immunological considerations jason ahee, md matheson a ......orbital congestion with increased...
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THYROID EYE
DISEASE:
Jason Ahee, MD
Matheson A. Harris, MD
Immunological Considerations
Utah Oculoplastic Consultants
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GRAVES’ DISEASE
12th Century ACE Persian Physician
First account of neck swelling associated with
exophthalmos
1786 Caleb Parry (Bath Medical Soc)
Read a paper presenting a 37 y/o female with
goiter, exophthalmos, and lid retraction
Was published posthumously in 1825
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GRAVES’ DISEASE
1835 Robert J. Graves (Dublin)
Described 3 cases with cardiac palpitations,
goiter, 1 with exophthalmos, and lid retraction
1840 Carl Adolph von Basedow (Germany)
Published 4 patients with similar findings and
reviewed the literature
His name was first associated with this disease in
1860 by Trousseau in France
His name was first associated with this disease in
1859 by Charcot
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THE THYROID
GLAND _ TRH
Hypothalmus
primary factor
regulating growth
and differentiation
of thyroid
follicular cells
T4, T3
cellular metabolism
growth & development
TSH
+
acts on the
anterior pituitary
to synthesize and
release thyroid
stimulating
hormone (TSH)
binds to TSH receptors
on thyrocytes
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Immune-mediated disorders
Reactive immune cells are directed against
“self- antigens”
Common auto-immune diseases are:
AUTO-IMMUNE DISEASES
type 1 diabetes
rheumatoid arthritis
multiple sclerosis
Crohn’s disease
lupus
Graves’ disease
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STEPS IN CHRONIC AUTOIMMUNE
DISEASE
Initial phase: loss of specific self-tolerance
Afferent phase: recognition of self antigens by APCs,
and transport to peripheral lymph nodes
Activation phase: T-cell activation and proliferation
Effector phase: T-cell migration to the target
tissues, help other cells, and participate in inducing
the inflammatory process
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IMMUNE SELF TOLERANCE
some B- and T-cells with low specific
affinity escape censorship
anti-self
anti-self
Bone marrow
B T
T cell
Thymus
B cell anti-self
high ag affinity
anti-self
high ag affinity
intra-thymic
negative selection
intra-marrow
negative selection
T cell
deletion
B cell
deletion
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MHC I
MHC II
T cell cross-reactive stimulation
APC
anti-self
T cell
Thyrocyte
apoptosis
anti-self
T cell
TCR
foreign cross-reactive or native
peptide epitope fragment
low affinity receptor
hi affinity receptor
Initiation of Autoimmune
Disease
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Loss of Self-Tolerance
Viral infection or epitope immune activation
APC Thyrocyte
Anti-self
T cell
apoptosis
MHC II
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GRAVES’ DISEASE
Autoimmune etiology
A chronic organ-specific systemic disease
Primarily involves the
thyroid gland
Secondarily involves
other tissues
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GRAVES’ DISEASE Genetic
Predisposition:
25% – 35% concordance
rate among MONOzygotic
twins
1.9% concordance rate
among DIzygotic twins
0.45% incidence of GD among all twins
0.16% incidence of GD among 1st
degree relatives of affected twins
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GRAVES’ DISEASE Environmental
Factors:
Stress
Smoking
Exogenous Iodine
intake
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GRAVES’ DISEASE Smoking:
Graves’ Disease: smokers = 83%
Normal Controls: smokers = 46%
N = 1730
Normal controls: smokers = 30%
Graves’ Disease: smokers = 48%
Graves’ Orbitopathy: smokers = 64%
Vestergaard, 2002: Review of 25 studies
Graves’ Disease = odds ratio: ever vs never smoker = 1.9
TED = odds ratio: ever vs never smoker = 4.4
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GRAVES’ DISEASE Smoking:
Improvement after steroids: non-smokers = 64%
Improvement after steroids: smokers = 15%
Improvement after RT: non-smokers = 94%
Improvement after RT: smokers = 68%
Karadimas et al. 2003: 85 smokers with TED
warned to quit, followed for 1 year;
cessation rate = 0%
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GRAVES’ DISEASE Smoking:
How does smoking influence the occurrence of GD?
- unknown
- ?epiphenomenon related to stress
- smoke constituents can up-regulate
expression of HLA-DR
-smoke constituents can increase specific
cytokine secretion and adhesion
molecule expression, implicated in GD
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GRAVES’ DISEASE Stress:
Relationship between stress and GD suggested
since the early 19th C
Now supported by numerous studies
Risk of GD 6.3 X – 7.7 X greater for those with
high scores on stressful life events (SLE)
questionnaires than those with lower scores
Incidence of Graves’ disease higher under
stressful situations, e.g. WWII in eastern Europe
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GRAVES’ DISEASE Stress:
How does stress influence the occurrence of GD?
- unknown
- may be related to the tight relationship between
the hypothalamic pituitary adrenocortical axis
and the autonomic NS and the immune system
-stress can activate this system resulting in
secretion of cytokines which are implicated in GD
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GRAVES’ DISEASE Environmental
Iodine:
Areas with higher ingestion of Iodine = greater
incidence of GD
Remission rate on therapy higher with low Iodine
ingestion, lower with high Iodine ingestion
Relapses more common in patients ingesting higher
levels of Iodine
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GRAVES’ DISEASE Environmental
Iodine:
How does exogenous Iodine influence the
occurrence of GD?
- unknown
- in vitro, Iodine can stimulate lymphocyte activity
- Iodine increases anti-TSHR antibody titers in GD
patients
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GRAVES’ DISEASE Demographics:
Females outnumber males
by 5:1
Responsible for 20% of all
unilateral and 80% of
all bilateral cases of
exophthalmos
Childhood to old-age, but most commonly
middle-aged adults
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GRAVES’ DISEASE
Primary Target of the Immune Response:
Thyrotropin (TSHR) receptor antigen of the thyrocyte
Stimulating abs activate the cAMP cascade
TSH receptor
anti-self
lymphocyte
Thyrocyte cAMP
may be
stimulating
or blocking T4, T3
Blocking abs block cAMP synthesis or prevent TSHR binding
X
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GRAVES’ DISEASE
Phalangeal Acropachy = 1% soft-tissue swelling (clubbing)
periosteal new bone formation
Immune Disease in the TSHR Ectodomain:
Thyroid-Associated Dermopathy = 8% “pre-tibial” inflammation
glycosaminoglycan deposition
edema
nodular fibrosis
Thyroid Eye Disease (TED) = 30% - 40%
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GRAVES’ DISEASE
Secondary Targets in the Orbit:
Orbital fibroblast and pre-adipocyte fibroblast
initiate homing of lymphocytes into the orbit
presence of mRNA encoding
exons 1-10 of human TSHR gene
presence of a TSHR-like protein
in fibroblasts of Graves’ patients
absence of these proteins in normal orbits
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GRAVES’ DISEASE Secondary Targets in the Orbit:
Relationship to eye muscle antigens (G2s, Fp)
70% of patients with TED
Most likely secondary to muscle injury from
orbital inflammation
Abs against eye muscle antigens seen in:
7% of normal controls
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Thyroid Eye Disease
Clinical Manifestations of TED:
Subtypes
Congestive orbitopathy
diffuse orbital edema
congested vascular tree
Myopathic orbitopathy
relatively normal muscles
enlarged extraocular muscles
minimal congestive findings
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Thyroid Eye Disease
Clinical Manifestations of TED:
Conjunctival injection and chemosis
Proptosis
Eyelid injection
Strabismus
Compressive optic
neuropathy
Dry eyes
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Thyroid Eye Disease
Conjunctival Injection and Chemosis:
Orbital congestion with increased venous pressure
Dilated anterior ciliary
arteries
?Inflammatory involvement
of conjunctival fibroblasts
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Thyroid Eye Disease
Dry Eyes
TOA patients show significant ocular surface damage
Related to decreased tear secretion
Lacrimal acinar cells express TSH receptor antigens
May be a focus of inflammatory damage resulting in
secretory impairment
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Increased orbital fat
volume from edema
Thyroid Eye Disease Proptosis:
Enlarged extraocular
muscle volume
mild moderate globe
prolaps
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Thyroid Eye Disease
Eyelid Retraction:
CT fibrosis
Contraction of the
levator muscle sheath
Shortening of fornix
suspensory ligaments
Fibrosis of Müller’s
muscle
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Thyroid Eye Disease
Diplopia:
Glycosaminoglycan
deposition
Fibrosis of EOM sheaths,
perimysium, & suspensory
fascia
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Thyroid Eye Disease
Compressive Optic Neuropathy:
Optic nerve compression by EOM’s
Fibrosis of Annulus
of Zinn
Orbital congestion &
fascial-compartment
syndrome
Short optic nerve
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Thyroid Eye Disease
Clinical Activity Index:
Orbital pain 0 = none 1 = at rest 2 = with movement
Chemosis 0 = none 1 = mild 2 = severe
Eyelid edema 0 = none 1 = mild 2 = severe
Conjunctival injection 0 = none 1 = present
Eyelid injection 0 = none 1 = present
Total 0 8
Orbitopathy: mild = 0-3 moderate = 4-5 severe = 6-8
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Thyroid Eye Disease
Natural History of Clinical Activity:
100%
50%
0%
time
clinical
activity disease severity
acute
inflammatory
phase
chronic
fibrotic phase
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increased fat
volume enlarged
EOM’s
Thyroid Eye Disease
Radiographic Findings:
best
evaluated on
coronal
sections
may involve only
one muscle
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Euthyroid Thyroid Eye Disease
No evidence of clinical
hyperthyroidism
Clinical manifestations of TAO
Radiographic evidence
of orbitopathy
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Euthyroid TAO patients:
Tend to be slightly older than hyperthyroid
TAO patients (56 yrs vs 52 yrs)
Tend to be less likely
female compared to
hyperthyroid TOA
patients
Euthyroid Thyroid Eye Disease
0
10
20
30
40
50
60
70
80
Hyperthyroid Euthyroid
Male
Female
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Euthyroid Thyroid Eye Disease
TSHR blocking abs can be found
in up to 29% of Graves’ patients
Variable activity subtypes of
TSHR abs
stimulating
anti TSHr
lymphocyte
Thyrocyte cAMP
blocking anti TSHr
lymphocyte
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Orbital TSH Receptor Epitope
anti-TSHR T-Cell
Orbital Fibroblast
TSH epitope
receptor site
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T-Cell Homing Mechanisms
TSH epitope
receptor site
TGF-1 receptor
upregulated 4-5 X
occupies same physical
space as TSHR
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TSH epitope
receptor site
TGF-1 receptor
T-Cell Homing Mechanisms
Graves’ specific IgG
Rantes
IL-16
T-cell traffic
signalling
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Fibroblast-T cell Interaction
inflammatory
mediators
transforming
growth factors
cytokine
s
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prostaglandins nitric oxide histamine proteases collagenases
inflammatory mediators
lymphatic
relaxation valve
incompetence,
stasis
vascular
dilatation
increased
blood flow
vascular
permeability
tissue
edema
Fibroblast-T cell Interaction
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augmented
expression of
TSHR; allows
it to serve as
an autoantigen
chaperone ag’s
APC
Fibroblast-T cell Interaction
INF
TNF
IL 1
IL 2, 6
cytokines
T cell migration ICAM -1
ICAM - 2
VCAM - 1
endothelial
adhesion
heat shock
proteins
APC HLA –
DR3
cytokine
release
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TNF-
T T
VCA
M
T
ICA
M
selectins
Adhesion
Molecules
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Glycosaminoglycan
synthesis
increased water binding and tissue edema
INF
TNF
IL 1
IL 2, 6
cytokines
altered
structure
and
distribution
pattern
Fibroblast-T cell Interaction
proptosis, enlarged EOMS, lid swelling
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INF
TNF
IL 1
IL 2, 6
cytokines
collagen
synthesis
CT Fibrosis
Fibroblast-T cell Interaction
eyelid
retraction,
EOM restriction
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INF
TNF
IL 1
IL 2, 6
cytokines
increased fat
volume pre-adipocyte differentiation
Fibroblast-T cell Interaction
proptosis
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T-cell
proliferation
transforming growth factors
TGF - platelet derived GF insulin-like GF
fibrosis
Fibroblast-T cell Interaction
EOM
restriction
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Thyroid Eye Disease
Rationale for Treatment:
Symptomatic therapy while disease is active
Medical treatment for significant congestion
Radiotherapy for severe congestion or early
optic nerve compression
Emergency intervention for vision-threatening signs
Definitive surgical correction after disease stabilizes
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Symptomatic Therapy
Artificial tears and punctal plugs for dry eyes
Fresnel prisms for diplopia
Botulinum toxin for lid retraction
Lateral tarsorrhaphy for proptosis and globe prolaps
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Steroid Therapy Indicated for acute congestive
inflammatory orbitopathy and
early compressive neuropathy
Improvement can be seen in
motility and vision in up to 50%
However, steroids are not a long-term treatment option
Pulsed IV steroids may be
more effective
Non-steroidal anti-inflammatory drugs
(Voltaren 50mg bid) a better option
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Radiation Therapy Indicated for congestive orbitopathy and early
compressive optic neuropathy
2000 cGy total, in 200 cGy fractions,
sparing lens, lacrimal gland,
and sella
Average dose to lens = 100 cGy
Risk for radiation-induced malignancy = 0.7%
No difference at 6 months between
1600 cGy vs 2400 cGy
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Radiation Therapy Produces favorable results
in 50 – 60% of cases
Poor results with longstanding
inactive disease
Generally not very useful for
diplopia or proptosis
Gorman, 2002: no benefit at 6 months
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Surgical Therapy
Requires stability of disease for best results
Staged Surgical Approach:
1. Orbital decompression
2. Strabismus surgery
3. Eyelid recession and blepharoplasty
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Orbital Decompression
Indications:
Compressive optic neuropathy
Corneal exposure
Orbital congestion
Uncontrolled glaucoma
Cosmetic improvement
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Orbital Decompression
Transconjunctival approach
to the orbital floor
Transcaruncular approach
to the medial wall
Removal of extraconal
and intraconal fat
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Orbital Decompression
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click on picture to start movie
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Strabismus Surgery
Indications:
Symptomatic stable diplopia
Cosmetic deformity
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Eyelid Recession
Indications:
Exposure keratopathy
Subluxation of globe
Cosmetic improvement
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Upper Eyelid Recession
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Lower Eyelid Recession
Disinsertion and recession of capsulopalpebral
fascia
Placement of interpositional graft:
hard palate mucosa
auricular cartilage
free tarsoconjunctival graft
Medpor interpositional disk
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Lower Eyelid Recession
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Blepharoplasty
Excision of excess skin and fat
Usually combined with eyelid recession
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Future Management Options Immunomodulation of specific T cell receptors
Interference with target APC presentation of antigen:
MHC expression, co-stimulatory molecule blockage
APC
Engineering of soluble human TSHR
neutralizing antigens in the ectodomain
T cell
TCR
Specific cytokine/chemokine inhibition
TNF-
TSHR