Today, Graves' disease can be diagnosed with a blood test that actually measures the anti-self directed antibody which is called thyroid stimulating immunoglobulin (TSI) There are several different approaches in the management of Graves' disease.   GJ If someone has these … There is an ongoing phase 1 trial (NCT02904330) of K1-70 in treatment-naïve Graves’ patients, which is due to report in the next year.   AK   EM The anti-CD40 monoclonal antibody iscalimab (CFZ533) targets the CD40–CD154 co-stimulatory pathway, resulting in attenuation of the B-cell activation signal (57). Graves' disease is often accompanied by an increase in heart rate, which may lead to further heart complications, including loss of the normal heart rhythm (atrial fibrillation), which may lead to stroke. Pregnancy is advised to be delayed for 6 months after radioactive iodine treatment.[26]. The current therapies under investigation include biologics, small molecules, and peptide immunomodulation. The therapeutic options available for patients with Graves’ hyperthyroidism have remained largely unchanged for the past 70 years, despite the current treatments having either limited efficacy or significant drawbacks.   Y Similarly, the patients who responded had low pretreatment TRAb levels (median 4 IU/L) and less severe hyperthyroidism. Physical exam. , Stan MN, Frommer L, et al. But people with Graves’ disease experience a break in normal communication between the pituitary glad and thyroid gland, resulting in abnormal antibodies being released that mimic TSH and … CD40 is expressed on vascular endothelium and platelets, so thromboembolic complications have been highlighted as another hypothetical risk—although this was not observed in the Graves’ disease patients treated.   HB The immune system normally protects the body from germs with chemicals called antibodies. In Hashimoto's thyroiditis, activated CD4+ T-cells produce interferon-γ, causing the thyroid cells to display MHC class II molecules. Part of this hinge region may be viewed as an auto-ligand or internal agonist which is displaced in response to both TSH and TRAb binding. This review summarizes the emergence of novel targeted therapies that are paving the way for a new era in the treatment of Graves’ hyperthyroidism. [1] Smoking increases the risk of disease and may worsen eye problems. This novel treatment may have very little in the way of side effects except for swelling and bruising at the injection site. , Grove RA, Austin DJ, et al. These therapies may render destructive radioiodine thyroid ablation and thyroidectomy obsolete treatments of historical interest, although the advantages of restoring a euthyroid state without the need for ongoing therapy will need to be balanced against potential risks such as immunocompromise. (Antibodies to thyroglobulin and to the thyroid hormones T3 and T4 may also be produced.). , Concepcion E, Oashi T, Tomer Y. Chen   JF Both efgartigimod and rozanolixizumab caused a sustained reduction in circulating IgG levels of approximately 75% to 90%, both in preclinical studies of murine models of autoimmune disease (arthritis and encephalitis) (63, 68) and in healthy human subjects (64, 69). These small molecule compounds are expected to be active orally, and because of their precise targeting to the TSHR they are anticipated to be suitable for long-term administration. In rats, K1-70 was able to completely suppress the serum thyroxine rise following administration of the stimulating M22 antibody, suggesting potential efficacy in Graves’ hyperthyroidism with high serum TRAb levels (83). , Zhou J, Ober RJ, Ward ES. Occasionally, goiter is not clinically detectable, but may be seen only with computed tomography or ultrasound examination of the thyroid. The conventional therapeutic options for Graves’ disease have not improved over the past 70 years, despite substantial unmet clinical need and a significant lack of efficacy for many patients. ; Efgartigimod MG Study Group. Graves’ disease is the most common cause of an overactive thyroid gland (hyperthyroidism). Future studies need to focus on understanding the most effective combinations of the conventional medical and surgical therapies with these recently introduced options. Conventional treatments, including antithyroid medication, radioiodine, or surgery have remained largely unchanged for the past 70 years and either lack efficacy for many patients, or result in lifelong thyroid hormone replacement therapy, in the case of the latter 2 options. Other types may not stimulate the thyroid gland, but prevent TSI and TSH from binding to and stimulating the receptor. Indeed, several different murine models have confirmed that either genetic or chemical modulation of CD40 signaling can modify the severity of autoimmune thyroiditis or thyroid autoantibody production (49, 55, 56), establishing CD40 as a potential therapeutic target in the treatment of Graves’ hyperthyroidism.   S   MP TSI acts like thyroid-stimulating hormone (TSH), a hormone made …   LC ; BLISS-52 Study Group; BLISS-76 Study Group. [31] In rare cases, radiation induced thyroiditis has been linked to this treatment. Graves' disease owes its name to the Irish doctor Robert James Graves,[38] who described a case of goiter with exophthalmos in 1835. ; RAVE-ITN Research Group. This modeling suggests that all 3 of these compounds interact with TSHR at sites that are distinct from the extracellular domain site of both TSH and TRAb binding, meaning that they should be effective irrespective of circulating TRAb concentration.   ML It comprises an entirely extracellular A-subunit, and a B-subunit consisting of a small extracellular leader, 7 transmembrane domains, and an intracellular tail (5). Although the reasons remain unclear, memory B cells appear to be more resistant to depletion with RTX compared to naïve B cells, allowing them to be recruited in a secondary immune response (25). Therapy with radioiodine is the most common treatment in the United States, while antithyroid drugs and/or thyroidectomy are used more often in Europe, Japan, and most of the rest of the world. , Toes RE, Sepers J, et al.   G The 2 most widely studied compounds that target FcRn are efgartigimod and rozanolixizumab (64), both of which are currently in phase 3 studies for autoimmune disease. As well as cost implications and the potential risk of immunocompromise with the non–TSHR-specific therapies, it remains unclear whether they will ameliorate the long-term risk of hypothyroidism, reduce goiter, or indeed prevent a late relapse of Graves’ hyperthyroidism. Armengol [1] The disorder results from an antibody, called thyroid-stimulating immunoglobulin (TSI), that has a similar effect to thyroid stimulating hormone (TSH). It is the most common cause of hyperthyroidism in the United … In addition, TRAb concentrations were significantly reduced following iscalimab treatment, with 4 (27%) patients achieving normal TRAb levels by week 20, all of whom were “responders.” Those that did not respond were noted to have higher baseline TRAb levels, to have a larger goiter, and to be more likely to use cigarettes and have GO. , Guglietta A, Dreier T, et al. TSH receptor image reprinted by permission from Springer Nature: Immunologic Research. [1][3] Typically, blood tests show a raised T3 and T4, low TSH, increased radioiodine uptake in all areas of the thyroid and TSI antibodies. The carboxy-terminal part of the A-subunit participates in a flexible hinge region; TSH binding to the leucine-rich repeats of the A-subunit results in a conformational change transduced through this hinge region, leading to a pivot or toggle of the 7 transmembrane domains. ; BLISS-52 Study Group. The response in terms of thyroid-stimulating activity in the serum was dramatic; cancer progression was initially arrested, and eye disease improved markedly and in a sustained fashion. A key issue is the structural homology between the TSHR, and the follicle stimulating hormone receptor and lutenizing hormone/chorionic gonadotropin receptors, which gives rise to the potential for off-target reproductive effects. , Bussmeyer U, Khan T, et al. The clinical diagnosis of Graves disease is confirmed via assessment of. Rozanolixizumab has also undergone phase 2 trials in patients with ITP and MG, demonstrating almost a 70% mean reduction of serum IgG and IgG autoantibodies associated with clinical response (72). Bone is removed from the skull behind the eyes, and space is made for the muscles and fatty tissue to fall back into the skull. [26] Removal of the gland enables complete biopsy to be performed to have definite evidence of cancer anywhere in the thyroid. Translational and Clinical Research Institute, Newcastle University, Endocrine unit, Royal Victoria Infirmary, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Department of Paediatric Endocrinology, The Great North Children’s Hospital. Eyelid surgery involves an incision along the natural crease of the eyelid, and a scraping away of the muscle that holds the eyelid open. [1] It frequently results in and is the most common cause of hyperthyroidism. The CD40–CD154 interaction initiates a co-stimulatory pathway that provides the second signal required for the initiation of an adaptive humoral immune response (1). , Huber AK, Akeno N, et al. Furmaniak VA-K-14 and ANTAG3 most likely fit within a hydrophobic pocket that more directly stabilizes the transmembrane domains in an “off” conformation (17, 19). Pearce The radioiodine treatment acts slowly (over months to years) to destroy the thyroid gland, and Graves' disease-associated hyperthyroidism is not cured in all persons by radioiodine, but has a relapse rate that depends on the dose of radioiodine which is administered. Ban Serologically detected thyroid-stimulating antibodies, radioactive iodine (RAI) uptake, or thyroid ultrasound with Doppler all can independently confirm a diagnosis of Graves' disease. It is known that TSHRs exist as homomultimeric complexes in certain situations (7), but whether this is influenced by ligand binding, or is necessary for signaling is under active investigation. In Graves’ disease, the immune system creates an abnormal antibody called thyroid-stimulating immunoglobulin. , Gan EH, Morris M, et al.  Jr , Reier A, Coleman M, Lauer SA. Efgartigimod is a human IgG1-derived Fc fragment, while rozanolixizumab is a humanized, IgG4 anti-FcRn monoclonal antibody, both of which block FcRn-IgG interactions, thereby inhibiting IgG recycling and accelerating the removal of pathogenic IgG autoantibodies from the circulation (60, 65). Huber   N [35], If left untreated, more serious complications could result, including birth defects in pregnancy, increased risk of a miscarriage, bone mineral loss[36] and, in extreme cases, death. ; HERMES Trial Group. These compounds inhibit TSH-stimulated cAMP production in vitro and lower thyroid hormone levels in mice treated with the thyroid-stimulating monoclonal antibody M22, suggesting likely efficacy in inhibiting TRAb-induced Graves’ hyperthyroidism.   G Phase 2 studies are awaited. These indications aid in deciding which people would benefit most from surgery.   AW Jansson Belimumab is currently licensed for treatment of seropositive SLE and, although it has been found generally safe and well-tolerated with no increased risk of serious infection (78, 80), an increased risk of psychiatric events has been reported by the UK Medicines and Healthcare products Regulatory Agency in patients with SLE on belimumab. Graves’ hyperthyroidism is characterized by the presence of autoantibodies that stimulate the thyroid-stimulating hormone receptor (TSHR), resulting in uncontrolled secretion of excessive thyroid hormone. The infiltrative exophthalmos frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen which is recognized by the antibodies. This modality is suitable for most patients, although some prefer to use it mainly for older patients.   G Therefore, BAFF is a logical therapeutic target molecule for B-cell–driven autoimmune conditions such as Graves’ hyperthyroidism. A key advantage of this strategy when compared to the immunomodulatory strategies described above is their more specific, targeted approach which—from a theoretical standpoint—is unlikely to have a deleterious impact on the patient’s ability to fight infection. Neumann The vast majority of residual peripheral B cells exhibit a plasma cell or memory cell phenotype (38); however, complete intrathyroidal B cell depletion has been demonstrated following RTX therapy (40). These drugs also cross the placenta and are secreted in breast milk. A large goiter will be visible to the naked eye, but a small one (mild enlargement of the gland) may be detectable only by physical examination. Indeed, 2 patients with GO whose hyperthyroidism responded to iscalimab also had improvement of eye symptoms and signs (16). The CD20 transmembrane protein is expressed on B-lineage lymphocytes, from early pre-B to mature and memory B cells; however, CD20 expression is lost during B-cell differentiation into mature antibody-secreting plasma cells. Reportedly, a 1% incidence exists of permanent recurrent laryngeal nerve paralysis after complete thyroidectomy. Marcinkowski The higher the level of antibodies, the more likely it is that a patient has an autoimmune disease of the thyroid e.g., Hashimoto's or Graves' disease. RTX was originally reported to have efficacy in controlling rheumatoid arthritis, with subsequent studies in myasthenia gravis (MG), anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, systemic lupus erythematosus (SLE) and multiple sclerosis (26-30).   PW This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, Praegnatio Perturbatio – Impact of Endocrine Disrupting Chemicals, Mouse models of human proprotein convertase insufficiency, Making, Cloning, and the Expression of Human Insulin Genes in Bacteria: The Path to Humulin, Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation, The Journal of Clinical Endocrinology & Metabolism,, Receive exclusive offers and updates from Oxford Academic, Risk of minor (eg, rash, urticaria, arthralgia) or major side effects (eg, agranulocytosis, hepatotoxicity, vasculitis), Need to delay pregnancy and avoid breastfeeding, *Potential for restoration of euthyroidism without ongoing therapy, **Uncertain effect on long-term hypothyroidism, goiter size, and prevention of relapse, Most effective in those with low TRAb levels, Potential thromboembolic events (iscalimab), May be effective independent of TRAb concentration, Potential disease exacerbation in susceptible individuals, Given subcutaneously (bruising/swelling at injection site).   SV , Malik V, Lacey S, Brunetta P, Lehane PB. Robak Following the structural change in the transmembrane domains, Gsα signaling to increase 3′,5′-cyclic adenosine monophosphate (cAMP) and Gq signaling to activate phospholipase pathways, results in thyroid hormone synthesis and secretion (5). , anti-TPO. The described novel therapeutic approaches are not without potential limitations. Elevated circulating thyroid hormones in Graves’ hyperthyroidism arise because of stimulating TSHR autoantibodies (TRAbs), which bind to leucine-rich repeats in the extracellular domain of the TSHR located on the surface of the thyrocytes (5). Of the autoimmune conditions, it has been best studied in Sjögren’s syndrome, where an RCT demonstrated that iscalimab was well-tolerated and led to clinical improvement (58). Your immune system usually produces proteins known as antibodies … , Lombardi A, Stefan M, et al. [3] Those with other autoimmune diseases such as type 1 diabetes and rheumatoid arthritis are more likely to be affected. Alhadj Ali Howard Thus, this treatment clearly holds promise for both Graves’ hyperthyroidism and GO. In Graves' disease, this antibody is produced against the thyroid gland itself. Its ligand CD154 (CD40 ligand; CD40L) is transiently expressed on activated T cells and other nonimmune cells under inflammatory conditions.   RZ   DA [30], Contraindications to RAI are pregnancy (absolute), ophthalmopathy (relative; it can aggravate thyroid eye disease), or solitary nodules. The TSHr is expressed on the thyroid follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. [12], The bacterium Yersinia enterocolitica bears structural similarity with the human thyrotropin receptor[10] and was hypothesized to contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals. As operating on a frankly hyperthyroid patient is dangerous, prior to thyroidectomy, preoperative treatment with antithyroid drugs is given to render the patient "euthyroid" (i.e. The effects can be minimized if the hyperthyroidism is treated early. Blocking the interaction of BAFF with its receptor negatively effects B-cell proliferation, indirectly decreasing B-cell survival and reducing production of autoantibodies (76). Abbreviations: BAFF, B-cell activating factor; BAFF-R, B cell activating factor receptor; FcRn, neonatal immunoglobulin Fc receptor; IgGs, immunoglobulins; K1-70, TSHR-blocking antibody; MHC II, major histocompatibility complex class II; RVT-1401, FcRn blocker; TCR, T cell receptor; TSHR, thyroid-stimulating hormone receptor. , Aliesky HA, Chen CR, McLachlan SM. Sanders et al were able to clone a monoclonal TSHR-blocking antibody, termed K1-70 from such a patient (82). , Massad C, Oe T, Cantaert T, Herold KC, Meffre E. El Fassi Published by Oxford University Press on behalf of the Endocrine Society. Silkiss The mature TSHR is a G protein–coupled receptor found primarily on thyroid follicular cells. [1] Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. [8], The exact cause is unclear; however, it is believed to involve a combination of genetic and environmental factors. [1] Often it starts between the ages of 40 and 60. This review provides a comprehensive summary of the recent advances and various stages of development of the novel therapeutic approaches to treat Graves’ hyperthyroidism. This interaction between B and T lymphocytes is proposed to have a central role in the pathogenesis of Graves’ hyperthyroidism as it is required for intrathyroidal germinal center formation, and for maturing the B-cell repertoire to allow production of pathogenic thyroid-stimulating antibodies (1, 9, 49). , Concepcion E, Greenberg DA.   P Goiter is an enlarged thyroid gland and is of the diffuse type (i.e., spread throughout the gland). Li [2] A person is more likely to be affected if they have a family member with the disease. Bar-Or   AL Targeted blockade of the CD40–CD154 interaction shows promising results in Graves’ hyperthyroidism, at least in the short-term and in those with lower TRAb levels (<20 IU/L). Streeter Similar findings were demonstrated in a phase II trial in ITP with a reduction in total IgG level associated with significantly increased platelet count and reduced bleeding (71). [1] The diagnosis may be suspected based on symptoms and confirmed with blood tests and radioiodine uptake. Besides this, the only remaining treatment will be levothyroxine, or thyroid replacement pills to be taken for the rest of the patient's life. , Juan M, Lucas-Martín A, et al. A series of compounds that inhibit TSHR function as inverse agonists (inhibiting basal as well as agonist-induced signaling) have been developed; the best studied compound has been termed ANTAG-3 (17, 18). , Kamerling SWA, de Rooij ENM, et al. Newland Antibodies binding to the extraocular muscles would cause swelling behind the eyeball. Elegant structural studies have shown that S37a binds TSHR in the juxta-membrane region between the C-terminal end of the extracellular domain, which has an internal agonist function, and the first extracellular loop (81). Measuring TSH-receptor antibodies with the h-TBII assay has been proven efficient and was the most practical approach found in one study.   CR Jacobson [28], Radioiodine (radioactive iodine-131) was developed in the early 1940s at the Mallinckrodt General Clinical Research Center.   D VA-K-14 gives minor antagonism of FSH signaling in vitro, whereas S37a appears to be more specific. Evans Graves' disease is caused by a malfunction in the body's disease-fighting immune system, although the exact reason why this happens is still unknown.One normal immune system response is the production of antibodies designed to target a specific virus, bacterium or other foreign substance.   D [14] These were administered to HLA-DR3 transgenic mice that had been primed for hyperthyroidism by TSHR cDNA immunization, and the TSHR peptide-pretreated mice showed a profound reduction in induced TRAbs and lower thyroid hormone levels (88). The B-cell depleting therapy rituximab (RTX) has been used for more than 20 years to treat lymphoproliferative malignancies, such as lymphoma, with increasing use over the past decade to treat autoimmune disease. Biopsy to obtain histiological testing is not normally required, but may be obtained if thyroidectomy is performed. Some, but not all, studies have shown a reduction in serum TRAb antibody levels following RTX therapy (14, 15, 31), but the reduction does not correlate with the extent of B-cell depletion achieved (15, 32), nor does the effect seem to be greater than that expected with antithyroid medication alone (14). There have also been reports of articular and gastrointestinal symptoms, specifically colitis, related to circulating immune complexes following RTX (42). As a humorally driven condition, the essential role of B cells in Graves’ hyperthyroidism provides a logical therapeutic target for immunomodulatory treatment.   J The BAFF monoclonal antibody belimumab binds to and antagonizes the biological activity of soluble BAFF. Although neither rozanolixizumab nor efgartigimod have been investigated in Graves’ hyperthyroidism, a phase 2 trial with another biologic FcRn blocker, RVT-1401, is about to report (NCT03922321) and it seems likely that these approaches are worthy of further exploration in Graves’ hyperthyroidism. A Graves’ disease patient has a thyroid that produces too much thyroid hormone. Genes believed to be involved include those for thyroglobulin, thyrotropin receptor, protein tyrosine phosphatase nonreceptor type 22, and cytotoxic T-lymphocyte–associated antigen 4, among others. , Vannucchi G, Currò N, et al. [7] People with hyperthyroidism may experience behavioral and personality changes, including psychosis, mania, anxiety, agitation, and depression. But with an autoimmune disease, the immune system sees the body's normal tissue as strange and then attacks it. Efficacy of belimumab alone, or in combination with RTX, has been demonstrated in SLE, with significant improvements in long-term organ damage (78, 79). Several of these therapeutic options have the potential to translate into clinical practice in the near future. Iscalimab was found to be safe and well-tolerated, with no serious treatment-related adverse events reported. The demand for innovative therapeutic options has led to the emergence of novel approaches in the treatment of Graves’ hyperthyroidism, including biologic, small molecule, and peptide immunomodulation, several of which have translational potential into clinical practice in the near future. Human leukocyte antigen DR (especially DR3) appears to play a role. A genetic predisposition for Graves' disease is seen, with some people more prone to develop TSH receptor activating antibodies due to a genetic cause. Thyroid stimulating immunoglobulin (TSI) — presence of this antibody is diagnostic for Graves disease; Thyroid stimulating hormone receptor antibody (TRAb) — less specific than TSI; Anti-thyroid peroxidase antibody (anti-TPO) — this autoantibody is found in most people with Graves disease … Most patients will have complete (>99%) B-cell depletion following a single 500mg dose of RTX, and this persists for 5 to 20 months before recovery of the peripheral B-cell compartment (38), with recent evidence suggesting that much lower doses of RTX (100 mg) are equally effective (39). Oxford University Press is a department of the University of Oxford. With Graves disease, antibodies cause the thyroid gland to make too much thyroid … Small molecule agonists and antagonists have the potential to directly stimulate or inhibit TSHR signaling that could lead to highly potent therapies for thyroid dysfunction. Carayanniotis The result is very high levels of circulating thyroid hormones and a low TSH level. [19], Thyroid-associated ophthalmopathy (TAO), or thyroid eye disease (TED), is the most common extrathyroidal manifestation of Graves' disease. was a collaborator/subinvestigator for the peptide immunotherapy study. These are associated with Graves’ disease.   P Even then, upon cessation of the drugs, the hyperthyroid state may recur. [4] It also often results in an enlarged thyroid. has received speaker fees from Quidel, Sanofi, Berlin Chemie. Hypertrophy of the extraocular muscles, adipogenesis, and deposition of nonsulfated glycoaminoglycans and hyaluronate, causes expansion of the orbital fat and muscle compartments, which within the confines of the bony orbit may lead to dysthyroid optic neuropathy, increased intraocular pressures, proptosis, venous congestion leading to chemosis and periorbital edema, and progressive remodeling of the orbital walls. , Hiepe F, Latinis KM, et al. , Guzmán RM, Gallacher AE, et al. [1] The resulting hypothyroidism is treated with synthetic thyroid hormones. Some actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Graves' disease may present clinically with one or more of these characteristic signs: Two signs are truly 'diagnostic' of Graves' disease (i.e., not seen in other hyperthyroid conditions): exophthalmos and nonpitting edema (pretibial myxedema). Efgartigimod is currently being investigated in MG, immune thrombocytopenia (ITP), and pemphigus vulgaris. , Huang W, Eliseeva E, Titus S, Thomas CJ, Gershengorn MC. It is a form of idiopathic lymphocytic orbital inflammation, and although its pathogenesis is not completely understood, autoimmune activation of orbital fibroblasts, which in TAO express the TSH receptor, is thought to play a central role.[20]. Castro M, Lauer SA Akeno N, et al Morris M, YF! The cells in your gland to produce excess thyroid hormones T3 and T4 ] surgery to remove thyroid. Options for Graves ’ hyperthyroidism provides a logical therapeutic target for immunomodulatory treatment. 16... Median 4 graves disease antibodies ) and aplastic anemia Flajani, and antibody-dependent cellular cytotoxicity all appear to contribute to efficacy... Some actually act as if TSH itself is binding to its receptor, thus inducing function!, Stefan M, Vannucchi G, Ehrenstein MR, Isenberg DA given for months. 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