Fat-suppression T2 relaxation time and water fraction predict response to intravenous glucocorticoid therapy for thyroid-associated ophthalmopathy.

OBJECTIVE: To investigate the value of fat-suppression (FS) T2 relaxation time (T2RT) derived from FS T2 mapping and water fraction (WF) derived from T2 IDEAL to predict the treatment response to intravenous glucocorticoids (IVGC) in patients with thyroid-associated ophthalmopathy (TAO) based on texture analysis. MATERIALS AND METHODS: In this study, 89 patients clinically diagnosed with active and moderate-to-severe TAO were enroled (responsive group, 48 patients; unresponsive group, 41 patients). The baseline clinical characteristics and texture features were compared between the two groups. Multivariate analysis was performed to identify the independent predictors of treatment response to IVGC. ROC analysis and the DeLong test were used to assess and compare the predictive performance of different models. RESULTS: The responsive group exhibited significantly shorter disease duration and higher 90th percentile of FS T2RT and kurtosis of WF in the extraocular muscle (EOM) and 95th percentile of WF in the orbital fat (OF) than the unresponsive group. Model 2 (disease duration + WF; AUC, 0.816) and model 3 (disease duration + FS T2RT + WF; AUC, 0.823) demonstrated superior predictive efficacy compared to model 1 (disease duration + FS T2RT; AUC, 0.756), while there was no significant difference between models 2 and 3. CONCLUSIONS: The orbital tissues of responders exhibited more oedema and heterogeneity. Furthermore, OF is as valuable as EOM for assessing the therapeutic efficacy of IVGC. Finally, WF derived from T2 IDEAL processed by texture analysis can provide valuable information for predicting the treatment response to IVGC in patients with active and moderate-to-severe TAO. CLINICAL RELEVANCE STATEMENT: The texture features of FS T2RT and WF are different between responders and non-responders, which can be the predictive tool for treatment response to IVGC. KEY POINTS: Texture analysis can be used for predicting response to IVGC in TAO patients. TAO patients responsive to IVGC show more oedema and heterogeneity in the orbital tissues. WF from T2 IDEAL is a tool to predict the therapeutic response of TAO.

A single-center analysis of visual outcomes and associated factors after intravenous methylprednisolone treatment for dysthyroid optic neuropathy.

BACKGROUND: Dysthyroid optic neuropathy (DON) is a serious threatening vision loss in Graves' ophthalmopathy (GO). Although the European Group on Graves' Ophthalmopathy (EUGOGO) recommend intravenous methylprednisolone therapy for first line treatment, some characteristics predicting the response are still inconclusive. AIM: To study the efficacy of intravenous pulse methylprednisolone (IVMP) in treating dysthyroid optic neuropathy (DON) and to identify factors predicting poor response to the treatment. METHODS: All patients diagnosed with DON between January 2010 and December 2021 at Rajavithi Hospital, Thailand, receiving IVMP 1 g/ day for 3 consecutive days were analyzed. The efficacy at 1 week and 3, 6, 12-months in terms of improvement of best corrected visual acuity (BCVA) and proptosis were compiled. RESULTS: Of the entire 57 DON cases that received IVMP, 50.9% gained at least 0.2 Logarithm of the Minimum Angle of Resolution (logMAR) at 1 week, and the improvement from initial to 1-week BCVA was 0.63 ± 0.63 logMAR (p < 0.001) and the decrease in proptosis was 1.8 ± 1.36 mm (p < 0.001). The remaining 23 orbits underwent orbital decompression and were excluded from the long-term efficacy analysis. In the last 12-months' follow-up time, there was an improvement of BCVA (0.53 ± 0.47 logMAR) and proptosis (0.59 ± 0.66 mm) (both p < 0.001). At last visit, there was an improvement of BCVA (0.2 logMAR) and proptosis (2 mm) in 76.5, and 5.9% respectively. Significant predictive factors of poor treatment response were age ≥ 55 years (odds ratio [OR]: 8.28, 95% confidence interval [CI]: 1.368-50.121, p = 0.021); longer onset duration before treatment (OR: 5.10, 95%CI: 1.061-24.501, p = 0.042); and proptosis at baseline (OR: 9.31, 95%CI: 1.872-46.280, p = 0.006). The strongest risk factor for predicting poor response to IVMP was poor initial visual acuity (OR: 10.26, 95%CI: 1.363-77.234, p = 0.024). CONCLUSIONS: IVMP is effective for both short- and long-term treatment to improve visual acuity greater than proptosis. Older age, longer disease duration, poor initial visual acuity, and proptotic orbits were identified as risk factors for predicting poor response to IVMP treatment in Thai population. DON patients having those risk factors should be suspected, and treated early with IVMP to preserve their future vision.

Management of Graves ophthalmopathy - 2022 update.

Graves ophthalmopathy (GO) occurs in 25-50% cases of Graves disease. Most cases are just mild, only 5% represents eye threatening diseases. About 5-10% of cases could be euthyroid and 10% hypothyroid, respectively. All patients with GO should be assessed for activity (clinical activity score - CAS) and severity of the disease. Essential conditions of the successful treatment are well controlled thyroid dysfunction, smoking cessation and to refer patients with moderate to severe and sight threatening GO to specialized thyroid eye centers as soon as possible. Local therapy to maintain wet eye (lubricants) and supplementation of selenium deficiency is adequate in mild cases of GO. In cases of moderate to severe and sight threatening GO, administration of intravenous glucocorticoids in thyroid eye centers is first line treatment and a combination with mycophenolate or radiotherapy could be considered. When the first-line treatment fails or a contraindication/intolerance to them is present, non-steroid immunosuppressive drugs (mycophenolate, ciclosporin), rituximab, or radiotherapy could be considered. In rare cases of sight threatening GO urge surgical orbital decompression or tarsorrhaphy is warranted.

Low signal intensities of MRI T1 mapping predict refractory diplopia in Graves' ophthalmopathy.

OBJECTIVE: In Graves' ophthalmopathy (GO), fibrosis in extraocular muscles (EOMs) may be related to intravenous glucocorticoid (ivGC)-resistant diplopia. Signal intensity (SI) of magnetic resonance imaging (MRI) T1 mapping can quantify properties of EOM components, including fibrosis. We investigated EOM features of GO patients with diplopia using T1 mapping SI and the predictive value of T1 mapping SI in the response of diplopia to ivGCs. DESIGN: We performed a cross-sectional study that included 13 active GO patients, 34 inactive GO patients with history of diplopia, including 20 with a history of diplopia disappearance, 14 GO patients with refractory diplopia and 35 control subjects. In nine active GO patients, the relationship between T1 mapping SI at pretreatment and at diplopia outcome after ivGC treatment was prospectively investigated. METHODS: T1 mapping SI of left and right inferior rectus and medial rectus muscles was measured in all participants. RESULTS: T1 mapping SI in inactive GO patients with refractory diplopia was significantly lower than that of other groups in all evaluated EOMs. Diagnostic accuracy for refractory diplopia by T1 mapping SI in GO patients with a history of diplopia disappearance was excellent (AUC 0.89) compared with other assessments. Furthermore, among nine active GO patients, pretreatment T1 mapping SI in four patients with ivGC-resistant diplopia tended to be low compared with the other five patients with improved diplopia. CONCLUSIONS: Low intensity T1 mapping in EOMs is likely to be associated with refractory diplopia and may be useful in predicting the response of diplopia to ivGCs.

Clinical utility of TSH receptor antibody levels in Graves' orbitopathy: a comparison of two TSH receptor antibody immunoassays.

INTRODUCTION: Thyroid stimulating hormone (TSH) receptor antibodies (TRAB) play a role in the development of Graves' orbitopathy (GO), and measurements of the TRAB level may be helpful in monitoring GO treatment. AIM OF THE STUDY: To assess the correlation of TRAB levels measured with two different assays: third-generation TRAB assay (TRAB Cobas) and novel Immulite assay (TRAB Immulite), in patients with moderate-to-severe GO treated with intravenous glucocorticoid pulse therapy (ivGCs). MATERIAL AND METHODS: Forty patients with active, moderate-to-severe GO underwent clinical and laboratory evaluation before, in the middle, and after ivGCs therapy. The correlation of TRAB levels with GO signs was evaluated. Laboratory and clinical findings were compared according to the response to ivGCs. TRAB concentration was measured with Immulite TSI assay and with Elecsys IMA. RESULTS: All patients were TRAB positive in both assays at the beginning of the treatment. The decrease of both TRAB Immulite and Cobas levels in serum during ivGCs was statistically significant. We observed strong correlation between both TRAB levels before and after ivGCs. There was no statistically significant difference in antibody levels between patients with good response and no response to the treatment. We did not find any correlation between antibody levels and GO features before the therapy, but measurements during ivGCs showed comparable correlation of both TRAB levels with GO activity. CONCLUSIONS: We found similarity between Immulite assay and third-generation TRAB assay in the assessment of patients with GO treated with ivGCs. Both TRAB levels showed comparable correlation with GO activity during ivGCs therapy.

Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves' orbitopathy?

PURPOSE: Intravenous glucocorticoids (ivGCs) given as 12-weekly infusions are the first-line treatment for moderate-to-severe and active Graves' orbitopathy (GO), but they are not always effective. In this study, we evaluated whether response at 6 weeks correlated with outcomes at 12 (end of intervention) and 24 (follow-up) weeks, particularly in patients initially unresponsive. METHODS: Our database (Bartalena et al. J Clin Endocrinol Metab 97:4454-4463, 10), comprising 159 patients given three different cumulative doses of methylprednisolone (2.25, 4.98, 7.47 g) was analyzed, pooling data for analyses. Responses at 6 weeks were compared with those at 12 and 24 weeks using three outcomes: overall ophthalmic involvement [composite index (CI)]; quality of life (QoL); Clinical Activity Score (CAS). Responses were classified as "Improved", "Unchanged", "Deteriorated", compared to baseline. RESULTS: Deteriorated patients at 6 weeks for CI (n = 8) remained in the same category at 12 weeks and 7/8 at 24 weeks. Improved patients at 6 weeks for CI (n = 51) remained in the same category in 63% and 53% of cases at 12 and 24 weeks, respectively. Unchanged patients at 6 weeks (n = 100) eventually improved in 28% of cases (CI), 58% (CAS), 32% (QoL). There was no glucocorticoid dose-dependent difference in the influence of early response on later outcomes. CONCLUSIONS: Patients who deteriorate at 6 weeks after ivGCs are unlikely to benefit from continuing ivGCs. Patients unresponsive at 6 weeks still have a significant possibility of improvement later. Accordingly, they may continue ivGC treatment, or, alternatively, possibly stop ivGCs and be switched to a second-line treatment.

Factors predictive of poor visual outcome in indirect traumatic optic neuropathy: A retrospective cohort study.

INTRODUCTION: The gold standard treatment for indirect traumatic optic neuropathy (ITON) has not yet been conclusively established, and it is essential to gain an understanding of visual prognosis and to counsel patients regarding the predictive risk factors of poor visual outcomes. Currently, there is limited information regarding ITON in Thai populations; therefore, this study aimed to determine the risk factors of poor visual outcome in patients with this condition. METHODS: A retrospective review was conducted of all ITON cases diagnosed at Rajavithi Hospital and Sawanpracharak Hospital between January 2016 and December 2022 in order to determine clinical characteristics and evaluate associated risk factors of poor visual prognosis using binary logistic regression analysis. RESULTS: The mean age of this cohort of 101 patients was 36.17 years, with a male predominance of 73.3 %. Motor vehicle accidents were the most common cause of ITON, with a statistically significant 79.2 % of cases. The patients were categorized into an "improved group" of 29 patients and an "unimproved group" of 72. The unimproved group had a significantly older mean age and poorer initial visual acuity of 20/200 (p-values 0.001 and p < 0.001 respectively). There was no significant difference between Computed Tomography (CT) findings in the two groups. The improved group had significantly better visual acuity (VA) at 1-month and final follow-up visit than the unimproved group (both p < 0.001). Differences between gender, Glasgow coma score, associated underlying diseases, and duration from trauma to intravenous glucocorticoids therapy in the two groups were not statistically significant. Multivariable logistic regression analysis identified patient age of 40 years or more (Odds ratio (OR) 3.447, 95 % CI, 1.085-10.955, p = 0.036) and poor baseline VA (OR 6.628, 95 % Confidence Interval (CI), 2.308-19.036, p < 0.001) as significant risk factors for poor visual outcome in ITON patients. CONCLUSIONS: No clear benefit was found of intravenous glucocorticoids in treatment of ITON. Patients aged 40 years or more and/or with poor baseline visual status should be advised that they are at increased risk of poor final visual outcomes.

Predictive markers for anti-inflammatory treatment response in thyroid eye disease.

Anti-inflammatory treatment is the primary and vital therapeutic approach for active, moderate-to-severe thyroid eye disease (TED). Accurate pretreatment prediction of treatment response is of paramount importance for the prognosis of patients. However, relying solely on the clinical activity score asa determinant of activity has led to unsatisfactory treatment outcomes. In recent years, significant advancements have been made in identifying predictive markers for anti-inflammatory treatment response in TED, clinical markers, body fluid biomarkers and imaging biomarkers. Several clinical studies have developed prediction models based on these markers. However, there is still a lack of comprehensive elucidation or comparison between the different markers. Therefore, this review aims to provide a detailed analysis of the definition, characteristics, and application of predictive markers for anti-inflammatory treatment response in TED. Through detailed literature search, 26 articles applying anti-inflammatory treatment effect prediction with a total of 1948 TED patients were used for analysis and discussion. By gaining a better understanding of the current research on predictive markers, we can accelerate and guide the exploration of treatment prediction strategies, leading us towards an era of precise therapy for TED.

Glucocorticoid therapy as first-line treatment in primary hypophysitis: a systematic review and individual patient data meta-analysis.

Objectives: High-dose glucocorticoids are associated with improved recovery of deficits in primary autoimmune hypophysitis (PAH), but optimal dosing, route, and duration are unclear. Design: We reviewed literature for first-line glucocorticoid treatment in PAH until December 2021 and performed an individual patient data meta-analysis to analyze clinical, hormonal, and radiological outcomes with respect to route, dose, and duration (<6.5 vs 6.5-12 vs >12 weeks) of glucocorticoid treatment according to disease severity. Results: A total of 153 PAH patients from 83 publications were included. The median age at presentation was 41 (32.5-48) years with a female preponderance (70.3%). Visual field recovery was significantly better with i.v. (91.7%) as compared to oral (54.5%) route and high dose (100%) and very high dose (90.9%) as compared to medium dose (20%) of glucocorticoids. Corticotroph axis recovery was greater in i.v. (54.8% vs 28.1% oral, P = 0.033) route and increasing glucocorticoid dose group (0% vs 38.1% vs 57.1%), attaining statistical significance (P = 0.012) with very high-dose. A longer duration of treatment (>6.5 weeks) was associated with better corticotroph and thyrotroph recovery. The need for rescue therapy was lower with i.v. route (38% vs 17.5%, P = 0.012) and with increasing glucocorticoid doses (53.3% vs 34.3% vs 17.3%, P = 0.016). In severe disease, visual field and corticotroph axis recovery were significantly higher with i.v. route and very high-dose steroids. The adverse effects of glucocorticoids were independent of dose and duration of treatment. Conclusions: Very high-dose glucocorticoids by i.v. route and cumulative longer duration (>6.5 weeks) lead to better outcomes and could be considered as first-line treatment of severe PAH cases.

Comparative effectiveness of different treatment modalities for active, moderate-to-severe Graves' orbitopathy: a systematic review and network meta-analysis.

To compare the effects of different treatment modalities on active, moderate-to-severe Graves' orbitopathy (GO). We searched PubMed and Embase for randomized controlled trials published up to 30 Nov 2020, of different modalities for the treatment of active, moderate-to-severe GO. We performed Bayesian network meta-analyses. This study is registered with PROSPERO (CRD42020166287). Fifteen RCTs were identified. Network meta-analysis showed that in comparison with placebo, teprotumumab, mycophenolate plus intravenous glucocorticoids (IVGCs), mycophenolate, rituximab, azathioprine, IVGCs, orbital radiotherapy, oral glucocorticoids (OGCs) were effective treatments (ordered from most effective to least effective). Teprotumumab was more efficacious in reducing proptosis than IVGCs. No significant difference in changes in diplopia grade was recorded between teprotumumab, rituximab, orbital radiotherapy and IVGCs. Low (4.5-5 g), middle (6 g) and high (7-8 g) cumulative doses of IVGCs were shown to be more effective than OGC in improving the overall response rate, but the very low-group (<3 g) seemed to have a lower risk of adverse events. We found that teprotumumab offered the highest level of efficacy in terms of the overall response rate and was more efficacious in reducing proptosis than IVGCs. With regard to different dosages of IVGCs, the cumulative dose of 4.5-5 g of IVGCs seems to be the most appropriate schedule in terms of efficacy and safety outcomes. Due to the limited number of patients treated with teprotumumab and the lack of comparison with other effective therapeutics, teprotumumab might not become the standard first-line therapy for active, moderate-to-severe GO.

Decrease in Bone Formation and Bone Resorption during Intravenous Methylprednisolone Pulse Therapy in Patients with Graves' Orbitopathy.

Background: Treatment with glucocorticoids (GCs) is associated with side effects. In contrast to the well-known negative impact on bone tissue exerted by oral GCs, few data are available regarding intravenous GCs. We investigated the influence of intravenous methylprednisolone (IVMP) on bone turnover markers (BTM): amino-terminal propeptide of type I procollagen (P1NP) and the C-terminal telopeptide of type I collagen (CTX), and on calcium metabolism parameters: 1,25-dihydroxyvitamin D (1,25(OH)2D), 25-hydroxyvitamin D (25(OH)D), calcium (Ca), phosphate (P), and intact parathormone (iPTH). Methods: In a prospective study, 23 consecutive subjects with Graves' orbitopathy were included and treated with IVMP according to the European Group on Graves' Orbitopathy recommendations. We evaluated effects on BTM occurring during the first 7 days after 0.5 g IVMP, and after the therapy with 12 IVMP pulses with a cumulative dose of 4.5 g. Results: We observed prompt but transient decrease of P1NP (p < 0.001) and the reduction of CTX (p = 0.02) after the first IVMP pulse. Following the full course of IVMP therapy, both P1NP and CTX were found decreased (p < 0.05 and p < 0.01, respectively). Conclusions: A single pulse of 0.5 g IVMP already decreases bone formation and resorption; however, this change is transient. The full therapy is associated with suppression of bone turnover.

Severe Graves' disease-associated orbitopathy: A rare case of frontal bone hemangioma.

Graves' orbitopathy might be severe, requiring treatment with high-dose glucocorticoids. A lytic bone lesion, malignant lesions, and diseases resulting from bone remodeling processes (eg, Paget's disease) must be excluded by markers and imagery. Outcomes of high-dose glucocorticoids and thyrotoxicosis must be screened and prevented.