The role of monoclonal antibodies against IL-6 or IL-6R in the treatment of thyroid eye disease

Thyroid eye disease (TED) is a chronic inflammatory autoimmune disorder characterized by expansion and fibrosis of orbital tissues, leading to eyelid retraction, proptosis, periorbital edema, restricted ocular motility, corneal ulceration, and (rarely) compressive optic neuropathy. The relationship between TED pathogenesis and interleukin 6 (IL-6)-mediated signaling has created considerable interest in the therapeutic potential of monoclonal antibodies (mAbs) against interleukin 6 (IL-6) or its receptor (IL-6R). A randomized controlled trial (RCT) and several non-RCTs have reported clinical benefits from off-label use of the anti–IL-6R mAb, tocilizumab, in terms of disease activity, proptosis, thyroid-stimulating autoantibody titers (a key trigger for TED), quality of life, and possibly diplopia. Compared with recommended first-line treatment options for TED (high-dose glucocorticosteroids, and in some cases teprotumumab, a mAb against insulin-like growth factor 1 receptor), tocilizumab is associated with fewer adverse events and considerably lower risk of TED relapse following treatment discontinuation. Furthermore, most TED treatment options involve intravenous infusion, whereas tocilizumab can be administered by subcutaneous injection and thereby reduce treatment burden on patients and healthcare systems. Ongoing RCTs evaluating the efficacy and safety of long-acting anti–IL-6/IL-6R mAbs should provide evidence for additional potential reductions in treatment burden. This review aims to provide an overview of IL-6–mediated signaling in TED pathogenesis, evaluate the evidence supporting the use of anti–IL-6/IL-6R mAbs in individuals with TED, and compare the potential benefits and limitations associated with different anti–IL-6/IL-6R mAbs.