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Background: Rituximab (RTX), a chimeric human-murine anti-CD20 monoclonal antibody, has been used for treatment of active moderate-severe Graves' orbitopathy (GO) since 2004 as second line therapy in patients unresponsive to intravenous steroids. We conducted an open label, prospective study (EUDRACT 2012-001980-53) in which patients were treated with a single infusion of only 100 mg RTX to analyze the efficacy and safety of this low dose.Methods: Seventeen patients, of whom nine had disease that was unresponsive to intravenous methylprednisolone, and eight with newly diagnosed GO were enrolled.Disease activity was assessed with the clinical activity score (CAS) and severity with a composite ophthalmic score. Long term surgical treatment and quality of life were also assessed, as well as treatment-related adverse events.Results: Mean baseline CAS was 4.56±0.96 and decreased to 1.25±1.14 at 24 weeks (P=0.001). Disease inactivation occurred within 24 weeks in >90% of patients and was unrelated to disease duration. Severity improved in about 60% of patients, with no relapses. All patients showed peripheral depletion of CD20 + and CD19 + cells at the end of the RTX infusion (60 minutes). Two patients required surgical orbital decompression because of optic neuropathy (ON). Among adverse events observed, there was one patient who developed a cytokine release syndrome.Conclusions: A dose of 100 mg RTX is effective in patients with active moderate-severe GO. Low doses are better tolerated, expose patients to immune suppression for a shorter period of time and are extremely cost effective, compared to higher doses. This dose, consistently with all other immunosuppressants, does not prevent the progression of GO to dysthyroid optic neuropathy.

Graves' Orbitopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease (GD). Its ultimate cause remains unclear, but it is commonly considered an autoimmune disorder due to self recognition of autoantigens constitutively expressed by orbital fibroblasts (OFs), and thyroid epithelial cells. High dose intravenous glucocorticoids (ivGC) are the most commonly used treatment for moderately severe and active GO. However, based on the complex pathogenesis of GO, a number of factors may have a protective and maybe a therapeutic role. The use of other medications improving the effect of GC may increase the overall effectiveness of the therapy and reduce GC doses, thereby limiting side effects. Recently, a possible protective role of 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, the so-called statins, and perhaps of lowering cholesterol levels, has been proposed. Thus, statins have been reported to be associated with a reduced frequency of GO in GD patients and in recent cross-sectional and retrospective studies a significant correlation was found between the occurrence of GO and both total and LDL-cholesterol in patients with a GD of relatively recent onset, suggesting a role of cholesterol in the development of GO. Moreover, a correlation was found between the GO clinical activity score and total as well as LDL-cholesterol in untreated GO patients, depending on GO duration, indicating a role of cholesterol on GO activity. Therefore, statin treatment may be beneficial for GO. Here we review this subject, which offers new therapeutic perspectives for patients with GO.

Context: RAI is a known risk factor for activation or de novo occurrence of Graves' orbitopathy (GO). Several studies demonstrated that GO can be prevented by glucocorticoids (GC) 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. Objective: To study the effect of prophylaxis with either oral GC (OGC) or intravenous (IVGC) on GO activation in patients with GDd <5 years with and without pre-existing GO. Patients and setting: 99 hyperthyroid patients without GO or with pre-existing inactive GO with GDd <5 years were randomized to receive IVGC (N=49) or OGC (N=50) prior to RAI; 22 patients with GDd >5 did not receive steroids and were studied as controls. Main Outcome Measures: All patients underwent ophthalmological assessment before and 45, 90 180 days and for a 5 year follow-up after RAI. Serum TRAb, thyroid hormones and thyroid volume (TV) were also measured in response to RAI therapy and steroid prophylaxis. Results: 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, that 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 to a higher prevalence of RAI-induced hypothyroidism. Serum TRAb increased significantly after RAI (P<0.0001) but less in patients receiving steroids than in those without prophylaxis at 45 days (P<0.01). Conclusions: 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.

BackgroundImmunosuppressive therapy of Graves’ orbitopathy (GO) is indicated during the active phase of disease. Intravenous steroids (IVGC) are effective in about 70% of patients, although unresponsiveness or relapse are observed. In previous studies, rituximab (RTX) has been shown to be effective in inactivating moderate-to-severe GO when used early in the disease, but its optimal dosage has never been studied in randomized clinical trials. Aim of this study was to compare the efficacy and safety of different doses of RTX, based on a post-hoc analysis of two open label studies and one prospective trial randomized to IVGC.Methodsof 40 patients (35 women, 5 men), with active moderate-to-severe GO treated with RTX, 14 received a single dose of 100 mg (Group 1), 15 a single dose of 500 mg (Group 2) and 11 two 1000 mg doses, administered one week apart (Group 3). Thyroid function, TSH-receptor antibodies (TRAb) and peripheral CD19+ cells were measured. Primary endpoint was disease inactivation, measured as a decrease of the Clinical Activity Score (CAS) of at least two points. Secondary endpoints were improvement of proptosis, diplopia, quality of life and safety.ResultsBaseline CAS decreased significantly in all groups (P&lt;0.0001), independently of GO duration or whether patients had newly occurring or relapsing GO after IVGC. Proptosis did not significantly change. There was an inverse correlation between the Gorman score for diplopia and RTX dose (P&lt;0.01). The appearance score of the GO-QoL improved in Group 1 (P=0.015), and the visual function score, in Group 2 (P=0.04). A reduction of serum TRAb was observed in Group 1 (P=0.002) and Group 2 (P&lt;0.0002), but not in Group 3. CD19+ cell decreased in all groups (P&lt;0.01), independently of the dose.ConclusionsWe studied the optimal dosage of RTX in the treatment of active moderate-to-severe GO. In this analysis, we considered the efficacy of RTX in inactivating GO, in changing its natural course, its effect on disease severity and on the patients’ quality of life. Based on our clinical findings, and balancing the cost of therapy, a single 500 mg dose regimen is suggested in the majority of patients.

The coronavirus disease 2019 (COVID-19) pandemic has represented an individual and collective trauma with an impact on mental health. Restrictive measures such as lockdowns have increased risk factors for the development or triggering of various psychopathologies. Timely psychological intervention has constituted a protective factor that has been indicated as a form of prevention. The main objective of this study was to measure changes in the levels of traumatic stress and anxiety in a clinical population of adolescents and young adults aged 13 to 24 years – already assisted by the local primary and specialty care services before the pandemic – following a trauma-focused psychotherapeutic group intervention according to the eye movement desensitization and reprocessing protocol, conducted remotely before the end of the first lockdown. The Impact of Event Scale-Revised (IES-R), State-Trait Anxiety Inventory (STAI) scales, and the Emotion Thermometer were administered pre- and post-treatment. At the end of the treatment, the Post-Traumatic Growth Inventory (PTGI) questionnaire was administered. The results show that there was a significant improvement pre- and post-intervention in the scores of the scales STAI, IES-R, and Emotion Thermometer with a reduction in post-traumatic symptoms related in particular to the domains of intrusiveness and hyperarousal. The domain of avoidance was less significantly modified by therapy. This overall clinical improvement did not correlate with any of the demographic variables of the sample. In addition, the results show a significant positive global perceived change (PTGI) that did not correlate with the reduction of anxiety or post-traumatic symptoms measured by the other self-report scales. The explored use of telemedicine has revealed a valuable clinical opportunity.