neoplasias Testiculares/diagnóstico , Oftalmopatía de Graves/diagnóstico , Tomografía Computarizada por Rayos X , Adulto , Imagen por Resonancia Magnética , Miositis Orbitaria/diagnóstico , Miositis Orbitaria/tratamiento farmacológico , Síndromes Paraneoplásicos Oculares/diagnóstico

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Background: Graves' orbitopathy (GO) occurs in approximately 25-40% of patients with Graves' disease (GD). High levels of anti-thyrotropin receptor antibodies (TRAbs), smoking habit, sex, older age, longer duration and amount of hyperthyroidism or hypothyroidism are well-recognized risk factors for the occurrence, severity and clinical course of GO. Oxidative stress (OX) has recently been shown to play a role in the pathogenesis of GO, and several clinical conditions related to OX have been investigated regarding the presentation and severity of GO. Aim: We aimed to evaluate the impact of clinical conditions related to oxidative stress on the outcome of intravenous glucocorticoid (ivGCs) therapy in a cohort of patients with active moderate to severe GO (AMS-GOs) treated at a single institution. Methods: We retrospectively studied a series of patients with AMS-GOs who were treated with ivGCs from January 2013 to May 2022. GO clinical evaluation was performed at baseline and at 6 (W6), 12 (W12) and 24 (W24) weeks after starting ivGCs by the seven-point clinical activity score (CAS) alone and by overall clinical criteria (CI) according to the European Group of Graves' Ophthalmopathy (EUGOGO). Total cholesterol and calculated LDL cholesterol (LDLc), triglyceride, body mass index (BMI), diabetes status, history of hypertension (HoH), smoking status, age and sex were used as covariates for the clinical outcome of GO to ivGCs. Results and conclusions: LDLc and HoH negatively and independently modulated the response of AMS-GOs to ivGCs. Notably, slightly elevated LDLc levels (> 130 mg/dl) reduced the response of orbital soft tissue to ivGCs, whereas more elevated LDLc levels (from 175 mg/dl to 190 mg/dl) and HoH were associated with poorer clinical response of eye motility and proptosis.

Asunto(s)

Glucocorticoides , Oftalmopatía de Graves , Índice de Severidad de la Enfermedad , Humanos , Oftalmopatía de Graves/tratamiento farmacológico , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Glucocorticoides/efectos adversos , Adulto , Resultado del Tratamiento , Estrés Oxidativo , Anciano

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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.

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Coroides , Oftalmopatía de Graves , Disco Óptico , Tomografía de Coherencia Óptica , Humanos , Coroides/irrigación sanguínea , Coroides/patología , Coroides/diagnóstico por imagen , Masculino , Femenino , Oftalmopatía de Graves/diagnóstico , Oftalmopatía de Graves/patología , Persona de Mediana Edad , Tomografía de Coherencia Óptica/métodos , Adulto , Disco Óptico/irrigación sanguínea , Disco Óptico/patología , Vasos Retinianos/patología , Vasos Retinianos/diagnóstico por imagen , Agudeza Visual , Angiografía con Fluoresceína/métodos

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PURPOSE: To evaluate the evidence for alterations of blood flow, vascular and perfusion densities in the choroid, macula, peripapillary region, and the area surrounding the optic nerve head (ONH) in patients with thyroid-associated ophthalmopathy (TAO) based on changes of OCTA parameters. METHODS: A systematic review of Pubmed, Google Scholar, Scopus, WOS, Cochrane, and Embase databases, including quality assessment of published studies, investigating the alterations of OCTA parameters in TAO patients was conducted. The outcomes of interest comprised changes of perfusion and vascular densities in radial peripapillary capillary (RPC), ONH, superficial and deep retinal layers (SRL and DRL), choriocapillaris (CC) flow, and the extent of the foveal avascular zone (FAZ). RESULTS: From the total of 1253 articles obtained from the databases, the pool of papers was narrowed down to studies published until March 20th, 2024. Lastly, 42 studies were taken into consideration which contained the data regarding the alterations of OCTA parameters including choriocapillary vascular flow, vascular and perfusion densities of retinal microvasculature, SRL, and DRL, changes in macular all grid sessions, changes of foveal, perifoveal and parafoveal densities, macular whole image vessel density (m-wiVD) and FAZ, in addition to alterations of ONH and RPC whole image vessel densities (onh-wiVD and rpc-wiVD) among TAO patients. The correlation of these parameters with visual field-associated parameters, such as Best-corrected visual acuity (BCVA), Visual field mean defect (VF-MD), axial length (AL), P100 amplitude, and latency, was also evaluated among TAO patients. CONCLUSION: The application of OCTA has proven helpful in distinguishing active and inactive TAO patients, as well as differentiation of patients with or without DON, indicating the potential promising role of some OCTA measures for early detection of TAO with high sensitivity and specificity in addition to preventing the irreversible outcomes of TAO. OCTA assessments have also been applied to evaluate the effectiveness of TAO treatment approaches, including systemic corticosteroid therapy and surgical decompression.

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Angiografía con Fluoresceína , Oftalmopatía de Graves , Vasos Retinianos , Tomografía de Coherencia Óptica , Humanos , Oftalmopatía de Graves/fisiopatología , Oftalmopatía de Graves/diagnóstico por imagen , Oftalmopatía de Graves/diagnóstico , Tomografía de Coherencia Óptica/métodos , Angiografía con Fluoresceína/métodos , Vasos Retinianos/diagnóstico por imagen , Vasos Retinianos/fisiopatología , Coroides/irrigación sanguínea , Coroides/diagnóstico por imagen , Disco Óptico/irrigación sanguínea , Disco Óptico/diagnóstico por imagen , Mácula Lútea/diagnóstico por imagen , Mácula Lútea/irrigación sanguínea , Fondo de Ojo , Flujo Sanguíneo Regional/fisiología , Agudeza Visual/fisiología

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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.

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Diplopía , Oftalmopatía de Graves , Femenino , Humanos , Masculino , Persona de Mediana Edad , Diplopía/etiología , Diplopía/epidemiología , Oftalmopatía de Graves/complicaciones , Oftalmopatía de Graves/epidemiología , Oftalmopatía de Graves/diagnóstico , Oftalmopatía de Graves/terapia , Pronóstico , Factores de Riesgo

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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.

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Fibroblastos , Oftalmopatía de Graves , Órbita , Proteínas Tirosina Quinasas , Humanos , Oftalmopatía de Graves/tratamiento farmacológico , Oftalmopatía de Graves/metabolismo , Oftalmopatía de Graves/patología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Femenino , Masculino , Órbita/patología , Órbita/efectos de los fármacos , Persona de Mediana Edad , Células Cultivadas , Adulto , Inhibidores de Proteínas Quinasas/farmacología , Interleucina-1beta/metabolismo , Fosforilación/efectos de los fármacos

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BACKGROUND: Following its Food and Drug Administration approval in January 2020, we examined the impact of teprotumumab on thyroid eye disease (TED) clinical practices. METHODS: Across 3 referral centers from January 1, 2018, to December 30, 2022, we retrospectively analyzed demographics, clinical features, treatment choices, and insurance status of patients with active, moderate to severe TED. RESULTS: Of 74 patients recommended for medical therapy, 53% received collaborative recommendations from endocrinologists and ophthalmologists in a TED clinic. Prior to teprotumumab availability, 19 patients were recommended medical therapy, and all received medical therapy (100%), which consists of corticosteroids (14, 73.7%) or tocilizumab (5, 26.3%). After teprotumumab became available, out of 55 patients that were recommended medical therapy, only 41 (74.6%) received medical therapy, mostly teprotumumab (33, 60%), followed by corticosteroids (5, 9.1%) or tocilizumab (3, 5.4%), while 14 (25.4%) did not receive medical therapy. Discordance between physicians' recommendations and therapy received or lack thereof was explained by patients' refusal (9, 64.3%), mostly due to side effect concerns (8, 88.9%), and insurance denial (5, 35.7%). Teprotumumab use was mostly associated with otic changes (10, 30.3%), weight loss (9, 27.3%), and hyperglycemia (6, 18.2%), but 2 (6.1%) patients developed serious infections. Corticosteroids were associated with insomnia (4, 21.1%), and 1 patient in the tocilizumab group had an infusion reaction requiring hospitalization. CONCLUSION: Teprotumumab introduction increased TED therapy evaluations, yet not all received recommended treatment due to safety concerns or accessibility issues. Enhancing collaborative care, medication accessibility, and adverse effect management is crucial.

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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.

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Autofagia , Estrés del Retículo Endoplásmico , Endorribonucleasas , Fibroblastos , Oftalmopatía de Graves , Proteínas Serina-Treonina Quinasas , Humanos , Autofagia/fisiología , Oftalmopatía de Graves/metabolismo , Oftalmopatía de Graves/patología , Oftalmopatía de Graves/genética , Fibroblastos/metabolismo , Endorribonucleasas/metabolismo , Endorribonucleasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Estrés del Retículo Endoplásmico/genética , Factor de Crecimiento Transformador beta/metabolismo , Fibrosis , Masculino , ARN Interferente Pequeño/genética , Macrólidos/farmacología , Macrólidos/uso terapéutico , Femenino , Células Cultivadas , Adulto , Persona de Mediana Edad

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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.

RESUMEN

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.

Asunto(s)

Exosomas , Fibroblastos , Fibrosis , Oftalmopatía de Graves , Inflamación , MicroARNs , Órbita , Humanos , Exosomas/metabolismo , Oftalmopatía de Graves/patología , Oftalmopatía de Graves/sangre , Oftalmopatía de Graves/genética , MicroARNs/genética , MicroARNs/metabolismo , MicroARNs/sangre , Fibroblastos/metabolismo , Fibroblastos/patología , Órbita/patología , Inflamación/patología , Femenino , Masculino , Proliferación Celular , Persona de Mediana Edad , Adulto , Ácido Hialurónico/sangre , Ácido Hialurónico/metabolismo , Citocinas/metabolismo , Antígenos Thy-1/metabolismo

RESUMEN

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.

Asunto(s)

Oftalmopatía de Graves , Humanos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Inmunoglobulinas Estimulantes de la Tiroides , Oftalmopatía de Graves/tratamiento farmacológico , Estudios Retrospectivos , Receptores de Tirotropina , Tirotropina

RESUMEN

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.

RESUMEN

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?

RESUMEN

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.