A Randomized Clinical Trial to Evaluate the Effects of Atorvastatin on Graves' Orbitopathy (GO): the STAGO-2 Study

Overview

Graves' orbitopathy (GO) is the most common extra-thyroidal manifestation of Graves' disease (GD). Based on its clinical signs and symptoms, GO is graded as mild, moderate-to-severe, or severe, and active or inactive, the latter feature being established on a 5/7-scale score named Clinical Activity Score (CAS). The European Group on Graves Orbitopathy (EUGOGO) has recently formulated and published up-to-date guidelines for the management of GO, according to which high dose intravenous (iv) glucocorticoids (GC) (ivGC) is the first line treatment for moderate-to-severe and active GO. A protective effect of atorvastatin on the development of GO in patients with GD has been reported, based on which we recently conducted a phase II, randomized, open label clinical trial and found that atorvastatin improves the response of GO to ivGCs in hypercholesterolemic patients. The effect was unrelated to cholesterol levels, suggesting that it may be the consequence of a direct action of atorvastatin. To investigate this issue further and to introduce atorvastatin in the clinical practice, we designed the present Phase III, double-blinded, multicenter, randomized, adaptive, superiority, no profit, clinical trial to evaluate the effects of atorvastatin on Graves' Orbitopathy (GO) in patients with moderate-to-severe and active GO subjected to intravenous glucocorticoid therapy, regardless of cholesterol levels.

Graves' orbitopathy (GO) is the most common extra-thyroidal manifestation of Graves' disease (GD). GO profoundly impairs the quality of life of affected patients. The pathogenesis is autoimmune, reflecting cross-reactivity against antigens shared by thyroid epithelial cells and orbital fibroblasts. Once the autoimmune reaction is initiated, a series of molecular mechanisms involving T and B cells, antibodies, cytokines, and oxidative stress, lead to fibroblast proliferation and release of glycosaminoglycans, resulting in the clinical manifestations of the disease, namely exophthalmos (or proptosis), soft tissue inflammation, diplopia, and in the most severe cases sight reduction or loss, due to corneal damage or to compression of the optic nerves, the so called optic neuropathy. Based on its clinical signs and symptoms, GO is graded as mild, moderate-to-severe, or severe, and active or inactive, the latter feature being established on a 5/7-scale score named Clinical Activity Score (CAS). The European Group on Graves Orbitopathy (EUGOGO), a scientific Society involving several European Centers, including some of the Centers participating in the present study, has formulated and published up-to-date guidelines for the management of GO, which is referred to across the present study protocol. According to EUGOGO guidelines, high dose intravenous (iv) glucocorticoids (GC) (ivGC) is the first line treatment for moderate-to-severe and active GO. The use of systemic glucocorticoids takes advantage from their immunosuppressive and anti-inflammatory actions, resulting in an overall beneficial effect ranging from \~35 to \~60% of patients in various studies. Recent studies have provided evidence for the best balance in terms of effectiveness/risks for a total methylprednisolone dose of 4.5 g, given in 12 weekly administrations, six of 500 and six of 250 mg, which is therefore recommended. Besides genetic and demographical variables, risk factors associated with the development of GO in GD patients are known to be inadequate control of hyperthyroidism, radioiodine treatment, and smoking. In a large retrospective study conducted in more than 8,000 individuals with GD, it was reported that treatment with 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, better known as statins, especially atorvastatin, is associated with a \~40% reduced risk of developing GO in GD patients. The findings were interpreted as the consequence of the anti-inflammatory action of statins, being GO an autoimmune, inflammatory condition. Statins influence autophagic events and it has been shown that they induce cell death of human fibroblasts through a complex mechanism involving co-regulation of apoptosis, autophagy, and unfolded protein response (UPR). Thus, statins may reduce GO risk by modulating both apoptosis and autophagy activities. The molecular mechanisms that determine autophagy, apoptosis, and their interaction are not fully established, but the impact of statins on these two processes and their interplay in different cell types may provide a novel explanation for their pleiotropic effects in GO. Shih et al. found a positive correlation between macrophage count in the Muller's muscle and severity of upper lid retraction and concluded that the degree of inflammatory cell infiltration of Muller's muscle is associated with clinical severity of upper eyelid retraction in GO. Because some statins potently affect macrophage viability in vitro through the induction of apoptotic process, it is plausible that the early autophagic flux induced by statin treatment may be a potential mechanism to induce apoptosis of Muller's muscle infiltrating macrophages in patients with GO, thus eliciting a beneficial effect. In addition to a possible direct action of statins on the eye, the possibility exists that the action of statins in GO may additionally reflect lowering of cholesterol. Thus, in a recent cross-sectional study a direct correlation between total and LDL-cholesterol levels and the presence and activity of GO in unselected patients with a GD of recent onset was observed, suggesting a direct link between cholesterol and GO. In addition, LDL-cholesterol was found to be a predictor of response to treatment. The mechanisms responsible for the relation between the presence of GO and cholesterol may be related to the altered inflammatory state of hypercholesterolemia. Thus, it is well known that disorders of lipid metabolism are associated with a state of mild-to-moderate, systemic, chronic inflammation. The increase load of free fatty acids on the liver, present in hyperlipemic states, causes dysfunction of the mitochondria and endoplasmic reticulum of hepatocytes, leading to the release of reactive oxygen radical species. In addition, free fatty acid can indirectly cause the release of pro-inflammatory cytokines, namely interleukin-6 and tumor necrosis factor-α, both involved in the pathogenetic mechanisms of GO. Based on these findings, the investigators recently conducted a phase II, randomized, open label, external ophthalmological investigator-blinded, pilot, clinical trial, to determine whether administration of statins increases the efficacy of ivGC in patients with moderate-to-severe, active GO. Atorvastatin improved the response of GO to ivGCs in hypercholesterolemic patients. The effect was unrelated to cholesterol levels, suggesting that it may be the consequence of a direct action of atorvastatin. To investigate this issue further and to introduce atorvastatin in the clinical practice, the present Phase III, double-blinded, multicenter, randomized, adaptive, superiority, no profit, clinical trial was designed to evaluate the effects of atorvastatin on Graves' Orbitopathy (GO) in patients with moderate-to-severe and active GO subjected to intravenous glucocorticoid therapy, regardless of cholesterol levels.