BACKGROUND: Thyroid eye disease (TED) is characterized by orbital inflammation 
and complicated by extraocular muscle fibrosis. Treatment with 
rapamycin/sirolimus has been reported to improve ocular motility and disease 
manifestations in TED. Whether this resulted from a primary antifibrotic effect 
on fibroblasts or was secondary to immune-suppression is unclear.
METHODS: In vitro contractility studies of primary orbital fibroblasts. Cells 
from patients with TED and controls were treated with rapamycin [mechanistic 
target of rapamycin an (mTOR) inhibitor] and MHY1485 (an mTOR stimulator) as 
well as inhibitors upstream in the same signaling cascade (saracatinib and 
befatinib).
RESULTS: At concentrations consistent with the therapeutic dosing range in 
humans, rapamycin/sirolimus significantly reduces fibrosis in orbital 
fibroblasts from TED patients and controls in vitro. This effect is separate 
from, and in addition to, its immune suppressive effect. mTOR-driven fibrotic 
activity is greater in TED-derived fibroblasts and can be blocked also upstream 
of mTOR by inhibition of src. There was no adverse effect on cell survival.
CONCLUSION: The authors present evidence for a direct antifibrotic effect of 
rapamycin/sirolimus in primary orbital fibroblasts. Targeting mTOR signaling 
presents a further and adjunctive treatment of TED alongside other 
immune-suppressive agents. By acting downstream of IGF1-R, sirolimus may offer a 
cost-effective alternative to teprotumumab therapy. Clinical case reports, now 
supplemented by this in vitro evidence, support the initiation of a clinical 
trial to treat the fibrotic sequelae of TED with this already-approved agent. 
Such an "off-the-shelf" therapy is a welcome prospect for TED treatment, 
particularly one available at a low price.