Sirolimus for the treatment of Graves' orbitopathy.

OBJECTIVES: A role of mTOR (mammalian target of rapamycin) in the pathogenesis of Graves' Orbitopathy (GO) has been proposed and rapamycin, better known as sirolimus, an mTOR inhibitor, was recently used in patients with GO. Here we review the available studies evaluating the role of mTOR in GO pathogenesis and the effects of sirolimus on GO. DESIGN: A comprehensive search of PubMed was conducted using the following keywords: "Graves' orbitopathy", or "thyroid eye disease", or "Graves' ophthalmopathy", or "thyroid-associated ophthalmopathy"; and: "mTOR", or "sirolimus", or "rapamycin". INCLUSION CRITERIA: 1) original articles (preclinical and clinical studies); 2) English language. The articles that did not adequately explore the role of mTOR in GO pathogenesis and those in which the effects of sirolimus on GO were not investigated were excluded. At the end of the screening process, nine studies were included in this systematic review. RESULTS: mTOR signaling pathway was found to be upregulated in patients with GO. In addition, studies in a mouse model of GO, in orbital fibroblasts and peripheral blood mononuclear cells (PBMCs) derived from GO patients showed a significant reduction in inflammatory mediators, adipogenesis and fibrosis after treatment with sirolimus. In 2007 and 2019 two cases of patients with GO unresponsive to glucocorticoids and successfully treated with sirolimus were described. Consistently with these results, two retrospective investigations showed that treatment with sirolimus, used at low dosage for 12 weeks, was followed by a greater overall response of GO compared with methylprednisolone at 24 weeks. In addition, a good response in diplopia and ocular motility restriction after treatment with sirolimus was reported by two case series. All of these studies reported a good tolerability of sirolimus. Finally, GO response to treatment was shown to correlate with the serum levels of sirolimus at the end of treatment. CONCLUSIONS: Sirolimus may represent a cheap, effective, and safe alternative treatment for GO. In addition, serum levels of sirolimus may be used to predict the response to treatment. Randomized clinical trials are needed to confirm the efficacy of sirolimus on GO and establish the best possible treatment protocol.