thyroid eye disease past, present, and future · 3. thyroid antibody levels may provide early...

Thyroid Eye Disease – Past, Present, and Future

Deepak Ramesh, MDSomerset, NJ

Nov 19, 2020

Contact Information

Deepak Ramesh, MD

Somerset, NJ – USA

609-608-0142

info@deepakrameshmd.com

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.