Novel Approaches for Immunosuppression in Graves’ Hyperthyroidism and Associated Orbitopathy

Abstract

Background: Both Graves’ hyperthyroidism (GH) and Graves’ orbitopathy (GO) are associated with significant adverse health consequences. All conventional treatment options have limitations regarding efficacy and safety. Most importantly, they do not specifically address the underlying immunological mechanisms. We aim to review the latest development of treatment approaches in these two closely related disorders. Summary: Immunotherapies of GH have recently demonstrated clinical efficacy in preliminary studies. They include ATX-GD-59, an antigen-specific immunotherapy which restores immune tolerance to the thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 costimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor-blocking monoclonal antibody. Novel treatment strategies have also become available in GO. Mycophenolate significantly increased the overall response rate combined with standard glucocorticoid (GC) treatment compared to GC monotherapy. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, displayed strong anti-inflammatory action in GC-resistant cases. Teprotumumab, an anti-insulin-like growth factor 1 receptor monoclonal antibody, resulted in remarkable improvement in terms of disease activity, proptosis, and diplopia. Further, rituximab appears to be useful in active disease of recent onset without impending dysthyroid optic neuropathy. Key Messages: Therapeutic advances will continue to optimize our management of GH and associated orbitopathy in an effective and safe manner.

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).…”

Current concepts regarding Graves’ orbitopathy

“…Active moderate-to-severe forms of GO affect a minority of patients but are a major challenge and dilemma because established medical treatments often achieve incomplete results [192,193]. GCs still constitute the mainstay in the management of active moderate-to-severe and sight-threatening GO [80], but recent advances using either old drugs with new applications or novel biological agents have expanded the armamentarium available for treatment [194,195].…”

“…GCs have been used for decades for their potent anti-inflammatory and immunosuppressive effects achieved through interference with T-and B-cell functions, decreased recruitment of monocytes and macrophages, reduced secretion of proinflammatory cytokines and increased secretion of antiinflammatory cytokines, and decreased synthesis of glycosaminoglycans [195,196]. High doses of GCs are required, and both the oral route and intravenous (iv) route can be used, while locally administered GCs are poorly effective [1].…”

Traditional Chinese medicine in thyroid-associated orbitopathy

“…Over the past two decades, important pharmacological advances in the management of TAO remarkably improved patients' outcomes and quality of life. However, the current treatment options have limitations in terms of response rates, potential toxicities, geographical availability, and affordability, therefore the search for novel treatment strategies is warranted and ongoing [5,[13][14][15][16][17]. Importantly, various active ingredients of traditional Chinese medicine (TCM) demonstrated potential therapeutic benefits in in-vitro and animal studies of TAO.…”