Drugs

https://doi.org/10.1007/s40265-018-1045-9

THERAPY IN PRACTICE

Current and Emerging Treatment Strategies for Graves’ Orbitopathy

Natalia Genere1 · Marius N. Stan1 

© Springer Nature Switzerland AG 2019

Abstract
Graves’ orbitopathy is a debilitating disorder which occurs in patients with autoimmune thyroid disease, mainly Graves’ dis-
ease, and adds layers of complexity to management of both conditions. We conducted a comprehensive review of literature for
publications relating to established and new management options for Graves’ orbitopathy and have summarized key articles
in this review. Initial evaluation of patients with Graves’ disease should also include clinical evaluation for orbitopathy. If
eye disease is present, patients are best managed by a multi-specialty team including an endocrinologist and ophthalmolo-
gist. All patients with Graves’ orbitopathy benefit from risk factor modification and normalization of thyroid function tests.
Patients with active, mild disease generally benefit from local therapies and selenium, while patients with moderate-to-severe
disease usually require the addition of intravenous glucocorticoid therapy. If there is an inadequate response to glucocor-
ticoid therapy, several second-line therapies have been investigated for use, including orbital radiotherapy (with additional
glucocorticoids), rituximab, cyclosporine, mycophenolate mofetil, and methotrexate. Use of new biologic agents, mainly
teprotumumab and tocilizumab, have demonstrated impressive reductions in disease activity and severity. If these results are
confirmed, the treatment paradigm is likely to change in the future. Finally, there are several novel immunotherapies being
investigated for Graves’ disease, which may have treatment implications for Graves’ orbitopathy as well. Overall, there are
many encouraging advances in the therapy of Graves’ orbitopathy that are making the future more promising for patients
suffering from this disease.

Key Points 
The evaluation of Graves’ orbitopathy should determine
its clinical activity, its severity, and the impact it has on a
patient’s quality of life.
Current standard of managing Graves’ orbitopathy spans
from local supportive measures and selenium supple-
mentation to intravenous glucocorticoids and rehabilita-
tive surgery.
Multiple new treatments are being explored for Graves’
orbitopathy and Graves’ disease, mainly focusing on
immunomodulatory approaches. Teprotumumab and tocili-
zumab are leading the way, but there are many other prom-
ising options at various levels of development, exploiting
the now better understood pathophysiology of the disease.
* Marius N. Stan
stan.marius@mayo.edu
1
Division of Endocrinology, Diabetes, Metabolism
and Nutrition, Mayo Clinic, 200 1st St SW, Rochester,
MN 55905, USA
1 Introduction
Graves’ orbitopathy (GO) is an autoimmune, inflamma-
tory disorder of the orbit and represents the most common
extra-thyroidal manifestation of Graves’ disease, present in
anywhere between 25 and 70% of cases, depending on the
diagnostic modality employed (clinical vs CT imaging) [1].
Onset of GO commonly concurs with onset of autoimmune
thyroid disease, but subclinical eye disease may sometimes
be present before the clinical syndrome becomes evident.
While most cases of GO are associated with hyperthyroid-
ism, a minority of patients (about 10%) may be hypothy-
roid or euthyroid [2]. Typically, the natural history of the
disease includes an active, inflammatory stage (ranging
3–6 months), followed by clinical stabilization (ranging
1–3 years) and quiescence with return towards baseline ocu-
lar status [3, 4]. This paradigm has been illustrated by Run-
dle’s curve, named after the physician who first described
the progression of GO in two of his patients. For this review,
we focus on available and emerging medical therapies for
patients with active GO.

Vol.:(0123456789)

2 Evaluation of Patient with Graves
Orbitopathy (GO)
Crucial to timely and effective management of GO is the
clinician’s familiarity with manifestations of orbital dis-
ease and their grading [5, 6]. All patients diagnosed with
Graves’ disease should be evaluated clinically for presence
or absence of orbitopathy. If orbitopathy is present, its evalu-
ation should include three important elements: (1) degree of
activity, (2) degree of severity, and (3) impacts on a patient’s
quality of life. The algorithm for approaching a patient with
GO is summarized in Fig. 1.
2.1 Assessing Disease Activity
GO activity can be evaluated using a validated scoring sys-
tem called the clinical activity score (CAS), which repre-
sents a quantitative measurement of the degree of active
Fig. 1  Algorithm for the treatment of Graves’ orbitopathy (GO). IVGC intravenous glucocorticoid, QOL quality of life
N. Genere, M. N. Stan
inflammation of the orbit [7]. Consequently, the CAS score
is an important predictor of response to anti-inflammatory
therapies. The CAS measurement awards one point for each
of the following criteria: spontaneous retrobulbar pain, pain
on attempted upwards or downwards gaze, redness of the
eyelids, redness of the conjunctiva, swelling of the caruncle
or plica, swelling of the eyelids and swelling of the con-
junctiva (Table 1). Scores of CAS < 3 suggest inactive GO
while scores ≥3 suggest active GO. An expanded, 10-point
CAS scoring system is applicable for patients who have
subsequent assessments, with additional points allocated for
decreases in visual acuity, worsening diplopia, and increas-
ing proptosis, with scores ≥4 indicative of clinically active
disease [7].
2.2 Assessing Disease Severity
GO severity is qualified by categories of mild, moderate-
to-severe, and sight-threatening, based on the presence and
Current and Emerging Treatment Strategies for Graves’ Orbitopathy

degree of lid retraction, soft tissue involvement, proptosis,
diplopia, corneal exposure, and optic nerve involvement
(Table 2) [5]. Mild GO is the most common form of GO and
encompasses approximately 75% of the impacted group [8].
Mild GO is defined by absent or minimal features in severity
factors, and absent signs of corneal or optic nerve involve-
ment. Patients with moderate-to-severe GO have increased
soft tissue involvement with at least one advanced sever-
ity parameter, but without sight-threatening complications.
Finally, very severe GO, or sight-threatening GO, includes
any patient with dysthyroid optic neuropathy, corneal break-
down, or evidence of globe subluxation. Sight-threatening
disease, whether active or inactive, requires immediate oph-
thalmologic evaluation and consideration of urgent medical
and surgical therapies.
2.3 Quality of Life Evaluation
GO-related impairments can be substantial and carry sub-
stantial psychosocial and financial implications for impacted
patients [9, 10]. Several questionnaires have been validated
specifically for use in GO patients, in an effort to estab-
lish quantifiable markers for impacts of orbitopathy on a
patient’s quality of life [10–12]. While specific questions
vary amongst questionnaires, key concepts of importance
include impact of GO on daily visual functioning, impacts
on appearance and self-perception, and impacts on mood
and overall perceptions of wellness.
While we review the management options categorized,
based on levels of severity, it is important to include qual-
ity-of-life status and patient preferences in determining the

Table 1  Graves’ orbitopathy activity assessment according to CAS

Clinical activity parameter Points score

 Spontaneous retrobulbar pain 1
 Pain on attempted upward or downward gaze 1
 Redness of eyelid 1
 Redness of conjunctiva 1
 Swelling of caruncle and plica 1
 Swelling on eyelids 1
 Swelling on conjunctiva (chemosis) 1
Scoring of initial CAS (of 7)
CAS <3 = inactive GO
CAS ≥3 = active GO
Clinical activity subsequent evaluation Additional points
 Increase in proptosis of ≥2 mm during a period of 1–3 months 1
 Decrease of eye movements in any direction ≥ 5° during a period of 1–3 months 1
 Decrease of visual acuity of ≥1 line(s) on the Snellen chart (using a pinhole) during a period of 1–3 months 1
Scoring of subsequent CAS (of 10)
CAS <4 = inactive GO
CAS ≥4 = active GO

CAS clinical activity score, GO Graves’ orbitopathy

Table 2  Graves’ orbitopathy severity assessment according to EUGOGO

Degree of severity Lid retraction Soft tissue involve- Proptosisa Diplopia Corneal exposure Optic nerve status
ment

Mild (≥ 1 of the fol- < 2 mm Mild < 3 mm Absentb or intermit- Absent Normal
lowing) tent
Moderate-to-severe ≥ 2 mm Moderate or severe ≥ 3 mm Inconstantb or Mild Normal
(≥ 1 of the follow- constant
ing)
Sight threatening Not contributory Not contributory Not contributory Not contributory Ulceration Compromised
(one of the last 2
categories)
a
 Proptosis refers to variation from the normal for each race and gender or to the patient’s baseline, if applicable
b
 Transient diplopia refers to presence of symptoms at times of fatigue; inconstant diplopia refers to presence of symptoms at extremes of gaze;
constant diplopia is presence of symptoms at all times

appropriate treatment plan. For example, a patient with mild
GO may still benefit from corticosteroid treatment if the ret-
roocular or eye-movement induced ocular pain prohibits her
from successfully completing her occupation as an account-
ant. Now, we will turn to reviewing medical management
options for active GO and its supporting literature; selected
prominent studies of therapeutic interventions for GO are
highlighted in Table 3.
3 Risk Factor Modification for Management
of GO
All patients at risk for or with established GO, regardless
of disease status, benefit significantly from modification of
their risk factors for onset and progression of GO. While
some risk factors are not readily altered, like age, sex, and
serum thyrotropin receptor antibody (TRAb) level, modifi-
cation of smoking status and thyroid function are crucial in
management of the condition [8, 13, 14].
Cigarette smoking has been strongly linked to risk for devel-
opment and progression of GO. Amongst patients with Graves’
disease, smoking patients were more likely to have orbital
involvement compared to non-smokers [8, 15]. GO patients
who smoke have been found to follow a more severe clinical
course as well as a poorer responsiveness to standard therapies
[15–18]. Severity of orbital symptoms seems to be dependent on
the dose of the exposure to cigarettes, and active smokers have
significantly more symptoms compared to former smokers [17,
19]. Therefore, discussion of smoking cessation is of crucial
importance and is emphasized by major GO guidelines [5, 20].
Normalization of thyroid function is important in mitigat-
ing the severity of GO. The majority of patients with GO are
initially hyperthyroid and require normalization of thyroid
function. The degree of a patient’s hyperthyroidism has been
associated with the perceived severity of GO [21]. Euthy-
roidism can typically be achieved by use of anti-thyroid
medications, but surgery is also a valid option after under-
standing a patient’s values and preferences and it might be
preferred in a subset of cases [22]. Use of radioactive iodine
(RAI) in patients with active GO is associated with a small
but significant risk for worsening of GO, more prominently
in smokers, and can be possibly circumvented with concur-
rent use of steroids [23, 24]. Care must be used to actively
prevent development of overt hypothyroidism, which has
also been associated with disease progression [25, 26].
4 Management of Mild Disease
Because more than half of patients with mild GO experience
spontaneous resolution of ocular symptoms within about
6 months, management of mild GO is focused on low-risk
N. Genere, M. N. Stan
measures to help with symptom management [27]. Current
therapies for GO and their mechanisms of action are sum-
marized in Fig. 2.
Local therapies alleviate symptoms associated with mild
orbitopathy and can be useful in both active and inactive
GO [5]. Ocular lubrication with artificial tears or gels can
alleviate dryness and foreign body sensation. This is particu-
larly helpful for patients with a large palpebral aperture due
to lid retraction. For patients who are particularly troubled
by morning symptomatology due to lagophthalmos, thicker
ointments or gels can be protective from nocturnal ocular
drying. Prisms or eye patching (if divergence is large) can
be beneficial for patients with symptoms of diplopia. Small
studies have used sub-conjunctival botulinum toxin A injec-
tions for reduction of upper eyelid retraction, but the benefits
seem to be clinically small and transient [28–30].
In addition to local measures, patients with mild, active
GO may benefit from oral selenium supplementation, par-
ticularly those in selenium-deficient areas. Selenium is a
trace element that contributes to normal thyroid function
[31]. In 2011, Marcocci et al, under the European Group
on GO (EUGOGO) umbrella, conducted a randomized,
placebo-controlled trial in 5 European countries, compar-
ing the efficacy of selenium (100 µg twice daily), pen-
toxifylline, and placebo for ocular symptoms of mild GO
[32]. Euthyroid patients were treated with 6 months of
supplementation followed by 6 months of observation.
At the completion of the study, investigators found that
there were significantly more patients in the selenium
group with symptomatic improvement (61% vs 36% in
placebo group), and significantly fewer patients with dis-
ease progression (7% vs 26% in placebo group). No sig-
nificant adverse effects were noted in the selenium group.
Of note, the study was conducted in six European centers
with various degrees of selenium sufficiency, and whether
this impacted the generalizability of the study results is
unclear. A retrospective review of 84 patients with GO
from Germany, a majority of whom were selenium deplete,
suggested that GO severity did not correlate with selenium
or selenoprotein P concentrations [33]. The role of sele-
nium supplementation in selenium-sufficient areas, like
the USA, is still unclear, but is a low-risk intervention for
patients with mild, active GO.
For most patients with mild GO, local therapies and sele-
nium are helpful in supporting patients through the natu-
ral disease course. However, for patients who progress and
develop significant impairments to quality of life, consid-
eration should be given to approaching them in a manner
similar to that of patients with moderate-to-severe GO. Dis-
cussion of risks and benefits to therapeutic options should
be discussed prior to initiation of therapy. These will be
discussed further in the next section.
Table 3  Prominent studies of medical therapies of Graves’ orbitopathy
Study [References] Year of Intervention and comparator Type of study Num- Outcome measures Result
Publica- ber of
tion patients

Marcocci et al. [32] 2011 Selenium vs RCT, double-blind 159 Ophthalmic ­indexa,b Selenium is superior to placebo in
pentoxifylline vs GO-QOLb mild GO (improved symptoms and
placebo CAS prevented disease progression)
Gorman diplopia score
Kahaly et al. [36] 2005 IV vs oral GC RCT, single-blind 70 Ophthalmic ­indexa,b IV MP was superior to oral daily pred-
QL- SF-36b nisone in patients with M-T-S GO
CAS
Bartalena et al. [39] 2012 IV GC at cumulative doses of 7.47 g RCT, double-blind 159 Ophthalmic ­indexa,b Moderate dose if IV MP (5 g) has best
vs 4.98 g vs 2.25 g GO-QOLb risk-benefit profile compared with
CAS high dose (7.5 g) or low dose (2.3 g)
Gorman diplopia score in patients with M-T-S GO
Prummel et al. [44] 2004 Retrobulbar orbital radiotherapy vs RCT, double-blind 88 Ophthalmic ­indexa,b Orbital radiotherapy superior to pla-
placebo CAS cebo, mainly for diplopia (no impact
GO-QOL on QOL) in patients with mild GO
Cost effectiveness
Current and Emerging Treatment Strategies for Graves’ Orbitopathy

Need for follow-up

Oeverhaus et al. [50] 2017 IV GC with vs without orbital Retrospective 148 Ophthalmic ­indexa Orbital radiotherapy + IV MP had
radiotherapy CAS higher improvement in severity,
NOSPECS particularly in ocular motility, in
M-T-S GO
Salvi et al. [51] 2015 Rituximab vs IV GC RCT, double-blind 32 CASb Rituximab was superior to IV MP at
Ophthalmic ­indexa reaching clinically inactive disease in
NOSPECS M-T-S GO of short disease duration
Gorman diplopia score
GO-QOL
Stan et al. [52] 2015 Rituximab vs placebo RCT, double-blind 25 CASb Rituximab was equivalent to placebo,
Ophthalmic ­indexa regarding CAS reductions but had
Gorman diplopia score more frequent serious adverse events
SF-12 QOL in M-T-S GO of median 1-year
disease duration
Kahaly et al. [54] 1986 Cyclosporine with oral GC vs oral RCT, blinding not mentioned 40 Ophthalmic ­indexa Cyclosporine + prednisone was
GC alone Orbital CT superior to prednisone alone regard-
ing CAS reductions in patients with
M-T-S GO
Ye et al. [56] 2017 MMF vs IV/oral GC RCT, single-blind 74 Ophthalmic ­indexa,b MMF was superior to GC in reducing
CAS ophthalmic involvement and CAS in
patients with M-T-S GO


Table 3  (continued)
Study [References] Year of Intervention and comparator Type of study Num- Outcome measures Result
Publica- ber of
tion patients

Kahaly et al. [58]
Strianese et al. [61]
Rajendram et al. [64]
Baschieri et al. [65]
Stan et al. [69]
Smith et al. [73]
Perez-Moreiras et al. [78] 2018
Ayabe et al. [80]
2018 MMF with IV GC vs IV GC alone RCT, single-blind 164 Ophthalmic ­indexa,b Addition of MMF to standard IV
CAS GC therapy did not meaning-
GO-QOL fully improve clinical response at
12 weeks, but may improve certain
symptoms and QOL, in patients with
M-T-S GO
2014 Methotrexate Retrospective 36 Ophthalmic ­indexa In patients with GC intolerance,
CAS methotrexate monotherapy was asso-
ciated with reductions in CAS and
improvements in motility in patients
with M-T-S GO
2018 Azathioprine + oral GC vs orbital RCT, double-blind, 2 × 2 factorial 126 Ophthalmic ­indexa,b Addition of azathioprine to GC did not
radiotherapy + oral GC vs azathio- CASb improve GO clinical severity param-
prine + orbital radiotherapy +oral eters in patients with M-T-S GO
GC vs oral GC alone
1997 IVIG vs IV GC Prospective, non-randomized, single- 65 Ophthalmic ­indexa IVIG and IV MP had similar efficacy
blinded NOSPECS in GO, with a safer profile in the
Orbital CT IVIG therapy group
2006 Octreotide long-acting release vs RCT, double-blind 29 CAS,b Octreotide LAR resulted in small
placebo Ophthalmic ­indexa reductions in CAS and in lid retrac-
Orbital CT tion, at the cost of gastrointestinal
side effects in a minority of patients
2017 Teprotumumab vs placebo RCT, double-blind 88 Ophthalmic ­indexa,b Teprotumumab was superior to pla-
CAS cebo at reducing CAS and proptosis
GO-QOL in patients with M-T-S GO
Tocilizumab vs placebo RCT, double-blind 32 CASb Tocilizumab was superior to placebo
Ophthalmic ­indexa at reducing CAS and proptosis in
EUGOGO severity corticosteroid-resistant patients with
GO-QOL M-T-S GO
2014 Adalimumab, with varied prior Retrospective 10 Ophthalmic ­indexa Adalimumab was not associated with
treatments significant reductions in inflamma-
tory parameters, and recurrence rate
was high after drug discontinuation

CAS clinical activity score [7], EUGOGO European Group on Graves’ Orbitopathy, GC glucocorticoids, GO Graves’ orbitopathy, GO-QOL Graves’ Ophthalmopathy Quality of Life assessment
[12], IVIG intravenous immune globulin, MMF mycophenolate mofetil, M-T-S moderate-to-severe, MP methylprednisolone, NOSPECS classification for severity of eye disease [5], RCT​ rand-
omized controlled trial, QL-SF-36 and SF-12 QOL are both non-disease specific, validated quality of life questionnaires
a
 Ophthalmic index varied between studies but commonly included several variables such as proptosis, eyelid aperture, soft tissues involvement, diplopia/motility. Adverse events were men-
tioned in multiple studies, and these results are mentioned in results, where pertinent
b
 Primary outcome, if listed
N. Genere, M. N. Stan
Current and Emerging Treatment Strategies for Graves’ Orbitopathy

Fig. 2  Summary of mecha-
nisms of action for therapies
for Graves’ orbitopathy. IGF-1r
Ab insulin-like growth factor 1
receptor antibody, IL-6 inter-
leukin-6, IL-6R interleukin-6
receptor, MMF mycophenolate
mofetil, TNFα tumor necrosis
factor alpha, TNFαR tumor
necrosis factor alpha recep-
tor, TSHr thyrotropin receptor,
TSHr Ab thyrotropin receptor
antibody

5 Management of Moderate‑to‑Severe GO
Patients with active, moderate-to-severe GO have sufficient
symptoms and orbital changes to warrant immunosuppres-
sive treatments but do not have evidence for sight-threaten-
ing disease. As mentioned above, patients with significant
impairment in quality of life may warrant more aggressive
treatment compared to those with less severe manifesta-
tions. The trend of disease progression over the most recent
3 months is used by most clinicians as guide to patient’s
natural history and as basis for deciding on the risk-bene-
fit ratio of any intervention. GCs are considered first-line
therapy for management of active, moderate-to-severe GO.
We will present available data regarding nuances of ster-
oid management, followed by alternate therapies in cases of
GC failure or intolerance. Two elements which complicate
the interpretation of the efficacy of treatment are: (1) lack
of a uniform outcome assessment, with studies employing
CAS, severity measures (diplopia, proptosis etc.), quality
of life or a mixture of all these in analyzing response, mak-
ing between-studies comparison difficult and (2) lack of a
control group in many studies that would account for the
natural history of the disease, raising questions about the
actual impact of the specific intervention tested.
5.1 Glucocorticoids
The mainstay of treatment for moderate-to-severe GO are
systemic GC therapies, which can be delivered orally or
via intravenous (IV) administration. Multiple randomized
controlled trials (RCTs) have looked at the impact of route
of administration with respect to improvements in clinical

activity and markers of severity of GO [34, 35]. Stiebel-
Kalish et al. conducted a systematic review and meta-analy-
sis of 33 RCTs, including 1367 patients comparing efficacies
of available treatments of GO [35]. Of these, there were 4
trials, including 206 patients, specifically comparing efficacy
of oral versus IV GC therapies in patients with active GO of
varying severity. In patients with moderate-to-severe GO, IV
pulse steroids were significantly more effective at reducing
CAS [standardized mean difference − 0.64, 95% confidence
interval (CI) − 1.11 to − 0.17].
Furthermore, IV GCs were associated with significantly
lower rates of adverse events compared to oral GCs (OR 0.12,
95% CI 0.05–0.26) [35]. Side effect profiles between the two
routes also varied. Patients who received oral GCs experi-
enced weight gain (26%), hypertension (8%), and cushingoid
features (7%) while patients in the IV group experienced
symptoms within 24 h of infusion consisting of flushing
(20%), transient dyspepsia (15%), and palpitations (8%), and
fewer metabolic complications (3–4%). Insomnia is a com-
monly reported problem with IV steroids the night after the
infusion. Treatment was discontinued in four patients in the
oral corticosteroid group and none in the IV corticosteroids
group. The use of IV GCs was also associated with improved
quality of life and fewer subsequent surgeries [36]. There have
been reports of acute, fatal hepatotoxicity in patients treated
with high doses of IV GCs, with most patients receiving
cumulative doses of >8 g or daily doses of ≥ 589 mg meth-
ylprednisolone [37]. Currently available data suggest that IV
steroids are the preferred method for treatment of active GO,
although one must account also for cost and convenience dif-
ferences between these two routes when deciding manage-
ment for a given patient. Therefore, attention to the different
regimens employed over time in the various studies is needed,
and likely will identify a certain degree of heterogeneity.
Historically, oral prednisone was used at starting doses
of 40–100  mg/day with tapering over 10–24  weeks for
cumulative doses of 2–6 g [38]. The preferred regimen of
administering IV GCs has been the topic of more recent
investigation. After Kahaly et al. identified IV methylpred-
nisolone at 6 weekly doses of 500 mg followed by another
6 weekly doses of 250 mg to be superior to oral daily pred-
nisone (for a similar total amount of GCs), Bartalena et al.
randomized 159 patients with moderate-to-severe GO to
receive cumulative doses of methylprednisolone 2.3 g, 5.0 g,
or 7.5 g over 12 weekly infusions [36, 39]. At 12 weeks,
there was significantly more ophthalmic improvement (CAS
and ocular mobility) in the high-dose group (52%), com-
pared to the moderate- and low-dose groups (35% and 28%,
respectively). These differences between the groups were
not evident by the 24-week follow-up, suggesting that the
superiority of the high-dose therapy was short lived. During
the study, six patients developed dysthyroid optic neuropathy
(DON), three in the low-dose and three in the moderate-dose
N. Genere, M. N. Stan
group; after the 12-week protocol, there were three patients
in the high-dose group with rebound DON after completion
of treatment. Other adverse events occurred more commonly
in the high-dose group, including severe psychiatric mani-
festations, new diabetes, and severe infections requiring hos-
pitalization. None of the patients in this study experienced
severe hepatotoxicity. Based on these findings, the authors
concluded that the moderate dose (5.0 g) provided the best
benefit-to-risk ratio for the majority of patients.
At the same cumulative dose, weekly administrations
of IV GCs appear to be superior to daily administrations,
and there was no significant difference between weekly and
monthly dosing [40, 41]. Early deterioration despite pulse
IV GCs at 6 weeks of therapy may be predictive of future
GC failure, and other treatment options should be considered
[42]. European Group on Graves Orbitopathy (EUGOGO)
guidelines currently recommend IV GCs as first-line therapy
for active, moderate-to-severe GO [5]. Cumulative doses
across treatments should not exceed 8 g and it is important
that physicians are attuned to the multiple contraindications
for pulse corticosteroids. The most commonly employed reg-
imen remains the one tested by Kahaly et al. and described
above (methylprednisolone 0.5 g weekly for 6 weeks, fol-
lowed by 0.25 g weekly for 6 weeks, for cumulative dose of
4.5 g) [36]. The most severe cases may benefit from high-
dose therapy, of 0.75 g/infusion for 6 weeks, followed by
0.5 g/infusion for an additional 6 weeks (7.5 g cumulative).
Overall, significant progress has been made in the last
decade with regard to optimal use of steroids in GO. IV
GCs represent the standard of care, and first-line treatment
of moderate-to-severe, active GO. However, in cases of
poor response or unacceptable side effects from IV GCs, a
number of second-line therapies have been proposed. These
treatment options have been far less tested than steroid-based
therapies and evidence for these treatments is rarely based
on adequately powered RCTs.
5.2 Second‑Line Therapies for Moderate‑To‑Severe
GO
5.2.1 Orbital Radiotherapy
with and without Glucocorticoids
Radiotherapy has been employed extensively for GO man-
agement, although its use has not been without controversy.
While one RCT conducted by Gorman et al. found no evi-
dence of benefit using 20 Gy of external beam radiation ther-
apy compared to sham radiation, most other trials have found
benefit of radiation therapy to some GO parameters [43–45].
A meta-analysis conducted by Bradley et al. found that radi-
ation therapy to the orbits is likely to lead to improvement in
diplopia but no other consistent effects could be identified in
the group of trials that used this approach [46].
Current and Emerging Treatment Strategies for Graves’ Orbitopathy
Oral and IV GCs have been combined with orbital radio-
therapy with the hopes of improving severity parameters
and also limiting cumulative GC exposure. Combination
therapy with GCs and orbital radiotherapy may be superior
to monotherapy. Ng et al. compared 52-week outcomes of
15 patients treated with GC regimen (three doses of IV fol-
lowed by an oral taper for approximately 3 months) to those
who received the same steroid course, as well as 20 Gy over
2 weeks [47]. Patients completing combined therapy had
significant improvements in activity and severity measures
compared to the monotherapy group, without any severe
adverse events. These results concurred with prior studies of
combination therapy with oral GCs [48, 49]. More recently,
Oeverhaus et al. retrospectively analyzed 148 patients with
active, moderate-to-severe GO treated with IV GCs versus
IV GCs in addition to orbital radiation, and again found
that combined approach to treatment was associated with
more reductions in severity [50]. While those who received
combined treatment had more severe disease at the start
of treatment, subsequent subgroup analysis with matched
severity had similar results. These studies point to the effec-
tiveness of a multi-modality approach with GCs (oral or IV)
and orbital radiotherapy, particularly in patients with more
severe disease. However, whether this combination therapy
is able to avoid rehabilitative surgeries or significantly
improved quality of life remains to be seen.
5.2.2 Rituximab
Rituximab was the first of several biologic therapies applied
to treatment of active GO. After early case series suggested
substantial improvement in CAS in patients with prior GC
failure, two randomized controlled trials compared the effi-
cacy of rituximab to either placebo or IV GCs [51, 52]. Stan
et al. found no difference of rituximab (2 g total dose) com-
pared to placebo in clinical disease activity, but Salvi et al.
[51] found that rituximab (at both 0.5 g and 2 g dosing) had
improved disease activity (CAS declined from 4.4 ± 0.7
at baseline to 0.6 ± 0.3 by 24 weeks; p < 0.01) and led to
increased disease inactivation compared to high-dose (7.5 g)
IV GCs (CAS ≤ 3 achieved in 100% rituximab patients vs
68.7% corticosteroid patients; p = 0.04). Both studies tar-
geted patients with moderate-to-severe and active GO with
CAS ≥ 4; however, the cohort in the placebo-controlled
study had significantly longer disease duration, was older,
had higher proportions of males, and had higher TRAb lev-
els, all of which may have contributed to a lower respon-
siveness to therapy in this group [53]. Of note, there was an
increased percentage of smokers in the IV GC-controlled
study, which predicted a reduced response to immunosup-
pressive therapy in previous trials, yet interestingly it did
not seem to diminish the response to rituximab in this trial.
The placebo-controlled trial reported two patients in the
rituximab group developing DON and the IV GC-controlled
trial reported two patients in the rituximab group with acute
visual loss related to an acute cytokine release reaction
(which resolved within hours following administration of
100 mg of hydrocortisone). A number of other side effects
were reported in both studies, including many infusion reac-
tions. Overall, it appears that rituximab may show promise
in a select group of patients with short disease duration, but
further trials are warranted to confirm this and to explore the
concerns regarding DON development. EUGOGO guide-
lines currently recommend use of rituximab as one of sev-
eral options in those patients who do not have a satisfactory
response to IV GC therapy [5].
5.2.3 Cyclosporine
Cyclosporine has been tested extensively in transplanta-
tion medicine due to its ability to inhibit the calcineurin
pathway, thus decreasing the IL-2 secretion from T cells.
The combination of cyclosporine with GCs may also be an
effective treatment for patients with moderate-to-severe GO
disease, while cyclosporine monotherapy is not superior to
GC therapy alone. Two randomized controlled trials have
compared combination therapy with cyclosporine (starting
doses ranging 5–7.5 mg/kg) plus oral GCs (starting doses
ranging 50–100 mg, tapering down per protocol) compared
to monotherapy, and found superior reduction in GO severity
in the combined therapy group after 10–12 weeks of inter-
vention [54, 55]. The first study used combination therapy
in moderate-to-severe GO patients who had not had treat-
ment to date, while the second offered combination therapy
to non-responders to single drug therapy. Besides clinical
improvement in GO signs, combined therapy was associ-
ated with a reduction in relapses of GO, but perhaps with
adverse renal and infectious side effects, gingival hyperpla-
sia and reversible elevations in blood pressure. Given this
profile, it can probably be considered as add-on combination
to GCs in patients who had a partial response to that agent
as monotherapy.
5.2.4 Mycophenolate Mofetil
Mycophenolate mofetil (MMF) is another agent that has an
immunosuppresive effect, achieved through depleting the
guanosine nucleotides from the T and B cells. Due to this
property, MMF was studied in patients with active, moder-
ate-to-severe GO both as monotherapy and as combination
therapy with GCs. Ye et al. randomized 174 patients to receive
24 weeks of therapy, either 1 g daily of MMF or with a com-
bination of IV (3 g over 2 weeks) and oral GC therapy (start-
ing at 60 mg/day) tapering over the treatment duration [56].
Patients in both groups had ocular symptoms for approxi-
mately 6 months, had mean CAS scores of 5.2, and most had

at least one prior therapy. There was a higher response rate to
therapy in the MMF group (91% vs 68%) at the 24th week,
and degree of CAS reduction was higher in the MMF group
as well (reduction to CAS 1.9 ± 0.8 vs 2.5 ± 1.4). Rate of
adverse events was substantially lower in the MMF group
(5.0% vs 28.2%) and the reported events were not serious
(mild hypokalemia, mild transaminitis). Other reports of MMF
use in GO describe somewhat higher rate of adverse events,
including the occurrence of optic neuropathy [57]. Recently,
the EUGOGO group published results of the MINGO trial,
which randomized patients with active moderate-to-severe
GO to receive IV GCs versus IV GCs with MMF [58]. In
both groups, IV GCs were delivered per current EUGOGO
recommendations, a total of 4.5 g methylprednisolone over
12 weeks. Mycophenolate was administered at 360 mg twice
daily. Ocular evaluation as performed at 12 weeks, 24 weeks,
and 36 weeks. Response rates at week 12 (one of the primary
outcomes), were not significantly different between the two
groups (49% monotherapy vs 63% combined therapy, OR 1.8,
95% CI 0.9–3.4). Relapse rates at weeks 24 and 36 (the other
primary outcomes) were also similar between groups. How-
ever, a post-hoc analysis suggested that at week 24 there were
significantly more responders in the combined therapy group
(53% monotherapy vs 71% combination, 95% CI 1.09–4.25).
Adverse events happened at similar rates in both treatment
groups. The authors concluded that addition of MMF to IV
GCs was not impactful in terms of initial response to therapy
and rate of relapse, but that there may be benefit with longer
duration of therapy. It is also worth mentioning that combi-
nation therapy had promising signs in terms of improvement
in QOL and ocular symptoms. These somewhat conflicting
results are likely related to a combination of factors: the rapid
response expected in the MINGO trial (as opposed to what
might be a positive response at 6 months) and on the other
hand the substandard GC regimen used by Ye et al. Based on
these results, one would hope that a multicenter RCT with
adequate blinding will be performed in order to understand
the potential utility of MMF for GO.
5.2.5 Methotrexate
Methotrexate (MTX) has also been evaluated for possible
utility in GO management [59–61]. Strianese et al. [61] pub-
lished a retrospective trial of 36 patients with intolerance to
GCs, who were subsequently started on oral MTX therapy,
at doses of 7.5–10 mg, based on weight. In this open-label,
uncontrolled study, 67% of patients had a clinical response
to treatment at 3 months, with 94% having clinical improve-
ment at 1 year. At 3 months, mean CAS score reduced from
4.1 ± 1.1 to 2.5 ± 1.1. More than half of the patients were
smokers and had a median time of 8 months since their prior
attempt at treatment. It is important to note that the study
cannot differentiate between improvements due to the natural
N. Genere, M. N. Stan
history of the disease in contrast to the true impact of ther-
apy. Another retrospective study included 23 patients with
active, moderate-to-severe GO who were treated with MTX
and IV GCs. Approximately half needed at least one addi-
tional steroid-sparing agent during the time of observation
[62]. Authors report an average cumulative dose of IV GCs
of 2.72 g in patients receiving combination therapy, which is
significantly lower than the EUGOGO protocol of cumula-
tive grams. However, the study is limited by the variety of
regimens used for patients who did not respond to or did not
tolerate MTX, which may mask the true efficacy of combina-
tion therapy. A few other retrospective studies also suggest
that use of MTX is associated with successful tapering off of
GC therapy. However, more randomized prospective data are
needed to delineate the utility of MTX as monotherapy, or as
combination therapy for treatment of active GO.
5.3 Additional Agents
5.3.1 Azathioprine
Azathioprine is a purine analog that works as an antime-
tabolite and is also used mainly in transplantation medicine
but has proved useful in some autoimmune disorders (e.g.
rheumatoid arthritis, inflammatory bowel disease). Unfor-
tunately, use of azathioprine as monotherapy has not gained
momentum in treatment of GO since this agent was not
effective in improving GO compared to control patients [63].
Recently, a large double-blinded, randomized controlled trial
re-tested this hypothesis and compared in a 2 × 2 factorial
design, the use of azathioprine, orbital radiotherapy, both
therapies, or neither in parallel with an oral GC course [64].
There was a surprisingly high discontinuation rate (>50%)
and, in the intention-to-treat analysis, the addition of aza-
thioprine was not found to be beneficial for reducing clinical
activity compared to GC therapy alone.
5.3.2 Intravenous Immunoglobulins
Intravenous immunoglobulins (IVIG) have been found to be
as effective as some corticosteroid regimens in treatment of
active, moderate-to-severe GO, as measured by clinical and
radiographic assessments [65, 66]. Kahaly et al. compared
IVIG 1 g/kg given for 2 days every 3 weeks to oral predniso-
lone tapered from 100 mg/day, each for 20 weeks. Baschieri
et al. compared a different dosing schedule of 400 mg/kg
daily for 5 days, repeated every 3 weeks for 5 months, com-
pared to tapering doses of daily IV methylprednisolone
from 80 mg/day. Response rate was found to be between 62
and 76%, with low rates of adverse events seen in the IVIG
group. Of note, neither study compared IVIG to weekly,
moderate dose pulses of IV GCs, which are superior to dos-
ing regimens included. However, due to the difficult logistics
Current and Emerging Treatment Strategies for Graves’ Orbitopathy
and costs associated with this approach, there has been no
further research since the late 1990s and currently this agent
is not being utilized in GO.
5.3.3 Somatostatin Analogs
Somatostatin analogs appeared to be an attractive treat-
ment option for GO because of their immunomodulatory
effects as well as the presence of somatostatin receptors on
orbital fibroblasts. Four randomized, placebo-controlled
trials compared long-acting release formulations of octreo-
tide or lanreotide versus placebo, with treatment durations
of 3–8 months and follow-up durations of up to 14 months
[67–70]. The results were fairly consistent, and a subsequent
meta-analysis concluded that there was a small, statistically
significant reduction in CAS (mean − 0.63, 95% CI − 0.098
to − 0.28) that was unlikely to be clinically relevant. Further-
more, there was no benefit in other clinical outcomes such
as diplopia, proptosis, and lid aperture [35]. Additionally,
about 60% of patients treated with somatostatin developed
significant gastrointestinal side effects. Based on the small
overall impact in somatostatin treatments and concerns over
adverse effects, somatostatin analogs are not considered
helpful options for treatment of active GO.
6 Emerging Therapies for GO
New therapies for GO are targeting specific pathophysi-
ologic mechanisms involved in GO. The known pathways
are summarized in Fig. 2. Pharmaceutically targeting these
molecular mechanisms of GO could provide more effec-
tive therapy without the undesired side effects of some of
the non-GO specific approaches. We will review here the
biologic therapies currently under investigation for GO.
6.1 Teprotumumab
Orbital fibroblasts express not only thyrotropin receptors,
but also insulin-like growth factor 1 receptors (IGF-1R).
IGF-1R is actually overexpressed in orbital fibroblasts,
and lymphocytes, of patients with GO [71, 72]. Tepro-
tumumab is a human monoclonal blocking antibody that
binds to the extracellular portion of the IGF-1R. IGF-1R
normally increases thyrotropin action synergistically at the
cellular level. After several promising in vitro studies, the
first clinical trial of teprotumumab for GO was published
in 2017 [73]. The trial was a multicenter, randomized,
placebo-controlled study of 88 patients who were rand-
omized to receive teprotumumab or placebo infusion every
3 weeks for a total of 8 IV infusions. Teprotumumab dose
was 10 mg/kg for the first dose, followed by 20 mg/kg for
the remaining 7 doses. The study enrolled adult patients
who developed GO within 9 months of the start of the
trial, had CAS ≥ 4 and had not received any prior therapy
with the exception of oral GCs. The trial was funded by
the manufacturer. In the intention-to-treat group, 20% of
the placebo group and 69% of the teprotumumab group
experienced significant clinical improvement (CAS score
reduction ≥ 2 and proptosis reduction ≥T2 mm) by week
24 (OR 8.9; p < 0.01). Patients treated with teprotumumab
were also more likely to respond early and to have more
pronounced responses to therapy. GO-QOL visual func-
tion score increased significantly throughout the trial, but
appearance score did not. Adverse events were generally
mild and self-resolving, but 5 patients developed more
serious complications (diarrhea, inflammatory bowel
disease, Escherichia coli sepsis, autoimmune encepha-
lopathy, urinary retention). One patient in the placebo
group developed DON. Hyperglycemia was noted in both
the teprotumumab and placebo groups (5 and 2 patients,
respectively), with more significant hyperglycemia occur-
ring only in the teprotumumab group, in patients with pre-
existing diabetes, and was easily managed with adjust-
ment of anti-hyperglycemic medications. Overall, the trial
showed strong data for teprotumumab being a safe and
effective treatment for patients with active, moderate-to-
severe GO of recent onset. Therefore, presently there is a
second RCT ongoing (NCT03298867) that aims to validate
these findings, focusing primarily on the expected benefit
in proptosis of ≥2 mm.
6.2 Tocilizumab
Tocilizumab (TCZ) is a recombinant humanized monoclo-
nal antibody directed against the IL-6 receptor. IL-6 is a
pro-inflammatory cytokine, which is also overexpressed in
GO orbital tissues, so blockade of this cytokine was hypoth-
esized to reduce the ongoing inflammation in GO [74]. TCZ
has been successfully used to treat resistant rheumatoid
arthritis and other rheumatologic conditions, with few seri-
ous adverse effects [75]. Perez-Moreiras et al. published the
first prospective non-randomized study of 18 patients with
clinically active (CAS ≥ 4) and GC-resistant disease and
treated them with TCZ 8 mg/kg every 4 weeks, until CAS
≤ 1 or thyroid-stimulating immunoglobulins were negative
[76]. Patients in this study were predominantly women,
mean age of 48 ± 8.6 years, and 50% were smokers. Fol-
low-up period was at least 9 months but ranged from 9 to
27 months. During the study period, clinical activity scores
decreased from 6.5 to 0.6, with specific improvements noted
in eye motility, diplopia, and visual acuity. TRAb decreased
by approximately 40% as well. Side effects were generally
mild (fatigue, musculoskeletal complaints), and did not
require discontinuation of therapy. Two patients developed

neutropenia and required a slight dose reduction. Atienza-
Mateo et al. recently presented an abstract of 29 patients
with similar improvements in disease activity and sever-
ity noted in a multicenter study of apparently open-label
TCZ (reductions in CAS from 5.0 ± 1.7 to 1.0 ± 0.9 over
the course of 1 year) [77]. The first RCT with TCZ was
recently published, and after 4 monthly infusions of TCZ,
there was improvement in CAS by at least 2 points in 93% of
TCZ-treated patients compared with 59% of placebo-treated
patients (CI 1.3–73.2) [78]. Proptosis also improved by a
median of 1.5 mm (compared with 0 mm in the placebo
group). The number of adverse effects was double in the
TCZ group compared with placebo and 2 such events were
deemed serious. Overall, TCZ appears to be quite promising
for corticosteroid-resistant disease if the data are confirmed
in subsequent studies.
6.3 Tumor Necrosis Factor α Inhibitors
There is evidence that early in the course of GO there is
an abundance of tumor necrosis factor α (TNFɑ). This
cytokine is tied with the Th1 driven response that dominates
the immuno-pathophysiology of the disease at that stage.
Etanercept, adalimumab and infliximab are all TNFα inhib-
itors that work by binding the eponymous cytokine. This
class of medication had been approved for use in rheuma-
toid arthritis, inflammatory bowel disease, and some other
autoimmune conditions. Available literature on the use of
these agents in GO is limited, without any RCT performed
or planned, to our knowledge. Ten patients with active,
mild-to-moderate GO were treated with etanercept 25 mg
twice weekly for 12 weeks [79]. While on treatment, CAS
decreased from a mean of 4 to 1.6 at 12 weeks; however, 3
of the 10 patients developed recurrence of symptoms after
discontinuation of the drug. Use of adalimumab was ret-
rospectively reviewed in 10 patients with GO onset within
9 months of the start of therapy [80]. Patients were included
if they had at least 1 sign of disease activity, and most were
treated with concurrent moderate dose IV glucocorticoids
for the first 6 weeks of adalimumab therapy. After 12 weeks
of therapy, there were reduced inflammatory signs in 6 of
10 patients, and increased inflammation in 3 of the patients.
One patient was admitted to the hospital with sepsis and
diarrhea. The applicability of these finding is unclear; some
patients experienced worsening symptoms on therapy, and
those who improved may have done so because of the con-
comitant GCs, adalimumab or natural history of the disease.
Finally, the only report of infliximab was a case of its use in
a patient with DON, which resulted in a decrease in clini-
cal activity score and improvements in vision [81]. Overall,
the use of TNFα inhibitors has resulted in a questionable
benefit regarding the inflammatory status, no evidence of
benefit regarding disease severity, and further trials would
N. Genere, M. N. Stan
be necessary to determine if these agents could play a role
in the management of GO.
6.4 Immunotherapy for Graves’ Disease
with Potential Translation to GO
A number of other agents aiming to reshape the immune
response in GD and GO are making their way in early tri-
als. Most such agents are being tested first in Graves’ dis-
ease given the larger affected population, better understood
pathophysiology as well as the more straightforward out-
come assessment. If found promising in Graves’ disease
therapy, the likely next step will be to test them for GO
given the pathophysiological similarities between the two
disorders.
One such agent is CFZ533, an antibody that has been
tested in a number of autoimmune conditions (e.g. rheu-
matoid arthritis, Sjögren’s syndrome, myasthenia gravis)
and in the field of organ transplantation due to its ability
to interfere with CD40-CD154 interaction. The drug is
an Fc-silenced fully human anti-human CD40 monoclonal
antibody that is thus able to inhibit the activation of CD40
pathway. This pathway is essential for further activation
of humoral immunity after antigen presentation by antigen
presenting cells (APC), therefore the hypothesis is that
CFZ533 will be able to inhibit germinal center formation,
affinity maturation and, consequently, antigen-specific
memory B cell generation. CFZ533 has been tested in
Graves’ disease in an open label fashion (ClinicalTri-
als.gov Identifier: NCT02713256) and 15 patients were
included in the results reported on Clinicaltrials.gov. The
primary outcome was normalization of thyroid-stimulat-
ing hormone (TSH) at 12 weeks—that outcome was not
achieved by any of participants. However, the trial found
that one-third of participants did have improvement in T3
and T4 values at the same time point and there was only
one case with a serious adverse event. A full publication
of the trial results is expected in the near future.
A more specific approach to reversing the immune abnor-
malities associated with Graves’ disease/GO is being pur-
sued by a group of investigators in the UK that are attempt-
ing to harness the action of regulatory T cells (T-regs).
Once activated through the antigen presentation process,
these cells are able to suppress the immune response tar-
geting the antigen they have been exposed to, in this case
the TSH receptor. The product being tested is ATX-GD-59
(ClinicalTrials.gov Identifier: NCT02973802), which repre-
sents a mixture of three peptides derived from the structure
of the TSH receptor. The mixture has been administered
intradermally in a manner similar to a vaccine preparation,
but the formulation does not include the typical stimulating
adjuvants that are present in vaccines and thus the hope is
that only T-regs will be activated, with the expected result
Current and Emerging Treatment Strategies for Graves’ Orbitopathy
being suppression of TSHr antibody production. The trial
was completed in February, 2018, and the results are yet to
be released. To take this approach a step further, there are
investigators who are looking at a more controlled exposure
of T-regs to a specific antigen. The so-called “training” of
T-regs would occur in-vitro after the cells have been col-
lected from a patient, and they would then be exposed to the
antigen that is known to be involved in the pathogenesis of
the disease, specifically TSH receptor in the case of Graves’
disease/GO. Re-administering the cells would be expected
to lead to an immune suppression specific only to the antigen
that was targeted in the “training” phase; thus, limiting the
risk of infectious complications. Ongoing studies are testing
various methodologies that could lead to the desired speci-
ficity of the “training” phase [82].
Another specific mechanism for targeting the pathophysi-
ology of Graves’ disease and presumably GO is to “mask”
the TSH receptor from the action of thyroid-stimulating
immunoglobulin (TSI). This is being pursued with the use
of a TSH receptor antagonist, K1-70 [83]. This agent
was developed as a monoclonal antibody and is now being
tested in an open-label clinical trial (NCT02904330) that
will assess both safety and dosing regimen for a larger trial
focusing on the efficacy of controlling hyperthyroidism in
Graves’ disease and hopefully in reversing ocular changes
in GO.
6.5 Revisiting Some Old Agents
Utilizing some well-known drugs in a different manner
might also offer rewards in GO. A different modality of
delivering glucocorticoids, liposomal encapsulated pred-
nisolone, could potentially reduce the systemic impact of
cumulative glucocorticoid dose and avoid adverse effects of
chronic bolus glucocorticoid use. A Phase II clinical study
is currently recruiting GO patients (EudraCT Number:
2017-001158-33 s). Statins have been found to improve GO
outcome in a retrospective cohort and a prospective trial is
about to test that hypothesis by comparing IVGC + atorvas-
tatin with IVGC = placebo, in active and moderate-to-severe
GO (NCT03110848) [84].
7 Management of Sight‑Threatening
Disease
Corneal ulceration, dysthyroid optic neuropathy, and globe
subluxation are sight-threatening emergencies that require
immediate treatment [85]. Clinicians must evaluate for sight-
threatening complications at the time of the patient’s presen-
tation and throughout a given treatment course. Sight-threat-
ening corneal breakdown occurs due to excessive corneal
exposure due to proptosis and lid retraction, as well as lack
of full closure of the eye. Treatments include lubrication,
topical antibiotics, as well as surgical procedures to cover
the area of ulceration. Orbital decompression may be nec-
essary if proptosis is the primary reason for corneal expo-
sure. Dysthyroid optic neuropathy is defined by stretching
of the optic nerve as it becomes compressed by surrounding
extraocular muscles. Current management consists of the
use of high doses of IV glucocorticoids (500–1000 mg meth-
ylprednisolone daily for 3 consecutive or alternating days),
with a repeat course in 1 week if clinically indicated [5]. If
no improvement is seen with GC treatment, or there is rapid
deterioration, then decompressive surgery should be pursued
immediately. Globe subluxation is caused by expansion of
the orbital content with immediate threatening impact on
the function of the optic nerve and integrity of the cornea.
In this case the treatment is exclusively surgical, needs to be
instituted on an emergent basis and ranges from tarsorrhaphy
to orbital decompression.
8 Management of Inactive GO
Patients with inactive GO lack the acute inflammation of
active disease, and therefore do not benefit from immu-
nomodulatory therapies previously described [5]. Mild
disease can be managed with local measures, but more sig-
nificant GO often requires rehabilitative surgeries. Waiting
for at least 6 months of inactive disease is very important,
as this helps to establish a new clinical baseline and can
reduce the number of rehabilitative surgeries needed. The
recommended surgical progression is to start with orbital
decompression, followed by extraocular muscle surgery, and
then followed by eyelid procedures. Discussion of specific
surgical considerations and procedures is beyond the scope
of this review.
9 Summary
GO is a rare yet challenging disease that significantly
decreases the quality of life of affected patients. It should
be considered together with Graves’ disease, particularly
as some of the therapeutic tools tested for hyperthyroidism
could easily be extrapolated to the eye pathology. The initial
evaluation of all patients with GD should include an evalu-
ation for GO and, when present, particular attention should
be paid to disease activity, disease severity, and the impact
on the patient’s quality of life. These elements will shape the
therapeutic approach which should be pursued in a multi-
disciplinary manner, with the endocrinologist and the oph-
thalmologists operating ideally under a combined Thyroid
Eye Clinic form of environment. Here we have presented a

review of the current treatment paradigm for GO and have
highlighted the avenues of therapeutic research currently
11. Fayers T, Dolman PJ. Validity and reliability of the TED-QOL:
under exploration as well as those noted on the horizon. All
patients with GO benefit from risk factor modification and
normalization of thyroid function tests. Patients with active,
mild disease generally benefit from local therapies and sele-
nium, while patients with moderate-to-severe disease ben-
efit most from GC therapy. We have explored some of the
second-line choices as well as the promising new agents that
aim to tackle the autoimmune mechanisms of GO, from the
TSHr to the IGF-1R, from the cytokine-mechanisms like
IL-6R and TNF-alpha to the Tregs and beyond. The future
will hopefully allow us to better understand the benefits of
each individual approach as well as the biological “price”
in adverse effects associated with each therapy. If we com-
bine these with a better understanding of the mechanisms
responsible for the heterogeneity of GO, we should be able
to match a particular intervention with the GO subgroup
that is most suited for that approach, the goal of the modern
individualized medicine.
Compliance with Ethical Standards  20. Bahn Chair RS, et al. Hyperthyroidism and other causes of thy-
Conflict of interest  NG reports no conflicts of interest. MNS reports
participating in Advisory Board meeting with Horizon Pharma, manu-
facturer of teprotumumab.
Funding  No funding was received for the preparation of this manuscript.
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