Thyroid-Associated Ophthalmopathy and Dermopathy

  • Wilmar M. Wiersinga
Part of the Contemporary Endocrinology book series (COE)


Graves’ ophthalmopathy [thyroid-associated ophthalmopathy (TAO)] and dermopathy [thyroid-associated dermopathy (TAD)] are extrathyroidal manifestations of Graves’ disease, which should be viewed as a multisystem autoimmune disease involving thyrocytes but also orbital and pretibial fibroblasts. Smoking is a risk factor for TAO, and cessation of smoking is useful in the primary, secondary and tertiary prevention of TAO. The immunopathogenesis of TAO and TAD looks very similar. Fibroblasts expressing functional thyroid-stimulating hormone (TSH) receptors have been identified as the target cells of the autoimmune attack. T cells sensitized to thyroid antigens (or TSH receptor stimulating antibodies, TSAb, in later stages) may recognize shared antigens on fibroblasts, inducing release of cytokines. This results in the production of hydrophylic glycosaminoglycans, causing tissue swelling. Recent findings point to the insulin-like growth factor (IGF)-1 receptor on fibroblasts as another likely autoantigen. TAO appears to be primarily a Th1-cell-mediated disease. Intravenous methylprednisolone pulses are now recommended as the treatment of choice in severe active TAO and topical corticosteroids under occlusive dressings for TAD. Rehabilitative surgery for TAO should wait until the disease has become inactive. Promising new but still experimental treatment modalities involve monoclonal antibodies against particular cytokines or T-cell surface molecules.


Thyroid eye disease pretibial myxoedema immunopathogenesis thyrotropin receptor IGF-1 receptor treatment smoking. 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves’ disease (pretibial myxoedema). Review of 150 cases. Medicine (Baltimore) 1994; 73: 1–7.Google Scholar
  2. 2.
    Wall JR. Graves’ disease is a multi-system autoimmune disorder in which extraocular muscle damage and connective tissue inflammation are variable. Thyroid 2002; 12: 35–36.PubMedCrossRefGoogle Scholar
  3. 3.
    Gerding MN, Terwee CB, Dekker FW, Koornneef L, Prummel MF, Wiersinga WM. Quality of life in patients with Graves’ ophthalmopathy is markedly decreased: measurement by the medical outcomes study instrument. Thyroid 1999; 7: 885–889.Google Scholar
  4. 4.
    Bartley GB. The incidence of Graves’ ophthalmopathy in Olmsted County, Minnesota. Am J Ophthalm 1995; 120: 511–517.Google Scholar
  5. 5.
    Prummel MF, Wiersinga WM. Smoking and risk of Graves’ disease. JAMA 1993; 269: 479–482.PubMedCrossRefGoogle Scholar
  6. 6.
    Weetman AP, Wiersinga WM. Current management of thyroid-associated ophthalmopathy in Europe: results of an international survey. Clin Endocrinol 1998; 49: 21–28.CrossRefGoogle Scholar
  7. 7.
    Perros P, Kendall-Taylor P. Natural history of thyroid eye disease. Thyroid 1998; 8: 423–425.PubMedGoogle Scholar
  8. 8.
    Prummel MF, Bakker A, Wiersinga WM, et al. Multi-center study on the characteristics and treatment strategies of patients with Graves’ orbitopathy: the first European Group on Graves’ orbitopathy experience. Eur J Endocrinol 2003; 148: 491–495.PubMedCrossRefGoogle Scholar
  9. 9.
    Burch HB, Wartofsky L. Graves’ ophthalmopathy: current concepts regarding pathogenesis and management. Endocr Rev 1993; 14: 747–793.PubMedCrossRefGoogle Scholar
  10. 10.
    Khoo DH, Eng PH, Ho SC, et al. Graves’ ophthalmopathy in the absence of elevated free thyroxine and triiodothyronine levels: prevalence, natural history, and thyrotropin receptor antibody levels. Thyroid 2000; 10: 1093–1100.PubMedGoogle Scholar
  11. 11.
    Wiersinga WM. Genetic and environmental contributions to pathogenesis. In: Bahn RS (ed.), Thyroid Eye Disease. Kluwer Academic Publishers, Boston/Dordrecht/London 2001, p. 99–118.Google Scholar
  12. 12.
    Vaidya B, Imric H, Perros P, et al. Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphism confers susceptibility to thyroid associated orbitopathy. Lancet 1999; 354: 743–744.PubMedCrossRefGoogle Scholar
  13. 13.
    Allahabadia A, Heward JM, Nithiyananthan R, et al. MHC class II region, CTLA-4 gene, and ophthalmopathy in patients with Graves’ disease. Lancet 2001; 358: 984–985.PubMedCrossRefGoogle Scholar
  14. 14.
    Bednarczuk T, Hiromatsu Y, Fukutani T, et al. Association of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) gene polymorphism and non-genetic factors with Graves’ ophthalmopathy in European and Japanese populations. Eur J Endocrinol 2003; 148: 13–18.PubMedCrossRefGoogle Scholar
  15. 15.
    Vestergaard P. Smoking and thyroid disorders – a meta-analysis. Eur J Endocrinol 2002; 146: 153–161.PubMedCrossRefGoogle Scholar
  16. 16.
    Krassas GE, Segni M, Wiersinga WM. Childhood Graves’ ophthalmopathy: results of a European questionnaire study. Eur J Endocrinol 2005; 153: 515–520.PubMedCrossRefGoogle Scholar
  17. 17.
    Belin RM, Astor BC, Powe NR, Ladenson PW. Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2004; 89: 6077–6086.PubMedCrossRefGoogle Scholar
  18. 18.
    Khoo DHC, Ho, SC, Seah LL, et al. The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves’disease identifies a group at markedly increased risk of ophthalmopathy. Thyroid 1999; 9: 1175–1180.Google Scholar
  19. 19.
    Metcalfe RA, Weetman AP. Stimulation of extraocular muscle fibroblasts by cytokines and hypoxia: possible role in thyroid-associated ophthalmopathy. Clin Endocrinol 1994; 40: 67–72.Google Scholar
  20. 20.
    Mack WP, Stasior GO, Cao HJ, et al. The effect of cigarette smoke constituents in the expression of HLA-DR in orbital fibroblasts derived from patients with Graves’ ophthalmopathy. Ophthalmic Plastic Reconstructive Surgery 1999; 15: 260–271.CrossRefGoogle Scholar
  21. 21.
    Bartalena L, Tanda ML, Piantanida E, et al. Oxidative stress and Graves’ ophthalmopathy: in vitro studies and therapeutic implications. Biofactors 2003; 19: 155–163.PubMedGoogle Scholar
  22. 22.
    George J, Levy Y, Schoenfeld Y. Smoking and immunity: an additional player in the mosaic of autoimmunity. Scand J Immunol 1997; 45: 1–6PubMedCrossRefGoogle Scholar
  23. 23.
    Wakelkamp IMMJ, Gerding MN, Meer JWC van der, Prummel MF, Wiersinga WM. Both Th1 and Th2-derived cytokines in serum are elevated in Graves’ ophthalmopathy. Clin Exp Immunol 2000; 121: 453–457.PubMedCrossRefGoogle Scholar
  24. 24.
    Wakelkamp IMMJ, Gerding MN, Meer JWC van der, Prummel MF, Wiersinga WM. Smoking and disease severity are independent determinants of serum adhesion molecules in Graves’ ophthalmopathy. Clin Exp Immunol 2002; 127: 316–320.PubMedCrossRefGoogle Scholar
  25. 25.
    Prabhakar BS, Bahn RS, Smith TJ. Current perspective on the pathogenesis of Graves’ disease and ophthalmopathy. Endocr Rev 2003; 24: 802–835.PubMedCrossRefGoogle Scholar
  26. 26.
    Hansen C, Rouhi R, Förster G, Kahaly GJ. Increased sulfatation of orbital glycosaminoglycans in Graves’ ophthalmopathy. J Clin Endocrinol Metab 1999; 84: 1409–1413.PubMedCrossRefGoogle Scholar
  27. 27.
    Bahn RS. Pathophysiology of Graves’ ophthalmopathy: the cycle of disease. J Clin Endocrinol Metab 2003; 88: 1939–1946.PubMedCrossRefGoogle Scholar
  28. 28.
    Weetman AP. Determinants of autoimmune thyroid disease. Nat Immunol 2001; 2: 769–770.PubMedCrossRefGoogle Scholar
  29. 29.
    Pappa A, Lawson JM, Calder V, Fells P, Lightman S. T cells and fibroblasts in affected extraocular muscles in early and late thyroid associated ophthalmopathy. Br J Ophthalmol 2000; 84: 517–522.PubMedCrossRefGoogle Scholar
  30. 30.
    Eckstein AK, Quadbeck B, Tews S, et al. Thyroid-associated ophthalmopathy: evidence for CD4+ γδ T cells: de novo differentiation of RED7+ macrophages, but not of RFD1+ dendritic cells; and loss of γδ and αβ T cell receptor expression. Br J Ophthalmol 2004; 88: 803–808.PubMedCrossRefGoogle Scholar
  31. 31.
    Avanduk AM, Avanduk MC, Pazarli H, et al. Immunohistochemical analysis of orbital connective tissue specimens of patients with active Graves’ ophthalmopathy. Curr Eye Res 2005; 70: 631–638.CrossRefGoogle Scholar
  32. 32.
    de Carli M, D’Elios M, Mariotti S, et al. Cytolytic T cells with Th-1 like cytokine profile predominate in retroorbital lymphocytic infiltrates of Graves’ ophthalmopathy. J Clin Endocrinol Metab 1993; 77: 1120–1124.PubMedCrossRefGoogle Scholar
  33. 33.
    Hiromatsu Y, Yang D, Bednarczuk T, Miyaki I, Nonaka K, Inoue Y. Cytokine profiles in eye muscle tissue and orbital fat tissue from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2000; 85: 1194–1199.PubMedCrossRefGoogle Scholar
  34. 34.
    Wakelkamp IMMJ, Bakker O, Baldeschi L, Wiersinga WM, Prummel MF. TSH-R expression and cytokine profile in orbital tissue of active vs inactive Graves’ ophthalmopathy patients. Clin Endocrinol 2003; 58: 280–287.CrossRefGoogle Scholar
  35. 35.
    Aniszewski JP, Valyasevi RW, Bahn RS. Relationship between disease duration and predominant orbital T cell subset in Graves’ ophthalmopathy. J Clin Endocrinol Metab 2000; 85: 776–780.PubMedCrossRefGoogle Scholar
  36. 36.
    Heufelder AE, Wenzel BE, Scriba PC. Antigen receptor variable region repertoires expressed by T cells infiltrating thyroid, retroorbital and pretibial tissue in Graves’disease. J Clin Endocrinol Metab 1996; 81: 3733–3739.PubMedCrossRefGoogle Scholar
  37. 37.
    Pappa A, Calder V, Fells P, Lightman S. Adhesion molecule expression in vivo on extraocular muscles (EOM) in thyroid-associated ophthalmopathy (TAO). Clin Exp Immunol 1997; 108: 309–313.PubMedCrossRefGoogle Scholar
  38. 38.
    Pritchard J, Horst N, Cruikshank W, Smith TJ. IgGs from patients with Graves’disease induce the expression of T cell chemoattractants in their fibroblasts. J Immunol 2002; 168: 942–950.PubMedGoogle Scholar
  39. 39.
    Drexhage HA. Are there more than antibodies to the TSH receptor that meet the eye in Graves’ disease? Endocrinology 2006; 147: 9–12.PubMedCrossRefGoogle Scholar
  40. 40.
    Kumaz S, Bahn RS. Relative overexpression of macrophage-derived cytokines in orbital adipose tissue from patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab 2003; 88: 4246–4250.CrossRefGoogle Scholar
  41. 41.
    Sempowski G, Rozenblat J, Smith T, Phipps R. Human orbital fibroblasts are activated through CD40 to induce proinflammatory cytokine production. Am J Physiol 1998; 274: C707–C714.PubMedGoogle Scholar
  42. 42.
    Cao HJ, Wang HS, Zhang Y, Lin HY, Phipps RP, Smith TJ. Activation of human orbital fibroblasts through CD40 engagement results in a dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression: insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy. J Biol Chem 1998; 273: 29615–29625.PubMedCrossRefGoogle Scholar
  43. 43.
    Grubeck-Loebenstein B, Trieb K, Sztankay A, Holter W, Anderl H, Wiek G. Retrobulbar T cells from patients with Graves’ ophthalmopathy are CD8+ and specifically recognize autologous fibroblasts. J Clin Invest 1994; 3: 2738–2743.Google Scholar
  44. 44.
    Otto EA, Ochs K, Hansen C, Wall JR, Kahaly GJ. Orbital tissue-derived T lymphocytes from patients with Graves’ ophthalmopathy recognize autologous orbital antigens. J Clin Endocrinol Metab 1996; 81: 3045–3050.PubMedCrossRefGoogle Scholar
  45. 45.
    Feldon SE, Park DJJ, O’Loughlin CW, et al. Autologous T-lymphocytes stimulate proliferation of orbital fibroblasts derived from patients with Graves’ ophthalmopathy. Invest Ophthal Vis Sci 2005; 46: 3913–3921.PubMedCrossRefGoogle Scholar
  46. 46.
    Starkey KJ, Janezic A, Jones G. Jordan N, Baker G, Ludgate M. Adipose thyrotrophin receptor expression is elevated in Graves’ and thyroid eye diseases ex vivo and indicates adipogenesis in progress in vivo. J Mol Endocrinol 2003; 30: 369–380.PubMedCrossRefGoogle Scholar
  47. 47.
    Valyasevi RW, Erickson DZ, Harteneck DA, et al. Differentiation of human orbital preadipocyte fibroblasts induces expression of functional thyrotropin receptor. J Clin Endocrinol Metab 1999; 84: 2557–2562.PubMedCrossRefGoogle Scholar
  48. 48.
    Valyasevi RW, Jyonouchi SC, Dutton CM, Munsakul N, Bahn RS. Effect of TNFα, IFNγ, and TGFβ on adipogenesis and expression of thyrotropin receptor in human orbital preadiocyte fibroblasts. J Clin Endocrinol Metab 2001; 86: 903–908.PubMedCrossRefGoogle Scholar
  49. 49.
    Jyonouchi SC, Valyasevi RW, Harteneck D, Dutton CM, Bahn RS. Interleukin-6 stimulates thyrotropin receptor expression in human orbital preadipocyte fibroblasts from patients with Graves’ ophthalmopathy. Thyroid 2001; 11: 929–935.PubMedCrossRefGoogle Scholar
  50. 50.
    Kumar S, Coenen MJ, Scherer PE, Bahn RS. Evidence for enhanced adipogenesis in the orbits of patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab 2004; 89: 930–935.PubMedCrossRefGoogle Scholar
  51. 51.
    Valyasevi RW, Harteneck DA, Dutton CM, Bahn RS. Stimulation of adipogenesis, PPARγ, and thyrotropin receptor by PPARγ agonist in human orbital preadipocyte fibroblasts. J Clin Endocrinol Metab 2002; 87: 2352–2358.PubMedCrossRefGoogle Scholar
  52. 52.
    Starkey K, Heufelder A, Baker G, et al. Peroxisome proliferator-activated receptor-γ in thyroid eye disease: contraindication for thiazolidinedione use? J Clin Endocrinol Metab 2003; 88: 55–59.PubMedCrossRefGoogle Scholar
  53. 53.
    Kumar S, Leontovich A, Coenen MJ, Bahn RS. Gene expression profiling of orbital adipose tissue from patients with Graves’ophthalmopathy: a potential role for secreted frizzled-related protein-1 in orbital adipogenesis. J Clin Endocrinol Metab 2005; 90: 4730–4735.PubMedCrossRefGoogle Scholar
  54. 54.
    Smith TJ, Koumas L, Gagnon A, et al. Orbital fibroblast heterogeneity may determine the clinical presentation of thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2002; 87: 385–392.PubMedCrossRefGoogle Scholar
  55. 55.
    Smith TJ. Novel aspects of orbital fibroblast pathology. J Endocrinol Invest 2004; 27: 246–253.PubMedGoogle Scholar
  56. 56.
    Sciaky D, Brazer W, Center DM, Cruikshank WW, Smith TJ. Cultured human fibroblasts express constitutive IL-16 mRNA: cytokine induction of active IL-16 protein synthesis through a caspase-3-dependent mechanism. J Immunol 2000; 164: 3806–3814.PubMedGoogle Scholar
  57. 57.
    Kaback LA, Smith TJ. Expression of hyaluronan synthase mRNA’s and their induction by interleukin-1β in human orbital fibroblasts: potential insight into the molecular pathogenesis of thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 1999; 84: 4079–4084.PubMedCrossRefGoogle Scholar
  58. 58.
    Gerding MN, Meer JWC van der, Broenink M, et al. Association of thyrotropin receptor antibodies with the clinical features of Graves’ ophthalmopathy. Clin Endocrinol 2000; 52: 267–271.CrossRefGoogle Scholar
  59. 59.
    Baker G, Mazziotti G, von Ruhland C, Ludgate M. Reevaluating thyrotropin receptor-induced mouse models of Graves’ disease and ophthalmopathy. Endocrinology 2005; 146: 835–844.PubMedCrossRefGoogle Scholar
  60. 60.
    Weightman DR, Perros P, Sherif IH, Kendall-Taylor P. Autoantibodies to IGF-1 binding sites in the thyroid associated ophthalmopathy. Autoimmunity 1993; 16: 251–257.PubMedCrossRefGoogle Scholar
  61. 61.
    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 IGF-1 receptor pathway. J Immunol 2003; 170: 6348–6354.PubMedGoogle Scholar
  62. 62.
    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-1 receptor. J Clin Endocrinol Metab 2004; 89: 5076–5080.PubMedCrossRefGoogle Scholar
  63. 63.
    Krassas GE, Pontikides N, Kaltsas T, et al. Free and total 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.PubMedCrossRefGoogle Scholar
  64. 64.
    Mizokami T, Salvi M, Wall JR. Eye muscle antibodies in Graves’ ophthalmopathy: pathogenic or secondary epiphenomenon? J Endocrinol Invest 2004; 27: 221–229.PubMedGoogle Scholar
  65. 65.
    Lisi S, Botta R, Agretti P, et al. Poorly specific binding of thyroglobulin to orbital fibroblasts from patients with Graves’ ophthalmopathy. J Endocrinol Invest 2005; 28: 420–424.PubMedGoogle Scholar
  66. 66.
    Ajjan RA, Weetman AP. New understanding of the role of cytokines in the pathogenesis of Graves’ ophthalmopathy. J Endocrinol Invest 2004; 27: 237–245.PubMedGoogle Scholar
  67. 67.
    Lantz M, Vondrichova T, Parikh H, et al. Overexpression of immediate early genes in active Graves’ophthalmopathy. J Clin Endocrinol Metab 2005; 90: 4784–4791.PubMedCrossRefGoogle Scholar
  68. 68.
    Bartalena L, Pichera A, Marcocci C. Management of Graves’ ophthalmopathy: reality and perspectives. Endocr Rev 2000; 21: 168–199.PubMedCrossRefGoogle Scholar
  69. 69.
    Dickinson AJ, Perros P. Controversies in the clinical evaluation of active thyroid-associated orbitopathy: use of a detailed protocol with comparative photographs for objective assessment. Clin Endocrinol 2001; 55: 283–303.CrossRefGoogle Scholar
  70. 70.
    Eckstein AK, Plicht M, Lax H, et al. Clinical results of anti-inflammatory therapy in Graves’ ophthalmopathy and association with thyroidal antibodies. Clin Endocrinol 2004; 61: 612–618.CrossRefGoogle Scholar
  71. 71.
    Forbes G, Gorman CA, Brennan MD, Gehring DG, Ilstrup DM, Earnest F. Ophthalmopathy of Graves’ disease: computerized volume measurements of the orbital fat and muscle. Am J Neuroradiol 1986; 7: 651–656.PubMedGoogle Scholar
  72. 72.
    Kahaly G. Recent developments in Graves’ ophthalmopathy imaging. J Endocrinol Invest 2004; 27: 254–258.PubMedGoogle Scholar
  73. 73.
    Savastano S, Pivonello R, Acampa W, et al. Recombinant thyrotropin-induced orbital uptake of [111In-diethylenetriamine-pentacetic acid-D-The1]octreotide in a patient with inactive Graves’ ophthalmopathy. J Clin Endocrinol Metab 2005; 90: 2440–2444.PubMedCrossRefGoogle Scholar
  74. 74.
    Galuska L, Leovey A, Szues-Farkas Z, et al. SPECT using 99mTc-DTPA for the assessment of disease activity in Graves’ ophthalmopathy: comparison with the results of MRI. Nucl Med Commun 2002; 23: 1211–1216.PubMedCrossRefGoogle Scholar
  75. 75.
    Burggasser G, Hurth I, Hauff W, et al. Orbital scintigraphy with the somatostatin receptor tracer 99mTc-P829 in patients with Graves’ disease. J Nucl Med 2003; 44: 1547–1558.PubMedGoogle Scholar
  76. 76.
    Konuk O, Atasever T, Űnal M, et al. Orbital Gallium-67 scintigraphy in Graves’ophthalmopathy. Thyroid 2002; 12: 603–608.PubMedCrossRefGoogle Scholar
  77. 77.
    Yanik B, Conkbayir I, Acaroglu G, Hekimoglu B. Graves’ ophthalmopathy: comparison of the Doppler sonography parameters with the clinical activity score. J Clin Ultrasound 2005; 33: 375–380.PubMedCrossRefGoogle Scholar
  78. 78.
    Wiersinga WM. The philosophy of Graves’ ophthalmopathy. Orbit 2005; 24: 165–171.PubMedCrossRefGoogle Scholar
  79. 79.
    Wiersinga WM, Bartalena L. Preventing Graves’ophthalmopathy. Thyroid 2002; 12: 855–860.PubMedCrossRefGoogle Scholar
  80. 80.
    Pfeilschiffer J, Ziegler R. Smoking and endocrine ophthalmopathy: impact of smoking severity and current vs lifetime cigarette consumption. Clin Endocrinol 1996; 45: 477–481.CrossRefGoogle Scholar
  81. 81.
    Glinoer D, de Nayer P, Bex M, et al. Effects of L-thyroxine administration, TSH-receptor antibodies and smoking on the risk of recurrence in Graves’ hyperthyroidism treated with antithyroid drugs. Eur J Endocrinol 2001; 144: 475–483.PubMedCrossRefGoogle Scholar
  82. 82.
    Bartalena L, Marcocci C, Tanda ML, et al. Cigarette smoking and treatment outcomes in Graves’ ophthalmopathy. Ann Int Med 1998; 129: 632–635.PubMedGoogle Scholar
  83. 83.
    Eckstein A, Quadbeck B, Mueller G, et al. Impact of smoking on the response to treatment of thyroid associated ophthalmopathy. Br J Ophthalmol 2003; 87: 773–776.PubMedCrossRefGoogle Scholar
  84. 84.
    Prummel MF, Wiersinga WM, Mourits M Ph, et al. Effect of abnormal thyroid function on the severity of Graves’ ophthalmopathy. Arch Int Med 1990; 150: 1098–1101.CrossRefGoogle Scholar
  85. 85.
    Tallstedt L, Lundell G, Torring O, et al. Occurrence of ophthalmopathy after treatment for Graves’ hyperthyroidism. N Engl J Med 1992; 326: 1733–1738.PubMedCrossRefGoogle Scholar
  86. 86.
    Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 1998; 338: 73–78.PubMedCrossRefGoogle Scholar
  87. 87.
    Wiersinga WM, Preventing Graves’ ophthalmopathy. N Engl J Med 1998; 338: 121–122.PubMedCrossRefGoogle Scholar
  88. 88.
    Perros P, Kendall-Taylor P, Neoh C, Frewin S, Dickinson J. A prospective study of the effects of radioiodine therapy for hyperthyroidism in patients with minimally active Graves’ophthalmopathy. J Clin Endocrinol Metab 2005; 90: 5321–5323.PubMedCrossRefGoogle Scholar
  89. 89.
    Marcocci C, Bruno-Bossio G, Manetti L, et al. The course of Graves’ ophthalmopathy is not influenced by near-total thyroidectomy: a case-control study. Clin Endocrinol 1999; 51: 503–506.CrossRefGoogle Scholar
  90. 90.
    Järhult J, Rudberg C, Larsson E, et al. Graves’ disease with moderate-severe endocrine ophthalmopathy – long term results of a prospective, randomized study of total or subtotal thyroid resection. Thyroid 2005; 15: 1157–1164.PubMedCrossRefGoogle Scholar
  91. 91.
    Moleti M, Mattina F, Salamone I, et al. Effects of thyroidectomy alone or followed by radioiodine ablation of thyroid remnants on the outcome of Graves’ ophthalmopathy. Thyroid 2003; 13: 653–658.PubMedCrossRefGoogle Scholar
  92. 92.
    Wiersinga WM, Prummel MF. Retrobulbar radiation in Graves’ ophthalmopathy. J Clin Endocrinol Metab 1995; 80: 345–347.PubMedGoogle Scholar
  93. 93.
    Kalmann R, Mourits M Ph. Diabetes mellitus: a risk factor in patients with Graves’ orbitopathy. Br J Ophthalmol 1999; 83: 463–465.PubMedGoogle Scholar
  94. 94.
    Wakelkamp IMMJ, Baldeschi L, Saeed P, Mourits M Ph, Prummel MF, Wiersinga WM. Surgical or medical decompression as a first-line treatment of optic neuropathy in Graves’ ophthalmopathy? A randomized controlled trial. Clin Endocrinol 2005; 63: 323–328.CrossRefGoogle Scholar
  95. 95.
    Terwee CB, Gerding MN, Dekker FW, Prummel MF, Wiersinga WM. Development of a disease-specific quality of life questionnaire for patients with Graves’ ophthalmopathy. Br J Ophthalmol 1998; 82: 773–779.PubMedCrossRefGoogle Scholar
  96. 96.
    Prummel MF, Terwee CB, Gerding MN, et al. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves’ ophthalmopathy. J Clin Endocrinol Metab 2004; 89: 15–20.PubMedCrossRefGoogle Scholar
  97. 97.
    Mourits M Ph, van Kempen-Harteveld ML, Garcia MBG, Koppeschaar HPF, Tick L, Terwee CB. Radiotherapy for Graves’ orbitopathy: randomized placebo-controlled study. Lancet 2000; 355:105–109.Google Scholar
  98. 98.
    Gorman CA, Garrity JA, Fatourechi V, et al. A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves’ ophthalmopathy. Ophthalmology 2001; 108: 1523–1534.PubMedCrossRefGoogle Scholar
  99. 99.
    Kahaly GJ, Rösler HP, Pitz S, et al. Low- versus high-dose radiotherapy for Graves’ ophthalmopathy: a randomized, single-blind trial. J Clin Endocrinol Metab 2000; 85: 102–108.PubMedCrossRefGoogle Scholar
  100. 100.
    Gerling J, Kommerell G, Henne K, et al. Retrobulbar irradation for thyroid-associated orbitopathy: double-blind comparison between 2.4 and 16 Gy. Int J Radiat Oncol Biol Phys 2003; 55: 182–189.PubMedCrossRefGoogle Scholar
  101. 101.
    Schaefer U, Hesselmann S, Micke O, et al. A long-term follow-up study after retro-orbital irradiation for Graves’ ophthalmopathy. Int J Radiat Oncol Biol Phys 2002; 52: 192–197.PubMedCrossRefGoogle Scholar
  102. 102.
    Marcocci C, Bartalena L, Rocchi R, et al. Long-term safety of orbital radiotherapy for Graves’ ophthalmopathy. J Clin Endocrinol Metab 2003; 88: 3561–3566.PubMedCrossRefGoogle Scholar
  103. 103.
    Wakelkamp, IMMJ, Tan H, Saeed P, et al. Orbital irridiation for Graves’ ophthalmopathy. Is it safe? A long-term follow-up study. Ophthalmology 2004; 111: 1557–1562.PubMedCrossRefGoogle Scholar
  104. 104.
    Robertson DM, Buettner H, Gorman CA, et al. Retinal microvascular abnormalities in patients treated with external radiation for Graves’ ophthalmopathy. Arch Ophthalmol 2003; 121: 652–657.PubMedCrossRefGoogle Scholar
  105. 105.
    Terwee CB, Prummel MF, Gerding MN, Kahaly GJ, Dekker FW, Wiersinga WM. Measuring disease activity to predict therapeutic outcome in Graves’ ophthalmopathy. Clin Endocrinol 2005; 62: 145–155.CrossRefGoogle Scholar
  106. 106.
    Marcocci C, Bartalena L, Tanda ML, et al. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ophthalmopathy: results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab 2001; 86: 3652–3657.CrossRefGoogle Scholar
  107. 107.
    Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single-blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab 2005; 90: 5234–5240.PubMedCrossRefGoogle Scholar
  108. 108.
    Marino M, Morabito E, Brunetto MR, et al. Acute and severe liver damage associated with intravenous glucocorticoid pulse therapy in patients with Graves’ ophthalmopathy. Thyroid 2004; 14: 403–406.PubMedCrossRefGoogle Scholar
  109. 109.
    Salvi M, Vannuchi G, Sbrozzi F, et al. Onset of autoimmune hepatitis during intravenous steroid therapy for thyroid-associated ophthalmopathy in a patient with Hashimoto’s thyroiditis: a case report. Thyroid 2004; 14: 631–634.PubMedCrossRefGoogle Scholar
  110. 110.
    Dickinson JA, Vaidya B, Miller B, et al. Double-blind, placebo-controlled trial of octreotide long-acting repeatable (LAR) in thyroid associated ophthalmopathy. J Clin Endocrinol Metab 2004; 89: 5910–5915.PubMedCrossRefGoogle Scholar
  111. 111.
    Wèmeau JL, Caron P, Beckers A, et al. Octreotide (long-acting release formulation) treatment in patients with Graves’ orbitopathy: clinical results of a four-month, randomized, placebo-controlled, double-blind study. J Clin Endocrinol Metab 2005; 90: 840–848.Google Scholar
  112. 112.
    Bouzas EA, Karadimas P, Mastorakos G, Koutras D. Anti-oxidant agents in the treatment of Graves’ ophthalmopathy. Am J Ophthalmol 2000; 129: 618–622.PubMedCrossRefGoogle Scholar
  113. 113.
    Balazs Cs, Kiss E, Vamos A, Molnar I, Farid NR. Beneficial effect of pentoxifylline on thyroid associated ophthalmopathy: a pilot study. J Clin Endocrinol Metab 1997; 82: 1999–2002.PubMedGoogle Scholar
  114. 114.
    Bahn RS. Cytokines in thyroid eye-disease: potential for anticytokine therapy. Thyroid 1998; 8: 415–418.PubMedGoogle Scholar
  115. 115.
    Paridaens D, Bosch WA van den, Loos Th van der, Krenning EP, Hagen PM van. The effect of etanercept on Graves’ ophthalmopathy: a pilot study. Eye 2004; :1–4.Google Scholar
  116. 116.
    El Fassi D, Nielsen CH, Hasselbalck HC, Hegedüs L. Successful B lymphocyte depletion with rituximab in a patient with recurrent Graves’ disease and severe ophthalmopathy (abstract). Thyroid 2005; 15 (Suppl 1): S28.Google Scholar
  117. 117.
    Schwartz KM, Fatourechi V, Ahmed DDF, Pond GR. Dermopathy of Graves’ disease (pretibial myxoedema): long-term outcome. J Clin Endocrinol Metab 2002; 87: 438–446.PubMedCrossRefGoogle Scholar
  118. 118.
    Rapoport B, Alsabek R, Aftergood D, McLachlan S. Elephantiasic pretibial myxoedema: insight into and a hypothesis regarding the pathogenesis of the extrathyroidal manifestations of Graves’ disease. Thyroid 2000; 10: 685–692.PubMedCrossRefGoogle Scholar
  119. 119.
    Daumerie C, Ludgate M, Costagliola S, Many MC. Evidence for thyrotropin receptor immunoreactivity in pretibial connective tissue from patients with thyroid-associated dermopathy. Eur J Endocrinol 2002; 146: 35–38.PubMedCrossRefGoogle Scholar
  120. 120.
    Rotman-Pikielny P, Brucker-Davis F, Turner ML, Sarlis NJ, Skarulis MC. Lack of effect of long-term octreotide therapy in severe thyroid-associated dermopathy. Thyroid 2003; 13: 465–470.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Wilmar M. Wiersinga

There are no affiliations available

Personalised recommendations