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.

Conflict of interest statement

Conflict of interest

All authors are doctors who manage patients with thyroid eye disease. The authors declare that they have no conflict of interest.

As an anonymised retrospective report no institutional review board authorisation was necessary.

Dr. Murthy serves as guarantor of this work. It is an honest, accurate and transparent account of the study being reported; no important aspects of the study have been omitted.

Figures

Fig. 1

Plot of field of binocular single vision (BSV) testing performed 2 weeks after starting sirolimus, on adopting an abnormal head posture (a). A small island of BSV subtending 4 quadrilaterals has appeared inferiorly indicated by the shaded area. b shows an increase in the area of BSV to 17 quadrilaterals, 8 months after starting sirolimus and performed with a reduced chin up head posture. c Fifteen months after the start of treatment, the BSV has increased to 46 quadrilaterals and the test was performed without a compensating head posture. d The effect persists even after cessation of treatment, seen here 3 years later with a BSV subtending 63 quadrilaterals