The n e w e ng l a n d j o u r na l of m e dic i n e

review article

mechanisms of disease

Graves’ Ophthalmopathy
Rebecca S. Bahn, M.D.

G
From the Division of Endocrinology, Dia- raves’ ophthalmopathy, also called Graves’ orbitopathy, is a
betes, Metabolism, and Nutrition, Mayo potentially sight-threatening ocular disease that has puzzled physicians
Clinic, Rochester, MN. Address reprint
requests to Dr. Bahn at the Division of and scientists for nearly two centuries.1-3 Generally occurring in patients
Endocrinology, Diabetes, Metabolism, with hyperthyroidism or a history of hyperthyroidism due to Graves’ disease,
and Nutrition, Mayo Clinic, 200 First St. Graves’ ophthalmopathy is also known as thyroid-associated ophthalmopathy or
SW, Rochester, MN 55905, or at bahn
.rebecca@mayo.edu. thyroid eye disease, because it sometimes occurs in patients with euthyroid or hypo-
thyroid chronic autoimmune thyroiditis. The condition has an annual adjusted in-
N Engl J Med 2010;362:726-38. cidence rate of 16 women and 3 men per 100,000 population.4
Copyright © 2010 Massachusetts Medical Society.
This review explores the perplexing relationship between Graves’ ophthalmopa-
thy, hyperthyroidism, and thyroid dermopathy, the associated skin condition. I ex-
amine clinical features, histologic findings, and laboratory studies, with an empha-
sis on mechanisms that could be targeted in the development of new treatments for
this debilitating disease.

Cl inic a l a nd L a bor at or y Fe at ur e s

The close clinical and temporal relationships between hyperthyroidism, Graves’
ophthalmopathy, and thyroid dermopathy suggest that these conditions evolve from
a single underlying systemic process with variable expression in the thyroid, eyes,
and skin. Bilateral ocular symptoms and hyperthyroidism most often occur simul-
taneously or within 18 months of each other, although occasionally Graves’ ophthal-
mopathy precedes or follows the onset of hyperthyroidism by many years.5 Almost
half of patients with Graves’ hyperthyroidism report symptoms of Graves’ ophthal-
mopathy, including a dry and gritty ocular sensation, photophobia, excessive tear-
ing, double vision, and a pressure sensation behind the eyes. The most common
clinical features of Graves’ ophthalmopathy are upper eyelid retraction, edema, and
erythema of the periorbital tissues and conjunctivae, and proptosis (Fig. 1). Ap-
proximately 3 to 5% of patients with Graves’ ophthalmopathy have severe disease
with intense pain, inflammation, and sight-threatening corneal ulceration or com-
pressive optic neuropathy.6 Subclinical eye involvement is common: in nearly 70%
of adult patients with Graves’ hyperthyroidism, magnetic resonance imaging or
computed tomographic scanning reveals extraocular-muscle enlargement.7 Although
clinically unilateral Graves’ ophthalmopathy occurs occasionally, orbital imaging
generally confirms the presence of asymmetric bilateral disease.8 Thyroid dermop­
athy (also called pretibial myxedema), a nodular or diffuse thickening of the pretib-
ial skin, sometimes progresses to debilitating disease. Although diagnosed on phys-
ical examination in only 13% of patients with severe Graves’ ophthalmopathy,
subclinical involvement of the skin of the legs and other regions of the body occurs
more commonly.9 Approximately 20% of patients with thyroid dermopathy have
thyroid acropachy, which manifests as clubbing of the fingers and toes.

726 n engl j med 362;8  nejm.org  february 25, 2010

The New England Journal of Medicine
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18 The orbit. 7. Patients with crowding of enlarged mus- strong association between Graves’ ophthalmo. Figure has been redrawn and type has been reset. including direct effects of ciga. decreased blinking. cles at the orbital apex and minimal proptosis pathy and smoking suggests the involvement of are at particular risk for compressive optic neu- additional factors. or scar- ophthalmopathy arise from soft-tissue enlarge. . Cigarette smoking is the strongest modifiable Panel A shows a 59-year-old woman with excess prop- tosis. and impairment velops as the globe protrudes. lids. are evident. with prolapse of Revised the rettes smoked daily. The infe- rior rectus is the most commonly involved A nat omic a l a nd His t ol o gic muscle.11 The 5% of patients with Graves’ ophthalmopathy B who are euthyroid or hypothyroid generally have low titers of anti–thyrotropin-receptor antibod- ies.8  nejm. 2010 727 The New England Journal of Medicine Downloaded from nejm. of moderate superior limbic keratoconjunctivitis. and erythema with mod- risk factor for Graves’ ophthalmopathy (odds erate ICMeyelidAUTHOR Bahn retraction RETAKE Con- affecting all four eyelids. erally restrictive rather than paralytic.22 Patients under 40 years Anatomical and mechanical features of the of age tend to have fat expansion. proptosis de- duction of natural killer T cells.21 Most patients have eyelid retraction. with excess H/T H/T minimal bilateral in- FILL Combo 16p6 jection. 1st ratio among smokers vs. tear evaporation.org  february 25. with a predominance of one or the during sleep. 2). Periorbital edema is n engl j med 362. She also had evidence. Patients with Graves’ Ophthalmopathy.12 Levels of anti–thyrotropin-receptor anti- bodies correlate positively with clinical features of Graves’ ophthalmopathy13 and influence the prognosis14.10 The presence of anti–thyrotropin-recep- tor antibodies in virtually all patients with Graves’ ophthalmopathy suggests that immunoreactivity against the thyrotropin receptor underlies both Graves’ ophthalmopathy and hyperthyroidism. Upper-eyelid retraction is caused by in- Findings creased sympathetic stimulation of Müller’s muscle. on slit-lamp more likely to respond less well to immunosup. ring between the levator and surrounding tis- ment in the orbit. ropathy. which are difficult to detect in some as- says. Symptomatic corneal dryness is due to within the bony cavity. moderate eyelid edema. pressive therapies.15 Figure 1.23 In some patients. Please check carefully. whereas pa. Panel Line B shows 4-C a 40-year- SIZE Enon ophthalmopathy. re. and chemosis with slight erythema of the eye- severe disease is more likely to develop and is AUTHOR. increased enlargement of both extraocular muscle and adi. orbit and lower extremities may be important in tients over 60 years of age have more extraocular. nonsmokers. old womanARTIST: mst proptosis. All rights reserved. decompressing the of humoral and cell-mediated immunity.17 Smoking is associated with many autoimmune diseases.7). perhaps owing to JOB: 36208 ISSUE: 2-25-10 nonspecific suppression of T-cell activation. as compared with nonsmokers.16 In smokers with Graves’ EMail right caruncle. mechanisms of disease Graves’ hyperthyroidism is caused by autoan- tibodies that bind to the thyrotropin receptor on A thyroid follicular endothelial cells and thereby stimulate excess production of thyroid hor- mone. For personal use only. these antibody levels are especially elevated in patients with thyroid dermopathy. PLEASE NOTE: examination. expression of the disease. and incomplete eyelid closure pose tissue. and FIGURE 1a&b REG F chemosis junctival (edema) and erythema with 2nd 3rd the risk is proportional to the number of ciga. muscle swelling. other in some (Fig. CASE edema bilateral TITLE of the caruncles.org on May 6. leading to increased pressure sues. overaction of the levator muscle as it Many clinical signs and symptoms of Graves’ contracts against a tight inferior rectus. Copyright © 2010 Massachusetts Medical Society.20. No other uses without permission. rette toxins19 and trauma from heat transmitted Diplopia develops from inflammation and from the ethmoid sinuses through the lamina swelling of the extraocular muscles and is gen- papyracea (the thin medial orbital wall). 2017.

2010 H/T H/T FILL Combo 16p6 The New England Journal of Medicine AUTHOR.27 The polyan- ionic charge and extremely high osmotic pres- sure of this matrix substance make it extremely hydrophilic and capable of binding many times its weight in water. can worsen thyroid dermopathy.24 Moreover.26 The extraocular muscles are widely separated by an amorphous accumulation of granular material consisting primarily of colla. PLEASE NOTE: Downloaded from nejm. primarily congestive and most likely reflects decreased venous drainage due to vascular com- pression within the orbital space. All rights reserved. trauma itself may be a stimulus.9 ICM AUTHOR Bahn RETAKE 1st REG F FIGURE 2a-c 2nd CASE 3rd TITLE Revised EMail Line 4-C SIZE 728 Enon ARTIST: n engl j med 362. . when venous and lymphatic flow is compromised. C gen fibrils and glycosaminoglycans. However. Computed Tomographic Scans of Patients with Graves’ Ophthalmopathy and of a Normal Subject. Copyright © 2010 Massachusetts Medical Society. In inactive dis- ease. among which hyaluronan predominates (Fig. it has long been observed that thyroid dermopathy may develop at sites of trauma to the skin of the shoulders. Normal orbits are shown (Panel C) for comparison. de- pendent edema after prolonged standing.org on May 6. such as the volume or shape of the orbits25 or variations in venous B or lymphatic drainage. For personal use only. 3). atrophy and fibrosis of muscle bundles are evident. although with less abundant lymphocytic infiltration and no evidence of fat expansion. indi- vidual anatomical variability.9 Histologic studies of Graves’ ophthalmopathy have focused on extraocular muscles. Similarly. Consequently. Please check carefully.8  nejm. The n e w e ng l a n d j o u r na l of m e dic i n e Figure 2. electron microscopy reveals intact extraocular muscle fibers in such pa- tients. may increase the risk of extrathyroidal manifestations in patients with Graves’ disease. or other regions. owing to their obvious enlargement in patients with the disease. A Axial images of patients with Graves’ ophthalmopathy reveal generalized enlargement of the extraocular mus- cles with marked bilateral proptosis (Panel A) and marked bilateral proptosis and asymmetric involve- ment of the extraocular muscles with expansion of the orbital fat bilaterally (Panel B). In Graves’ ophthalmopathy. with hyaluronan accumulation in the reticular dermis. permission. arms. 2017.Figure has been No other uses redrawn without and type has been reset. the muscle bodies become edematous and may enlarge to many times their normal size. with extension of fibrous strands into adjacent adipose tissues.org  february mst 25. Histologic features of thyroid dermopathy are similar to those seen in the orbit.

indicating on- going cell-mediated immunity within the orbit.33 tralizing interleukin-1–receptor antagonist is rela- Cel lul a r Or igins tively low. B cells. participate in inflammation. tion of prostaglandin E2.42 Likewise.45 When exposed to TGF-β. but there are also minor populations of CD8+ cells.34. 6. mechanisms of disease Focal and diffuse mononuclear-cell infiltra- tion occurs within the extraocular and levator muscles.34 and a subgroup prominent cytoplasmic actin filaments that can of orbital fibroblasts can differentiate into ma.41 Although orbital fibroblasts Investigators have long postulated that the thyro­ produce high levels of the proinflammatory cyto­ tropin receptor is a target of autoimmunity with- kine interleukin-1.38. and hy- bital fibroblast proteins. 2010 729 The New England Journal of Medicine Downloaded from nejm. Indeed. The cell-surface marker Thy-1 (CD90) gens in Graves’ ophthalmopathy derives in part is overexpressed in orbital tissues in Graves’ from the finding that orbital T cells obtained ophthalmopathy44 and defines a population of from patients with Graves’ ophthalmopathy pro. lacrimal glands. relative proportions of Thy-1+ and Thy-1− that supports and cushions the globe. as compared with fibroblasts from other sites.40 suggesting whether muscle or fat expansion predominates that orbital fat may be especially prone to robust and the extent of fibrosis that develops. and other orbital structures.31 Macrophages. type 1 helper T cells predominate and pro- duce the cytokines interleukin-2. of differentiation into mature fat cells. fibro. extraocu. ture adipocytes37 that have increased expression Although fibroblasts within the extraocular mus- of thyrotropin receptor. plasma cells. including interleukins 1.43 suggests that their normal functions are dysreg. cles are almost exclusively Thy-1+. including orbital disorders are inflammatory.org  february 25.org on May 6. orbital fibroblasts treated with interferon-γ or leukoregulin synthesize par- Current evidence points to orbital fibroblasts as ticularly high levels of prostaglandin E2. All rights reserved. Copyright © 2010 Massachusetts Medical Society. Most TGF-β may affect disease expression.in the orbit and that its recognition by a circu- n engl j med 362. For personal use only. In disease of longer duration. a media- the target cells in Graves’ ophthalmopathy and tor with important roles in inflammation. .35 blasts exhibiting phenotypic and functional het- The concept that fibroblast proteins are autoanti. and adipose tissues in active Graves’ ophthalmopathy. their expression of the neu. Within the Orbital adipose tissue is a unique fat depot orbit.39 These cellular chang. approximately es lead to the characteristically enlarged eye half the fibroblasts within the adipose tissue muscles and expansion of orbital fat of patients lack this marker and are preadipocytes capable with Graves’ ophthalmopathy. aluronan. erogeneity. 16 and transforming growth factor β (TGF-β) within the orbit. The orbit contains subpopulations of fibro- ulated through autoimmune mechanisms. and adipocytes produce other inflamma.29. 2017.28 These cells are primarily CD4+ T cells. fibroblasts capable of cytokine-induced produc- liferate when exposed in vitro to autologous or. and macrophages. these fibro- blasts secrete large quantities of hyaluronan in blasts differentiate into myofibroblasts with response to various cytokines. interferon-γ.32. interleukin-5. intact striated extraocular muscle fibers widely sepa- tory mediators.36 These orbital fibro. interleukin-8. Figure 3. orbital fibroblasts Mol ecul a r Mech a nisms show exaggerated inflammatory responses to various stimuli. and interleukin-10 are dominant and propagate The focal and perivascular interstitial inflammatory autoantibody production. No other uses without permission. and tumor necrosis factor (TNF). fibroblasts and their degree of exposure to lar muscles. and fibrosis. and rated by amorphous granular material.46 inflammatory reactions. Histologic Appearance of Extraocular Muscle in Graves’ Ophthalmopathy (Hematoxylin and Eosin).30 In early stages of the dis- ease. repair. type 2 helper T cells that produce interleukin-4. mononuclear cell infiltrate is in close association with blasts.8  nejm.

68 Several reports The type I insulin-like growth factor receptor have described progressive proptosis in patients (IGF-IR) may be another important autoantigen in with a history of Graves’ ophthalmopathy. 4). on orbital ­f ibroblasts and. and thymus. in orbital fibroblasts. No other uses without permission. .67 PPAR-γ agonists stimulate adipogenesis directly contributes to the soft-tissue changes and expression of the thyrotropin receptor in cul.39.58-60 In the pretibial skin of patients with thyroid der.46. the level of the thyrotropin receptor is treatment of type 2 diabetes mellitus with elevated. and secrete interleukin-2 and interferon-γ.73 Thyrotropin can stimu- tified for Graves’ disease. 2017.74 In (PPAR-γ). leading to hyperplasia and in- levels of anti–thyrotropin-receptor antibodies in creased production of the thyroid hormones triiodothy- ronine (T3) and thyroxine (T4). support the concept that tor antibodies also recognize the thyrotropin receptor the thyrotropin receptor is the primary autoanti. suggesting that activation of the thyrotropin ing peroxisome-proliferator–activated receptor γ receptor initiates new fat-cell development. produced by activated T cells through the activ- bital anatomy between humans and rodents. tropin-Receptor Autoimmunity in Graves’ Ophthalmopathy mopathy.org  february 25. along with the close association crete anti–thyrotropin-receptor antibodies.47-49 The cloning of the thyrotropin re. including those gesting that thyrotropin-receptor ligation by anti– encoding PPAR-γ. complex (MHC) class II antigens.72 and T cells from such patients unclear whether there is a genetic susceptibility produce prostaglandins that induce adipogenesis to Graves’ ophthalmopathy apart from that iden. characteristic of Graves’ ophthalmopathy. particular sensitivity to PPAR-γ liga- methods have been used to induce the produc. Copyright © 2010 Massachusetts Medical Society. Orbital fibroblasts in 730 n engl j med 362.63 perhaps owing partly to differences in or. tured orbital preadipocytes. includ. interact with autoreac- with Graves’ ophthalmopathy. to helper T cells. For personal use only. as Graves’ ophthalmopathy. in association with major histocompatibility Subsequent studies showed elevated thyrotropin. initiate the tissue changes detected in several extrathyroidal tissues. receptor expression in orbital tissues in patients These cells become activated. ligands. much has been learned about the ge.57 the differentiation of B cells into plasma cells that se- These findings.71 This enzyme is up- Similarly. and thyrotropin-receptor antibodies within the orbit leptin. 2010 The New England Journal of Medicine Downloaded from nejm.65 Evidence that adipogenesis is active orbital fibroblasts that were transfected with in the orbit in Graves’ ophthalmopathy includes an activating mutant thyrotropin-receptor con- the results of microarray studies showing up.org on May 6.64 late adipogenesis in mouse embryonic stem cells. The n e w e ng l a n d j o u r na l of m e dic i n e lating thyrotropin-like factor explains the link Figure 4 (facing page).62 However. allows for the development of and several groups reported a low abundance of autoimmunity directed against this receptor. sug- and other adipocyte-related genes.75. A low creted type 1 helper T cytokines interferon-γ and tu- abundance of thyrotropin receptor can also be mor necrosis factor (TNF). characteristic of Graves’ ophthalmopathy.70 In animal models of Graves’ disease.69. All rights reserved. regulated in the orbit of patients with Graves’ netic basis of thyroid autoimmunity. tion may be a characteristic of orbital preadipo- tion of anti–thyrotropin-receptor antibodies. Anti-thyrotropin-recep- Graves’ ophthalmopathy. pression of this receptor in extrathyroidal tissues. Model of the Initiation of Thyro­ between hyperthyroidism and Graves’ ophthal. induction of transcriptional regulators. includ. A failure of T cells to tolerate the thyrotropin receptor. kidney. for unknown reasons.55 tides. tive B cells through CD154–CD40 bridges. the results have provided valuable insights into Factors that might stimulate adipogenesis the pathogenesis of hyperthyroidism. These anti- between Graves’ ophthalmopathy and Graves’ bodies stimulate the thyrotropin receptor on thyroid hyperthyroidism and the consistently elevated follicular epithelial cells. ity of cyclooxygenase-2. adrenal gland.51 enabled direct assessment of the ex. adiponectin. interleukin-6. which are proadipogenic prostaglandins ed. These cytokines induce est levels in those with clinically active disease. The thyro­ tropin receptor is internalized and degraded by antigen- thyrotropin receptor in cultured orbital fibro- presenting cells that present thyrotropin-receptor pep- blasts52-54 and in normal orbital-adipose tissues. Adipogenesis requires growth arrest and the even in the absence of other adipogenic factors. after the mopathy. in conjunction with the se- gen in Graves’ ophthalmopathy (Fig.56 with the high. but it is ophthalmopathy. and cytes. and Its Consequences. struct. various Therefore.8  nejm.76 both early adipocyte differentiation regulation of immediate early adipogenic genes66 and hyaluronan production were stimulated. well as in those without such a history. ing skin. ceptor50. within the orbit in patients with Graves’ oph- reproducible ocular changes resembling those in thalmopathy include naturally occurring PPAR-γ Graves’ ophthalmopathy have not been report.61 PPAR-γ agonists of the thiazolidinedione type.

org on May 6. mechanisms of disease Thyroid Hyperplastic gland thyroid follicle T3 T4 Thyroid follicular endothelial cell Interferon-γ Interleukin-2 Thyrotropin receptor Helper T cell CD154 B cell CD40 T-cell Thyrotropin-receptor receptor peptides MHC class II Antigen-presenting cell Anti–thyrotropin- TNF receptor antibody Interferon-γ Orbital Expanded orbital fibroblast tissues patients with the disease express higher levels of RANTES (regulated upon activation normal T-cell IGF-IR than F I G U R E fibroblasts. blocks IGF-IR and by transfecting fibroblasts Title blasts ME from patients with Graves’ ophthalmopathy with a dominant-negative mutant IGF-IR.8  nejm.org  february 25. sug- to synthesize interleukin-16 and the chemokine DE gesting that signaling through IGF-IR mediates Artist SBL AUTHOR PLEASE NOTE: Figure has been redrawn and type has been reset n engl j med 362.77 In addition. 2017. factors that enhance the IgGDraft 5fraction of pooled serum samples ob- 02/08/10 trafficking of CD4+ T cells. inhibited by a specific monoclonal antibody that tains Fig # autoantibodies 4 that stimulate orbital fibro. All rights reserved. Copyright © 2010 Massachusetts Medical Society. . 2010 731 Please check carefully The New England Journal of Medicine Issue date Downloaded from nejm. C O L O Rnormal expressed and secreted).78 This effect was tained from Author Bahn patients with Graves’ disease con. No other uses without permission. For personal use only.

For personal use only.83 In ad. which aug- the synthesis of hyaluronan and prostaglandin ments B-cell maturation and increases the production E2 by orbital fibroblasts. a subgroup of orbital fibroblasts (termed preadipocytes) begins to differentiate into adipocytes with increased ships between IGF-IR and the thyrotropin recep- thyrotropin-receptor expression. it is difficult to predict wheth- flammatory cytokines by macrophages. resulting in fibro- a costimulatory protein present on the surface of blast production of interleukin-1. can also stimulate production of hyaluronan and differentiation of the Thy- orbital fibroblasts to express adhesion molecules 1+ subgroup into myofibroblasts that participate in the that promote direct interaction between target development of ­f ibrosis. as a result. by fibroblasts most likely acts in an autocrine mopathy are opposed by others that mitigate fashion to stimulate hyaluronan synthesis84 and these effects. which stimulates both tients with Graves’ disease. formation of CD40–CD154 bridges. fibroblasts into myofibroblasts46 while it also cytes. the intact extraocular muscle fibers and within the orbit- such fibroblasts proliferate82 and produce high al adipose tissues to enlarge the volume of these tis- levels of interleukin-1 and interleukin-6. especially in late stages of the cells and inflammatory cells. and resident macrophag- expressing the CD40 ligand (also called CD154) es secrete interleukin-1.org on May 6. work. er the biologic agents that are effective in. Similarly. is proinflammatory and enhances B-cell inhibits adipogenesis in these cells. All rights reserved.84-86 Interleukin-1 and of anti–thyrotropin-receptor antibodies by plasma cells interferon-γ. Moreover. fibroblasts. No other uses without permission. Adipo- by resident fibroblasts and macrophages) increase cytes and fibroblasts produce interleukin-6. and thyrocytes.79 Tsui and colleagues80 have proposed When activated by anti–thyrotropin-receptor antibodies. 5). further expanding the tissue volume. The expression of CD154 in T cells allows for their direct interaction with orbital fibroblasts through the thalmopathy (Fig. These cytokines stimulate orbit- al fibroblasts to produce high levels of prostaglandin E2 directly activate orbital fibroblasts through the and hydrophilic hyaluronan that accumulates between formation of CD40–CD154 bridges.89 Finally. 2017. (regulated upon activation normal T-cell expressed and it has yet to be confirmed by other investigators. Interleukin-6. a product of activated the differentiation of the Thy-1+ subgroup of T cells. macrophages. mono. leukoregulin and interferon-γ (products mopathy also produce proadipogenic prostaglandins that stimulate preadipocytes to differentiate into mature of activated T cells) and interleukin-1 (secreted fat cells. cytes. to in- specifically blocks IGF-IR inhibits thyrotropin. including macrophages. stimu- induced kinase signaling. The disease-producing effects of some soluble mediators within the orbit in Graves’ ophthal. which enhance recruitment of activated Orbital fibroblasts participate in the autoim. sues. These cells express CD40. Our understanding of Graves’ ophthalmopathy pin-receptor expression in cultured orbital fibro. Therefore. differentiation and antibody production but also reduces the strength of many inflammatory Ther a peu t ic Impl ic at ions activities of interleukin-1. T cells and other mononuclear immune cells into the mune process within the orbit in Graves’ oph. T cells in patients with early Graves’ ophthalmopathy lymphocytes. and interferon-γ inhibit adipogenesis and thyrotro. crease their production of hyaluronan. orbit. Although some endogenous munotherapy for this disease. as suggested by colocalization studies and the antigen Thy-1 are stimulated by cytokines. within the orbit. Activated T cells in patients with Graves’ ophthal- dition. and adipo.8  nejm. that there are physical and functional relation.81 CD4+ T cells produce interferon-γ and TNF.org  february 25. and adipocytes. Model of Interactions between Graves’ disease stimulates hyaluronan synthesis Orbital Fibroblasts and the Autoimmune Process Leading by orbital fibroblasts from patients with Graves’ to the Tissue Changes Characteristic of Graves’ ophthalmopathy but not by normal orbital-cell ­Ophthalmopathy. TNF. as well as IgG obtained from pa. 2010 The New England Journal of Medicine Downloaded from nejm. points to several potential therapeutic targets and blasts88 and thus may counteract PPAR-γ ligation suggests difficulties in designing effective im- within the orbit. TGF-β produced rheumatoid arthritis91 will be useful in treating 732 n engl j med 362. secreted). disease. Copyright © 2010 Massachusetts Medical Society. including the finding that a monoclonal antibody that interferon-γ and tumor necrosis factor (TNF). The n e w e ng l a n d j o u r na l of m e dic i n e the process. say.73 others oppose additional roles within the adaptive immune net- inflammation by inhibiting production of in. IgG from patients with Figure 5 (facing page). cultures.90 The immune me- PPAR-γ ligands produced by activated T cells diators that cause pathogenic orbital changes have trigger adipocyte differentiation.87 TGF-β. Activated type 1 helper many types of cells. Orbital fibroblasts also produce trans- forming growth factor β (TGF-β). Although a role for lation of the insulin-like growth factor receptor (IGF-I receptor) expressed on orbital fibroblasts results in the IGF-IR and antibodies targeting this receptor in secretion of the chemokines interleukin-16 and RANTES Graves’ ophthalmopathy is potentially important. while others bearing tor. .

8  nejm. For personal use only. pathy. macrophage-attracting protein. Fig # such as the self-limited duration of preadipocytes of chemoattractant protein 1. All rights reserved. a 5 active Title disease and the central role of tissue ex. ophthalmopathy might affect the production by Author Bahn mopathy. since they have a benefi- the interleukin-6 receptor (Table 1).org  february 25.113 The findings pansion ME rather than destruction. such as anti-TNF agents92 and has been redrawn and type has been reset Please check carefully Graves’ ophthalmopathy. . Antioxidants such as agents 93 or Issue date targeting the interleukin-1 receptor selenium may be useful.101 n engl j med 362. 2017. Targeting TNF in patients with Graves’ countDraft for the4 unique 02/08/10 features of Graves’ ophthal.org on May 6. open study96 DE Agents that neutralize cytokine-induced in. CD154 T cell receptor antibody Orbital fibroblast T cell Interferon-γ Thy-1 TNF Proadipogenic prostaglandins Hyaluronan Interleukin-1 Prostaglandin E2 TGF-β Orbital adipocytes Macrophage Extraocular Interleukin-6 muscle Interleukin-1 Myofibroblast Expanded adipose tissue B cell Plasma cell Elevated Extraocular anti–thyrotropin. of a case report95 and a small. Copyright © 2010 Massachusetts Medical Society. should encourage the performance of random- Artist SBL flammation or production of hyaluronan by or- AUTHOR PLEASE NOTE: ized trials of anti-TNF therapy in patients with bitalFigurefibroblasts. Fibrosis muscle enlargement receptor antibody levels Graves’ ophthalmopathy. Answers will come tive potential treatments for Graves’ ophthalmo- COLOR FIGURE from randomized clinical trials designed to ac. mechanisms of disease Orbital Thyrotropin fibroblast Interleukin-16 IGF-I receptor RANTES receptor CD40 Helper Anti–thyrotropin. are attrac.94 cial effect on autoimmunity in Graves’ disease. 2010 733 The New England Journal of Medicine Downloaded from nejm. No other uses without permission.

.* Target Current Agent Description Potential Benefit Reference TNF Infliximab.107 protein CD154 IDEC-131 Humanized CD154-specific monoclonal Modulation of costimulatory pathways Kalunian et al. m e dic i n e and Glass110 Somatostatin receptor SOM230 Synthetic high-affinity somatostatin Inhibition of orbital preadipocyte proliferation Cozma et al.109 Straus Copyright © 2010 Massachusetts Medical Society. GC1008 TGF-β–specific monoclonal antibodies Reduction in fibrosis Pohlers et al. Mertens and Singh. Kwan-Morley and Albert.95 and hyaluronan production TNF receptor Etanercept TNF receptor–IgG Fc fusion molecule Reduction in inflammation.org on May 6. Feldmann. 2010 PPAR-γ Selective PPAR modulators Novel selective PPAR-γ antagonists Reduction in inflammation and orbital adipogenesis Knouff and Auwerx. Feldmann. leukocyte recruitment. Smolen et al. and TNF tumor necrosis factor.100 Oxygen free radicals Selenium Essential trace element Antiinflammatory activity Wertenbruch et al. No other uses without permission. Tsokos.99 clonal antibody and hyaluronan production TGF-β Lerdelimumab. . leukocyte recruitment.8  nejm. PPAR peroxisome-proliferator–activated receptor.105 CD3 ChAglyCD3 Fc-mutated CD3-specific monoclonal Induction of tolerance Keymeulen et al. For personal use only. 734 Table 1.97 Tan et al. Inhibition of orbital adipogenesis and hyaluronan Neumann et al.104 receptor antibody production Salvi et al. TGF transforming growth factor. leukocyte recruitment. adalimumab TNF-specific monoclonal antibodies Reduction in inflammation.108 antibody n engl j med 362.106 antibody n e w e ng l a n d j o u r na l The New England Journal of Medicine of CD28 Abatacept CTLA-4–immunoglobulin recombinant Modulation of costimulatory pathways Kremer et al.102 El Fassi et al. Potential Therapeutic Targets in Graves’ Ophthalmopathy.103 ofatumumab specific monoclonal antibodies tion.112 Downloaded from nejm. leukocyte recruitment. All rights reserved.96 and hyaluronan production The Interleukin-1 receptor Anakinra Interleukin-1–receptor antagonist Reduction in inflammation. Reduction in inflammation.101 CD20 Rituximab.111 analogue Thyrotropin receptor NIDDK/CEB-52 Low-molecular-weight thyrotropin.98 and hyaluronan production Interleukin-6 receptor Tocilizumab Interleukin-6 receptor–specific mono.92 Paridaens et al. Partially or fully humanized CD20.92 Durrani et al. ocrelizumab. Decreased antigen presentation and T-cell activa. 2017.org  february 25. possible modulation of anti–thyrotropin. receptor antagonist production * CTLA denotes cytotoxic T-lymphocyte–associated antigen 4.

Ele. is another suggests that various antibodies may activate possible approach. Newly observed affection of 2. References 1.115 Several case reports have suggested that ticular anti–thyrotropin-receptor antibodies or rituximab might be effective in active Graves’ other autoantibodies produced. These might be tailored to specific disease ease prevention in predisposed persons. Delineation of ophthalmopathy.120 and now we have the means the thyrotropin receptor-A–subunit protein. stration that some anti–thyrotropin-receptor an- mental than in those with the active disease. Many studies support a role may also be of benefit. unique signaling cascade not used by thyrotropin an anti-CD20 monoclonal antibody. which Unraveling the Graves’ ophthalmopathy co- potentially decrease production of both auto­ nundrum would enable the design of effective antibodies and inflammatory cytokines. Diseases of the heart. The quality of of benefit.org on May 6. Lond Med ments Pathol Ther 1825.103. learned. 2017. Copyright © 2010 Massachusetts Medical Society. rituximab decreased the total anti– therefore possible that various clinical phenotypes. The thyrotropin receptor on orbital fibro. and that immunoreactivity directed against IGF-IR the patients with this disease who have taught me so much. emphasizes the importance of performing ran- tablished hyperthyroidism. 3. For personal use only. the members of my laboratory who have target in the disease. and recent findings sug- with inactive Graves’ ophthalmopathy. be affected by the molecular signature of the par- ies. inhibitors of the cellular onists. von Basedow K.100 tibodies signal within the thyrocyte through a Targeting autoreactive B cells with rituximab. All rights reserved.114 In a study of Graves’ hyper. Although major C onclusions challenges remain. multicenter trials of cur- lar thyrotropin-receptor epitopes was achieved. attenuated subsequent hyper. hypertrophie des zellgewebes in der augen­ the thyroid: clinical lectures. n engl j med 362.8  nejm. controlled the functional heterogeneity of anti–thyrotropin- trials of this agent in Graves’ ophthalmopathy receptor antibodies and the signaling pathways are being led by Bahn117 and Salvi (Salvi M: per. Although recent studies suggest that there are Supported in part by a grant from the National Institute of novel mechanisms involved in the development Diabetes and Digestive and Kidney Diseases (DK77814). Exophthalmos durch 204. Graves R. rent treatments and new therapies on the hori- therefore.6:197- Surg J 1835. No potential conflict of interest relevant to this article was of Graves’ ophthalmopathy. The important role of disease mechanisms and may suggest new ap- cellular immunity in Graves’ ophthalmopathy proaches to therapy. such as euthyroid Graves’ ophthalmopathy or the mally but markedly reduced (66%) the subgroup predominance of muscle or fat enlargement.119 It is thyroidism.107 A recent study of a mouse model of life is markedly decreased in patients with Graves’ Graves’ disease showed that pretreatment with ophthalmopathy. I thank Drs. Similarly. zon. in whom gest that autoantibodies may also directly affect countering the antiinflammatory and antiadipo. The recent. much remains to be reported. excellent consensus statement on thyroidism by directing the autoantibody response therapy for Graves’ ophthalmopathy developed away from pathogenic epitopes.7:516-7. this approach may be useful for dis.2:111-28. patients with Graves’ ophthal- mopathy should benefit from these efforts. including perhaps the use of suggests that targeting CD3 on T cells106 may low-molecular-weight thyrotropin-receptor antag- hold promise. The recent demon- genic effects of this cytokine may be less detri. to precisely measure the effect of new therapies fore immunization with an adenovirus bearing on quality of life and specific clinical end points.118 Although ad. the same subunit. especially in patients for cellular immunity. Parry C. somewhat different signaling networks. .112 interactions necessary for T-cell signaling.org  february 25. involved will improve our understanding of orbital sonal communication). may of stimulatory anti–thyrotropin-receptor antibod. Marius Stan. blasts is likely to be an important autoimmune and George Bartley for their review of the manuscript and very helpful suggestions. No other uses without permission. höhle.116 and randomized. be. domized. 2010 735 The New England Journal of Medicine Downloaded from nejm. Wochenschr Heilkunde 1840. thyrotropin-receptor antibody levels only mini. and early evidence suggests studied Graves’ ophthalmopathy with me over many years. may be means of prevention or treatment. mechanisms of disease Neutralizing the profibrotic effects of TGF-β may also be involved. James Garrity. controlled. the orbital disease process. tolerance to particu. by the European Group on Graves’ Orbitopathy121 ministration of the subunit did not reverse es. phenotypes or stages and use combination ther- apies to improve outcomes. Michael Brennan.

tor. histology. JR. Ilstrup DM. Thyroid 2008. natural history. Kahaly GJ. 1989. Fook-Chong S. For personal use only. Morris JC III. No other uses without permission. 22.88:1939-46. Am J Pathol 2003. tion and predominant orbital T cell subset blasts of patients with Graves’ ophthal- Management of Graves’ ophthalmopathy: in Graves’ ophthalmopathy. patients develop milder and significantly 26.47:975-9. J Clin Endocrinol Metab pathophysiology and treatment options.3:815-9. Inoue Y. Gorman CA.329:1468-75.15:737-45. Kriss JP. AJNR Am J Neuroradiol and indicates adipogenesis in progress in et al. its apical angular capacity. et Cell Physiol 2003.18:1291-6. Baker G.org  february 25. Thy-1 expression in 18. and of orbital disease.8  nejm. Temporal relationship 21. elevated free thyroxine and triiodothyro. Moriarty P. Lösch C. Teo 39.92: 20. Lax H. et al. Orbital fibroblast heterogeneity may deter- 736 n engl j med 362. J Clin Endocrinol sota. Tews S. Earnest F IV. pathogenesis of thyroid-associated orbit- receptor and bioassay methods. 27. crinol Metab 2000.52:267-71. Bahn Kumar S. proach. Deen-van Leeuwen L. Evidence of adipocyte differen- Ophthalmic Res 1989. Graves ophthalmop­ N. Ajjan R. Prabhakar BS. Br J Ophthal. Heufelder AE. 2010 The New England Journal of Medicine Downloaded from nejm. Valyasevi RW. Valyasevi RW. Feldon S. Koumas L. . Jiang al.18:983-8. 2017. Analy. Patrinely 37. Clinical pre. et al. ing and risk of Graves’ disease.85:1194-9. Clinical utility of thyrotropin-recep. Wiersinga WM. Pathogenesis Metab 2000. between onset of Graves’ ophthalmopa. Kumar S. Ochs K. Am J Clin Dermatol 2005. Riley FC. 46. Br J Ophthalmol 2004. Unique attributes of orbital fibroblasts and tures of Graves’ ophthalmopathy. Enzmann DR. Janezic A.63:707-17. athy: the cycle of disease. 25.109:362-9. Tsai CC. docrinol Metab 2003. mopathy. 45. Karlson EW.284:C1429-C1437. Dis- thy. TH. Prummel MF. Shih MJ.92:59-64. R. Eckstein AK. 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