thyroid eye disease past, present, and future · 3. thyroid antibody levels may provide early...
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Thyroid Eye Disease – Past, Present, and Future
Deepak Ramesh, MDSomerset, NJ
Nov 19, 2020
Thyroid Eye Disease
1. Pathophysiology
2. Clinical Manifestations
3. Medical Therapies
4. Surgical Therapies
5. Future Directions
Thyroid Eye Disease
1. Pathophysiology
2. Clinical Manifestations
3. Medical Therapies
4. Surgical Therapies
5. Future Directions
Pathophysiology
environmental factors
genetic factors
molecular biology
thyroid-stimulating antibodies
IGF-1
cytokines
Graves’ treatments
antithyroid medicine
radioactive iodine
thyroidectomy
Pathophysiology
25-50% of Graves’
disease patients
have TED
natural history:
improvement
(60%)
stabilization (25%)
worsening (15%)
Bartley 1994
A disease of the young!
A disease of the young!
A disease of the young!
Pathophysiology – Rundle’s curve
active phase: 18-
36 months
quiescent phase
reactivation: 10%
may be reactivated
by surgery
Rundle F et al. 1945
Pathophysiology – Genetics
females more likely to
have disease
males more likely to have
severe disease
euthyroid family members
of TED patients have
early signs (retraction)
twin studies: Graves’ is
partially heritable (30%
monozygotic vs 3%
dizygotic twins) Ardley et al. 2012
Pathophysiology – Environment
gut microbiome
Yersinia enterocolitica
infection can lead to TSH-R
cross-reactivity
smoking
RR: 2-7X
correlates to # of cigarettes
smoked after Graves’ onset
partially reversible
reactive oxygen species
Pathophysiology – Environmental [trace minerals]
selenium
cofactor for antioxidant and anti-
inflammatory proteins
100μg daily reduced progression in mild
TED
European trial – selenium-deficient soil?
Marcocci et al. 2011
Liu et al. 2018
Pathophysiology – Environmental [trace minerals]
Liu et al. 2018
Pathophysiology – Environmental [Vitamin D]
Vitamin D
deficiency associated with
various autoimmune diseases
found to be decreased in
Graves’ patients compared to
normal
not correlated to antibody
concentrations or clinical
severity
Planck et al. 2018
Pathophysiology – Molecular Biology
Smith et al. 2018
Pathophysiology – Molecular Biology
Smith et al. 2018
Pathophysiology – Molecular Biology
circulating antibodies
anti-TSHR (thyroid-
stimulating hormone
receptor)
anti-TPO (thyroid
peroxidase)
anti-Tg (thyroglobulin)
Bahn et al. 1998
1. Thyroid-related proteins are expressed in the orbit.
2. Antibody levels are directly correlated with disease severity and can be predictive.
Pathophysiology – Molecular Biology
Pathophysiology – Molecular Biology
Smith et al. 2018
Pathophysiology – Molecular Biology
IGF-1 (insulin-like growth factor)
activates cell growth pathways
co-localizes with TSH-R
synergistic but not identical stimulation
Tsui et al. 2008
TSHR IGF-1 combined
Pathophysiology – Molecular Biology
Smith et al. 2018
Pathophysiology – molecular biology
antithyroid medicine: methimazole, propylthiouracil
inhibit thyroid hormone formation
does not change levels of circulating antibody
30-40% recurrence after stopping medicine
radioactive iodine
uptake by tissues with Na/I cotransporter, kills the cell
surgical thyroidectomy
leads to permanent hypothyroidism afterwards
small risk of parathyroid gland dysfunction, nerve injury, thyroid
storm intraoperatively (~1% combined)
Pathophysiology Bartalena et al. 1998
Tallstedt et al. 1992
Laurberg et al. 2008
RAI increases likelihood of TED and
worsens severity
steroid pretreatment can help
surgery slightly better than medicine
RAI + steroids vs surgery?
Pathophysiology
1. TED pathogenesis is complicated and poorly understood.
2. Genetic, environmental, and nutritional factors play a role.
3. Thyroid antibody levels may provide early diagnosis.
past: wait and watch
present: may detect early cases with antibody levels
future: combination of genetic analysis, vitamin status, and antibody levels
to predict which Graves’ patients will develop TED – treat
prophylactically.
Thyroid Eye Disease
1. Pathophysiology
2. Clinical Manifestations
3. Medical Therapies
4. Surgical Therapies
5. Future Directions
Clinical Manifestations
1. Ocular Surface Disease
2. Eyelid
3. Muscle
4. Orbit
Clinical Manifestations – Ocular Surface
SLK
inflammatory dry
eye
exposure
keratopathy
Huang et al. 2012
Clinical Manifestations – Ocular Surface
OSDI vs CAS
p-value Odds ratio
Sex 0.294 0.220
Age 0.853 0.995
CAS score 0.034* 2.018
Any lagophthalmos 0.609 1.760
Any PEE 0.996 0.995
Any SLK 0.834 0.713
Mean MRD1 0.800 0.905
p-value Odds ratio
Sex0.253 0.336
Age0.441 1.021
CAS score0.249 1.533
Any lagophthalmos0.604 1.540
Any PEE0.029* 5.886
Any SLK0.943 1.127
Mean MRD10.179 0.725
>9 months
<9 months
Rootman et al. (unpublished)
Clinical Manifestations – Eyelid
eyelid
retraction
lagophthalmos
lid lag
Clinical Manifestations – Myopathy
strabismus
elevated IOP
in upgaze
Clinical Manifestations – Myopathy
© Dr. Ralph Eagle
Clinical Manifestations – Orbit
proptosis
optic neuropathy
orbital congestion
34
Clinical Manifestations
watch out for subtle manifestations in patients and
family members
retraction
Clinical Manifestations
watch out for subtle manifestations in patients and
family members
proptosis
Thyroid Eye Disease
1. Pathophysiology
2. Clinical Manifestations
3. Medical Therapies
4. Surgical Therapies
5. Future Directions
Medical Therapies
1. Vitamin Supplementation
2. Topical Therapy
3. Injectable Steroids
4. Systemic Steroids
5. Orbital Radiation
6. Biologic Therapy
Medical Therapy - Vitamins
selenium 100μg
daily
mild disease
reduced severity
reduced progression
improved QoL
Vitamin D
in vitro may have
anti-inflammatory
effect
no in vivo trials
39
Marcocci et al. 2011
Borgogni et al. 2008
Medical Therapy – Topical
inflammatory dry eye
topical steroids
(loteprednol)
watch IOP
throughout course,
exposure
lubrication
Medical Therapy – Injectable Steroids
triamcinolone (Kenalog)
40mg/1mL injections to
orbit, qmonthly
symptomatic relief in
mild-moderate disease
not disease-modifying
risks: globe perforation,
corneal melt, elevated
IOP
Medical Therapy – Injectable Steroids
Medical Therapy – Systemic Steroidsdirect anti-inflammatory effects
modulate transcriptome
IV >> oral (80% vs 50% response
rate, significantly fewer side effects)
once weekly 500mg IV
methylprednisolone x 12w
max dose: 6-8g total (liver failure, death)
reduces CAS
not disease-modifying, but helps soft
tissue signs
10% steroid-resistant, recur
optic neuropathy: 40-50% of patients
can avoid immediate surgeryWakelkamp et al. 2005
Medical Therapy – Orbital Radiationdepletes orbital lymphocyte replication
reduces cytokines, reduces GAG formation
20Gy over 10 fractions
low side effect profile (retinopathy >35Gy,
neuropathy >50Gy)
side effects: cataract >10Gy, keratopathy
>10GyChundury et al. 2016
1. synergistic with steroids.
2. may improve diplopia,
soft tissue signs.
Medical Therapy – Biologics
steroid-sparing therapy, disease-modifyingSmith et al. 2018
Medical Therapy – Biologics
anti-TNFα
adalimumab (Humira)
infliximab (Remicade)
etanercept (Enbrel)
Moore et al. 2014
1. only small case series
2. anecdotal
improvement
Medical Therapy – Biologics
rituximab
(Rituxan)
anti-CD20
depletes B, T cells
47
Stan et al. 2015
1. two trials
2. conflicting results
– may help
disease
Salvi et al. 2015
Medical Therapy – Biologics
tocilizumab
(Actemra)
anti-IL-6
1. case reports:
reduction in CAS,
proptosis
2. trial complete, not
yet publishedPerez-Moreiras et al. 2014
Medical Therapy – Biologics
teprotumumab
(RV 001)
anti-IGF-1
1. trial: reduction in
CAS and proptosis
(69% vs 20%)
2. sustained, disease-
modifying
Smith et al. 2017
Medical Therapy – Biologics
teprotumumab
anti-IGF-1Douglas et al. 2020
Medical Therapy – Biologics
Douglas et al. 2020
Medical Therapy
1. Medical therapy is aimed at improving symptoms and
stopping progression.
2. Numerous molecular targets are available, and new
medicines are in the pipeline.
past: wait and watch until disease burns itself out
present: treat symptoms, frequent steroid use
future: customized molecular therapy to halt progression
before onset of fibrosis or other permanent sequelae.
Thyroid Eye Disease
1. Pathophysiology
2. Clinical Manifestations
3. Medical Therapies
4. Surgical Therapies
5. Future Directions
Surgical Therapies
1. Orbital Decompression
2. Strabismus Surgery
3. Eyelid Surgery
4. Cosmetic Surgery
Surgical Therapy – Decompression
mainstay for
rehabilitation
corneal exposure
optic neuropathy
cosmesis
Surgical Therapy – Decompression
Surgical Therapy – Decompression
Surgical Therapy – Strabismus
difficult, need
experienced
strabismologist
must be
performed after
decompression
62
Surgical Therapy – Strabismus
Surgical Therapy – Eyelid Retraction
difficult, contour
deformity
common
lower lid retraction
more predictable
than upper lid
Surgical Therapy – Eyelid Retraction
65
Surgical Therapy – Cosmesis
hourglass
deformity: eyelid,
eyebrow, deep
facial fat expansion
prominent eye with
inferior scleral
show
66
Surgical Therapy – Cosmesis
Surgical Therapy – Cosmesis
Thyroid Eye Disease
1. Pathophysiology
2. Clinical Manifestations
3. Medical Therapies
4. Surgical Therapies
5. Future Directions
Future Directions
Future Directions
1. Predict TED onset in euthyroid or
early Graves’ patients.
2. Treat and halt progression of active
disease.
3. Reverse fibrosis after it occurs.