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BackgroundGraves' hyperthyroidism and its associated Graves' orbitopathy are common autoimmune disorders associated with significant adverse health impact. Current standard treatments have limitations regarding efficacy and safety, and most do not specifically target the pathogenic mechanisms. We aim to review the latest development of targeted immunotherapies in these two closely related disorders.SummaryTargeted immunotherapies of Graves' hyperthyroidism have recently demonstrated clinical efficacy in early phase clinical studies. They include rituximab, an anti-CD20 monoclonal antibody which causes rapid B cell depletion; ATX-GD-59, an antigen specific immunotherapy which restores immune tolerance to thyrotropin receptor; iscalimab, an anti-CD40 monoclonal antibody which blocks the CD40-CD154 co-stimulatory pathway in B-T cell interaction; and K1-70, a thyrotropin receptor blocking monoclonal antibody. Furthermore, there have been major therapeutic advances in the management of Graves' orbitopathy. Mycophenolate has a dual mechanism of action both inhibiting the proliferation of activated B & T cells as well as the mammalian target of rapamycin growth intracellular pathway. Rituximab appears to be effective in active disease of recent onset without impending dysthyroid optic neuropathy. Both tocilizumab (anti-interleukin 6 receptor monoclonal antibody) and sirolimus (mammalian target of rapamycin inhibitor) showed promise in glucocorticoid resistant active disease. Teprotumumab, an anti-insulin-like growth factor-1 receptor monoclonal antibody, demonstrated remarkable all-round efficacy across a wide disease spectrum. Linsitinib, a dual small molecule inhibitor of insulin-like growth factor-1 receptor and insulin receptor, displayed significant proptosis reduction in its phase 2b/3 study. Finally, Batoclimab, an anti-neonatal fragment crystallizable receptor monoclonal antibody, which blocks recycling of pathogenic thyrotropin receptor antibody, showed promising signals for significant proptosis reduction, disease inactivation, overall response, and improvement of quality of life.ConclusionTherapeutic advances will continue to optimize our management of Graves' hyperthyroidism and its associated orbitopathy in an effective and safe manner.

Current therapies for Graves' disease (GD) primarily aim to manage hyperthyroidism through synthetic antithyroid drugs, radioiodine, or surgery. However, these approaches are often limited by their incomplete efficacy and the risk of inducing hypothyroidism. The latest advances in understanding the autoimmune mechanisms driving GD have paved the way for novel therapies targeting the thyrotropin receptor (TSH-R) or immune pathways. Overall, key targets include cluster of differentiation 20 (CD20), cluster of differentiation 40 (CD40), protein tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T lymphocyte antigen-4 (CTLA-4), B cell-activating factor (BAFF), and the Fc receptor-like protein 3 (FcRL3). Recent preclinical studies and clinical trials testing targeted therapies have shown promising results in terms of efficacy and safety. Here, we present a narrative review of the literature on emerging therapeutic approaches for GD that are currently under investigation.

IntroductionChimeric antigen receptor (CAR) T cells have recently become an important treatment for hematological cancers by efficiently eliminating B cells. B cell depleting CAR T cells are also in clinical trials for their use in treating severe autoimmune diseases and have shown promise in patients who have exhausted other treatment options; however, they do result in immunosuppression due to B cell depletion. Specifically eliminating the disease-causing B cells while leaving the healthy B cells untouched could address this limitation.MethodsA chimeric autoantibody receptor (CAAR) has an autoantigen as the binding domain of the CAR T cell and could allow for specific targeting of autoreactive B cell populations. In Graves' Disease (GD), pathogenesis is centered around autoreactive B cells which are specific for thyroid stimulating hormone receptor (TSHR). By engineering epitopes of TSHR as the binding domain, our CAAR was able to bind to anti-TSHR antibodies and B cell receptors.ResultsThese TSHR CAAR T cells specifically eliminated anti-TSHR B cells, without exhibiting cytotoxicity against healthy B cells. We hypothesized that soluble autoantibodies and thyroid stimulating hormone (TSH) could bind to the CAAR, potentially causing overactivation or inhibition. When evaluated, we found that one construct was significantly impacted by soluble autoantibodies, while the other construct was uninhibited. Soluble TSH did not significantly affect either construct. The TSHR CAAR T cells were also effective at eliminating anti-TSHR B cells in the presence of plasma from various GD patients.DiscussionThus, TSHR CAAR T cells show promise in eliminating the disease-causing autoreactive B cells in GD without eliminating healthy cells. This treatment mechanism also has the potential to be used in other B cell-mediated autoimmune diseases.

PurposeWe examined the effect of selenium vs placebo on remission rate and quality of life (QoL) in the Graves' selenium supplementation (GRASS) trial (ID: NCT01611896).MethodsDouble-blinded, placebo-controlled, multi-centre trial in individuals with newly diagnosed Graves' hyperthyroidism randomised to daily supplementation with 200 μg selenium or placebo tablets during 24-30 months, depending on the timing of antithyroid drug (ATD) withdrawal. The primary outcome was the proportion of participants with non-remission, defined as receiving ATD or remaining hyperthyroid (thyroid stimulating hormone ResultsBetween Dec 7th 2012 and Dec 3rd 2018, 430 participants with Graves' hyperthyroidism were recruited. Non-remission was observed in 114 (53.3%) participants in the placebo group and 118 (54.6%) in the selenium group (OR = 1.0 (95% CI: 0.7-1.5); P = 0.98). There was no beneficial effect of selenium, as compared with placebo, on any ThyPRO scale. The participants' QoL at the end of the study was comparable to that of the general population sample. Thyrotropin receptor antibody levels were similar in the groups at the 18-month and end-of-study follow-up visits.ConclusionIn individuals with newly diagnosed Graves' hyperthyroidism, daily supplementation with selenium did not have any effects compared with placebo as add-on to standard antithyroid drugs. The GRASS trial findings do not support the use of selenium supplementation in Graves' hyperthyroidism.