Management of Graves Thyroidal and Extrathyroidal Disease: An Update

Abstract

Context: Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO).

Evidence acquisition: Guidelines, pertinent original articles, systemic reviews, and meta-analyses.

Evidence synthesis: Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistently high TSH-R-Abs and/or persistent hyperthyroidism at 18 months, or with a relapse after completing a course of MMI, can opt for a definitive therapy with radioactive iodine (RAI) or total thyroidectomy (TX). Continued long-term, low-dose MMI administration is a valuable and safe alternative. Patient choice, both at initial presentation of GD and at recurrence, should be emphasized. Propylthiouracil is preferred to MMI during the first trimester of pregnancy. TX is best performed by a high-volume thyroid surgeon. RAI should be avoided in GD patients with active GO, especially in smokers. Recently, a promising therapy with an anti-insulin-like growth factor-1 monoclonal antibody for patients with active/severe GO was approved by the Food and Drug Administration. COVID-19 infection is a risk factor for poorly controlled hyperthyroidism, which contributes to the infection-related mortality risk. If GO is not severe, systemic steroid treatment should be postponed during COVID-19 while local treatment and preventive measures are offered.

Conclusions: A clear trend towards serological diagnosis and medical treatment of GD has emerged.

Keywords: Graves disease; TSH receptor antibodies; antithyroid drugs; diagnosis; management; radioactive iodine; thyroidectomy; treatment.

Figure 1.

Algorithm for the management of Graves hyperthyroidism. TSH-R-Ab, thyrotropin receptor antibodies; FT4, free thyroxine; T3, triiodothyronine; scan, thyroid scintigraphy; MMI, Methimazole; RAI, radioactive iodine; TX, total thyroidectomy; GO, Graves orbitopathy; mo., months.

Figure 2.

(A) Sites of action of novel treatments for Graves hyperthyroidism. Four (I-IV) mechanisms of action are represented. (I) K1-70 is a human anti-TSH-R blocking mAb. (II) Iscalimab is an anti-CD40 mAb blocking CD40-CD40 ligand (CD154) costimulatory pathway. (III) ATX-GD-59 is an “apitope” restoring immune tolerance to the TSH-R. (IV) Rituximab is an anti-CD20 Mab that inhibits B-cells and reduces autoantibody production. (B) Sites of action of novel treatments for Graves orbitopathy. Seven (I-VII) mechanisms of action are represented. (I) Mycophenolate has a dual antiproliferative effect on B and T cells. (II) Anticytokine therapies inhibit inflammatory molecules, for example, proinflammatory cytokines, chemoattractants, adhesion molecules, growth factors, etc., and include an anti-IL-6R mAb, tocilizumab, as well as anti-TNFα Ab. (III and IV) B cell targeting therapies include rituximab, an anti-CD20 mAb causing B cell depletion, and an anti-BAFF mAb (belimumab) preventing BAFF from interacting with its receptors. (V) Teprotumumab, an anti-IGF-1R mAb blocking the activation of orbital target cells (fibroblasts) with subsequent excess release of hydrophilic acidic mucopolysaccharides (GAG) and signaling of IGF-1R has been recently cleared by the FDA. (VI) K1-70 is an anti-TSH-R mAb blocking TSH-R activation by stimulatory TSH-R-Ab. (VII) Small molecules bind to the transmembrane domain of the TSH-R blocking its activation. mAb, monoclonal antibody; BAFF, B cell activating factor; CD40L, CD40 ligand; IGF-1R, insulin-like growth factor-1 receptor; IL-6R, interleukin-6 receptor; TNFα, tumor necrosis factor-α; TSH-R, thyrotropin receptor; TSH-R-Ab, thyrotropin receptor antibody; MHC class II, major histocompatibility class II molecule.