Relationship between longitudinal behaviour of some markers of eye autoimmunity and changes in ocular findings in patients with Graves' ophthalmopathy receiving corticosteroid therapy.
De Bellis Annamaria,Bizzarro Antonio,Conte Marisa,Coronella Concetta,Solimeno Stefano,Perrino Silvia,Sansone Daniela,Guaglione Mariangela,Wall Jack R,Bellastella Antonio
Clinical endocrinology
OBJECTIVE:To investigate whether variations over time of TSH-receptor antibodies (TRAb) and antibodies against G2s (G2sAb) and extraocular muscles (EMAb) can predict worsening of ophthalmopathy in Graves' patients treated with intravenous glucocorticoid (IVGC) therapy. PATIENTS:Of 65 consecutive patients with treated Graves' disease and severe and active ophthalmopathy (GO) chosen to undergo IVGC treatment, only 57 patients, persistently euthyroid under methimazole therapy, were studied longitudinally for ocular parameters, TRAb, G2sAb and EMAb before therapy, at the end of therapy and, subsequently, every month for 21 months. MEASUREMENTS:TRAb was detected by radioimmunoassay (RIA), G2sAb by enzyme-linked immunosorbent assay (ELISA) and EMAb by indirect immunofluorescence. RESULTS:Forty-three out of 57 patients (75.4%, group 1) responded positively to therapy [improvement in diplopia and decrease in proptosis and clinical activity score (CAS)] but 14 (24.6%) did not (group 2). During follow-up after IVGC therapy, 12 out of 43 patients in group 1 (28%) showed a worsening in GO (group 1a), while 31 (72%) had stable ocular conditions or further improvement (group 1b). At the start of the study, TRAb, G2sAb and EMAb were not significantly different among the three groups. At the end of IVGC therapy TRAb levels decreased significantly with respect to starting values in all three groups of patients, whereas G2sAb and EMAb decreased significantly in groups 1a and 1b but not in group 2. During the subsequent follow-up, 10 patients in group 1a one/two months before and all 12 patients at the time of GO worsening showed an increase in G2sAb and EMAb but not in TRAb, which were consistently absent or present at low titre in all patients in this group. In group 1b TRAb, G2sAb and EMAb further decreased or became negative during the follow-up period. In all patients, TRAb were positively correlated with both CAS and proptosis only at the start of the study; by contrast, a significant correlation between both G2sAb and EMAb and diplopia was observed in groups 1a and 1b at all the times during the study, except one/two months before the worsening of GO in group 1a. CONCLUSIONS:Our results indicate that TRAb, G2sAb and EMAb can be considered sensitive markers of Graves' ophthalmopathy during the initial stages of ophthalmopathy, but that only G2sAb and EMAb seem to be good predictive markers of the outcome in patients after corticosteroid therapy. Thus, taking into account the cost/benefit ratio, a longitudinal evaluation of either EMAb or G2sAb could be useful in monitoring the intravenous glucocorticoid therapy in patients with severe and active ophthalmopathy to predict a possible worsening of Graves' ophthalmopathy.
Safety of non-standard regimen of systemic steroid therapy in patients with Graves' orbitopathy: a single-centre experience.
Pharmacological reports : PR
BACKGROUND:Graves' orbitopathy (GO) is an autoimmune disorder of the orbit and retro-ocular tissues and the primary extrathyroidal manifestation of Graves' disease. In moderate-to-severe and active GO iv glucocorticoids (GCs) are recommended as first-line treatment. The aim was to assess the safety profile of methylprednisolone administered intravenously for three consecutive days at 1 g in patients with active, moderate-to-severe or sight-threatening Graves' orbitopathy. METHODS:We retrospectively evaluated 161 medical records of patients with GO treated with high-dose systemic GCs in the Department of Endocrinology, Metabolic Disorders, and Internal Medicine in Poznań between 2014 and 2021. Clinical data included age, gender, laboratory results, activity and severity of GO, smoking status, disease duration, and presented side effects. RESULTS:The presence of mild side effects was observed during 114 (71%) hospitalizations. The most common complications were hyperglycemia (n = 95) and elevated aminotransferases (n = 31). Increased levels of aminotransferases were more likely observed in smokers and GO duration above 12 months. Based on the multivariate logistic regression, higher TRAb and CAS values were significantly associated with lower odds of hyperglycemia. In turn, the increased odds of elevated aminotransferases were significantly correlated with higher initial ALT levels, female gender, and GO duration above 12 months. In addition, the multidimensional correspondence analysis (MPA) showed that GO patients who declared smoking and had not L-ornithine L-aspartate applied demonstrated a higher probability of elevated aminotransferases. CONCLUSIONS:Active GO treatment with high-dose systemic GCs is not associated with serious side effects. Hyperglycemia is the most common steroid-induced complication.
10.1007/s43440-023-00567-0
Clinical efficacy of combined rituximab treatment in a woman with severe Graves' ophthalmopathy.
Liu Xiaomei,Guo Hui,Liu Juan,Shi Bingyin
Experimental and therapeutic medicine
The present study reports the case of a female Chinese patient with Graves' disease (GD) and severe Graves' ophthalmopathy (GO) in its active phase, who was treated with propylthiouracil and oral prednisolone for 2 months at a local hospital. However, a lack of improvement in symptoms meant that the patient was transferred to the First Affiliated Hospital of Xi'an Jiaotong University (Xi'an, China), whereupon the patient received high-dose intravenous methylprednisolone pulse therapy, although with limited efficacy. Subsequently, rituximab (RTX; anti-CD20 monoclonal antibody) combined with orbital irradiation treatment was initiated. The patient responded positively to the combined treatment; the clinical symptoms and enlargement of the extraocular muscles were ameliorated, and there were marked decreases in the clinical activity and NOSPECS grading scores. Furthermore, the serum levels of anti-thyrotropin receptor antibodies (TRAb) were markedly decreased at 2 months following RTX therapy. The patient was maintained in a euthyroid state by treatment with methimazole during and following RTX therapy. It was concluded that RTX treatment may attenuate severe GO by depleting lymphocytes, and may promote the recovery of GD by reducing the serum levels of TRAb.
10.3892/etm.2016.3367
Tocilizumab in glucocorticoid-resistant graves orbitopathy. A case series report of a mexican population.
Ceballos-Macías José Juan,Rivera-Moscoso Raúl,Flores-Real Jorge Alberto,Vargas-Sánchez Joel,Ortega-Gutiérrez Guillermo,Madriz-Prado Ramón,Velasco-Ramos Pablo de la Cruz,Muñoz-Monroy Omar Eloy,Meneses-Pérez Anna Carolina,Fernández-Morales Irma Nancy,Hernández-Moreno Alfredo
Annales d'endocrinologie
PURPOSE:To describe pre- to post-treatment changes in clinical activity score (CAS) and exophthalmometry in patients with Graves orbitopathy treated with tocilizumab (TCZ). MATERIAL AND METHODS:Eight Mexican patients presenting with active Graves orbitopathy (CAS>3/7) previously treated with glucocorticoids received 1 monthly dose of TCZ for 6 months. CAS, EUGOGO severity assessment and exophthalmometry were used to evaluate clinical status, with serum measurement of thyroid-stimulating hormone receptor antibodies (TR-Ab) for biochemical evaluation before and after application of TCZ. RESULTS:Eight patients were analyzed: 6 male (75%), 2 female (25%): mean age, 45.9±11.2 years; mean weight, 85±18.3 kg. Mean TR-Ab level at treatment outset was 291.9±96.4%, mean CAS 4.1±0.3 and mean exophthalmometry 21.2±3.2 mm. After TCZ treatment, mean TR-Ab level fell to 172.7±54% (P=0.001), mean CAS to 1.1±0.6 (P=0.001) and mean exophthalmometry to 19.3±2 mm (P=0.02). CONCLUSIONS:TCZ is a therapeutic option for glucocorticoid-resistant orbitopathy, and should be considered in second line due to the cost of treatment or in first line in patients with contraindications to intravenous GC pulse therapy.
10.1016/j.ando.2020.01.003
Clinical utility of TSH receptor antibody levels in Graves' orbitopathy: a comparison of two TSH receptor antibody immunoassays.
Bluszcz Gabriela A,Bednarczuk Tomasz,Bartoszewicz Zbigniew,Kondracka Agnieszka,Walczak Klaudia,Żurecka Zuzanna,Demkow Urszula,Miśkiewicz Piotr
Central-European journal of immunology
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.
10.5114/ceji.2018.80224
Prevention of Orbitopathy by Oral or Intravenous Steroid Prophylaxis in Short Duration Graves' Disease Patients Undergoing Radioiodine Ablation: A Prospective Randomized Control Trial Study.
Vannucchi Guia,Covelli Danila,Campi Irene,Currò Nicola,Dazzi Davide,Rodari Marcello,Pepe Giovanna,Chiti Arturo,Guastella Claudio,Lazzaroni Elisa,Salvi Mario
Thyroid : official journal of the American Thyroid Association
Radioiodine (RAI) is a known risk factor for activation or occurrence of Graves' orbitopathy (GO). Several studies demonstrated that GO can be prevented by glucocorticoids (GCs) in patients with pre-existing GO. We have previously shown that Graves' disease duration (GDd) <5 years is a risk factor for RAI-induced GO. We studied the effect of prophylaxis with either oral GCs (OGCs) or intravenous GCs (IVGCs) on GO activation in patients with GDd. In total, 99 hyperthyroid patients without GO or with pre-existing inactive GO with GDd <5 years were randomized to receive IVGCs ( = 49) or OGCs ( = 50) before RAI; 22 patients with GDd >5 did not receive steroids and were studied as controls. All patients underwent ophthalmological assessment before and 45, 90, 180 days and for a 5-year follow-up after RAI. Serum thyrotropin (TSH) receptor antibodies (TRAbs), thyroid hormones, and thyroid volume (TV) were also measured in response to RAI therapy and steroid prophylaxis. No patient on prophylaxis developed GO after RAI. One woman of the control group, without steroid prophylaxis, and who had a marked elevation of her TSH, showed transient reactivation of GO, which spontaneously improved after restoring euthyroidism. On follow-up at 12 and 20 months after RAI, two patients developed overt optic neuropathy. A smaller TV was associated with a higher prevalence of RAI-induced hypothyroidism. Serum TRAbs increased significantly after RAI ( < 0.0001) but less in patients receiving steroids than in those without prophylaxis at 45 days ( < 0.01). The risk of RAI-induced GO can be prevented in all patients with GDd <5 years by steroids. Such treatment may not be necessary in patients with GDd >5 years. The blunting of TRAb elevation after RAI may be related to the prophylactic effect of steroids.
10.1089/thy.2019.0150
Effects of glucocorticoid pulse therapy on thyroid function and thyroid antibodies in children with graves' disease.
Hu Yanyan,Man Yulin,Sun Xuemei,Xue Yongzhen
Italian journal of pediatrics
BACKGROUND:Glucocorticoid treatment is used in children with Graves' disease (GD) only in cases of exophthalmos. The purpose of this study was to observe the effects of glucocorticoid pulse therapy on thyroid function and thyroid antibodies in children with GD. METHODS:Twenty children who were treated by intravenous methylprednisolone pulse therapy (MPT) followed by oral prednisolone administration and antithyroid drugs were included in the pulse group. Twenty children who were treated with antithyroid drugs alone were included in the control group. Serum concentrations of free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), and thyrotropin receptor antibodies (TRAb) were recorded at baseline and 10 days, 30 days, and 60 days after treatment. RESULTS:Significant differences in FT3, FT4, TSH, TPOAb, TGAb, and TRAb levels were found in the pulse group and the control group from baseline to follow-up time points (all p < 0.05). On the 30th day, the TRAb level in the pulse group was significantly lower than that in the control group (p = 0.023). However, the level of TRAb rose on the 60th day. For values of TRAb at baseline, 10 days, and 60 days after treatment, there were no significant differences respectively between the pulse group and the control group (all p > 0.05). No significant differences were observed in FT3, FT4, TSH, TPOAb, and TGAb levels between the pulse group and the control group (all p > 0.05). CONCLUSIONS:The results suggested that the effect of intravenous MPT followed by oral prednisolone on TRAb level was temporary in children with GD. Glucocorticoid pulse therapy was not beneficial for the sustained recovery of thyroid function.
10.1186/s13052-021-00999-5
The efficacy and safety of intravenous tocilizumab to treat Graves' ophthalmopathy: A systematic review and single-arm meta-analysis.
The Journal of clinical endocrinology and metabolism
PURPOSE:This study aims to evaluate the efficacy and safety of intravenous tocilizumab (TCZ) in the treatment of Graves' ophthalmopathy (GO). METHODS:A comprehensive search was conducted across the Web of Science, PubMed, Embase, Cochrane Library, World Health Organization International Clinical Trials Registry Platform, and https://ClinicalTrials.gov databases from inception to April 2024. Randomized controlled trials (RCTs) and cohort studies that utilized intravenous TCZ for treating GO were included. RESULTS:Twelve studies encompassing 219 patients with active, steroid-resistant GO were analyzed. The meta-analysis demonstrated significant improvements in Clinical Activity Score (CAS) response (effect size [ES] = 0.98, 95% confidence interval [CI]: 0.93-1.00), proptosis response (ES = 0.50, 95% CI: 0.27-0.73), and diplopia response (ES = 0.48, 95% CI: 0.24-0.74). The ES for adverse events was 0.27 (95% CI: 0.22-0.33), with only three severe cases necessitating treatment discontinuation, and a low reactivation rate (ES = 0.01, 95% CI: 0.00-0.04). TCZ treatment led to a mean CAS reduction of 4.60 points (95% CI: 3.88-5.32) across 10 studies, a mean proptosis reduction of 2.04 mm (95% CI: 1.42-2.65) across 7 studies, and a mean decrease in thyroid-stimulating hormone receptor antibodies (TRAb) levels of 10.62 IU (95% CI: 4.67-10.62) across 5 studies. CONCLUSIONS:This meta-analysis provides robust evidence supporting the efficacy and safety of intravenous TCZ in patients with GO who are resistant to glucocorticoid therapy. The results highlight TCZ's comparable efficacy to glucocorticoids and suggest that TCZ could significantly expand clinical management options for GO. In the future, more high-quality, large-scale RCTs are still needed to confirm these findings.
10.1210/clinem/dgae711
T Cell Subsets are Associated with Clinical Activity and Efficacy of 4.5g Intravenous Glucocorticoid for Moderate-To-Severe Thyroid-Associated Ophthalmopathy.
Endocrine research
BACKGROUND:Intravenous glucocorticoid (IVGC) remains the main treatment for moderate-to-severe and active thyroid-associated ophthalmopathy (TAO). However, a substantial number (20-30%) of active moderate-to-severe TAO patients may not respond to IVGC. Some patients may have disease progression despite IVGC treatment or relapse after steroid withdrawal. OBJECTIVES:To analyze risk factors for clinical activity and predictive factors for clinical outcomes of 4.5 g IVGC therapy in patients with moderate-to-severe TAO. DESIGN AND METHODS:Our study was performed in two steps: step 1 involved 110 moderate-to-severe TAO patients and analyzed risk factors for TAO activity; step 2 involved 53 active moderate-to-severe TAO patients from step 1 who were treated with 4.5 g IVGC therapy and analyzed predictive factors for clinical outcomes of IVGC therapy. Multivariate logistic regression analysis was used to identify the independent predictors and establish the predictive model. RESULTS:Abnormal TRAb (OR = 4.717; = 0.019) and the percentage of CD3+CD4+ T cell (OR = 1.092; = 0.028) were independently associated with the activity of moderate-to-severe TAO patients. The pretreatment CAS-max in both eyes (OR = 7.221; = 0.013) and the percentage of pretreatment CD3+T cell (OR = 0.718; = 0.037) were independently associated with therapeutic efficacy. The pretreatment CAS-max in both eyes (OR = 156.53; = 0.028) and the percentage of post-treatment CD3+T cell (OR = 0.554; = 0.043) were independently associated with therapeutic efficacy. Besides, multivariable prediction models were established, which were better in the forecasting aspect than single-variable prediction models. CONCLUSIONS:Based on the findings of this study, we should monitor the peripheral blood T cell subsets for TAO, which could be helpful to timely judge the condition of clinical manifestation and effect of treatment for TAO patients. Multivariable prediction models have been established, which have great significance for clinical work.
10.1080/07435800.2023.2219734
Short and long-term effects of high-dose intravenous methylprednisolone pulse therapy on thyroid-associated ophthalmopathy.
Liu Xiaomei,Wang Shu,Qin Li,Qiang Wei,Dahal Mahesh,Fan Ping,Gao Shan,Shi Bingyin
Experimental and therapeutic medicine
The majority of previous studies on high-dose intravenous methylprednisolone pulse (IVMP) therapy have observed the clinical conditions of patients prior to and following treatment without any long-term follow-up, and these studies have predominantly focused on combined treatment. The present prospective clinical study aimed to assess the long-term effects and safety of high-dose IVMP therapy in thyroid-associated ophthalmopathy (TAO), as well as the significance of thyrotropin receptor antibody (TRAb) and soluble intercellular adhesion molecule-l (sICAM-1) during IVMP therapy. A total of 58 patients with TAO were treated with high-dose IVMP therapy, and their clinical characteristics and indices were recorded before, during and after therapy, with a 12-57 month (mean, 28.4 months) follow-up. Before treatment and on the second day after each IVMP therapy, serum TRAb and sICAM-1 levels were evaluated in 23 patients with TAO via a competitive radioimmunoassay and enzyme-linked immunosorbent assay, respectively. The results of the present study demonstrated that the symptoms of eyelid swelling, ophthalmodynia, photophobia, lacrimation and diplopia, and visual acuity, ocular motility, proptosis and clinical activity score (CAS) indices were all significantly improved after IVMP therapy. In addition, analysis of covariance demonstrated that alterations in the levels of serum TRAb during the course of treatment were associated with CAS of TAO, whereas the change in serum sICAM-1 was not. In conclusion, high-dose IVMP therapy is an effective, safe, stable and well-tolerated treatment for TAO, which is associated with rare, minor adverse effects. Furthermore, serum TRAb levels are correlated with the CAS of TAO and may serve as a predictor of the response to methylprednisolone therapy.
10.3892/etm.2016.3446
Prognostic significance of thyroid-stimulating hormone receptor antibodies in moderate-to-severe graves' orbitopathy.
Frontiers in endocrinology
Design:Retrospective study. Purpose:The purpose of this retrospective study was to assess the changes in thyroid-stimulating hormone receptor (TSH-R) antibody levels following treatment in patients with moderate-to-severe and active Graves' orbitopathy (GO) and to investigate the correlation between these antibodies and treatment response. Methods:The subjects of this study comprised of patients newly diagnosed with moderate-to-severe and active GO within the age range of 19 to 79 years. All participants underwent intravenous methylprednisolone (IVMP) therapy for a duration of 12 weeks. Patients with a clinical activity score (CAS) decrease to or less than 3 and no symptom recurrence for at least 3months after the last dose of IVMP were classified as "Group 1". Those with a CAS equal to or greater than 4 were classified as "Group 2". TSH-R antibody levels were measured prior to and following IVMP treatment and treatment response was evaluated after the completion of IVMP therapy. All patients were monitored for a minimum of 6 months post-treatment, with ocular examinations and laboratory tests at the initial visit being included in the analysis. Results:The medical records of the 96 patients with GO were retrospectively reviewed. Seventy-five patients (78.1%) were response and 21 (21.9%) were non-responsive to IVMP treatment. A higher TSH-R antibody (TRAb) and thyroid-stimulating antibody (TSAb) following treatment were associated with a high risk of no treatment response ( = 0.017; = 0.047, respectively). TRAb and TSAb levels before treatment were significantly related to TRAb and TSAb levels after treatment ( < 0.001, respectively). The cut-off values for the prediction of poor treatment response of the TRAb and TSAb before and after treatment were 8.305 IU/L, 5.035 IU/L and 449.5%, 361%, respectively ( = 0.027, =0.001 and = 0.136, = 0.004, respectively). Conclusion:It was observed that elevated levels of TRAb and TSAb prior to IVMP treatment were positively correlated with post-treatment levels of these antibodies. Furthermore, in cases of non-response to IVMP therapy, a diminished decline in both antibodies was observed, and elevated levels of TRAb and TSAb post-treatment were found to be a significant predictor of poor treatment outcome. Measurement of TRAb and TSAb throughout the course of treatment in moderate-to-severe and active cases of GO may offer valuable insights into treatment prognosis and aid in the decision-making process regarding the potential need for increased IVMP dosage or alternative therapeutic strategies.
10.3389/fendo.2023.1153312