REVIEW

CURRENT
OPINION Update on the clinical assessment and
management of thyroid eye disease
Jonathan C.P. Roos and Rachna Murthy

Purpose of review
To offer an update on advances and controversies in the assessment, investigation and treatment of thyroid
eye disease (TED), a disfiguring orbital autoimmune disease, which can manifest with diplopia and
threaten not only sight – but also life.
Recent findings
Developments in biomarkers and imaging are helping to tailor the management of patients. Emerging
therapies target different pathways in the disease and are informed by studies into TED pathogenesis: the
last 2 years has, for example, seen the culmination of a two-decade long bench-to-bedside story in which
an original focus on the IGF1 receptor has translated into an effective treatment for proptosis in thyroid eye
disease. Whether this will result in a real-world reduction in TED-related morbidity will depend on access;
commercial pricing decisions may preclude widespread adoption of novel therapies.
Summary
Thyroid eye disease research is enjoying a renaissance with advances in both monitoring and
treatment coupled with a renewed emphasis on a holisitic approach, which includes aesthetic care for
patients; this is perhaps the most exciting time to be part of the international thyroid eye disease
community in decades – for physicians, surgeons and patients. The commercial window for break-
through drugs are narrowing with an array of new therapeutic agents in the pipeline over the coming
decade.
Keywords
anti-thyroid stimulating hormone receptor antibody, decompression, Grave’s orbitopathy, methotrexate,
mycophenolate, pricing, quality of life, sirolimus, teprotumumab, thyroid eye disease

INTRODUCTION which have been updated to include psychometric

&

Thyroid eye disease (TED) is associated with disfig-
urement, impaired quality of life and socioeco-
nomic status. Those are dry medical terms. The
reality for these patients is one of social stigmatiza-
assessment [5 ] and show good discriminant validity
for severity in different cultures [6–8]. Such studies
show that although physicians view TED as a self-
limiting disease, only 2% of patients consider them-
&&

tion – their eyes have been shown to be stared at by
observers [1] – and a significant increased risk of
&&
suicide [2 ] with a hazard ratio of 2.71. Here we
review advances in the assessment, pathogenesis,
treatment and management of TED.
selves recovered [9 ] and more than two-thirds
suffer depression [10]. The modern multidisciplin-
ary team should, therefore, have input from psy-
chologists [10].

ADVANCES IN CLINICAL ASSESSMENT: A

FOCUS ON PATIENT EXPERIENCE
The established clinical scores [3] remain popular as
they are ubiquitous and require no expensive equip-
ment. However, they correlate poorly unless binary
(present/absent), which in turn reduces their useful-
&
ness in grading severity [4 ]; as disease activity wanes
such scores normalize – but patient morbidity per-
sists. This is better reflected in quality-of-life scores,
Thyroid Eye Disease Service, Department of Ophthalmology, Cambridge
University Hospitals NHS Foundation Trust, Cambridge, UK
Correspondence to Jonathan C.P. Roos, PhD, FRCOphth, FEBO,
Thyroid Eye Disease Service, Cambridge University Hospitals NHS
Foundation Trust, Hills Road, Cambridge CB2 2QQ, UK.
Tel: +44 7766501933; e-mail: jcpr2@cam.ac.uk
Curr Opin Ophthalmol 2019, 30:401–406
DOI:10.1097/ICU.0000000000000596

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Oculoplastic and orbital surgery
KEY POINTS
 TED confers a significantly increased risk of death
by suicide.
 With current therapies, only a small minority of patients
feel cured after the disease has settled.
 Novel assessments are providing objective clinical
severity and activity scores.
 New therapies can address previously difficult to treat
aspects of the disease, such as proptosis.
 The clinical success of these therapies will depend on
access, and therefore pricing.
 Multiple new therapies will reach market in the
next decade.
 The aesthetic aspect of TED rehabilitation should not be
delayed or overlooked.
ADVANCES IN OBJECTIVE
MEASUREMENTS
There have been numerous developments in objective
assessments. Visual field changes in TED [11] have
been correlated with severity of dysthyroid optic neu-
ropathy [12] and found to result primarily from
involvement of the superior rectus complex [13].
Multiple studies have shown that TSH receptor
antibodies (TRAb) correlate with TED disease activ-
ity [14]. Serial TRAb measurements show that levels
are associated with smoking, thyroidectomy, and
immune modulation allowing it to be used to guide
&&
treatment decisions [15 ]. Use of this marker, inter
alia, has resulted, in a significant reduction in need
&&
for decompression surgery [16 ]. Circulating anti-
bodies to the insulin-like growth factor-1 receptor
are unlikely to be a helpful biomarker as they are
found only in a fourth of Grave’s patients and
regardless of whether TED is present [17].
&
Proteomic studies of tears [18,19,20 ] and lipi-
domics of serum and urine [21] have led to the
discovery of a promising array of biomarkers, some
which have already been shown to correlate with
activity scores [22]. However, as these are not yet
widely available they remain of limited clinical use.
Other emerging modalities, such as spectral micros-
copy of corneal nerves [23], thermography [24] and
Scheimpflug assessment of corneal dynamic proper-
ties [25] are in the early clinical stages of evaluation
DEVELOPMENTS IN THE IMAGING OF
THYROID EYE DISEASE
Optical coherence tomography (OCT) can provide
objective measurements of structures affected by
402 www.co-ophthalmology.com
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TED. Measurements of choroidal thickness [26],
optic nerve blood vessel density [27], nerve fibre
layer thickness and rectus muscles size [28]
have shown to be altered by TED but do not always
correlate with other measures of activity [29,30]
but may improve after decompression [31]. Choroi-
dal thickening resulting in retinal folds can
indicate impending vessel occlusion [32] and should
prompt intervention.
Doppler ultrasound to determine the blood flow
rates in the internal carotid artery, ophthalmic
artery and central retinal artery can detect early
signs of TED [33]; decompression leads to a marked
reduction in the resistance to flow [34], suggesting
that it could be another useful objective marker of
disease severity.
The strength of MRI signals vary with time and
between machines. This necessitates the use of ratios
between tissues of interest and other structures to
create a numerical value. However, Das et al. gener-
ated an objective absolute number using T2-relaxa-
tion mapping and extraocular muscle fat fraction
assessment. This correlates with Clinical activity
score scores and improves with treatment [35] and
may supersede conventional Short tau inversion
recovery sequences and diffusion weighted imaging
[36], which do not always provide strong disease
correlation in TED [37]. More excitingly still, techne-
tium scans have recently been shown to accurately
diagnose [38] and quantify TED activity [39] and
reflect improvement with steroid treatment [40].
TRIALS OF TRADITIONAL THYROID EYE
DISEASE THERAPIES
National surveillance of dysthyroid optic neuropa-
thy in the UK showed that most patients receive
initial medical therapy with corticosteroid yet
almost 50% require surgical orbital decompression
[41]. A recent large retrospective study has shown
that radiotherapy combined with corticosteroid can
avert surgical decompression in 94% of patients
&
[42 ]. Current multicentre studies including the
Combined Radiotherapy and Intravenous Steroid
for Early Progressive Thyroid Eye Disease (CRI-
SEPTED) study and Combined Radiotherapy and
Intravenous Steroid for Dysthyroid Optic Neuropa-
thy (CRISDON) study aim to prospectively investi-
gate the efficacy of combination of radiotherapy and
steroid. Though second line agents and radiother-
apy have been used to avoid adverse events thought
to be associated with high-dose steroids, recent evi-
dence suggests that pulsed methylprednisolone is
well tolerated up to a cumulative dose of 7.5 [43] or
even 9 g [44] and does not affect bone mineral
density in TED patients [45].
Volume 30  Number 5  September 2019
 Clinical assessment and management of TED Roos and Murthy
UPDATE ON STEROID-SPARING
THERAPIES
Steroid-sparing agents can also be effective in TED
treatment. In Cambridge, close endocrine control
and the early introduction of ciclosporin after initial
steroid-based immunosuppression has resulted in a
seven-fold reduction in decompression surgery
compared with the rest of the UK [46]. In 75 patients
with DON, 93% recovered premorbid visual acuity
and 92% visual field; only 5 required decompression
because of complicated or delayed presentation. In
Oxford [47] and Singapore [48], similar regimens but
with early addition of methotrexate have shown
good clinical efficacy and accelerated suppression
of moderate-to-severe disease and hastening of
visual recovery [48] with a marked reduction in
overall steroid load compared with the EUGOGO
regime [47].
Disappointingly, however, two large well con-
ducted trials failed to prove efficacy for other ste-
roid-sparing agents: in the CIRTED trial [49], neither
radiotherapy nor azathioprine conferred a clinical
benefit over oral prednisolone. Numerous patients
withdrew from the study and a post hoc analysis of
those who completed the trial suggested some late
improvements in those treated with azathioprine
[49]. Similarly, in the MINGO trial [50], addition of
mycophenolate to steroid therapy did not show an
improvement in the rate of response at 12 weeks or
rate of relapse at 24 and 36 weeks, though some
benefit was suggested in a post hoc analysis [50].
Another recent randomized controlled trial of
prostaglandin analogues for the treatment of prop-
tosis has also failed to demonstrate efficacy [51].
This UK study followed from an original clinical
observation by Murthy a decade ago that topical
prostaglandin analogues are associated with perioc-
ular fat atrophy [52]. This effect has been confirmed
by in-vitro studies showing that bimatoprost inhib-
its adipogenesis [53]. The clinical trial may have
failed because deep orbital penetration to affect
proptosis was unlikely; the drug may still prove
useful for the periocular lid swelling seen in TED,
which was the original observation.
A NEW ERA: DAWN OF THE BIOLOGICS
The most successful recent TED trial has been
the remarkable confirmation of Smith’s [54] two-
decade long exploration of the role of the IGF1R
receptor in the pathogenesis of TED. In a large
randomized controlled trial, his team showed a
significant reduction in proptosis in patients treated
with a monoclonal antibody directed at that recep-
&&
tor [55 ]. In a subsequent confirmatory phase 3 trial
– OPTIC– the investigators found that 82.9% of 41
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teprotumumab-treated patients achieved a 2 mm or
more reduction of proptosis compared with 9.5% of
42 placebo patients (P < 0.001) with few side-effects
[56]. The IGF1R undoubtedly plays a critical role in
TED and targeting it has led to the development of
the first drug to effectively treat proptosis. As these
were placebo-controlled trials rather than against
prednisolone – the current standard of care – fur-
ther studies may be needed to evaluate the added
value of the drug in terms of health econometric
assessments. Whether this drug ultimately is of
benefit to patients will depend on commercial
pricing decisions.
Two other biologic agents also show promise in
the treatment of TED: tocilizumab, an antibody
directed at IL-6 and rituximab – a B-cell-depleting
anti CD-20. Although there are currently no ran-
domized controlled studies demonstrating the effi-
cacy of Tocilizumab [57], several case reports have
demonstrated efficacy in treating moderate-to-
severe TED [58–60]. Rituximab, more extensively
studied, is effective at low doses (100 mg) with ste-
roid and second line steroid-sparing agent as
required [61] or at moderate doses (400 mg) where
conventional therapy with steroid and radiotherapy
has failed [62]. Higher doses, though well tolerated,
offer no added clinical advantage in TED [63]. A
meta-analysis of randomized controlled trials found
that rituximab was superior to steroid alone [64].
UNDERSTANDING PATHOGENESIS POINT
TO FUTURE THERAPIES
Scarring is a hallmark of late TED, and therefore, an
attractive therapeutic target. Fibrosis is affected in
part by signalling through the mTOR pathway and
&
case reports [65,66 ] suggest that blocking mTOR
signalling with rapamycin, a licensed medication
for immunosuppression, can improve symptoms
of TED, such as by reducing diplopia. Other anti-
fibrotic agents show early in-vitro promise as TED-
directed therapies [67,68].
The microbiome is increasingly thought to play
a role in TED pathogenesis and offers novel treat-
ment options. Evidence for bacterial involvement
include that the recti most frequently involved lie
close to the sinuses most affected by colonization.
Recently TED patients have been shown to have
increased levels of Haemophilus spp. in their gut
microbiome [69] and murine studies also suggest
that TED is affected by bacterial colonisation [70].
Despite limited evidence, antibiotic treatment for
TED has been the norm in Cambridge for over a
decade: every patient is tested and treated for nasal
staphylococci and this may account for the reduced
need for surgery for DON in our unit [71].
www.co-ophthalmology.com 403
Oculoplastic and orbital surgery
Statins may offer a third off-label already avail-
able treatment for TED. Statin use has been shown to
significantly reduce the risk of developing TED
amongst patients with Grave’s disease [72]. Total
and low-density lipoprotein (LDL) cholesterol both
correlate with risk of developing TED [73], suggest-
ing a pathogenic role for cholesterol, the levels do
not correlate with disease activity or severity [74]. In
a retrospective review, TED patients taking statins
required fewer decompressions, had better ocular
motility and needed fewer strabismus procedures
than patients not on statins despite having more
risk factors for severe TED including smoking [75]. A
trial will be necessary to determine correlation or
therapeutic effect.
Finally, two small molecule inhibitors are in
development for TED. High throughput screening
identified S37, which directly blocks TSHR activa-
tion both by the hormone TSH or stimulating anti-
bodies [76]. If successful, this would be the first
treatment to directly target the TSHR and binding
of TRAb.
Mutations in CD40 affect the risk of developing
autoimmune disease including TED [77]; interac-
tions with CD40 ligand activates lymphocytes and
induces Sphingosine-1-phosphate formation – a
signalling molecule associated with fibrosis, inflam-
mation and adipogenesis. In vitro, TED fibroblasts
produce greater amounts of sphingosine-1-phospi-
tate when stimulated than controls [78]. CF2533 is a
newly developed blocker and may prove useful in
TED treatment in the future.
ADVANCES IN THE SURGICAL AND
NONSURGICAL APPROACH TO THYROID
EYE DISEASE
Orbital wall decompression is a well established
treatment for sight-threatening TED [79] as well
as rehabilitation and was recently expertly
&
reviewed [80 ]. A recent controlled trial suggests
that balanced medial and lateral wall surgery can
offer increased efficacy with similar risk to lateral
wall alone [81]; the risks are not negligible and
include risk to vision and intractable diplopia
[71]. Due to the inflammatory nature of TED and
resulting unpredictability of results, a staged surgi-
cal approach has been favoured for TED: first
orbital decompression, then strabismus surgery
followed by lid positioning and periocular fat
debulking [82]. This three-decade paradigm has
been challenged by a study in which 40 consecutive
patients were treated with combined orbital
decompression and aesthetic eyelid surgery
&&
[83 ], resulting in high patient satisfaction and
reduced number of operations. Combined, and
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therefore, earlier surgical rehabilitation can
address better psychosocial aspects of TED [84].
Such a holistic approach has also led to increased
use of nonsurgical treatments, such as hyaluronic
acid filler and botulinum toxin [85]. Though sur-
gery rarely triggers reactivation of disease [86],
nonsurgical approaches are thought to be less likely
to and can be used both for cosmetic rehabilitation
and ocular surface protection.
Surgical thyroidectomy has been shown to
reduce the risk of patients with Grave’s disease
developing TED by 74% compared with radioactive
iodine treatment [72]. Excision of the gland reduces
circulating TRAb levels in TED [87,88], and signifi-
cantly reduced proptosis in 12/15 patients in a small
prospective study [89]. A larger controlled trial,
aiming to recruit 60 TED patients to compare thy-
roidectomy with antithyroid medication, is now
underway [90].
CONCLUSION
TED is a highly stigmatizing disease, which can
affect both quality and length of life. Increased focus
on patient-reported outcomes is resetting research
and clinical agendas away from the activity and
severity of inflammation to address scarring and
facial rehabilitation. Oculoplastic surgeons should
be familiar with surgical and nonsurgical aesthetic
treatments so that they can provide early cosmetic
improvement. Control of inflammation remains
important and can be achieved by steroid and ste-
roid-sparing agents, such as ciclosporin and metho-
trexate. Options to reduce proptosis include surgical
thyroidectomy, decompression and teprotumumab
treatment. The latter will be regarded as a bench-to-
bedside triumph if the price meets funding thresh-
olds. Multiple new therapies are emerging, includ-
ing some which are already licensed including
sirolimus antibiotics and statins. Objective biomark-
ers including serial TRAb measurements and imag-
ing techniques will prove helpful in evaluating
therapeutic efficacy.
Acknowledgements
Declaration of interest statement: All authors are doctors
who manage patients with Thyroid disease.
Contributions Statement: All authors have contributed to
the writing.
Ethics Statement: As a review, no institutional review
board authorization was necessary.
License: The corresponding author has the right to grant
on behalf of all authors and does grant on behalf of all
authors, an exclusive licence on a worldwide basis to
permit this article to be published.
Guarantor: J.C.P.R. serves as guarantor of this work.
Volume 30  Number 5  September 2019

Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 30  Number 5  September 2019