Effectiveness of Different Treatment Modalities in Initial and Chronic Phases of Thyroid Eye Disease: A Systematic Review With Meta-analysis.

BACKGROUND: Thyroid eye disease (TED), a common extrathyroidal manifestation of Graves disease, poses significant management challenges due to potential disfigurement, visual impairment, and decreased quality of life. Uncertainties remain about the optimal treatment approach, especially regarding TED duration and its impact on outcomes. OBJECTIVE: This meta-analysis evaluates the effects of various treatments on inflammatory markers and severity endpoints in TED, stratified by disease duration, distinguishing between treatments initiated within the first 6 months (initial phase) and those initiated thereafter (subacute/chronic phase). METHODS: Following PRISMA guidelines, a systematic search of multiple electronic databases yielded 26 studies meeting predefined inclusion criteria. Methodological quality was assessed, and data were meticulously extracted and analyzed. RESULTS: In the initial phase, treatments like corticosteroids and teprotumumab showed significant improvements in clinical activity score, proptosis, and diplopia. In the subacute/chronic phase, the efficacy of methylprednisolone and teprotumumab is reduced. A "critical window" effect was observed, with treatments showing diminished efficacy after 6 months of TED duration. CONCLUSION: This meta-analysis highlights the importance of tailoring treatment strategies based on TED duration, emphasizing early interventions to maximize benefits. The findings guide clinicians in selecting optimal treatments and underscore the need for further research to refine evidence-based approaches, ultimately enhancing patient outcomes and quality of life.

Monoclonal Antibodies for the Treatment of Graves Orbitopathy: Precision Medicine?

PURPOSE: To summarize the development, nomenclature, and rationale of the reported use of monoclonal antibodies (Mabs) in Graves Orbitopathy (GO) and to undertake a systematic review of the management of GO with Mabs. METHODS: The Pubmed and Embase databases and the Federal Brazilian searching site (Periódicos-CAPES) were screened. The authors searched all the keywords "monoclonal antibodies," "adalimumab," "belimumab," "infliximab," "rituximab," "teprotumumab," and "tocilizumab" combined with the terms "Graves Orbitopathy," "Graves eye disease" and "thyroid eye disease." All the articles published in English, French, and Spanish from 2000 to May 2022 were screened. Only publications with quantitative data on the activity of orbitopathy, proptosis, or both were included. RESULTS: Seventy-six articles of the 954 screened records met the inclusion criteria. Seven Mabs were described for treating GO. The three most reported Mabs were Rituximab, Tocilizumab, and Teprotumumab. Only eight randomized clinical trials compared the effect of these three Mabs and Belimumab with the effect of steroids or placebos. Adalimumab, Infliximab, and K1-70 only appeared in a few case series and case reports. Frequent mild-to-moderate and few major side effects occurred with the three most used Mabs. Relapse rates ranged from 7.4% for Tocilizumab to at least 29.4% for Teprotumumab. No randomized clinical trials compared Mabs head-to-head. CONCLUSION: Considering the lack of head-to-head comparisons between Mabs, the relapse rate, the possibility of severe collateral effects, and the cost of Mabs, it is not clear which Mab is the safest and most useful to treat GO.

Trends in Graves' orbitopathy research in the past two decades: a bibliometric analysis.

PURPOSE: This study was conducted to identify trends in Graves' orbitopathy research in the past two decades and to elaborate on hot topics in the field. METHODS: The Web of Science database was used to extract articles on Graves' orbitopathy or its synonyms. Full data and references were exported to VOSviewer software to be analyzed. Visualization maps and charts were constructed accordingly. RESULTS: We retrieved 1067 articles on Graves' orbitopathy from the Web of Science database. The United States ranked first in terms of the article count (25), followed by Italy (141) and the People's Republic of China (120). Wiersinga's and the University of Amsterdam's articles received the highest citation count (1509 and 3052, respectively). The University of Pisa and Thyroid published the highest number of articles (65 and 93, respectively). Co-authorship analysis showed four clusters of country collaborations: red cluster, European countries; green cluster, the United States, Brazil, Canada, South Korea, and Taiwan; a yellow cluster, People's Republic of China; and blue cluster, Japan, Australia, and Poland. Keyword analysis revealed five clusters of topics: pathogenesis, management, association, quality of life, and surgery. Analysis of co-cited references also revealed five clusters: pathogenesis, management, risk factors, clinical assessment, and surgical management. CONCLUSION: Research on Graves' orbitopathy has grown during the past two decades. Hot research topics are pathogenesis, management, risk factors, quality of life, and complications. Research trends have changed in the past two decades. Increasing interest in exploring Graves' orbitopathy mechanisms and associations is evident. European countries are cooperating in this field of research. The United States has established more extensive international cooperation than other countries. We believe that more international collaboration involving developing countries is required.

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

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

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

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

Outcomes in Relapsed Graves' Disease Patients Following Radioiodine or Prolonged Low Dose of Methimazole Treatment.

BACKGROUND: Low doses of antithyroid drugs (ATD) for extended periods may be an alternative for Graves' disease (GD) patients who relapse after a course of ATD. METHODS: Patients with GD relapse (n = 238) after discontinuation of ATD therapy for 12-24 months were retrospectively analyzed in a nonrandomized study. Radioiodine (RAI) treatment and L-thyroxine replacement was used in 114 patients, and a low dose of methimazole (MMI; 2.5-7 mg/daily) was used in 124 patients. Thyroid dysfunction, Graves' ophthalmopathy (GO) evolution, quality of life (QoL), and body weight were evaluated during the follow-up. RESULTS: The mean follow-up was 80.8 ± 35.3 months for the RAI group, and 71.3 ± 40.3 months for the low-dose MMI group. No notable side effects were observed in either group. Thyroid dysfunction was predominant in the RAI group (p < 0.001), and euthyroidism was more common in the MMI group (p < 0.001). GO deterioration was mainly evaluated by clinical activity score (CAS)--it was higher in the RAI group (p < 0.0005) over all periods of follow-up. Multivariate logistic analysis showed that RAI treatment was associated with no improvement in CAS during follow-up (24 months: OR = 3.51 [CI 1.02-12.03], p < 0.05; 36 months: OR = 8.46 [CI 1.47-48.58], p < 0.05; 48 months: OR = 19.52 [CI 1.70-223.10], p < 0.05; 60 months: OR = 21.1 [CI 1.5-298], p < 0.05). Kaplan-Meier survival analysis confirmed this finding (p < 0.0003). Assessment of QoL using the Short Form Health Survey's 36 parameters in stable euthyroid patients (at least six months) was similar in both groups. The RAI group patients gained more weight (p < 0.005), particularly after 24 months of follow-up. CONCLUSIONS: The use of low doses of MMI is efficient and safe, and offers better outcomes for GO than RAI treatment. Prolonged low doses of MMI may be an alternative choice for relapsed GD patients, particularly for GO patients or for patients who refuse a definitive treatment.

Resultados del tratamiento de la orbitopatía tiroidea y factores que influyen sobre la respuesta terapéutica / Results of the treatment of thyroid orbinopathy and factors affecting the therapeutic response

Objetivo: evaluar los resultados del tratamiento de la orbitopatía tiroidea y determinar cuáles son los factores que influyen sobre ellos. Métodos: se realizó un estudio observacional en una cohorte de 82 pacientes con orbitopatía tiroidea, durante el período 1997-2009. Resultados: en los casos con orbitopatía tiroidea activa, la corticoterapia se inició a los 19 meses de evolución y no fue satisfactoria en la mayoría de ellos, por lo que para preservar la visión se realizaron varias intervenciones quirúrgicas. Los factores que influyeron sobre la respuesta terapéutica fueron el tabaquismo y la actividad de la orbitopatía tiroidea (OR= 30,479 y OR= 14,557, respectivamente). Se obtuvieron buenos resultados con el uso de la toxina botulínica A y con la cirugía en la corrección del estrabismo y la retracción. Conclusiones: el diagnóstico y el tratamiento precoz es la conducta terapéutica ideal para los pacientes con orbitopatía tiroidea. El tabaquismo y la actividad de la orbitopatía tiroideainterfirieren en la respuesta terapéutica. La toxina botulínica A y la cirugía son efectivas en la corrección del estrabismo y la retracción palpebral de la orbitopatía tiroidea(AU)

Objective: to evaluate the results of the treatment of thyroid orbinopathy and to determine the factors affecting them. Methods: observational study of a cohort of 82 patients with thyroid orbinopathy during the 1997-2009 period. Results: corticosteroid-bases therapy began nineteen months after the onset of disease and was unsatisfactory in most of cases with active thyroid orbitopathy, so it was necessary to perform several surgeries to preserve the vision. The influential factors on the therapeutic response were smoking and thyroid orbinopathy activity (OR= 30,479 and OR= 14,557, respectively). Good results were attained with botilinum toxin A and strabismus correction surgery and retraction. Conclusions: early diagnosis and treatment is the best therapy for patients with thyroid orbinopathy. Smoking and thyroid orbinopathy negatively affect the therapeutic response. Botulinum toxin A and surgery are effective options in the strabismus correction and palpebral retractions of thyroid orbinopathy(AU)

Graves upper eyelid retraction.

Graves upper eyelid retraction (GUER) is the most common and characteristic sign of Graves orbitopathy. Despite being well recognized since the 19th century, GUER is still a subject of controversy. We review GUER, including historical aspects, diagnosis, methods of measurements, ocular surface abnormalities, etiology, and medical and surgical treatments. There is no consensus about the mechanisms of its etiology or the best surgical correction. There is a need for quantitative studies on the effects of GUER on lid movements.

Color Doppler imaging of the superior ophthalmic vein in patients with Graves' orbitopathy before and after treatment of congestive disease.

OBJECTIVE: To compare superior ophthalmic vein blood flow parameters measured with color Doppler imaging in patients with congestive Graves' orbitopathy before and after treatment and in normal controls. METHODS: Twenty-two orbits from 12 patients with Graves' orbitopathy in the congestive stage and 32 orbits from 16 normal controls underwent color Doppler imaging studies. Color Doppler imaging was repeated after treatment in the group of patients with Graves' orbitopathy, which included orbital decompression in 16 orbits and corticosteroids in six orbits. The findings for each group were compared. RESULTS: In the group of orbits with congestive disease, superior ophthalmic vein flow was detected in 17 orbits (anteroposteriorally in 13 and in the opposite direction in four) and was undetectable in five. After treatment, superior ophthalmic vein flow was detected and anteroposterior in 21 and undetected in one orbit. In normals, superior ophthalmic vein flow was detected anteroposterior in 29 orbits and undetectable in three orbits, indicating a significant difference between groups. There was also a significant difference between controls and congestive Graves' orbits and between congestive orbits before and after treatment, but not between controls and patients after treatment. A comparison of superior ophthalmic vein flow parameters revealed a significant difference between the groups. The superior ophthalmic vein flow was significantly reduced in the congestive stage compared with the flow parameters following treatment and in the untreated controls. CONCLUSIONS: Superior ophthalmic vein flow was significantly reduced in the orbits affected with congestive Graves' orbitopathy and returned to normal following treatment. Congestion appears to be a contributing pathogenic factor in the active inflammatory stage of Graves' orbitopathy.

Color Doppler imaging of the superior ophthalmic vein in patients with Graves' orbitopathy before and after treatment of congestive disease

OBJECTIVE: To compare superior ophthalmic vein blood flow parameters measured with color Doppler imaging in patients with congestive Graves' orbitopathy before and after treatment and in normal controls. METHODS: Twenty-two orbits from 12 patients with Graves' orbitopathy in the congestive stage and 32 orbits from 16 normal controls underwent color Doppler imaging studies. Color Doppler imaging was repeated after treatment in the group of patients with Graves' orbitopathy, which included orbital decompression in 16 orbits and corticosteroids in six orbits. The findings for each group were compared. RESULTS: In the group of orbits with congestive disease, superior ophthalmic vein flow was detected in 17 orbits (anteroposteriorally in 13 and in the opposite direction in four) and was undetectable in five. After treatment, superior ophthalmic vein flow was detected and anteroposterior in 21 and undetected in one orbit. In normals, superior ophthalmic vein flow was detected anteroposterior in 29 orbits and undetectable in three orbits, indicating a significant difference between groups. There was also a significant difference between controls and congestive Graves' orbits and between congestive orbits before and after treatment, but not between controls and patients after treatment. A comparison of superior ophthalmic vein flow parameters revealed a significant difference between the groups. The superior ophthalmic vein flow was significantly reduced in the congestive stage compared with the flow parameters following treatment and in the untreated controls. CONCLUSIONS: Superior ophthalmic vein flow was significantly reduced in the orbits affected with congestive Graves' orbitopathy and returned to normal following treatment. Congestion appears to be a contributing pathogenic factor in the active inflammatory stage of Graves' orbitopathy.

Patogenia y tratamiento médico de la orbitopatía de graves / Pathogenesis and medical treatment of graves' orbitopathy

La Orbitopatía de Graves se presenta clínicamente en aproximadamente 50 por ciento de los casos de Enfermedad de Graves. La mayoría de las veces es leve y sólo en menos del 5 por ciento pone en riesgo la visión, pese a lo cual deteriora significativamente la calidad de vida de los pacientes. Hasta el momento no se conoce totalmente la patogenia, siendo posiblemente el receptor de TSH el blanco de la autoinmunidad. En cuanto al tratamiento, las medidas preventivas como lograr el eutiroidismo y la suspensión del tabaco son útiles en los distintos grados de la enfermedad. Para los casos más severos se han investigado diferentes medicamentos pero ninguno ha demostrado ser superior a los Glucocorticoides. Actualmente los consensos concuerdan en que es imprescindible clasificar al paciente según grado de actividad y severidad para orientar la terapia con mayor eficacia. Las investigaciones en curso pretenden encontrar una droga que supere el rendimiento existente

Graves' orbitopathy occurs clinically in approximately 50 percent of Graves' Disease. Most often it is mild and only less than 5 percent can threaten vision, despite which it significantly impairs the quality of life of this patients. So far its pathogenesis is not completely understood, but possibly TSH receptor is the target of autoimmunity. In relation to treatment, preventive measures such as achieving euthyroidism and the suspension of tobacco are useful in varying degrees of the disease. For more severe cases, different drugs have been investigated but none has shown superior efficacy to that of Glucocorticoids. Currently, different consensus agrees that it is essential to classify the patient according to levels of activity and severity to guide therapy more effectively. Ongoing investigations aim to find a drug that exceeds the existing performance

Management of Graves' orbitopathy in Latin America: an international questionnaire study compared with Europe.

CONTEXT: Management of Graves' orbitopathy (GO) and dysthyroid optic neuropathy (DON) continues to be challenging. Other surveys have been successful in elucidating trends in GO management. Knowledge of current practice by members of the Latin American Thyroid Society (LATS) who manage patients with GO was targeted by distribution of a questionnaire. We compared our results with a previously reported European Thyroid Association (ETA) survey. OBJECTIVES: To determine how endocrinologists in Latin America access and treat patients with GO and compare the results with the same European survey. RESULTS: One hundred and two responders representing endocrinologists from 10 countries participated in the survey. Most (57%) participate in a multidisciplinary setting for GO management. Access to a surgeon for orbital decompression was available only 'within months' according to 48.3% of responders. Despite suspected DON, 32.4% were reluctant to recommend urgent referral to an eyecare physician. Steroids were preferred as the first-option therapy by 88.2% of responders (by intravenous route by 57.8% of these). The presence of diabetes reduced the use of steroids to 64.7% (P < 0.001) and increased the use of other immunosuppressive agents (from 1% to 9.8%, P < 0.01). Development of cushingoid features resulted in a reduction in steroid use to 40.2% (P < 0.001), with increased preference for irradiation (from 23.5% to 52.9%, P < 0.001) and nonsteroidal immunosuppressive drugs (from 1% to 10.8%, P < 0.01), along with a nonsignificant trend to higher indication of orbital surgery (from 24.5% to 34.3%). CONCLUSION: Some potential deficiencies in the diagnosis and management of DON and hyperthyroidism were observed in our survey, highlighting the need for improvement in specialist education and the quality of care offered to patients with GO in Latin America.