Therapeutic targets for fibro-inflammation in Graves' orbitopathy

Abstract

Graves' orbitopathy (GO), a complex autoimmune disorder, remains the most common extrathyroidal manifestation of Graves' disease. Its pathogenesis is characterized by a progressive transition from inflammation to fibrosis, leading to debilitating ocular complications. While high-dose intravenous glucocorticoids have been the standard treatment for active moderate-to-severe GO, their lack of specificity to GO pathogenesis and limited efficacy in the fibrotic phase underscore the need for targeted therapies. This review explores emerging therapeutic targets in GO, focusing on pathways implicated in both inflammatory and fibrotic mechanisms. Teprotumumab, an insulin-like growth factor 1 receptor (IGF-1R) inhibitor, has revolutionized GO treatment, demonstrating clinical efficacy in reducing proptosis and inflammation. Interleukin-6 (IL-6) inhibitors including satralizumab are undergoing clinical trials. New studies on molecular pathways have been conducted regarding inflammation and fibrosis of GO, including platelet-derived growth factor/fibroblast growth factor signaling, yes-associated protein 1/transcriptional coactivator with PDZ-binding motif mechanotransduction, sphingosine-1-phosphate (S1P)/S1P receptor axis, bone morphogenic protein 7, IL-11, IL-17 and microRNAs as well as, IGF-1R/thyroid-stimulating hormone receptor crosstalk, and IL-6 trans-signaling. Most studies focus on exploring the potential of therapeutic agents through preclinical investigations but represent promising therapeutic avenues. Therapies targeting these pathways may offer a promising potential efficacy across the entire disease spectrum, from inflammation to fibrosis, thus overcome the limitations of conventional glucocorticoid therapy and expand therapeutic options in GO. Advances in in vivo GO models may bring forward a new era of GO treatment.