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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.

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.