Sirolimus (rapamycin) for the targeted treatment of the fibrotic sequelae of Graves’ orbitopathy

Abstract

Background Rapamycin (alternatively known as sirolimus) is a macrolide immunosuppressant commonly used for organ transplantation. It acts both on lymphocytes through the mechanistic target of rapamycin (mTOR) pathway to reduce their sensitivity to interleukin-2 (IL-2) and, importantly, also has anti-fibrotic properties by acting on myofibroblasts. The latter have been implicated in the pathogenesis of thyroid eye disease (TED). Aim To describe successful treatment and reversal of extraocular muscle fibrosis in TED with sirolimus. Methods Case report and literature review with clinic-pathological correlation. Results A patient with Graves' orbitopathy (GO) developed significant ocular motility restriction, which was unresponsive to steroids and conventional immunosuppression. Unlike these prior treatments, rapamycin therapy improved the diplopia and fields of binocular single vision over a period of months. There were no adverse effects directly attributable to the treatment. Conclusion With its low renal toxicity and ability to specifically target the underlying fibrotic pathways in GO, rapamycin may prove a useful adjunct to standard immunosuppressive regimes. We encourage further reporting of case series or the instigation of controlled trial. * Rachna Murthy

The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy

“…The fact that they may not be widely available or affordable, as well as the lack of information, say, on the need of subsequent rehabilitative surgery, further add to their current limitations. As multiple pathogenic pathways are implicated in GO, several targeted therapies are worth exploring in clinical trials, e.g., monoclonal antibodies and/or small molecules targeting the TSHR (187,188) or the CD40 molecule expressed in both thyrocytes and orbital fibroblasts (189), or anti-IL-23/anti-IL-17 for the IL-23/IL-17 axis and sirolimus for the mTOR pathway (190). Worthwhile is also a modulating impact on the microbiome in patients with GO (191).…”

The Epithelial-to-Mesenchymal Transition as a Possible Therapeutic Target in Fibrotic Disorders

“…Recent studies have shown an improvement in patients affected by fibrotic sequelae of Graves orbitopathy, or thyroid eye disease (TED), and the reversal of extraocular muscle fibrosis if treated with sirolimus (rapamycin). This drug has been shown to exert its anti-fibrotic activity by acting on myofibroblasts, the primary ECM-secreting cells during wound healing and fibrosis ( Roos and Murthy, 2019 ). Furthermore, glaucoma filtration surgery (GFS) is the most commonly used surgical procedure for glaucoma treatment but postoperative fibrosis is still a major threat for the success of this treatment.…”

Novel Approaches for Immunosuppression in Graves’ Hyperthyroidism and Associated Orbitopathy

“…The fact that they may not be widely available or affordable further adds to their limitations. As multiple pathogenic pathways are implicated in GO, several targeted therapies are worth exploring in clinical trials (e.g., anti-IL-23 or anti-IL-17 for the IL-23/IL-17 axis; sirolimus for the mTOR pathway [45,101,102]). However, the process of developing and evaluating novel therapeutic agents is usually time-consuming and costly.…”