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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.

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The New England Journal of Medicine


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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.10 The presence of antithyrotropin-recep-
tor antibodies in virtually all patients with Graves
ophthalmopathy suggests that immunoreactivity
against the thyrotropin receptor underlies both
Graves ophthalmopathy and hyperthyroidism.11
The 5% of patients with Graves ophthalmopathy B
who are euthyroid or hypothyroid generally have
low titers of antithyrotropin-receptor antibod-
ies, which are difficult to detect in some as-
says.12 Levels of antithyrotropin-receptor anti-
bodies correlate positively with clinical features
of Graves ophthalmopathy13 and influence the
prognosis14; these antibody levels are especially
elevated in patients with thyroid dermopathy.15 Figure 1. Patients with Graves Ophthalmopathy.
Cigarette smoking is the strongest modifiable Panel A shows a 59-year-old woman with excess prop-
tosis, moderate eyelid edema, and erythema with mod-
risk factor for Graves ophthalmopathy (odds
erate
ICMeyelidAUTHOR Bahn
retraction RETAKE Con-
affecting all four eyelids. 1st
ratio among smokers vs. nonsmokers, 7.7), and FIGURE 1a&b
REG F chemosis
junctival (edema) and erythema with
2nd
3rd
the risk is proportional to the number of ciga- CASE edema
bilateral TITLE of the caruncles, with prolapse of
Revised the
rettes smoked daily.16 In smokers with Graves EMail
right caruncle, are evident. Panel
Line B shows
4-C a 40-year-
SIZE
Enon
ophthalmopathy, as compared with nonsmokers, old womanARTIST: mst proptosis,
with excess H/T H/T
minimal bilateral in-
FILL Combo 16p6
jection, and chemosis with slight erythema of the eye-
severe disease is more likely to develop and is AUTHOR, PLEASE NOTE: examination,
lids. She also had evidence, on slit-lamp
more likely to respond less well to immunosup- Figure has been redrawn and type has been reset.
of moderate superior limbic keratoconjunctivitis.
Please check carefully.
pressive therapies.17 Smoking is associated with
many autoimmune diseases, perhaps owing to JOB: 36208 ISSUE: 2-25-10
nonspecific suppression of T-cell activation, re- muscle swelling.23 In some patients, proptosis de-
duction of natural killer T cells, and impairment velops as the globe protrudes, decompressing the
of humoral and cell-mediated immunity.18 The orbit. Patients with crowding of enlarged mus-
strong association between Graves ophthalmo- 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, including direct effects of ciga- ropathy.
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). erally restrictive rather than paralytic. The infe-
rior rectus is the most commonly involved
A nat omic a l a nd His t ol o gic muscle. Upper-eyelid retraction is caused by in-
Findings creased sympathetic stimulation of Mllers
muscle, overaction of the levator muscle as it
Many clinical signs and symptoms of Graves contracts against a tight inferior rectus, or scar-
ophthalmopathy arise from soft-tissue enlarge- ring between the levator and surrounding tis-
ment in the orbit, leading to increased pressure sues. Symptomatic corneal dryness is due to
within the bony cavity.20,21 Most patients have eyelid retraction, decreased blinking, increased
enlargement of both extraocular muscle and adi- tear evaporation, and incomplete eyelid closure
pose tissue, with a predominance of one or the during sleep.
other in some (Fig. 2).22 Patients under 40 years Anatomical and mechanical features of the
of age tend to have fat expansion, whereas pa- orbit and lower extremities may be important in
tients over 60 years of age have more extraocular- expression of the disease. Periorbital edema is

n engl j med 362;8 nejm.org february 25, 2010 727


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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. Computed Tomographic Scans of Patients


with Graves Ophthalmopathy and of a Normal Subject. 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). Normal orbits are
shown (Panel C) for comparison.

primarily congestive and most likely reflects


decreased venous drainage due to vascular com-
pression within the orbital space. Similarly, de-
pendent edema after prolonged standing, when
venous and lymphatic flow is compromised, can
worsen thyroid dermopathy.24 Moreover, indi-
vidual anatomical variability, such as the volume
or shape of the orbits25 or variations in venous B
or lymphatic drainage, may increase the risk of
extrathyroidal manifestations in patients with
Graves disease. In Graves ophthalmopathy,
trauma itself may be a stimulus; it has long been
observed that thyroid dermopathy may develop
at sites of trauma to the skin of the shoulders,
arms, or other regions.9
Histologic studies of Graves ophthalmopathy
have focused on extraocular muscles, owing to
their obvious enlargement in patients with the
disease. However, electron microscopy reveals
intact extraocular muscle fibers in such pa-
tients.26 The extraocular muscles are widely
separated by an amorphous accumulation of
granular material consisting primarily of colla- C
gen fibrils and glycosaminoglycans, among which
hyaluronan predominates (Fig. 3).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. Consequently, the muscle
bodies become edematous and may enlarge to
many times their normal size. In inactive dis-
ease, atrophy and fibrosis of muscle bundles are
evident, with extension of fibrous strands into
adjacent adipose tissues. Histologic features of
thyroid dermopathy are similar to those seen in
the orbit, with hyaluronan accumulation in the
reticular dermis, although with less abundant
lymphocytic infiltration and no evidence of fat
expansion.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;8 nejm.org february mst
25, 2010 H/T H/T
FILL Combo 16p6
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mechanisms of disease

Focal and diffuse mononuclear-cell infiltra-


tion occurs within the extraocular and levator
muscles, lacrimal glands, and adipose tissues in
active Graves ophthalmopathy.28 These cells are
primarily CD4+ T cells, but there are also minor
populations of CD8+ cells, B cells, plasma cells,
and macrophages.29,30 In early stages of the dis-
ease, type 1 helper T cells predominate and pro-
duce the cytokines interleukin-2, interferon-,
and tumor necrosis factor (TNF), indicating on-
going cell-mediated immunity within the orbit.
In disease of longer duration, type 2 helper T
cells that produce interleukin-4, interleukin-5, Figure 3. Histologic Appearance of Extraocular Muscle
in Graves Ophthalmopathy (Hematoxylin and Eosin).
and interleukin-10 are dominant and propagate
The focal and perivascular interstitial inflammatory
autoantibody production.31 Macrophages, fibro- mononuclear cell infiltrate is in close association with
blasts, and adipocytes produce other inflamma- intact striated extraocular muscle fibers widely sepa-
tory mediators, including interleukins 1, 6, and rated by amorphous granular material.
16 and transforming growth factor (TGF-)
within the orbit.32,33
tralizing interleukin-1receptor antagonist is rela-
Cel lul a r Or igins tively low.42 Likewise, orbital fibroblasts treated
with interferon- or leukoregulin synthesize par-
Current evidence points to orbital fibroblasts as ticularly high levels of prostaglandin E2, a media-
the target cells in Graves ophthalmopathy and tor with important roles in inflammation.43
suggests that their normal functions are dysreg- The orbit contains subpopulations of fibro-
ulated through autoimmune mechanisms.34,35 blasts exhibiting phenotypic and functional het-
The concept that fibroblast proteins are autoanti- erogeneity. 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- fibroblasts capable of cytokine-induced produc-
liferate when exposed in vitro to autologous or- tion of prostaglandin E2, interleukin-8, and hy-
bital fibroblast proteins.36 These orbital fibro- aluronan.45 When exposed to TGF-, these fibro-
blasts secrete large quantities of hyaluronan in blasts differentiate into myofibroblasts with
response to various cytokines,34 and a subgroup prominent cytoplasmic actin filaments that can
of orbital fibroblasts can differentiate into ma- participate in inflammation, repair, and fibrosis.
ture adipocytes37 that have increased expression Although fibroblasts within the extraocular mus-
of thyrotropin receptor.38,39 These cellular chang- cles are almost exclusively Thy-1+, 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. of differentiation into mature fat cells. Within the
Orbital adipose tissue is a unique fat depot orbit, relative proportions of Thy-1+ and Thy-1
that supports and cushions the globe, extraocu- fibroblasts and their degree of exposure to
lar muscles, and other orbital structures. Most TGF- may affect disease expression, including
orbital disorders are inflammatory,40 suggesting whether muscle or fat expansion predominates
that orbital fat may be especially prone to robust and the extent of fibrosis that develops.46
inflammatory reactions. Indeed, as compared with
fibroblasts from other sites, orbital fibroblasts Mol ecul a r Mech a nisms
show exaggerated inflammatory responses to
various stimuli.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, their expression of the neu- in the orbit and that its recognition by a circu-

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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). Model of the Initiation of Thyro
between hyperthyroidism and Graves ophthal- tropin-Receptor Autoimmunity in Graves Ophthalmopathy
mopathy.47-49 The cloning of the thyrotropin re- and Its Consequences.
ceptor50,51 enabled direct assessment of the ex- A failure of T cells to tolerate the thyrotropin receptor,
pression of this receptor in extrathyroidal tissues, for unknown reasons, allows for the development of
and several groups reported a low abundance of autoimmunity directed against this receptor. 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.55 tides, in association with major histocompatibility
Subsequent studies showed elevated thyrotropin- complex (MHC) class II antigens, to helper T cells.
receptor expression in orbital tissues in patients These cells become activated, interact with autoreac-
with Graves ophthalmopathy,39,56 with the high- tive B cells through CD154CD40 bridges, and secrete
interleukin-2 and interferon-. These cytokines induce
est levels in those with clinically active disease.57
the differentiation of B cells into plasma cells that se-
These findings, along with the close association crete antithyrotropin-receptor antibodies. These anti-
between Graves ophthalmopathy and Graves bodies stimulate the thyrotropin receptor on thyroid
hyperthyroidism and the consistently elevated follicular epithelial cells, leading to hyperplasia and in-
levels of antithyrotropin-receptor antibodies in creased production of the thyroid hormones triiodothy-
ronine (T3) and thyroxine (T4). Anti-thyrotropin-recep-
Graves ophthalmopathy, support the concept that
tor antibodies also recognize the thyrotropin receptor
the thyrotropin receptor is the primary autoanti- on orbital f ibroblasts and, in conjunction with the se-
gen in Graves ophthalmopathy (Fig. 4). A low creted type 1 helper T cytokines interferon- and tu-
abundance of thyrotropin receptor can also be mor necrosis factor (TNF), initiate the tissue changes
detected in several extrathyroidal tissues, includ- characteristic of Graves ophthalmopathy.
ing skin, adrenal gland, kidney, and thymus.58-60
In the pretibial skin of patients with thyroid der- well as in those without such a history, after the
mopathy, the level of the thyrotropin receptor is treatment of type 2 diabetes mellitus with
elevated.61 PPAR- agonists of the thiazolidinedione type.69,70
In animal models of Graves disease, various Therefore, particular sensitivity to PPAR- liga-
methods have been used to induce the produc- tion may be a characteristic of orbital preadipo-
tion of antithyrotropin-receptor antibodies, and cytes.
the results have provided valuable insights into Factors that might stimulate adipogenesis
the pathogenesis of hyperthyroidism.62 However, within the orbit in patients with Graves oph-
reproducible ocular changes resembling those in thalmopathy include naturally occurring PPAR-
Graves ophthalmopathy have not been report- ligands, which are proadipogenic prostaglandins
ed,63 perhaps owing partly to differences in or- produced by activated T cells through the activ-
bital anatomy between humans and rodents. ity of cyclooxygenase-2.71 This enzyme is up-
Similarly, much has been learned about the ge- regulated in the orbit of patients with Graves
netic basis of thyroid autoimmunity, but it is ophthalmopathy,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- in orbital fibroblasts.73 Thyrotropin can stimu-
tified for Graves disease.64 late adipogenesis in mouse embryonic stem cells,
Adipogenesis requires growth arrest and the even in the absence of other adipogenic factors,
induction of transcriptional regulators, includ- suggesting that activation of the thyrotropin
ing peroxisome-proliferatoractivated receptor receptor initiates new fat-cell development.74 In
(PPAR-).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- struct,75,76 both early adipocyte differentiation
regulation of immediate early adipogenic genes66 and hyaluronan production were stimulated, sug-
and other adipocyte-related genes, including those gesting that thyrotropin-receptor ligation by anti
encoding PPAR-, interleukin-6, adiponectin, and thyrotropin-receptor antibodies within the orbit
leptin.67 PPAR- agonists stimulate adipogenesis directly contributes to the soft-tissue changes
and expression of the thyrotropin receptor in cul- characteristic of Graves ophthalmopathy.
tured orbital preadipocytes.46,68 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, as Graves ophthalmopathy. Orbital fibroblasts in

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mechanisms of disease

Thyroid Hyperplastic
gland thyroid follicle

T3
T4

Thyroid follicular
endothelial cell

Interferon-
Interleukin-2
Thyrotropin
receptor

Helper
T cell

CD154 B cell

CD40
T-cell
Thyrotropin-receptor receptor
peptides
MHC
class II
Antigen-presenting
cell Antithyrotropin-
TNF receptor antibody
Interferon-

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.77 In addition,
C O L O Rnormal expressed and secreted), factors that enhance
the IgGDraft 5fraction of pooled serum samples ob-
02/08/10 trafficking of CD4+ T cells.78 This effect was
tained from
Author Bahn patients with Graves disease con- inhibited by a specific monoclonal antibody that
tains
Fig # autoantibodies
4 that stimulate orbital fibro- blocks IGF-IR and by transfecting fibroblasts
Title
blasts
ME
from patients with Graves ophthalmopathy with a dominant-negative mutant IGF-IR, 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
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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. Moreover, IgG from patients with


Figure 5 (facing page). 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.
cultures.79 Tsui and colleagues80 have proposed When activated by antithyrotropin-receptor antibodies,
that there are physical and functional relation- 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, while others bearing
tor, as suggested by colocalization studies and the antigen Thy-1 are stimulated by cytokines, including
the finding that a monoclonal antibody that interferon- and tumor necrosis factor (TNF), to in-
specifically blocks IGF-IR inhibits thyrotropin- crease their production of hyaluronan. Similarly, stimu-
induced kinase signaling. 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, (regulated upon activation normal T-cell expressed and
it has yet to be confirmed by other investigators. secreted), which enhance recruitment of activated
Orbital fibroblasts participate in the autoim- T cells and other mononuclear immune cells into the
mune process within the orbit in Graves oph- orbit. The expression of CD154 in T cells allows for their
direct interaction with orbital fibroblasts through the
thalmopathy (Fig. 5). These cells express CD40,
formation of CD40CD154 bridges, resulting in fibro-
a costimulatory protein present on the surface of blast production of interleukin-1. Activated type 1 helper
many types of cells, including macrophages, T cells in patients with early Graves ophthalmopathy
lymphocytes, and thyrocytes.81 CD4+ T cells produce interferon- and TNF, and resident macrophag-
expressing the CD40 ligand (also called CD154) es secrete interleukin-1. 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 CD40CD154 bridges; as a result, 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-6.83 In ad- sues. Activated T cells in patients with Graves ophthal-
dition, leukoregulin and interferon- (products mopathy also produce proadipogenic prostaglandins
that stimulate preadipocytes to differentiate into mature
of activated T cells) and interleukin-1 (secreted
fat cells, further expanding the tissue volume. Adipo-
by resident fibroblasts and macrophages) increase cytes and fibroblasts produce interleukin-6, which aug-
the synthesis of hyaluronan and prostaglandin ments B-cell maturation and increases the production
E2 by orbital fibroblasts.84-86 Interleukin-1 and of antithyrotropin-receptor antibodies by plasma cells
interferon-, as well as IgG obtained from pa- within the orbit. Orbital fibroblasts also produce trans-
forming growth factor (TGF-), which stimulates both
tients with Graves disease, 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, especially in late stages of the
cells and inflammatory cells. disease.
The disease-producing effects of some soluble
mediators within the orbit in Graves ophthal- by fibroblasts most likely acts in an autocrine
mopathy are opposed by others that mitigate fashion to stimulate hyaluronan synthesis84 and
these effects. Interleukin-6, a product of activated the differentiation of the Thy-1+ subgroup of
T cells, macrophages, fibroblasts, and adipo- fibroblasts into myofibroblasts46 while it also
cytes, is proinflammatory and enhances B-cell inhibits adipogenesis in these cells.
differentiation and antibody production but also
reduces the strength of many inflammatory Ther a peu t ic Impl ic at ions
activities of interleukin-1.87 TGF-, TNF, and
interferon- inhibit adipogenesis and thyrotro- Our understanding of Graves ophthalmopathy
pin-receptor expression in cultured orbital fibro- points to several potential therapeutic targets and
blasts88 and thus may counteract PPAR- ligation suggests difficulties in designing effective im-
within the orbit. Although some endogenous munotherapy for this disease.90 The immune me-
PPAR- ligands produced by activated T cells diators that cause pathogenic orbital changes have
trigger adipocyte differentiation,73 others oppose additional roles within the adaptive immune net-
inflammation by inhibiting production of in- work. Therefore, it is difficult to predict wheth-
flammatory cytokines by macrophages, mono- er the biologic agents that are effective in, say,
cytes, and adipocytes.89 Finally, TGF- produced rheumatoid arthritis91 will be useful in treating

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The New England Journal of Medicine


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mechanisms of disease

Orbital
Thyrotropin fibroblast
Interleukin-16 IGF-I
receptor
RANTES receptor
CD40 Helper
Antithyrotropin- CD154 T cell
receptor antibody
Orbital
fibroblast
T cell Interferon- Thy-1
TNF
Proadipogenic
prostaglandins

Hyaluronan
Interleukin-1
Prostaglandin E2

TGF-

Orbital
adipocytes
Macrophage

Extraocular
Interleukin-6 muscle
Interleukin-1

Myofibroblast

Expanded
adipose tissue
B cell

Plasma cell
Elevated
Extraocular
antithyrotropin- 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- pathy. Targeting TNF in patients with Graves
countDraft for the4 unique 02/08/10
features of Graves ophthal- ophthalmopathy might affect the production by
Author Bahn
mopathy,
Fig #
such as the self-limited duration of preadipocytes of chemoattractant protein 1, a
5
active
Title disease and the central role of tissue ex- macrophage-attracting protein.113 The findings
pansion
ME rather than destruction. of a case report95 and a small, open study96
DE Agents that neutralize cytokine-induced in- 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, 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, since they have a benefi-
the interleukin-6 receptor (Table 1), are attrac- 94 cial effect on autoimmunity in Graves disease.101

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734
Table 1. Potential Therapeutic Targets in Graves Ophthalmopathy.*

Target Current Agent Description Potential Benefit Reference


TNF Infliximab, adalimumab TNF-specific monoclonal antibodies Reduction in inflammation, leukocyte recruitment, Feldmann,92 Durrani et al.95
and hyaluronan production
TNF receptor Etanercept TNF receptorIgG Fc fusion molecule Reduction in inflammation, leukocyte recruitment, Feldmann,92 Paridaens et al.96
and hyaluronan production
The

Interleukin-1 receptor Anakinra Interleukin-1receptor antagonist Reduction in inflammation, leukocyte recruitment, Mertens and Singh,97 Tan et al.98
and hyaluronan production
Interleukin-6 receptor Tocilizumab Interleukin-6 receptorspecific mono- Reduction in inflammation, leukocyte recruitment, Smolen et al.99
clonal antibody and hyaluronan production
TGF- Lerdelimumab, GC1008 TGF-specific monoclonal antibodies Reduction in fibrosis Pohlers et al.100
Oxygen free radicals Selenium Essential trace element Antiinflammatory activity Wertenbruch et al.101
CD20 Rituximab, ocrelizumab, Partially or fully humanized CD20- Decreased antigen presentation and T-cell activa- Tsokos,102 El Fassi et al.,103
ofatumumab specific monoclonal antibodies tion; possible modulation of antithyrotropin- Kwan-Morley and Albert,104
receptor antibody production Salvi et al.105
CD3 ChAglyCD3 Fc-mutated CD3-specific monoclonal Induction of tolerance Keymeulen et al.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-4immunoglobulin recombinant Modulation of costimulatory pathways Kremer et al.107


protein
CD154 IDEC-131 Humanized CD154-specific monoclonal Modulation of costimulatory pathways Kalunian et al.108
antibody

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


PPAR- Selective PPAR modulators Novel selective PPAR- antagonists Reduction in inflammation and orbital adipogenesis Knouff and Auwerx,109 Straus

Copyright 2010 Massachusetts Medical Society. All rights reserved.


m e dic i n e

and Glass110
Somatostatin receptor SOM230 Synthetic high-affinity somatostatin Inhibition of orbital preadipocyte proliferation Cozma et al.111
analogue
Thyrotropin receptor NIDDK/CEB-52 Low-molecular-weight thyrotropin- Inhibition of orbital adipogenesis and hyaluronan Neumann et al.112

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receptor antagonist production

* CTLA denotes cytotoxic T-lymphocyteassociated antigen 4, PPAR peroxisome-proliferatoractivated receptor, TGF transforming growth factor, and TNF tumor necrosis factor.
mechanisms of disease

Neutralizing the profibrotic effects of TGF- may also be involved. Many studies support a role
may also be of benefit, especially in patients for cellular immunity, and recent findings sug-
with inactive Graves ophthalmopathy, in whom gest that autoantibodies may also directly affect
countering the antiinflammatory and antiadipo- the orbital disease process. The recent demon-
genic effects of this cytokine may be less detri- stration that some antithyrotropin-receptor an-
mental than in those with the active disease.100 tibodies signal within the thyrocyte through a
Targeting autoreactive B cells with rituximab, unique signaling cascade not used by thyrotropin
an anti-CD20 monoclonal antibody, is another suggests that various antibodies may activate
possible approach.114 In a study of Graves hyper- somewhat different signaling networks.119 It is
thyroidism, rituximab decreased the total anti therefore possible that various clinical phenotypes,
thyrotropin-receptor antibody levels only mini- such as euthyroid Graves ophthalmopathy or the
mally but markedly reduced (66%) the subgroup predominance of muscle or fat enlargement, may
of stimulatory antithyrotropin-receptor antibod- be affected by the molecular signature of the par-
ies.115 Several case reports have suggested that ticular antithyrotropin-receptor antibodies or
rituximab might be effective in active Graves other autoantibodies produced. Delineation of
ophthalmopathy,103,116 and randomized, controlled the functional heterogeneity of antithyrotropin-
trials of this agent in Graves ophthalmopathy receptor antibodies and the signaling pathways
are being led by Bahn117 and Salvi (Salvi M: per- involved will improve our understanding of orbital
sonal communication). The important role of disease mechanisms and may suggest new ap-
cellular immunity in Graves ophthalmopathy proaches to therapy, including perhaps the use of
suggests that targeting CD3 on T cells106 may low-molecular-weight thyrotropin-receptor antag-
hold promise. Similarly, inhibitors of the cellular onists.112
interactions necessary for T-cell signaling, which Unraveling the Graves ophthalmopathy co-
potentially decrease production of both auto nundrum would enable the design of effective
antibodies and inflammatory cytokines, may be means of prevention or treatment. The quality of
of benefit.107 A recent study of a mouse model of life is markedly decreased in patients with Graves
Graves disease showed that pretreatment with ophthalmopathy,120 and now we have the means
the thyrotropin receptor-Asubunit protein, be- to precisely measure the effect of new therapies
fore immunization with an adenovirus bearing on quality of life and specific clinical end points.
the same subunit, attenuated subsequent hyper- The recent, excellent consensus statement on
thyroidism by directing the autoantibody response therapy for Graves ophthalmopathy developed
away from pathogenic epitopes.118 Although ad- by the European Group on Graves Orbitopathy121
ministration of the subunit did not reverse es- emphasizes the importance of performing ran-
tablished hyperthyroidism, tolerance to particu- domized, controlled, multicenter trials of cur-
lar thyrotropin-receptor epitopes was achieved; rent treatments and new therapies on the hori-
therefore, this approach may be useful for dis- zon. These might be tailored to specific disease
ease prevention in predisposed persons. phenotypes or stages and use combination ther-
apies to improve outcomes. Although major
C onclusions challenges remain, patients with Graves ophthal-
mopathy should benefit from these efforts.
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).
No potential conflict of interest relevant to this article was
of Graves ophthalmopathy, much remains to be reported.
learned. The thyrotropin receptor on orbital fibro- I thank Drs. Michael Brennan, Marius Stan, James Garrity,
blasts is likely to be an important autoimmune and George Bartley for their review of the manuscript and very
helpful suggestions; the members of my laboratory who have
target in the disease, and early evidence suggests studied Graves ophthalmopathy with me over many years; and
that immunoreactivity directed against IGF-IR the patients with this disease who have taught me so much.

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