Graves disease: latest understanding of pathogenesis and treatment options

Graves disease is the most common cause of hyperthyroidism in iodine-sufficient areas. The main responsible mechanism is related to autoantibodies that bind and activate the thyrotropin receptor (TSHR). Although Graves hyperthyroidism is relatively common, no causal treatment options are available. Established treatment modalities are antithyroid drugs, which reduce thyroid hormone synthesis, radioactive iodine and surgery. However, emerging drugs that target the main autoantigen (monoclonal antibodies, small molecules, peptides) or block the immune pathway have been recently tested in clinical trials. Graves disease can involve the thyroid exclusively or it can be associated with extrathyroidal manifestations, among which Graves orbitopathy is the most common. The presence of Graves orbitopathy can change the management of the disease. An established treatment for moderate-to-severe Graves orbitopathy is intravenous glucocorticoids. However, recent advances in understanding the pathogenesis of Graves orbitopathy have allowed the development of new target-based therapies by blocking pro-inflammatory cytokine receptors, lymphocytic infiltration or the insulin-like growth factor 1 receptor (IGF1R), with several clinical trials providing promising results. This article reviews the new discoveries in the pathogenesis of Graves hyperthyroidism and Graves orbitopathy that offer several important tools in disease management. Graves disease, an autoimmune disease characterized by an enlarged and overactive thyroid gland, is the most common cause of hyperthyroidism in iodine-sufficient areas. In this Review, the authors describe the epidemiology, pathogenesis, and conventional treatment of Graves hyperthyroidism and Graves orbitopathy and discuss advances that have enabled development of novel treatment modalities. Graves disease is an autoimmune condition that can involve the thyroid exclusively or can be associated with extrathyroidal manifestations, of which Graves orbitopathy is the most common.The main mechanism responsible for Graves hyperthyroidism is the activation of the thyroid-stimulating hormone receptor (TSHR) by autoantibodies that act as agonists, causing thyrocyte proliferation and hyperfunction.None of the conventional treatments for Graves hyperthyroidism act on its pathogenesis; new molecules that target early recognition of TSHR peptides, T cell activation, B cell stimulation and survival, production of TSHR autoantibodies, and TSHR activation have been tested with encouraging results.Graves orbitopathy is characterized by immune-mediated inflammatory reactions against autoantigens shared by thyroid epithelial cells and orbital fibroblasts; intravenous glucocorticoids are, to date, the first-line treatments for Graves orbitopathy.New target-based therapies that block pro-inflammatory cytokine receptors, lymphocytic infiltration or the insulin-like growth factor 1 receptor (IGF1R) have been tested in several clinical trials and show promising results in Graves orbitopathy.