PDF icon PDF herunterladen
Horm Metab Res 2015; 47(10): 789-796
DOI: 10.1055/s-0035-1555901
Review
© Georg Thieme Verlag KG Stuttgart · New York

Future Prospects for the Treatment of Graves’ Hyperthyroidism and Eye Disease

S. Neumann
1   Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA
,
R. F. Place
2   Nova Therapeutics LLC, E Foothill Blvd, Pasadena, USA
,
C. C. Krieger
1   Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA
,
M. C. Gershengorn
1   Laboratory of Endocrinology and Receptor Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, USA
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 19. März 2015

accepted 26. Juni 2015

Publikationsdatum:
21. Juli 2015 (online)

Auch verfügbar aufeRef
   Lizenzen und Reprints
Preview

Abstract

Although there are adequate therapies for Graves’ hyperthyroidism, mild to moderate Graves’ orbitopathy (GO) is usually treated symptomatically whereas definitive therapy is reserved for severe, vision-threatening GO. Importantly, none of the treatment regimens for Graves’ disease used today are directed at the pathogenesis of the disease. Herein, we review some aspects of what is known about the pathogenesis of these 2 major components of Graves’ disease, specifically the apparent important roles of the TSH and IGF-1 receptors, and thereafter describe future therapeutic approaches directed at these receptors. We propose that targeting these receptors will yield effective and better tolerated treatments for Graves’ disease, especially for GO.

Key words

Graves’ hyperthyroidism - Graves’ orbitopathy - TSH receptor (TSHR) - IGF-1 receptor (IGF-1R)
 

  • References

  • 1 Vassart G, Dumont JE. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 1992; 13: 596-611
    CrossrefPubMedSuche in Google Scholar
  • 2 Williams GR. Extrathyroidal expression of TSH receptor. Ann Endocrinol (Paris) 2011; 72: 68-73
    CrossrefPubMedSuche in Google Scholar
  • 3 Davies TF, Ando T, Lin RY, Tomer Y, Latif R. Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest 2005; 115: 1972-1983
    Suche in Google Scholar
  • 4 Brent GA. Clinical practice. Graves’ disease. N Engl J Med 2008; 358: 2594-2605
    Suche in Google Scholar
  • 5 Bartalena L. Graves’ orbitopathy: imperfect treatments for a rare disease. Eur Thyroid J 2013; 2: 259-269
    Suche in Google Scholar
  • 6 Perros P, Krassas GE. Graves orbitopathy: a perspective. Nat Rev Endocrinol 2009; 5: 312-318
    CrossrefPubMedSuche in Google Scholar
  • 7 Feliciello A, Porcellini A, Ciullo I, Bonavolonta G, Avvedimento EV, Fenzi G. Expression of thyrotropin-receptor mRNA in healthy and Graves’ disease retro-orbital tissue. Lancet 1993; 342: 337-338
    Suche in Google Scholar
  • 8 Valyasevi RW, Erickson DZ, Harteneck DA, Dutton CM, Heufelder AE, Jyonouchi SC, Bahn RS. Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor. J Clin Endocrinol Metab 1999; 84: 2557-2562
    CrossrefPubMedSuche in Google Scholar
  • 9 van Zeijl CJ, van Koppen CJ, Surovtseva OV, de Gooyer ME, Plate R, Conti P, Karstens WJ, Timmers M, Saeed P, Wiersinga WM, Miltenburg AM, Fliers E, Boelen A. Complete inhibition of rhTSH-, Graves’ disease IgG-, and M22-induced cAMP production in differentiated orbital fibroblasts by a low-molecular-weight TSHR antagonist. J Clin Endocrinol Metab 2012; 97: E781-E785
    Suche in Google Scholar
  • 10 Wiersinga WM. Autoimmunity in Graves’ ophthalmopathy: the result of an unfortunate marriage between TSH receptors and IGF-1 receptors?. J Clin Endocrinol Metab 2011; 96: 2386-2394
    Suche in Google Scholar
  • 11 Smith TJ. Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases?. Pharmacol Rev 2010; 62: 199-236
    Suche in Google Scholar
  • 12 Pritchard J, Han R, Horst N, Cruikshank WW, Smith TJ. Immunoglobulin activation of T cell chemoattractant expression in fibroblasts from patients with Graves’ disease is mediated through the insulin-like growth factor I receptor pathway. J Immunol 2003; 170: 6348-6354
    Suche in Google Scholar
  • 13 Tramontano D, Cushing GW, Moses AC, Ingbar SH. Insulin-like growth factor-I stimulates the growth of rat thyroid cells in culture and synergizes the stimulation of DNA synthesis induced by TSH and Graves’-IgG. Endocrinology 1986; 119: 940-942
    CrossrefPubMedSuche in Google Scholar
  • 14 Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha HA, Gianoukakis AG, Douglas RS, Smith TJ. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of 2 antigens implicated in Graves’ disease. J Immunol 2008; 181: 4397-4405
    Suche in Google Scholar
  • 15 Krieger CC, Gershengorn MC. A modified ELISA accurately measures secretion of high molecular weight hyaluronan (HA) by Graves’ disease orbital cells. Endocrinology 2014; 155: 627-634
    CrossrefPubMedSuche in Google Scholar
  • 16 Smith TJ, Hoa N. Immunoglobulins from patients with Graves’ disease induce hyaluronan synthesis in their orbital fibroblasts through the self-antigen, insulin-like growth factor-I receptor. J Clin Endocrinol Metab 2004; 89: 5076-5080
    Suche in Google Scholar
  • 17 Krieger CC, Neumann S, Place RF, Marcus-Samuels B, Gershengorn MC. Bidirectional TSH and IGF-1 receptor cross-talk mediates stimulation of hyaluronan secretion by Graves’ disease immunoglobins. J Clin Endocrinol Metab 2014; 100: 1071-1077
    PubMedSuche in Google Scholar
  • 18 Smith TJ. TSH-receptor-expressing fibrocytes and thyroid-associated ophthalmopathy. Nat Rev Endocrinol 2015; 11: 171-181
    Suche in Google Scholar
  • 19 Mai VQ, Burch HB. A stepwise approach to the evaluation and treatment of subclinical hyperthyroidism. Endocr Pract 2012; 18: 772-780
    CrossrefPubMedSuche in Google Scholar
  • 20 Sundaresh V, Brito JP, Wang Z, Prokop LJ, Stan MN, Murad MH, Bahn RS. Comparative effectiveness of therapies for Graves’ hyperthyroidism: a systematic review and network meta-analysis. J Clin Endocrinol Metab 2013; 98: 3671-3677
    Suche in Google Scholar
  • 21 Cooper DS. Antithyroid drugs. N Engl J Med 2005; 352: 905-917
    CrossrefPubMedSuche in Google Scholar
  • 22 Azizi F, Yousefi V, Bahrainian A, Sheikholeslami F, Tohidi M, Mehrabi Y. Long-term continuous methimazole or radioiodine treatment for hyperthyroidism. Arch Iran Med 2012; 15: 477-484
    PubMedSuche in Google Scholar
  • 23 Elbers L, Mourits M, Wiersinga WM. Outcome of very long-term treatment with antithyroid drugs in Graves’ hyperthyroidism associated with Graves’ orbitopathy. Thyroid 2011; 21: 279-283
    Suche in Google Scholar
  • 24 Laurberg P, Berman DC, Andersen S, Bülow Pedersen I. Sustained control of Graves’ hyperthyroidism during long-term low-dose antithyroid drug therapy of patients with severe Graves’ orbitopathy. Thyroid 2011; 21: 951-956
    Suche in Google Scholar
  • 25 Abraham P, Avenell A, McGeoch SC, Clark LF, Bevan JS. Antithyroid drug regimen for treating Graves’ hyperthyroidism. Cochrane Database Syst Rev 2010; CD003420
    PubMedSuche in Google Scholar
  • 26 Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Curro N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marino M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM. Consensus statement of the European Group on Graves’ orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol 2008; 158: 273-285
    CrossrefPubMedSuche in Google Scholar
  • 27 Salvi M, Vannucchi G, Campi I, Curro N, Dazzi D, Simonetta S, Bonara P, Rossi S, Sina C, Guastella C, Ratiglia R, Beck-Peccoz P. Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol 2007; 156: 33-40
    CrossrefPubMedSuche in Google Scholar
  • 28 Salvi M, Vannucchi G, Beck-Peccoz P. Potential utility of rituximab for Graves’ orbitopathy. J Clin Endocrinol Metab 2013; 98: 4291-4299
    CrossrefPubMedSuche in Google Scholar
  • 29 Salvi M, Vannucchi G, Curro N, Campi I, Covelli D, Dazzi D, Simonetta S, Guastella C, Pignataro L, Avignone S, Beck-Peccoz P. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves’ orbitopathy: a randomized controlled study. J Clin Endocrinol Metab 2015; 100: 422-431
    Suche in Google Scholar
  • 30 Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS. Randomized controlled trial of rituximab in patients with Graves’ orbitopathy. J Clin Endocrinol Metab 2015; 100: 432-441
    Suche in Google Scholar
  • 31 Bahn RS. Emerging pharmacotherapy for treatment of Graves’ disease. Expert Rev Clin Pharmacol 2012; 5: 605-607
    CrossrefPubMedSuche in Google Scholar
  • 32 Smith TJ, Hegedus L, Douglas RS. Role of insulin-like growth factor-1 (IGF-1) pathway in the pathogenesis of Graves’ orbitopathy. Best Pract Res Clin Endocrinol Metab 2012; 26: 291-302
    CrossrefPubMedSuche in Google Scholar
  • 33 Kleinau G, Neumann S, Gruters A, Krude H, Biebermann H. Novel insights on thyroid-stimulating hormone receptor signal transduction. Endocr Rev 2013; 34: 691-724
    CrossrefPubMedSuche in Google Scholar
  • 34 Boutin A, Eliseeva E, Gershengorn MC, Neumann S. beta-Arrestin-1 mediates thyrotropin-enhanced osteoblast differentiation. FASEB J 2014; 28: 3446-3455
    CrossrefPubMedSuche in Google Scholar
  • 35 Kleinau G, Biebermann H. Constitutive activities in the thyrotropin receptor: regulation and significance. Adv Pharmacol 2014; 70: 81-119
    PubMedSuche in Google Scholar
  • 36 Furmaniak J, Sanders J, Rees Smith B. Blocking type TSH receptor antibodies. Autoimmune Highlights 2013; 4: 11-26
    PubMedSuche in Google Scholar
  • 37 Sanders J, Miguel RN, Furmaniak J, Rees Smith B. TSH receptor monoclonal antibodies with agonist, antagonist, and inverse agonist activities. Methods Enzymol 2010; 485: 393-420
    PubMedSuche in Google Scholar
  • 38 Gershengorn MC, Neumann S. Update in TSH receptor agonists and antagonists. J Clin Endocrinol Metab 2012; 97: 4287-4292
    Suche in Google Scholar
  • 39 Sanders J, Evans M, Betterle C, Sanders P, Bhardwaja A, Young S, Roberts E, Wilmot J, Richards T, Kiddie A, Small K, Platt H, Summerhayes S, Harris R, Reeve M, Coco G, Zanchetta R, Chen S, Furmaniak J, Rees Smith B. A human monoclonal autoantibody to the thyrotropin receptor with thyroid-stimulating blocking activity. Thyroid 2008; 18: 735-746
    Suche in Google Scholar
  • 40 Evans M, Sanders J, Tagami T, Sanders P, Young S, Roberts E, Wilmot J, Hu X, Kabelis K, Clark J, Holl S, Richards T, Collyer A, Furmaniak J, Rees Smith B. Monoclonal autoantibodies to the TSH receptor, one with stimulating activity and one with blocking activity, obtained from the same blood sample. Clin Endocrinol (Oxf) 2010; 73: 404-412
    Suche in Google Scholar
  • 41 Neumann S, Eliseeva E, McCoy JG, Napolitano G, Giuliani C, Monaco F, Huang W, Gershengorn MC. A new small-molecule antagonist inhibits Graves’ disease antibody activation of the TSH receptor. J Clin Endocrinol Metab 2011; 96: 548-554
    CrossrefPubMedSuche in Google Scholar
  • 42 Neumann S, Pope A, Geras-Raaka E, Raaka BM, Bahn RS, Gershengorn MC. A drug-like antagonist inhibits thyrotropin receptor-mediated stimulation of cAMP production in Graves’ orbital fibroblasts. Thyroid 2012; 22: 839-843
    CrossrefPubMedSuche in Google Scholar
  • 43 van Koppen CJ, de Gooyer ME, Karstens WJ, Plate R, Conti PG, van Achterberg TA, van Amstel MG, Brands JH, Wat J, Berg RJ, Lane JR, Miltenburg AM, Timmers CM. Mechanism of action of a nanomolar potent, allosteric antagonist of the thyroid-stimulating hormone receptor. Br J Pharmacol 2012; 165: 2314-2324
    Suche in Google Scholar
  • 44 Neumann S, Kleinau G, Costanzi S, Moore S, Jiang JK, Raaka BM, Thomas CJ, Krause G, Gershengorn MC. A low-molecular-weight antagonist for the human thyrotropin receptor with therapeutic potential for hyperthyroidism. Endocrinology 2008; 149: 5945-5950
    Suche in Google Scholar
  • 45 Neumann S, Huang W, Titus S, Krause G, Kleinau G, Alberobello AT, Zheng W, Southall NT, Inglese J, Austin CP, Celi FS, Gavrilova O, Thomas CJ, Raaka BM, Gershengorn MC. Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice. Proc Natl Acad Sci USA 2009; 106: 12471-12476
    Suche in Google Scholar
  • 46 Boutin A, Allen MD, Geras-Raaka E, Huang W, Neumann S, Gershengorn MC. Thyrotropin receptor stimulates internalization-independent persistent phosphoinositide signaling. Mol Pharmacol 2011; 80: 240-246
    CrossrefPubMedSuche in Google Scholar
  • 47 Neumann S, Huang W, Eliseeva E, Titus S, Thomas CJ, Gershengorn MC. A small molecule inverse agonist for the human thyroid-stimulating hormone receptor. Endocrinology 2010; 151: 3454-3459
    Suche in Google Scholar
  • 48 Jaschke H, Neumann S, Moore S, Thomas CJ, Colson AO, Costanzi S, Kleinau G, Jiang JK, Paschke R, Raaka BM, Krause G, Gershengorn MC. A low molecular weight agonist signals by binding to the transmembrane domain of thyroid-stimulating hormone receptor (TSHR) and luteinizing hormone/chorionic gonadotropin receptor (LHCGR). J Biol Chem 2006; 281: 9841-9844
    CrossrefPubMedSuche in Google Scholar
  • 49 Kleinau G, Krause G. Thyrotropin and homologous glycoprotein hormone receptors: structural and functional aspects of extracellular signaling mechanisms. Endocr Rev 2009; 30: 133-151
    CrossrefPubMedSuche in Google Scholar
  • 50 Neumann S, Nir EA, Eliseeva E, Huang W, Marugan J, Xiao J, Dulcey AE, Gershengorn MC. A selective TSH receptor antagonist inhibits stimulation of thyroid function in female mice. Endocrinology 2014; 155: 310-314
    CrossrefPubMedSuche in Google Scholar
  • 51 Hamidi S, Aliesky H, Chen CR, Rapoport B, McLachlan SM. Variable suppression of serum thyroxine in female mice of different inbred strains by triiodothyronine administered in drinking water. Thyroid 2010; 20: 1157-1162
    CrossrefPubMedSuche in Google Scholar
  • 52 Sanders J, Evans M, Premawardhana LD, Depraetere H, Jeffreys J, Richards T, Furmaniak J, Rees Smith B. Human monoclonal thyroid stimulating autoantibody. Lancet 2003; 362: 126-128
    Suche in Google Scholar
  • 53 Moshkelgosha S, So PW, Deasy N, Diaz-Cano S, Banga JP. Cutting edge: retrobulbar inflammation, adipogenesis, and acute orbital congestion in a preclinical female mouse model of Graves’ orbitopathy induced by thyrotropin receptor plasmid-in vivo electroporation. Endocrinology 2013; 154: 3008-3015
    CrossrefPubMedSuche in Google Scholar
  • 54 Wiesweg B, Johnson KT, Eckstein AK, Berchner-Pfannschmidt U. Current insights into animal models of Graves’ disease and orbitopathy. Horm Metab Res 2013; 45: 549-555
    Suche in Google Scholar
  • 55 Turcu AF, Kumar S, Neumann S, Coenen M, Iyer S, Chiriboga P, Gershengorn MC, Bahn RS. A small molecule antagonist inhibits thyrotropin receptor antibody-induced orbital fibroblast functions involved in the pathogenesis of Graves ophthalmopathy. J Clin Endocrinol Metab 2013; 98: 2153-2159
    Suche in Google Scholar
  • 56 LeRoith D, Werner H, Beitner-Johnson D, Roberts Jr CT. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 1995; 16: 143-163
    Suche in Google Scholar
  • 57 Weightman DR, Perros P, Sherif IH, Kendall-Taylor P. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity 1993; 16: 251-257
    Suche in Google Scholar
  • 58 Gianoukakis AG, Douglas RS, King CS, Cruikshank WW, Smith TJ. Immunoglobulin G from patients with Graves’ disease induces interleukin-16 and RANTES expression in cultured human thyrocytes: a putative mechanism for T-cell infiltration of the thyroid in autoimmune disease. Endocrinology 2006; 147: 1941-1949
    CrossrefPubMedSuche in Google Scholar
  • 59 Varewijck AJ, Boelen A, Lamberts SW, Fliers E, Hofland LJ, Wiersinga WM, Janssen JA. Circulating IgGs may modulate IGF-I receptor stimulating activity in a subset of patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab 2013; 98: 769-776
    Suche in Google Scholar
  • 60 Minich WB, Dehina N, Welsink T, Schwiebert C, Morgenthaler NG, Kohrle J, Eckstein A, Schomburg L. Autoantibodies to the IGF1 receptor in Graves’ orbitopathy. J Clin Endocrinol Metab 2013; 98: 752-760
    Suche in Google Scholar
  • 61 Krassas GE, Pontikides N, Kaltsas T, Dumas A, Frystyk J, Chen JW, Flyvbjerg A. Free and total insulin-like growth factor (IGF)-I, -II, and IGF binding protein-1, -2, and -3 serum levels in patients with active thyroid eye disease. J Clin Endocrinol Metab 2003; 88: 132-135
    CrossrefPubMedSuche in Google Scholar
  • 62 Schnitzer T, Kuenkele KP, Rebers F, Van Vugt M, Klein C, Lanzendorfer M, Mundigl O, Parren PWHI, van de Winkel JGJV, Schumacher R. Characterization of a recombinant, fully human monoclonal antibody directed against the human insulin-like growth factor-1 receptor. EJC Suppl 2006; 4: 66-67
    PubMedSuche in Google Scholar
  • 63 Chen H, Mester T, Raychaudhuri N, Kauh CY, Gupta S, Smith TJ, Douglas RS. Teprotumumab an IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1 action in fibrocytes. J Clin Endocrinol Metab 2014; 99: E1635-E1640
    CrossrefPubMedSuche in Google Scholar
  • 64 Mulvihill MJ, Cooke A, Rosenfeld-Franklin M, Buck E, Foreman K, Landfair D, O’Connor M, Pirritt C, Sun Y, Yao Y, Arnold LD, Gibson NW, Ji QS. Discovery of OSI-906: a selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor. Future Med Chem 2009; 1: 1153-1171
    CrossrefPubMedSuche in Google Scholar
  • 65 Jones RL, Kim ES, Nava-Parada P, Alam S, Johnson FM, Stephens AW, Simantov R, Poondru S, Gedrich R, Lippman SM, Kaye SB, Carden CP. Phase I study of intermittent oral dosing of the insulin-like growth factor-1 and insulin receptors inhibitor OSI-906 in patients with advanced solid tumors. Clin Cancer Res 2015; 21: 693-700
    CrossrefPubMedSuche in Google Scholar
  • 66 Puzanov I, Lindsay CR, Goff L, Sosman J, Gilbert J, Berlin J, Poondru S, Simantov R, Gedrich R, Stephens A, Chan E, Evans TR. A phase I study of continuous oral dosing of OSI-906, a dual inhibitor of insulin-like growth factor-1 and insulin receptors, in patients with advanced solid tumors. Clin Cancer Res 2015; 21: 701-711
    CrossrefPubMedSuche in Google Scholar
  • 67 Tognon CE, Sorensen PH. Targeting the insulin-like growth factor 1 receptor (IGF1R) signaling pathway for cancer therapy. Expert Opin Ther Targets 2012; 16: 33-48
    CrossrefPubMedSuche in Google Scholar