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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
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-
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
n engl j med 362;8 nejm.org february 25, 2010 731
Please check carefully
The New England Journal of Medicine
Issue date
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Copyright 2010 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e
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
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
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
Downloaded from nejm.org on May 6, 2017. For personal use only. No other uses without permission.
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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