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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.
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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 terapéuticoRESUMEN
TGF-ß plays a pivotal role in the pathogenesis of GO by promoting orbital tissue remodeling and fibrosis. This process involves the stimulation of orbital fibroblasts, leading to myofibroblast differentiation, increased production of inflammatory mediators, and hyaluronan accumulation. Studies have elucidated TGF-ß's role in driving fibrosis and scarring processes through both canonical and non-canonical pathways, particularly resulting in the activation of orbital myofibroblasts and the excessive accumulation of extracellular matrix. Additionally, recent in vitro and in vivo studies have been summarized, highlighting the therapeutic potential of targeting TGF-ß signaling pathways, which may offer promising treatment interventions for GO. This review aims to consolidate the current understanding of the multifaceted role of TGF-ß in the molecular and cellular pathophysiology in Graves' ophthalmopathy (GO) by exploring its contributions to fibrosis, inflammation, and immune dysregulation. Additionally, the review investigates the therapeutic potential of inhibiting TGF-ß signaling pathways as a strategy for treating GO.
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Oftalmopatía de Graves , Transducción de Señal , Factor de Crecimiento Transformador beta , Humanos , Oftalmopatía de Graves/metabolismo , Oftalmopatía de Graves/tratamiento farmacológico , Oftalmopatía de Graves/patología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Fibrosis , Terapia Molecular DirigidaRESUMEN
Background: Thyroid eye disease (TED) is an autoimmune orbital disease, with intravenous glucocorticoid (IVGC) therapy as the first-line treatment. Due to uncertain response rates and possible side effects, various prediction models have been developed to predict IVGC therapy outcomes. Methods: A thorough search was conducted in PubMed, Embase, and Web of Science databases. Data extraction included publication details, prediction model content, and performance. Statistical analysis was performed using R software, including heterogeneity evaluation, publication bias, subgroup analysis, and sensitivity analysis. Forest plots were utilized for result visualization. Results: Of the 12 eligible studies, 47 prediction models were extracted. All included studies exhibited a low-to-moderate risk of bias. The pooled area under the receiver operating characteristic curve (AUC) and the combined sensitivity and specificity for the models were 0.81, 0.75, and 0.79, respectively. In view of heterogeneity, multiple meta-regression and subgroup analysis were conducted, which showed that marker and modeling types may be the possible causes of heterogeneity (P < 0.001). Notably, imaging metrics alone (AUC = 0.81) or clinical characteristics combined with other markers (AUC = 0.87), incorporating with multivariate regression (AUC = 0.84) or radiomics analysis (AUC = 0.91), yielded robust and reliable prediction outcomes. Conclusion: This meta-analysis comprehensively reviews the predictive models for IVGC therapy response in TED. It underscores that integrating clinical characteristics with laboratory or imaging indicators and employing advanced techniques like multivariate regression or radiomics analysis significantly enhance the efficacy of prediction. Our research findings offer valuable insights that can guide future studies on prediction models for IVGC therapy in TED.
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Glucocorticoides , Oftalmopatía de Graves , Humanos , Administración Intravenosa , Glucocorticoides/administración & dosificación , Oftalmopatía de Graves/tratamiento farmacológico , Resultado del TratamientoRESUMEN
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.
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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 RetrospectivosRESUMEN
BACKGROUND: The first line treatment for moderate to severe active thyroid associated ophthalmopathy is glucocorticoid pulse therapy, but for patients with contraindications to hormone therapy or hormone resistance, it is urgent to find a suitable treatment plan. AIMS: To find a reliable alternative to hormone pulse therapy for thyroid associated ophthalmopathy by comparing the efficacy with first-line treatment regimens. METHODS: Search PubMed, Ovid, Web of science, Cochrane library, and Clinical Trials.gov for randomized controlled trials on the treatment of thyroid associated ophthalmopathy published as of July 7, 2024. Quality evaluation and Bayesian network analysis were conducted using RevMan 5.3 software, STATA15.0 software, and ADDIS 1.16.8 software. RESULTS: A total of 666 patients were included in 11 studies and 8 interventions. Network analysis showed that the three interventions of mycophenolate mofetil combined with glucocorticoids, Teprotumumab and 99Tc-MDP were superior to glucocorticoid pulse therapy in improving clinical activity scores and proptosis. The regimen of glucocorticoids combined with statins can improve the quality of life score and diplopia score of patients. Neither methotrexate combined with glucocorticoids nor rituximab alone showed additional advantages when compared with glucocorticoid pulse therapy. CONCLUSION: Mycophenolate mofetil combined with glucocorticoid therapy is very beneficial for moderate to severe active thyroid associated ophthalmopathy. Mycophenolate mofetil may be a good choice when patients have contraindications to hormone use or hormone resistance. Teprotumumab is very promising and may be able to avoid patients undergoing orbital decompression surgery. The durability and safety of its long-term efficacy need to be further observed.
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Teorema de Bayes , Glucocorticoides , Oftalmopatía de Graves , Humanos , Oftalmopatía de Graves/tratamiento farmacológico , Oftalmopatía de Graves/diagnóstico , Glucocorticoides/uso terapéutico , Glucocorticoides/administración & dosificación , Metaanálisis en Red , Calidad de Vida , Anticuerpos Monoclonales HumanizadosRESUMEN
OBJECTIVES: To evaluate otologic adverse reactions (OARs), including hearing loss (OARs-HL) among patients taking teprotumumab, a new biologic approved for the treatment of active thyroid eye disease, using publicly available pharmacovigilance reporting data. STUDY DESIGN: Retrospective database review. METHODS: The Food and Drug Administration Adverse Events Reporting System (FAERS) was queried for cases involving teprotumumab from 2020Q1 to 2023Q1. Patient demographics and adverse reactions (OAR and OAR-HL) were evaluated. Logistic regression was used to predict OAR and OAR-HL, and disproportionality analysis was performed using OpenVigil. RESULTS: A total of 2,109 teprotumumab-AR cases were reported, of which 296 (14.05%; mean age 55.46 yr) were OARs. Of these, 149 (7.06%) reported OAR-HL and 194 (9.20%) reported other OAR (e.g., tinnitus, ear discomfort, vertigo), with 47 (2.23%) reporting both. Disproportionality analysis showed a reported odds ratio (ROR) for OARs-HL of 44.33 (95% confidence interval [CI], 37.40-52.55; p < 0.001). Age was associated with RORs of 1.02 (95% CI, 1.01-1.04) and 1.04 (95% CI, 1.02-1.07) for developing OARs and specifically OARs-HL, respectively (p < 0.01). Age 50 and 65 years and older were associated with RORs of 2.54 (95% CI, 1.16-6.38) and 3.36 (95% CI, 1.75-6.53), respectively, for OARs-HL (p < 0.05). CONCLUSION: This study using FAERS data suggests an increased risk of OARs, specifically hearing loss, associated with teprotumumab. Increasing age was a significant predictor of OARs. Audiometric counseling and evaluation should be considered with teprotumumab therapy in Graves' orbitopathy patients, especially in older patients.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Anticuerpos Monoclonales Humanizados , Pérdida Auditiva , United States Food and Drug Administration , Humanos , Persona de Mediana Edad , Estados Unidos , Masculino , Femenino , Sistemas de Registro de Reacción Adversa a Medicamentos/estadística & datos numéricos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/epidemiología , Estudios Retrospectivos , Anciano , Adulto , Oftalmopatía de Graves/tratamiento farmacológico , Farmacovigilancia , Anciano de 80 o más Años , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Evolving understanding of thyroid eye disease (TED) has led to rapidly advancing therapeutic options. Most new treatments under development or recently available to patients are predicated on insights into disease mechanism. RECENT FINDINGS: TED, a disfiguring process, involves inflammation and remodeling of the connective tissues around the eye. TED most frequently presents as a component of Graves' disease. Advances in our understanding of cells involved in TED and their molecular interactions have led to novel therapeutic targets. Among these cell types are orbital fibroblasts and a subset comprising monocyte progenitor cells, known as CD34 + CXCR4 + fibrocytes. Among the attributes of fibrocytes is their expression of several autoantigens associated with Graves' disease, including TSHR, thyroglobulin and thyroperoxidase. Fibrocytes also express high levels of the insulin-like growth factor-I (IGF-I) receptor, thought to mediate fibroblast activation. Therapeutically targeting the TSHR/IGF-IR receptor complex using an IGF-I receptor antagonist, teprotumumab, has resulted in substantial clinical benefit for patients with TED. The neural axon repellent, Slit2, and its cognate receptor, ROBO1, appear to modulate the inflammatory phenotype of these orbit-infiltrating fibrocytes. SUMMARY: More detailed understanding of orbital fibroblasts and the distinctions between cell subsets comprising them should lead to more effective therapies with fewer side effects.
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Fibroblastos , Oftalmopatía de Graves , Órbita , Receptor IGF Tipo 1 , Receptores de Tirotropina , Humanos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Fibroblastos/metabolismo , Oftalmopatía de Graves/metabolismo , Oftalmopatía de Graves/tratamiento farmacológico , Órbita/patología , Receptor IGF Tipo 1/metabolismo , Receptores de Tirotropina/metabolismoRESUMEN
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.
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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 , AncianoRESUMEN
INTRODUCTION: Drug therapy for Graves' disease (GD) is the first-line treatment in Europe. The use of a specific regimen for the administration of anti-thyroid drugs (ATDs) is still controversial. The objective was to compare block-and-replace therapy (BRT) with a titration (T) regimen in terms of incidence of overt hypothyroidism and development of Graves' orbitopathy (GO) over 18 months of treatment. MATERIAL AND METHODS: Two databases (PubMed, Cochrane Library) and reference lists were searched. Prospective and retrospective observational cohort studies were included. Data collection and analysis were performed independently by 2 authors. RESULTS: Two studies with 716 GD patients (40.36% treated with BRT, 59.64% with T regimen) were included. No statistically significant differences were observed between the ATDs regimens used in terms of incidence of overt hypothyroidism during 18 months of treatment [Mantel-Haenszel (M-H) odds ratio (OR): 1.54, 95% confidence interval (CI): 0.75-3.16, p-value = 0.24]. GD patients who followed BRT were less likely to achieve control of thyroid function than patients on T regimen (M-H OR: 0.55, 95% CI: 0.34-0.88, p = 0.01). One study reported fewer thyroid function tests (TFT) during BRT than during the T regimen. The other study included patients without GO at baseline and reported a lower incidence of GO during BRT than in the T regimen (9.1% versus 17.8%), with no statistical difference between the 2 regimens (M-H OR: 0.47, 95% CI: 0.19-1.14, p = 0.10). CONCLUSION: BRT may be more useful than the T regimen for patients with complicated GD or for those who required fewer TFTs.
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Antitiroideos , Enfermedad de Graves , Humanos , Antitiroideos/uso terapéutico , Antitiroideos/administración & dosificación , Enfermedad de Graves/tratamiento farmacológico , Femenino , Masculino , Hipotiroidismo/tratamiento farmacológico , Adulto , Persona de Mediana Edad , Oftalmopatía de Graves/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Introduction: Thyroid eye disease (TED) is an autoimmune process characterized by extraocular muscle and orbital fat remodeling/expansion resulting in swelling, pain, redness, proptosis, and diplopia. Teprotumumab, an insulin-like growth factor-I receptor inhibitor, demonstrated improvements in TED signs and symptoms in three adequately powered clinical trials of 24 weeks duration. Here we analyze the long-term maintenance of responses with teprotumumab from these trials. Methods: A total of 112 patients who received 7 or 8 infusions of teprotumumab in the Phase 2, Phase 3 (OPTIC study), and OPTIC Extension (OPTIC-X) studies were included in this analysis. Responses, including clinical activity score (CAS ≥2-point improvement), the European Group of Graves' Orbitopathy ophthalmic composite outcome, diplopia (≥1 Gorman grade improvement), proptosis (≥2 mm improvement), Overall (improvement in proptosis + CAS), and disease inactivation (CAS ≤1), were assessed and pooled from study baseline to week 24 (formal study) and up to week 72 (formal follow-up). Graves' Ophthalmopathy quality-of-life (GO-QoL) scores were also assessed. Outcomes included the percentages of observed patient responses from the study baseline. Additional alternative treatments for TED were assessed as a surrogate of persistent benefit from week 24 through week 120 (extended follow-up). Studies differed in the timing of follow-up visits, and data from some visits were unavailable. Results: At week 72, 52/57 (91.2%), 51/57 (89.5%), 35/48 (72.9%), 38/56 (67.9%), and 37/56 (66.1%) of patients were responders for CAS, composite outcome, diplopia, proptosis, and Overall response, respectively. The mean reduction in proptosis was 2.68 mm (SD 1.92, n = 56), mean GO-QoL improvement was 15.22 (SE 2.82, n = 56), and disease inactivation (CAS ≤1) was detected in 40/57 (70.2%). Over 99 weeks following teprotumumab therapy, 19/106 (17.9%) patients reported additional TED therapy during formal and extended follow-up. Conclusion: The long-term response to teprotumumab as observed 51 weeks after therapy was similar to week 24 results in the controlled clinical trials. Inflammatory and ophthalmic composite outcome improvements were seen in 90% of patients with nearly 70% reporting improvement in diplopia and proptosis. Further, 82% of patients in this analysis did not report additional TED treatment (including surgery) over 99 weeks following the final teprotumumab dose.
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Anticuerpos Monoclonales Humanizados , Oftalmopatía de Graves , Humanos , Oftalmopatía de Graves/tratamiento farmacológico , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Persona de Mediana Edad , Resultado del Tratamiento , Estudios de Seguimiento , Adulto , Anciano , Exoftalmia/tratamiento farmacológico , Diplopía/tratamiento farmacológico , Receptor IGF Tipo 1/antagonistas & inhibidoresRESUMEN
BACKGROUND: Thyroid eye disease (TED) can result in proptosis and ocular misalignment, leading to eye pain, diplopia, and vision loss. Teprotumumab, a humanized antibody against insulin-like growth factor 1 receptor, was approved in 2020 for the treatment of TED. The purpose of this study was to describe the effect of a full course of teprotumumab on ocular misalignment. METHODS: The medical records of patients who underwent treatment with teprotumumab for active moderate-to-severe TED at a single institution from April 2020 to September 2023 were reviewed retroactively. Sensorimotor examination was performed at each visit using simultaneous prism-cover testing. Demographic information and previous history of radioactive iodine, steroids, strabismus surgery, and smoking were extracted from the record for analysis. RESULTS: A total of 19 patients were treated during the study period, of whom 11 had strabismus and diplopia. The initial absolute horizontal misalignment in these 11 was 6.0Δ ± 1.5Δ, vertical misalignment was 7.7Δ ± 2.4Δ, and total misalignment was 11.5Δ ± 2.0Δ. On completion of treatment, these measurements decreased by 2.0Δ ± 1.5Δ, 2.2Δ ± 1.0Δ, and 3.2Δ ± 1.6Δ, respectively (P = 0.10, 0.02, and 0.04, resp.). Eight patients (73%) had a decrease in their strabismus, and 5 (46%) reported complete resolution of their diplopia at the final visit. No factors were predictive of which patients would have resolution of their misalignment. Of the remaining 3 patients who had no improvement in ocular alignment, 2 (66%) underwent strabismus surgery. Of the 8 patients with improvement of strabismus, only a single patient (13%) underwent strabismus surgery for persistent diplopia. CONCLUSIONS: In our study cohort, a full course of teprotumumab coincided with complete resolution of diplopia in 46% of patients and a decrease in strabismus in 73% of patients.
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Anticuerpos Monoclonales Humanizados , Diplopía , Oftalmopatía de Graves , Humanos , Oftalmopatía de Graves/tratamiento farmacológico , Masculino , Femenino , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Persona de Mediana Edad , Estudios Retrospectivos , Diplopía/fisiopatología , Anciano , Adulto , Estrabismo/cirugía , Estrabismo/tratamiento farmacológico , Estrabismo/fisiopatología , Infusiones Intravenosas , Receptor IGF Tipo 1/antagonistas & inhibidoresRESUMEN
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 fármacosRESUMEN
Purpose: This study aims to report correlations between thyroid-stimulating immunoglobulin (TSI) and both clinical and radiological parameters in recent-onset symptomatic thyroid eye disease (TED) patients. Methods: A prospective cohort study of TED patients managed at the Chinese University of Hong Kong from January 2014 to May 2022. Serum TSI levels were determined with the functional assay. Outcomes included the Clinical Activity Score (CAS), marginal reflex distance1 (MRD1), extraocular muscle motility restriction (EOMy), exophthalmos, and diplopia. The radiological assessment included cross-sectional areas and signal of extraocular muscles on STIR-sequence MRI. Results: A total of 255 (197 female) treatment-naive patients, with an average onset age of 50 ± 14 years (mean ± s.d.), were included. Elevated pre-treatment TSI level was observed in 223 (88%) patients. There was a weak positive correlation between TSI and CAS (r = 0.28, P = 0.000031), MRD1 (r = 0.17, P = 0.0080), and the size of the levator palpebrae superioris/superior rectus complex (r = 0.25, P = 0.018). No significant correlation existed between TSI and STIR signals. The AUC and optimal cut-off value for clinical active TED were 0.67 (95% CI: 0.60-0.75) and 284% (specificity: 50%, sensitivity: 85%). In total, 64 patients received intravenous methylprednisolone (IVMP) during the study interval, and they had a higher baseline TSI level than those who did not have IVMP (P = 0.000044). Serial post-IVMP TSI among the 62 patients showed a significant reduction compared to the baseline level (P < 0.001). Both the baseline and post-IVMP TSI levels, and percentages of TSI changes were comparable between patients who responded and did not respond to the first course of IVMP. Conclusion: TSI can be a serum biomarker for the diagnosis, prognosis, and treatment response of TED. Further validation should be warranted.
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Oftalmopatía de Graves , Inmunoglobulinas Estimulantes de la Tiroides , Humanos , Femenino , Masculino , Oftalmopatía de Graves/sangre , Oftalmopatía de Graves/epidemiología , Oftalmopatía de Graves/tratamiento farmacológico , Persona de Mediana Edad , Estudios Prospectivos , Adulto , Inmunoglobulinas Estimulantes de la Tiroides/sangre , Anciano , Músculos Oculomotores/diagnóstico por imagen , Hong Kong/epidemiología , Imagen por Resonancia Magnética , Diplopía/epidemiología , Exoftalmia/epidemiología , Exoftalmia/sangreAsunto(s)
Anticuerpos Monoclonales , Oftalmopatía de Graves , Humanos , Administración Intravenosa , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Oftalmopatía de Graves/tratamiento farmacológico , Oftalmopatía de Graves/inmunología , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
KEY POINTS: Utilization of orbital decompressions (ODS) increased (CAGR: +3.2%) from 2000 to 2019. FDA approved teprotumumab in January 2020; ODS utilization decreased (CAGR: -14.9%) from 2019 to 2022. In 2022, total spending was substantially higher for teprotumumab ($325 million) than surgery ($580,000).
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Anticuerpos Monoclonales Humanizados , Descompresión Quirúrgica , Medicare , Humanos , Estados Unidos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Órbita/cirugía , Anciano , Masculino , Femenino , Oftalmopatía de Graves/cirugía , Oftalmopatía de Graves/tratamiento farmacológicoRESUMEN
Central retinal artery occlusion (CRAO) is a form of acute ocular ischemic syndrome that causes visual loss. Timely treatment is of great importance for visual recovery, but the prognosis is usually poor. By analyzing the pathogenesis, diagnosis, and treatment process of a CRAO case after peribulbar injection of triamcinolone acetonide in thyroid-associated ophthalmopathy (TAO), this study aims to investigate the association of CRAO with hemodynamics and orbital pressure, thereby providing references in safety improvement of diagnosis and treatment on TAO.
Asunto(s)
Oftalmopatía de Graves , Oclusión de la Arteria Retiniana , Triamcinolona Acetonida , Humanos , Triamcinolona Acetonida/administración & dosificación , Triamcinolona Acetonida/uso terapéutico , Oclusión de la Arteria Retiniana/inducido químicamente , Oftalmopatía de Graves/tratamiento farmacológico , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Persona de Mediana Edad , Masculino , Angiografía con FluoresceínaRESUMEN
PURPOSE: To assess the effectiveness of tocilizumab in reverting the signs and symptoms of dysthyroid optic neuropathy (DON) in thyroid eye disease and the need for emergency orbital decompression. The secondary outcomes are to identify the optimal number of tocilizumab cycles to achieve the primary outcome, to analyze the association between thyroid stimulating immunoglobulin (TSI), clinical activity score (CAS) and proptosis in response to the treatment and the need for rehabilitative orbital decompression. METHODS: Prospective longitudinal cohort study that included 13 patients who had unilateral or bilateral dysthyroid optic neuropathy (DON) due to severe and progressive sight-threatening thyroid eye disease based on the CAS system. Patients were seen in this facility starting from July 2017, and all had received intravenous tocilizumab. RESULTS: Initial visual acuity mean was 0.52 ± 0.38 and the final were 0.93 ± 0.11 with a mean difference of 0.41 and P < 0.00245. The mean CAS prior to the initiation of the treatment was 7.92 ± 0.66 and the final was 2.85 ± 1.03 with mean difference of 5.07 and P < 0.00001. Initial mean proptosis was 24.85 ± 2.31 and the final was 21.78 ± 2.18 with a mean difference of 3.07 and P < 0.000497. No emergency orbital decompression was performed. TSI was high initially in all cases with a wide range of 2.4 to 40 IU/L and with a mean of 10.70 ± 13.40. The final TSI mean was 2.90 ± 3.90 with a mean difference of 7.81 and significant P value (P < 0.0272). CONCLUSION: Tocilizumab use in optic nerve compression showed promising results as it can be the primary or an alternative treatment option.
Asunto(s)
Anticuerpos Monoclonales Humanizados , Oftalmopatía de Graves , Agudeza Visual , Humanos , Estudios Prospectivos , Masculino , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Oftalmopatía de Graves/complicaciones , Oftalmopatía de Graves/tratamiento farmacológico , Persona de Mediana Edad , Adulto , Enfermedades del Nervio Óptico/etiología , Enfermedades del Nervio Óptico/diagnóstico , Enfermedades del Nervio Óptico/tratamiento farmacológico , Descompresión Quirúrgica/métodos , Estudios de Seguimiento , Anciano , Resultado del Tratamiento , Síndromes de Compresión Nerviosa/etiología , Síndromes de Compresión Nerviosa/tratamiento farmacológico , Síndromes de Compresión Nerviosa/diagnósticoRESUMEN
Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves disease. There has been no effective medication to prevent proptosis in thyroid eye disease until 2020 when the anti-insulin-like growth factor 1 receptor (anti-IGF-1R) antibody, Teprotumumab, was approved by the US Food and Drug Administration, sparking increased interest in immune-based drug development. This study aims to review the newly developed drug therapy as well as conventional treatment for TED. Treatment of TED has traditionally been high-dose steroids and orbital radiotherapy, but recently there has been a paradigm shift in the treatment of TED in the United States with the introduction of the therapeutic agent teprotumumab, which dramatically reduces proptosis. However, concerns remain about the development of hearing impairment as a potentially fatal complication and long-term safety. Recently, several clinical trials are underway to assess the efficacy and safety of novel drugs targeting mammalian target of rapamycin complex 1, interleukin-6, fragment crystallizable receptor, and IGF-1R in treating TED. With the explosive increase in interest from academia and pharmaceutical companies in TED, there is anticipation for the development of drugs that are equivalent or superior to teprotumumab while being safer.