Review

Advances in treatment of active, moderate-to-severe Graves’

ophthalmopathy
Wilmar M Wiersinga

Graves’ ophthalmopathy is defined as autoimmune inflammation of extraocular muscles and orbital fat or connective Lancet Diabetes Endocrinol 2016
tissue, usually in patients with Graves’ disease. About one in 20 patients with Graves’ hyperthyroidism has moderate- Published Online
to-severe Graves’ ophthalmopathy. Corticosteroids have been the mainstay of treatment, but new evidence about June 23, 2016
http://dx.doi.org/10.1016/
immune mechanisms has provided a basis to explore other drug classes. Intravenous methylprednisolone pulses are
S2213-8587(16)30046-8
more effective and better tolerated than oral prednisone in the treatment of active, moderate-to-severe Graves’
Department of Endocrinology
ophthalmopathy. Rituximab has also been suggested as a possible replacement for intravenous corticosteroids. and Metabolism, Academic
Two randomised controlled trials of rituximab reached seemingly contradictory conclusions—rituximab was not Medical Centre, University of
better with respect to the primary outcome (clinical activity score) than placebo in one trial (which, however, was Amsterdam, Netherlands
(Prof W M Wiersinga MD)
confounded by rather long Graves’ ophthalmopathy duration), but was slightly better than intravenous
methylprednisolone pulses in the other (disease flare-ups occurred only in the latter group). On the basis of evidence Correspondence to:
Prof Wilmar M Wiersinga,
published so far, rituximab cannot replace intravenous methylprednisolone pulses, but could have a role in Department of Endocrinology
corticosteroid-resistant cases. Open-label studies of tumour-necrosis-factor-α blockade had limited efficacy, but other and Metabolism, Academic
studies showed that interleukin-6 receptor antibodies were effective. Results of randomised controlled trials Medical Centre, University of
Amsterdam, Meibergdreef 9,
investigating the efficacy of the IGF-1 receptor antibody teprotumumab and the interleukin-6 receptor antibody
Amsterdam 1105AZ,
tocilizumab are expected shortly. Approaches that target the causal mechanism of Graves’ ophthalmopathy (antibodies Netherlands
or antagonists that block thyroid-stimulating-hormone receptors) also look promising. w.m.wiersinga@amc.uva.nl

Introduction in the autoimmune attack of orbital tissues, which has

Graves’ ophthalmopathy is one of the remaining
enigmas in thyroidology. It is an autoimmune disease
that occurs predominantly in patients with Graves’
hyperthyroidism, which is caused by thyroid-stimulating-
hormone (TSH) receptor-stimulating antibodies
produced initially by lymphocytes in the thyroid gland
and neighbouring lymph nodes. Signs and symptoms of
Graves’ ophthalmopathy involve swollen extraocular
muscles and expansion of orbital fat and connective
tissue, and include swelling and redness of eyelids and
conjunctiva, exophthalmos, double vision, and, in severe
cases, corneal ulceration and decreased visual acuity.
The incidence of Graves’ hyperthyroidism was
210 per million per year in a population-based study
in Sweden, 20·1% of whom had symptoms of
Graves’ ophthalmopathy (non-infiltrative in 15·2% and
infiltrative in 4·9%).1 In a Danish study2 published in
2012, the incidence of moderate-to-severe Graves’
ophthalmopathy was 4·9% among patients with Graves’
hyperthyroidism. These figures are in good agreement
with a single-centre study3 from Italy in patients with
newly diagnosed Graves’ hyperthyroidism, in whom
the prevalence of mild, moderate-to-severe, and
sight-threatening Graves’ ophthalmopathy was 20·0%,
5·8%, and 0·3%, respectively. Thus, moderate-to-severe
disease occurs in about one in every 20 patients with
Graves’ hyperthyroidism.
A therapy targeting the most likely cause of Graves’
ophthalmopathy (ie, TSH receptor antibodies recognising
TSH receptors expressed on orbital fibroblasts) has not
yet been tested in human beings, and corticosteroids are
still used. However, considerable progress has been
made in unravelling the molecular mechanisms involved
led to several innovative therapies, including rituximab
and drugs that target orbital fibroblast receptors or
inflammatory cytokines.4
The precise pathogenesis of this thyroid-associated
ophthalmopathy remains incompletely understood,
although autoimmune mechanisms clearly play a part
(figure). Immunocompetent cells such as T cells, B cells,
monocytes, fibrocytes, macrophages, and mast cells are
recruited into the orbit. Macrophages, but also B cells,
might present the responsible autoantigen—most likely
the TSH receptor—to T cells, which are then stimulated
to recognise orbital fibroblasts, the target cells of the
orbital autoimmune attack. Activated infiltrating T cells
secrete cytokines and chemokines; in the early stages of
the disease T-helper-1-derived cytokines (interferon γ,
tumour necrosis factor α, interleukins 1β and 2)
predominate, whereas later T-helper-2 responses
(interleukins 4, 5, and 10) predominate. The release of
cytokines induces synthesis and release of large amounts
of glycosaminoglycans like hyaluronan by orbital
fibroblasts, which, as a result of their hydrophilic
nature, cause swelling of orbital tissues—especially of
extraocular muscles. Some cytokines also cause
differentiation of a subset of orbital fibroblasts called
preadipocytes (present in orbital fat but not in muscles)
into mature adipocytes via adipogenesis. Orbital
fibroblasts express TSH receptors, which are upregulated
in the active stages of the disease. TSH-receptor-
stimulating antibodies increase hyaluronan production
and adipogenesis in cultured human fibroblasts.
IGF-1-receptor expression is also increased in orbital
fibroblasts during active disease, and ligation with
IGF-1 also stimulates hyaluronan and adipogenesis.

www.thelancet.com/diabetes-endocrinology Published online June 23, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30046-8 1

 Review

Antigen-presenting cell
Corticosteroids
Ever since the report of Lord Brain in The Lancet in 1955,5
corticosteroids have been the mainstay of treatment of
severe Graves’ ophthalmopathy. The mode of
TSH receptor
MHC molecule administration has changed, however: meta-analyses of
(presenting TSH receptor randomised clinical trials clearly demonstrate that
peptide)
intravenous methylprednisolone pulses (IVMP) have
IGF-1 receptor
greater efficacy than oral prednisone (response rate 74%
T-cell receptor B cell vs 51%) and fewer side-effects (56% vs 81%).6,7
Consequently, guidelines recommend IVMP for active,
T cell
moderate-to-severe Graves’ ophthalmopathy—preferably
Cytokines
500 mg weekly for 6 weeks followed by 250 mg weekly
for another 6 weeks (cumulative dose 4·5 g).8
An alternative schedule with the same cumulative dose
TSH receptor antibodies
of 4·5 g administered over 4 weeks had lower efficacy
(41% vs 77%) and more side-effects than did the 12 week
Macrophage
regimen.9
CD40 L TSH receptor
Cytokine IGF-1 receptor Cumulative doses of 7·47 g, 4·98 g, and 2·25 g given
CD40
receptor over 12 weeks were compared in a large randomised
controlled trial.10 Clinical activity score (panel) decreased
with all doses, but a composite ophthalmic score
Orbital fibroblast
improved greatest with the highest dose (response rates
52%, 35%, and 28%, respectively) at the expense of more
side-effects. Flare-ups of Graves’ ophthalmopathy after
corticosteroid discontinuation occurred in 12% overall
(13% in the high-dose group, 7% in the intermediate-
dose group, and 11% in the low-dose group).10 It is
Hyaluronan production Adipocytes
Muscle swelling Adipogenesis
hypothesised that these flare-ups can be counteracted by
administering low doses of oral prednisone in between
pulses12 or by combining IVMP with orbital irradiation.13
Notably, orbital irradiation plus oral prednisone is more
effective than oral prednisone alone.14 The most effective
approach to counteracting flare-ups has yet to be proven
in randomised controlled trials.
Corticosteroids usually improve soft-tissue changes
(swelling and redness of eyelids and conjunctiva) and
eye-muscle motility (diplopia), but are less effective at
reducing exophthalmos. IVMP have been associated
Figure: Immunopathogenesis of Graves’ ophthalmopathy. with acute and severe liver damage, sometimes resulting
Cytokines released from T cells (activated by immunocompetent cells infiltrating the orbit) and TSH receptor
antibodies stimulate orbital fibroblasts to produce hyaluronan and to differentiate into adipocytes, thereby causing in fatal liver failure.15,16 A questionnaire survey17 among
swelling of extraocular muscles and orbital fat. CD40 L=CD40 ligand. TSH=thyroid-stimulating hormone. members of the European Thyroid Association showed
seven deaths (four due to acute liver failure, two due to
cerebrovascular disease, and one due to pulmonary
TSH-receptor and IGF-1-receptor signalling pathways embolism) occurring between 4 and 120 days after
overlap downstream of their receptors, but there is starting IVMP. All but one of the patients who died had
insufficient evidence that the IGF-1 receptor is a major received a cumulative dose of more than 8 g.17 Identified
autoantigen in Graves’ ophthalmopathy.4 risk factors for adverse effects from IVMP are dose, age
Corticosteroids have been the mainstay of treatment older than 53 years, daily pulses, and pre-existing
for Graves’ ophthalmopathy since the 1950s, but hepatitis.18–20 A 2011 review of IVMP in 1045 patients
increasing evidence about pathological mechanisms has showed a morbidity of 6·5% and mortality of 0·57%.21
provided a basis to explore other drug classes for disease Contraindications for IVMP are recent hepatitis, liver
treatment. In this Review, I discuss studies from the dysfunction (five-times increased liver enzymes), cardio-
past 5 years about safety and optimum dosage of vascular morbidity, severe hypertension, uncontrolled
corticosteroids, and whether new treatment modalities diabetes, and glaucoma.21 When administering IVMP,
like rituximab and other biologicals could replace cumulative doses greater than 8 g and administration on
corticosteroids in active, moderate-to-severe Graves’ consecutive days should be avoided (except in dysthyroid
ophthalmopathy. optic neuropathy—defined as loss of visual functions

2 www.thelancet.com/diabetes-endocrinology Published online June 23, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30046-8


caused by pressure of enlarged orbital tissues on the optic
nerve). Monthly monitoring of liver chemistry, glucose, and
blood pressure is warranted in all patients receiving IVMP.21
In a 2015 single-centre study22 following these
recommendations, acute liver damage (defined as an
alanine aminotransferase increase exceeding four times
the upper limit of normal) was reported in four of
376 patients (1%); there were no deaths. The cumulative
dose of 4·5 g is preferred, because this dose does not result
in suppression of the hypothalamus–pituitary–adrenal
axis.23 The 7·5 g schedule is an option in severe cases with
troubling diplopia. Administration of alendronate could
suppress IVMP-induced bone resorption, which can occur
in any patient receiving IVMP.24
Rituximab
Early evidence
Rituximab is a monoclonal antibody directed against
CD20, which is expressed by B cells but not stem cells or
B-cell precursors. It causes B-cell depletion, but antibody
production can be maintained because CD20 is not
expressed by antibody-producing plasma cells in the
bone marrow.25 Thus any decreases in serum
concentrations of TSH-receptor antibodies after treat-
ment of Graves’ ophthalmopathy appear unrelated to
B-cell depletion. The effect of rituximab in Graves’
ophthalmopathy might result from the blockade of
antigen presentation by B cells after anti-CD20-induced
lysis, resulting in decreased T-cell activation.25
In 2006, two case reports26,27 of spectacular improvement
of corticosteroid-resistant Graves’ ophthalmopathy after
treatment with rituximab were published. As of 2013,
reports had been published of 43 patients with Graves’
ophthalmopathy who had been treated with rituximab
(usually 1 g 2 weeks apart), mostly after previous
corticosteroid failure.25 Graves’ ophthalmopathy activity
and severity improved in 98% and 91% of patients,
respectively. Clinical activity score decreased from
4·9 (range 4·7–7·0) before therapy to 2·2 (0–7) after
16 weeks.25 Responses were observed in each of the
disease severity categories (panel). Side-effects occurred
in 13 patients (30%); they were minor in ten patients and
major in three patients. One patient developed dysthyroid
optic neuropathy.28 The overall favourable results in
these uncontrolled studies suggested the possibility that
rituximab might replace corticosteroids as first-line
treatment of active, moderate-to-severe Graves’
ophthalmopathy.
Efficacy
In February, 2015, the results of two randomised
controlled trials of rituximab in active, moderate-to-
severe Graves’ ophthalmopathy were published.
Rituximab was not better than placebo in improving
clinical disease activity (the primary outcome) in the
first trial, by Stan and colleagues,29 but was slightly
better than IVMP in the second, by Salvi and colleagues.30
www.thelancet.com/diabetes-endocrinology Published online June 23, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30046-8
Review
Panel: Assessment of Graves’ ophthalmopathy in terms of
disease activity and severity
Disease activity (based on the clinical activity score11
[maximum score 7])*
• Spontaneous retrobulbar pain
• Pain on attempted up, down, or side gaze
• Redness of the eyelids
• Redness of the conjunctiva
• Swelling of the eyelids
• Swelling of the caruncle or plica, or both
• Chemosis
Disease severity (NO SPECS as a mnemonic)
• No signs or symptoms
• Only signs, no symptoms
• Lid aperture in midline in mm
• Soft-tissue involvement
• Swelling and redness of eyelids and conjunctiva
• Proptosis
• Hertel in mm
• Extraocular muscle involvement
• Eye muscle ductions, diplopia†
• Corneal involvement
• Punctate keratopathy, ulcer
• Sight loss (as a result of optic nerve involvement)
• Best-corrected visual acuity, colour vision, optic disc,
visual fields
*Clinical activity score is the sum of all items present, with a maximum score of 7;
a score of 3 or higher suggests active Graves’ ophthalmopathy. †Score: 0=no diplopia,
1=intermittent diplopia (ie, when tired or upon waking), 2=inconstant diplopia
(ie, at extremes of gaze), 3=constant diplopia (ie, in primary or reading position).
The discrepant outcomes could be confusing because
the conclusions of both trials are mutually exclusive. If
rituximab is at least as effective as corticosteroids, as
shown in the second trial, why wasn’t this efficacy
detected in the first? If you accept that rituximab is not
better than placebo, you have to conclude that the effect
of corticosteroids in the second trial is inferior to that of
placebo, and it is hard to believe that corticosteroids are
devoid of efficacy. A placebo-controlled double-blind
randomised controlled trial31 showed that IVMP are
more efficacious than placebo in active, moderate-to-
severe disease (response rate 83% vs 11%, p<0·005).
So, how can the seemingly discrepant outcomes of
these trials29,30 be explained? The parallel double-blind
study designs of both trials were very similar: patients
with Graves’ ophthalmopathy of similar activity and
severity were included and initially given the same
rituximab dosage schedule, and the same primary
outcome measure at 24 weeks was used in both.
However, there were obvious baseline differences
between the studies with regard to smoking, duration
of disease, and previous corticosteroid use (table 1).
Smoking is associated with less favourable responses to
corticosteroids and retrobulbar irradiation in patients
3
 Review
Female
Age, years (SD)
Smoking
Disease duration
Previous corticosteroids
Corticosteroid-free period
before trial
TSHR antibodies, U/L
Lid aperture, mm (SD)
Proptosis, mm (SD)
Diplopia score (range)
Rituximab dosage
Baseline clinical activity
score (SD)
Clinical activity score at
24 weeks (SD)
Data are n (%) unless otherwise specified. In one trial, rituximab was compared with placebo,29 in the other it was
compared with intravenous corticosteroids.30 TSHR=thyroid-stimulating-hormone receptor.
Table 1: Baseline characteristics and primary outcomes (clinical activity score) of two randomised clinical
trials of rituximab in patients with active, moderate-to-severe Graves’ ophthalmopathy
4 www.thelancet.com/diabetes-endocrinology Published online June 23, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30046-8
with Graves’ ophthalmopathy.32,33 A possible interaction allowed interval between discontinuation of cortico-
between smoking and the response to rituximab has steroids and enrolment was shorter in the placebo-
not been assessed in Graves’ ophthalmopathy, but in controlled trial29 (at least 4 weeks) than in the
rheumatoid arthritis the response rate to the drug was corticosteroid-controlled trial30 (at least 12 weeks). The
lower in current smokers than in previous and never planned rituximab dose was initially the same in both
smokers (20% vs 61% vs 98%).33 Smoking was more trials (two intravenous doses of 1 g), but in the
prevalent in Salvi and coworkers’ trial30 than in Stan corticosteroid-controlled trial, ten patients received a
and colleagues’ trial,29 and therefore lower rituximab lower single dose of 500 mg, which was as efficacious as
efficacy might have been expected in the corticosteroid- the full dose in depleting B cells and improving clinical
controlled trial; the opposite, however, was observed. activity scores. Therefore differences in rituximab
Smoking is thus an unlikely explanation for the dosages are unlikely to have affected observed efficacy.
discrepant outcomes. On the basis of existing data, in my view it is
However, perhaps the long duration of disease in premature to conclude that rituximab is devoid of any
patients in the placebo-controlled trial29 could have efficacy in the treatment of Graves’ ophthalmopathy.
contributed to rituximab’s observed lack of efficacy The much longer duration of disease in Stan and
(table 1). Six patients had Graves’ ophthalmopathy for colleagues’ trial29 than in Salvi and colleagues’ trial30
more than 2 years.29 The longer the duration, the greater (probably reflecting different referral patterns) can
the chance the disease has reached its inactive, fibrotic explain at least partly why rituximab was not efficacious
stage, and the smaller the chance that immuno- in the placebo-controlled trial.
suppression will be effective.4 The high baseline clinical
activity score of 5·1 in the placebo-controlled trial29 is Extent of efficacy: primary and secondary outcomes
taken as evidence of active disease, but some items of The rate of decline in the primary outcome measure,
this disease measure (eg, redness) could be due to clinical activity score, over a year was the same in both
congestion as a result of long-standing Graves’ randomisation groups in the placebo-controlled trial,29
ophthalmopathy—a weakness of the clinical activity suggesting that the fall in clinical activity score might
score for determination of disease activity. reflect the natural history of Graves’ ophthalmopathy. In
Patients who had previously been treated with Salvi and colleagues’ trial,30 the decline in clinical activity
corticosteroids were included in both trials, but the score was the same in both groups up to 12 weeks;
thereafter it did not decrease any further in the IVMP
group (coinciding with corticosteroid discontinuation at
Stan et al29 Salvi et al30 12 weeks), but continued to decrease up to 24 weeks in
Rituximab (n=13) Placebo (n=12) Rituximab (n=15) Intravenous the rituximab group. With regard to secondary outcomes,
corticosteroids rituximab was superior to IVMP at 24 weeks in terms of
(n=16) effects on lid aperture (improvement 13% vs 0%,
9 (69%) 8 (67%) 14 (93%) 12 (75%) respectively) and eye-muscle motility (combined ductions
58 (13) 62 (11) 52 (13) 50 (11) 197 degrees vs 178 degrees out of a maximum of
2 (15%) 2 (17%) 10 (67%) 9 (56%) 210 degrees) but not proptosis (improvement in 0% vs
373 days (range 299 days (range 4·5 months 4·6 months 6%) or diplopia (improvement in 20% vs 19%). Thus, in
240–1080) 253–595) (SD 2·9) (SD 2·6) the first 24 weeks of treatment, the superiority of
4 (31%) 6 (50%) 6 (40%) 6 (38%) rituximab seems limited.
At least 4 weeks At least 4 weeks At least 12 weeks At least 12 weeks At 52 weeks rituximab was better than IVMP (in
clinical activity score, lid aperture, proptosis, and
20 (range 9–60) 20 (range 2–29) 10·7 (SD 9·1) 18·2 (SD 21·7)
diplopia score). None of the 15 patients in the rituximab
11·1 (2·8) 9·8 (2·0) 11·9 (2·3) 11·5 (1·8) group had disease relapses compared with five (31%) of
24·2 (3·3) 23·0 (2·4) 23·5 (3·5) 22·5 (3·7) 16 patients in the IVMP group.30 Additional surgical
2 (1–2·5) 2 (1–3·75) 1 (0–2·5) 1 (0–2) treatment was required more often in the IVMP group
2 × 1000 mg .. 2 × 1000 mg .. (ten [62%] of 16 vs three [20%] of 15 in the rituximab
(n=5) or 1 × 500 mg
(n=10)
group). Improvement by 6 or more points on the
4·9 (1·0) 5·3 (1·0) 4·4 (0·7) 4·7 (0·7)
disease-specific quality-of-life questionnaire was more
frequent in the rituximab than in the IVMP group at
3·7 (1·9) 3·8 (1·4) 0·6 (0·3) 2·3 (0·5) 52 weeks, both in terms of appearance (eight [62%] of
13 vs six [46%] of 13) and in the visual functioning scale
(ten [77%] of 13 vs seven [54%] of 13) . Thus, the greater
efficacy of rituximab compared with IVMP (given in a
high cumulative dose of 7·5 g) seems to become evident
after 24 weeks, especially in terms of the frequency of
relapse after discontinuation of corticosteroids.
 Review

Tolerability lower doses of ritumimab might be equally effective

In Stan and colleagues’ trial,29 11 adverse events occurred and are probably better tolerated. This subject is actively
in eight (80%) of ten patients in the rituximab group under investigation.
group (six minor and five moderate-to-severe, including
two cases of dysthyroid optic neuropathy), and four Feasibility of other novel therapies
adverse events occurred in three (27%) of 11 patients in Targeting of orbital fibroblasts
the placebo group (three minor, one moderate-to-severe). Table 2 lists possible targets of future therapies.
In Salvi and coworkers’ investigation,30 13 adverse events The stimulating effects of TSH-receptor-stimulating
occurred in 13 (87%) of 15 patients in the rituximab group antibodies on hyaluronan production and adipogenesis
(11 minor, two moderate-to-severe—both dysthyroid in cultured human orbital fibroblasts can be blocked in
optic neuropathy), and ten adverse events occurred in vitro by TSH-receptor-blocking monoclonal antibodies34,35
ten (62%) of 16 patients in the IVMP group (seven minor, and by small molecule TSH-receptor antagonists
three moderate-to-severe). (In the secondary outcomes (low-molecular-weight compounds binding in the
section of the Salvi trial,30 a patient randomly assigned transmembrane domain of the TSH receptor).36–38
to IVMP who developed optic neuropathy and was Blockade of TSH-receptor-mediated signalling holds
unresponsive to additional corticosteroids was described; great promise for the future as it directly interferes with
this patient, however, is not mentioned in the table listing the action of thyroid-stimulating immunoglobulins, the
all adverse events.) immediate cause of Graves’ disease.
Overall, dysthyroid optic neuropathy developed in four Postreceptor signalling pathways of TSH receptors and
(16%) of 25 patients who received rituximab compared IGF-1 receptors overlap, and ligation of IGF-1 receptors
with none of the 27 patients receiving placebo or with IGF-1 also results in increased hyaluronan production
corticosteroids. The rather acute loss of visual function and adipogenesis.45–47 There is good evidence that these
during or shortly after rituximab infusion was attributed in-vitro effects can be blocked by IGF-1-receptor-blocking
to rapid and massive release of cytokines, known as antibodies (eg, teprotumumab).48 A randomised controlled
cytokine-release syndrome. Alternatively, this effect trial in which teprotumumab is compared with placebo
might reflect progression of pre-existing orbitopathy in in active, moderate-to-severe Graves’ ophthalmopathy
patients in whom immunosuppression is not effective. (NCT01868997) has completed recruitment.
Loss of visual function was fortunately transient in two Orbital fibroblasts express PDGF receptors. PDGF
of the four patients; in the other two, urgent surgical isoforms AA, AB, and BB are all increased in orbital
decompression of the orbit was done (the outcome in
these patients was not reported, although orbital surgical Drug Evidence of efficacy
decompression is usually very effective in restoring
Orbital fibroblast
visual acuity in Graves’ ophthalmopathy).
TSH receptor TSH-receptor-blocking antibodies, In-vitro inhibition of hyaluronan and
TSH-receptor antagonist adipogenesis34–38
Role in therapy IGF-1 receptor IGF-1-receptor-blocking antibodies Placebo-controlled randomised controlled
Rituximab appears slightly more efficacious than (teprotumumab) trial (to complete in 2017; NCT01868997)
intravenous steroids, but its safety profile is less good PDGF Tyrosine-kinase inhibitors (imatinib, In-vitro inhibition of hyaluronan
than that of IVMP. On the basis of existing data, nilotinib, dasatinib) production39,40
rituximab should not replace IVMP as the treatment of Somatostatin Somatostatin receptor analogues None
receptor (pasireotide)
choice in active, moderate-to-severe Graves’ ophthal-
B cells
mopathy. It can be tried in severe corticosteroid-resistant
cases, although chances of a favourable response appear CD20 CD20 monoclonal antibody (rituximab) Two conflicting randomised controlled
trials29,30
lower with longer disease duration.
T cells
A few cases of optic neuropathy that have been
CD3 CD3 monoclonal antibody (teplizumab) None
successfully treated with rituximab have been
CTLA4 CTLA4 analogue (abatacept) None
described,25 but rituximab should not be given if
Cytokines
dysthyroid optic neuropathy is suspected. It is
Tumour Anti-tumour necrosis factor α (etanercept, Limited efficacy in open-label case series41–43
hypothesised that the patients who developed necrosis factor α infliximab, adalimumab)
dysthyroid optic neuropathy when given rituximab had Interleukin 1 Soluble-interleukin-1 receptor (rilonacept) In-vitro inhibition of hyaluronan
subclinical dysthyroid optic neuropathy already, and Interleukin-1-receptor antagonist production44
that rituximab induced a massive release of cytokines (anakinra)
that caused further acute swelling of orbital tissues, Interleukin 6 Interleukin-6-receptor monoclonal Good efficacy in open-label case series,
thereby compressing the optic nerve.28 Perhaps the antibody (tocilizumab) randomised controlled trial in progress
(NCT01297699 )
most important implications of both Stan and
colleagues’ and Salvi and colleagues’ trials29,30 are that TSH=thyroid-stimulating hormone.
the earlier you treat, the greater the chance of
Table 2: Possible targets of future therapies for active, moderate-to-severe Graves’ ophthalmopathy
immunosuppression being successful, and that much

www.thelancet.com/diabetes-endocrinology Published online June 23, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30046-8 5

 Review
tissues of patients with active and inactive Graves’
ophthalmopathy, and are produced by infiltrating
monocytes, macrophages, and mast cells. PDGF induces
proliferation and hyaluronan and cytokine production,
and increases expression of TSH receptors in cultured
orbital fibroblasts.39 Tyrosine-kinase inhibitors like
imatinib and nilotinib inhibit PDGF-receptor signalling
in orbital fibroblasts by preventing receptor auto-
phosphorylation upon ligand binding, but have serious
side-effects such as periorbital oedema, peripheral
arterial occlusive disease, and cerebrovascular events.49
More promising is dasatinib, which has the lowest IC50
of all tyrosine-kinase inhibitors for PDGF receptors.40
Orbital uptake on octreotide scintigraphy is increased
in active Graves’ ophthalmopathy but not in inactive
disease, and has been proposed as a disease-activity
parameter (it suggests involvement of somatostatin
receptors in disease).50 Compared with those from
controls with unrelated eye conditions (eg, trauma,
osteoma, strabismus), there is an upregulation of SST1
and SST5 in orbital fibroblasts from patients with
Graves’ ophthalmopathy.51 However, several randomised
controlled trials with the somatostatin analogues
octreotide and lanreotide showed no or marginal
improvement of eye changes in Graves’ ophthalmopathy.52
This lack of efficacy might be explained by the low
binding affinities of octreotide and lanreotide for SST1
and SST5.53 The new analogue pasireotide has much
higher binding affinities for somatostatin receptors,
especially for SST1 and SST5,54 and might thus be
effective in Graves’ ophthalmopathy. However, the
efficacy of pasireotide in Graves’ ophthalmopathy has
not been investigated.
Targeting of T and B cells
Given the pathological role of T cells in Graves’
ophthalmopathy (figure), antibodies targeting these
cells could be investigated as a potential therapy. For
example, CD3 antibodies (eg, otelixizumab, teplizumab)
deplete T cells, and have shown some benefit in
preservation of β-cell function in patients with type 1
diabetes when given in the early stages of the disease.55
Another approach could be treatment with abatacept (an
analogue of CTLA4 that limits further activation of
T cells), which has been used in corticosteroid-resistant
rheumatoid arthritis.56 Induction of T-cell tolerance to
target autoantigens with synthetic peptides has also
attracted much interest. Peptide immunotherapy is
highly effective at silencing autoimmune responses in
experimental autoimmune encephalomyelitis, an
animal model of multiple sclerosis.57 However, none of
these T-cell-directed interventions have been applied in
autoimmune thyroid disease.58
As discussed earlier, CD20 antibodies (eg, rituximab)
deplete B cells, but it will be another few years before the
right dose and indication for use in patients with Graves’
ophthalmopathy are settled upon.
6 www.thelancet.com/diabetes-endocrinology Published online June 23, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30046-8
Targeting of cytokines
Expression of cytokine mRNA in orbital fat and connective
tissue is much higher in active than in inactive disease for
several cytokines (eg, interleukins 1β, 2, 6, 8, 10), but
similar between both groups for others (eg, tumour
necrosis factor α, interferon γ, interleukin 1RA).59,60
Tumour-necrosis-factor-α blockade in patients with
Graves’ ophthalmopathy has not been tested in
randomised controlled trials, and results in small case
series have not been very successful. Etanercept improved
Graves’ ophthalmopathy in six of ten patients, more so in
terms of activity (ie, clinical activity score) than severity of
disease; after discontinuation of etanercept, a flare-up was
reported in three patients.41 There is one case report42 of a
patient with dysthyroid optic neuropathy, in whom clinical
activity score, colour vision, and visual acuity improved
after an infusion of infliximab. A case series43 showed
improvement in an inflammatory score in five of
ten patients given adalimumab (noted only in patients
with high baseline scores for inflammation); proptosis or
motility were not improved.
There is fair evidence that glycosaminoglycan
production in cultured human orbital fibroblasts is
inhibited by interleukin-1-receptor antagonists or soluble
interleukin-1 receptors,44 but such treatment has not been
tested in patients.
A non-randomised, open-label study61 showed remarkable
success with tocilizumab (an interleukin-6-receptor
monoclonal antibody) in 18 patients with active
corticosteroid-resistant Graves’ ophthalmopathy. Mean
disease duration was 16 months. 8 mg/kg of tocilizumab
was given per month (minimum 480 mg per session)
intravenously for a mean of five sessions (range 4–9), with
a follow-up of 15 (9–27) months. Improvement occurred in
all patients: clinical activity score decreased from
6·5 (SD 1·2) to 0·6 (0·8), proptosis decreased from
22·3 mm (3·2) to 19·8 mm (2·6), eye muscle motility
improved in 15 patients, diplopia in primary gaze was
present in 13 patients before treatment compared with
six afterwards, and visual acuity increased from
0·75 (0·19) to 0·86 (0·14). TSH-receptor antibodies
decreased by about 40%. The safety profile of tocilizumab
appears rather good: side-effects occur in 66% but are
mostly mild and transient in nature.62 The results are
almost too good to believe. However, treatment success is
claimed more often in uncontrolled studies than in studies
in which controls have been used; claims for the success of
a treatment are closely associated with the absence of
the means whereby these claims can be scientifically
substantiated.63 A randomised controlled trial comparing
tocilizumab with placebo has been completed
(NCT01297699) but the results have not yet been published.
Need for randomised clinical trials
As noted previously, moderate-to-severe Graves’ ophthal-
mopathy occurs in about one in every 20 patients with
Graves’ hyperthyroidism—a low incidence of around

10–16 patients per million people per year. There is also a
noteworthy trend towards less active and less severe
Graves’ ophthalmopathy: patients referred to the
European Group On Graves’ Orbitopathy centres in 2012
more often had inactive (63% vs 40%, p<0·01) or mild
(61% vs 41%, p<0·01) disease than did those referred in
2000.64 Possible explanations for the decline in incidence
and severity are secular trends toward lower prevalence of
smoking and earlier diagnosis and treatment of Graves’
hyperthyroidism. At the same time, the number of
potential novel therapies for Graves’ ophthalmopathy is
rising. The efficacy and tolerability of these new treatment
modalities have to be investigated in randomised
controlled trials, which should have an adequate sample
size (eg, 53 participants in each randomisation arm were
required to detect differences in response rates of 80%,
65%, and 55% with 80% power and a significance level of
p=0·05).10 There will probably be a shortage of patients
suitable for inclusion in trials. Multicentre cooperation is
thus required, and, against this background, consortiums
like the European Group On Graves’ Orbitopathy provide
the ideal environment for timely completion of
randomised controlled trials.
The most appropriate outcome measures of such trials
in active, moderate-to-severe Graves’ ophthalmopathy
should also be considered— standardisation would allow
better comparison between trials. In my opinion, there
should be two primary outcomes: one subjective measure
reported by the (blinded) patient (like the Graves’
ophthalmopathy quality-of-life questionnaire),65 and one
objective measure assessed by the (blinded) physician.
Nowadays, the clinical activity score is used most frequently
as the primary (objective) outcome measure. However, it is
pertinent to remember that the score was introduced in
1997 as a predictor of response to corticosteroids to
save non-responders from unnecessary exposure and
side-effects.11 Thus, a question arises about the goal of
immunosuppressive treatment in active, moderate-to-
severe Graves’ ophthalmopathy.66 If the aim is to inactivate
Graves’ ophthalmopathy to allow rehabilitative surgery
(eg, for diplopia) sooner, then the clinical activity score
seems adequate as primary outcome. However, if it is to
reduce inflammation and symptoms (like diplopia),
clinical activity score does not suffice as the primary
outcome, and assessment of lid aperture, proptosis, eye
muscle motility, and diplopia should be incorporated. To
this end, the European Group On Graves’ Orbitopathy has
designed a composite ophthalmic score as an objective
primary outcome measure,6 which takes into account
difficulties that can arise when improvement occurs in one
item but deterioration in another item or in the other eye.10
A reliable animal model of Graves’ ophthalmopathy, in
which the efficacy of novel therapies could be tested,
would be very useful. Paul Banga’s group has made
substantial progress in this respect: a mouse model of
Graves’ disease with some features mimicking Graves’
ophthalmopathy was created by genetic immunisation of
www.thelancet.com/diabetes-endocrinology Published online June 23, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30046-8
Review
TSH receptor cDNA.67,68 An animal model is, however,
unlikely to answer all remaining questions. Intriguing
clinical questions include why not all patients with
Graves’ hyperthyroidism develop clinically overt For the European Group On
ophthalmopathy, and why Graves’ ophthalmopathy Graves’ Orbitopathy see http://
www.eugogo.eu/
develops in about 13% of all cases in the absence of
hyperthyroidism. The most promising drugs in the near
future are presumably teprotumumab and tocilizumab.
Declaration of interests
I am a consultant for Riverside Vision Development Corporation,
New York, NY, USA.
References
1 Abraham-NordingM, Bystrom K, Torring O, et al. Incidence of
hyperthyroidism in Sweden. Eur J Endocrinol 2011; 165: 899–905.
2 Laurberg P, Berman DC, Bulow Pedersen I, Andersen S, Carle A.
Incidence and clinical presentation of moderate to severe Graves’
orbitopathy in a Danish population before and after iodine
fortification of salt. J Clin Endocrinol Metab 2012; 97: 2325–32.
3 Tanda ML, Piantanida L, Liparulo G, et al. Prevalence and natural
history of Graves’ orbitopathy in a large series of patients with
newly diagnosed Graves’ hyperthyroidism seen at a single center.
J Clin Endocrinol Metab 2013; 98: 1443–49.
4 Bahn R. Current insights into the pathogenesis of Graves’
ophthalmopathy. Horm Metab Res 2015; 47: 773–78.
5 Cortisone in exophthalmos: report on a therapeutic trial of cortisone
and corticotrophin (ACTH) in exophthalmos and exophthalmic
ophthalmoplegia by a panel appointed by the Medical Research
Council. Lancet 1955; 268: 6–9.
6 Stiebel-Kalish H, Robenshtok E, Hasanreisoglu M, Ezrachi D,
Shimon I, Leibovici L. Treatment modalities for Graves’
ophthalmopathy: systematic review and meta-analysis.
J Clin Endocrinol Metab 2009; 94: 2708–16.
7 Gao G, Dai J, Qian Y, Ma F. Meta-analysis of methylprednisolone
pulse therapy for Graves’ ophthalmopathy. Clin Exp Ophthalmol
2014; 42: 769–77.
8 Bartalena L, Baldeschi L, Dickinson A, et al. Consensus statement
of the European Group on Graves’ Orbitopathy (EUGOGO) on
management of GO. Eur J Endocrinol 2008; 158: 273–85.
9 Zhu W, Ye L, Shen L, et al. A propsective, randomized trial of
intravenous glucocorticoids therapy with different protocols for
patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab 2014;
99: 1999–2007.
10 Bartalena L, Krassas GE, Wiersinga W, et al. Efficacy and safety of
three different cumulative doses of intravenous methylprednisolone
for moderate to severe and active Graves’ orbitopathy.
J Clin Endocrinol Metab 2012; 97: 4454–63.
11 Mourits MP, Prummel MF, Wiersinga WM, Koornneef L.
Clinical activity score as a guide in the management of patients
with Graves’ ophthalmopathy. Clin Endocrinol 1997; 47: 9–14.
12 Nedeljkovic Beleslin B, Ciric J, Zarkovic M, et al. Efficacy and safety
of combined parenteral and oral steroid therapy in Graves’
orbitopathy. Hormones (Athens) 2014; 13: 222–28.
13 Bartalena L, Marcocci C, Chiovato L, et al. Orbital cobalt irradiation
combined with systemic corticosteroids for Graves’
ophthalmopathy: comparison with systemic corticosteroids alone.
J Clin Endocrinol Metab 1983; 56: 1139–44.
14 Marcocci C, Bartalena L, Bogazzi F, et al. Orbital radiotherapy
combined with high dose systemic glucocorticoids is more effective
than radiotherapy alone. Results of a prospective randomised study.
J Endocrinol Invest 1991; 14: 853–60.
15 Weissel M, Hauff W. Fatal liver failure after high-dose
glucocorticoid pulse therapy in a patient with severe thyroid eye
disease. Thyroid 2000; 10: 521.
16 Marino M, Morabito E, Brunetto MR, Bartalena L, Pinchera A,
Marcocci C. Acute and severe liver damage associated with
intravenous glucocorticoid pulse therapy in patients with Graves’
ophthalmopathy. Thyroid 2004; 14: 403–06.
17 Marcocci C, Watt T, Altea MA, et al. Fatal and non-fatal adverse
events of glucocorticoid therapy for Graves’ orbitopathy:
a questionnaire survey among members of the European Thyroid
Association. Eur J Endocrinol 2012; 166: 247–53.
7
 Review
18 Marino M, Morabito E, Altea MA, et al. Autoimmune hepatitis
during intravenous glucocorticoid pulse therapy for Graves’
ophthalmopathy treated successfully with glucocorticoids
themselves. J Endocrinol Invest 2005; 28: 280–84.
19 Moli R, Baldeschi L, Saeed P, Regensburg N, Mourits MP,
Wiersinga WM. Determinants of liver damage associated with
intravenous methylprednisolone pulse therapy in Graves’
ophthalmopathy. Thyroid 2007; 17: 357–62.
20 Sisti E, Coco B, Menconi F, et al. Age and dose are major risk
factors for liver damage associated with intravenous glucocorticoid
pulse therapy for Graves’ orbitopathy. Thyroid 2015; 25: 846–50.
21 Zang S, Ponto KA, Kahaly GJ. Clinical review: intravenous
glucocorticoids for Graves’ orbitopathy: efficacy and morbidity.
J Clin Endocrinol Metab 2011; 96: 320–32.
22 Sisti E, Coco B, Menconi F, et al. Intravenous glucocorticoid therapy
for Graves’ ophthalmopathy and acute liver damage:
an epidemiological study. Eur J Endocrinol 2015; 172: 269–76.
23 Giotaki Z, Fountas A, Tsirouki T, Bargiota A, Tigas S, Tsatsoulis A.
Adrenal reserve following treatment of Graves’ orbitopathy with
intravenous glucocorticoids. Thyroid 2015; 25: 462–63.
24 Gasinska T, Borowska A, Wichary H, Dec R. Effect of
methylprednisolone pulse therapy with and without alendronate on
biochemical markers of bone turnover in patients with Graves’
ophthalmopathy. Pol Arch Med Wewn 2012; 122: 341–47.
25 Salvi M, Vannucchi G, Beck-Peccoz P. Potential utility of rituximab
for Graves’ orbitopathy. J Clin Endocrinol Metab 2013; 98: 4291–99.
26 El Fassi D, Nielsen CH, Hasselbalch HC, Hegedus L.
Treatment-resistant severe, active Graves’ ophthalmopathy
successfully treated with B lymphocyte depletion. Thyroid 2006;
16: 709–10.
27 Salvi M, Vannuchi G, Campi I, et al. Efficacy of rituximab treatment
for thyroid-associated ophthalmopathy as a result of intraorbital
B-cell depletion in one patient unresponsive to steroid
immunosuppression. Eur J Endocrinol 2006; 154: 511–17.
28 Krassas GE, Stafilidou A, Boboridis KG. Failure of rituximab
treatment in a case of severe thyroid ophthalmopathy unresponsive
to steroids. Clin Endocrinol 2010; 72: 853–55.
29 Stan MN, Garrity JA, Carranza L, et al. Randomized controlled trial
of rituximab in patients with Graves’ orbitopathy.
J Clin Endocrinol Metab 2015; 100: 432–41.
30 Salvi M, Vannucchi G, Curro N, et al. Efficacy of B-cell targeted
therapy with rituximab in patients with active moderate-severe
Graves’ orbitopathy: a randomized controlled study.
J Clin Endocrinol Metab 2015; 100: 422–31.
31 Van Geest RJ, Sasim IV, Koppeschaar HP, et al. Methylprednisolone
pulse therapy for patients with moderately severe Graves’
orbitopathy: a prospective, randomized, placebo-controlled study.
Eur J Endocrinol 2008; 158: 229–37.
32 Wiersinga WM. Smoking and thyroid. Clin Endocrinol 2013;
79: 145–51.
33 Khan A, Scott DL, Batley M. Smoking, rheumatoid factor status and
responses to rituximab. Ann Rheum Dis 2012; 71: 1588–90.
34 Morshed SA, Davies TF. Graves’ disease mechanisms: the role of
stimulating, blocking, and cleavage region TSH receptor antibodies.
Horm Metab Res 2015; 47: 727–34.
35 Furmaniak J, Sanders J, Nunez Miguel R, Rees Smith B.
Mechanism of action of TSHR autoantibodies. Horm Metab Res
2015; 47: 735–52.
36 Van Zeijl CJ, van Koppen CJ, Surovtseva OV, et al.
Complete inhibition of rhTSH-, Graves’ disease IgG-, and
M22-induced cAMP production in differentiated orbital fibroblasts
by a low-molecular-weight TSHR antagonist.
J Clin Endocrinol Metab 2012; 97: E781–85.
37 Turcu AF, Kumar S, Neumann S, et al. A small molecule antagonist
inhibits thyrotropin receptor antibody-induced orbital fibroblast
functions involved in the pathogenesis of Graves’ ophthalmopathy.
J Clin Endocrinol Metab 2013; 98: 2153–59.
38 Neumann S, Place RF, Krieger CC, Gershengorn MC.
Future prospects for the treatment of Graves’ hyperthyroidism and
eye disease. Horm Metab Res 2015; 47: 789–96.
39 Virakul S, van Steensel L, Dalm VA, Paridaens D, van Hagen PM,
Dik WA. Platelet-derived growth factor: a key factor in the
pathogenesis of Graves’ ophthalmopathy and potential target for
treatment. Eur Thyroid J 2014; 3: 217–26.
8 www.thelancet.com/diabetes-endocrinology Published online June 23, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30046-8
40 Virakul S, Dalm VA, Paridaens D, et al. The tyrosine kinase
inhibitor dasatinib effectively blocks PDGF-induced orbital
fibroblast activation. Graefes Arch Clin Exp Ophthalmol 2014;
252: 1101–09.
41 Paridaens D, van den Bosch WA, van der Loos TL, Krenning EP,
van Hagen PM. The effect of etanercept on Graves’
ophthalmopathy: a pilot study. Eye 2005; 19: 1286–89.
42 Durrani OM, Reuser TQ, Murray PI. Infliximab: a novel treatment
for sight-threatening thyroid associated ophthalmopathy. Orbit
2005; 24: 117–19.
43 Ayabe R, Rootman DB, Hwang CJ, Ben-Artzi A, Goldberg R.
Adalimumab as steroid-sparing treatment of inflammatory-stage
thyroid eye disease. Ophthal Plast Reconstr Surg 2014; 30: 415–19.
44 Tan GH, Dutton CM, Bahn RS. Interleukin-1 (IL-1) receptor
antagonist and soluble IL-1 receptor inhibit IL-1 induced
glycosaminoglycan production in cultured human fibroblasts from
patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab 1996;
81: 449–52.
45 Smith TJ, Hegedus L, Douglas RS. Role of insulin-like growth
factor-1 (IGF-1) pathway in the pathogenesis of Graves’ orbitopathy.
Best Pract Res Clin Endocrinol Metab 2012; 26: 291–302.
46 Kumar S, Nadeem S, Stan MN, Coenen M, Bahn RS. A stimulatory
TSH receptor antibody enhances adipogenesis via phosphoinositide
3-kinase activation in orbital preadipocytes from patients with
Graves’ ophthalmopathy. J Mol Endocrinol 2011; 46: 155–63.
47 Kumar S, Iver S, Bauer H, Coenen M, Bahn RS. A stimulatory
thyrotropin receptor antibody enhances hyaluronic acid synthesis in
Graves’ orbital fibroblasts: inhibition by an IGF-1 receptor blocking
antibody. J Clin Endocrinol Metab 2012; 97: 1681–87.
48 Chen H, Mester T, Raychaudhuri N, et al. Teprotumumab, an
IGF-1R blocking monoclonal antibody inhibits TSH and IGF-1
action in fibrocytes. J Clin Endocrinol Metab 2014; 99: E1635–40.
49 Kim TD, Rea D, Schwarz M, et al. Peripheral artery occlusive
disease in chronic phase chronic myeloid leukemia patients treated
with nilotinib or imatinib. Leukemia 2013; 27: 1316–21.
50 Gerding MN, van der Zant FM, van Royen EA, et al.
Octreotide-scintigraphy is a disease-activity parameter in Graves’
ophthalmopathy. Clin Endocrinol 1999; 50: 373–79.
51 Pasquali D, Vassallo P, Esposito D, Bonavolonta G, Bellastella A,
Sinisi AA. Somatostatin receptor gene expression and inhibitory
effects of octreotide on primary cultures of orbital fibroblasts from
Graves’ ophthalmopathy. J Mol Endocrinol 2000; 25: 63–71.
52 Tanda ML, Bartalena L. Currently available somatostatin analogs are
not good for Graves’ orbitopathy. J Endocrinol Invest 2006;
29: 389–390.
53 Cozma I, Zhang L, Uddin J, Lane C, Rees A, Ludgate M.
Modulation of expression of somatostatin receptor subtypes in
Graves’ ophthalmopathy orbits: relevance to novel analogs.
Am J Physiol Endocrinol Metab 2007; 293: E1630–35.
54 Bruns C, Lewis I, Briner U, Meno-Tetang G, Weckbecker G.
SOM230: a novel somatostatin peptidomimetic with broad
somatotropin release inhibiting factor (SRIF) receptor binding
and a unique antisecretory profile. Eur J Endocrinol 2002;
146: 707–16.
55 Daifotis AG, Koenig S, Chatenoud L, et al. Anti-CD3 clinical trials
in type 1 diabetes mellitus. Clin Immunol 2013; 149: 268–78.
56 Herrero-Beaumont G, Martinez Calatrava MJ, Castaneda S.
Abatacept mechanism of action: concordance with its clinical
profile. Reumatol Clin 2012; 8: 78–83.
57 Anderton SM. Peptide immunotherapy in experimental
autoimmune encephalomyelitis. Biomed J 2015; 38: 206–214.
58 Bartalena L. Commentary: rituximab, adalimumab, etanercept,
tocilizumab—are biologicals the future for Graves’ orbitopathy?
Ophthal Plast Reconstr Surg 2014; 30: 420–23.
59 Wakelkamp IM, Gerding MN, van der Meer JW, Prummel MF,
Wiersinga WM. Both Th1- and Th2-derived cytokines are elevated in
Grvaes’ ophthalmopathy. Clin Exp Immunol 2000; 121: 453–57.
60 Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM,
Prummel MF. TSH-R expression and cytokine profile in orbital
tissue of active vs inactive Graves’ ophthalmopathy patients.
Clin Endocrinol 2003; 58: 280–87.
61 Perez-Moreiras JV, Alvarez-Lopez A, Gomez EC. Treatment of
active corticosteroid-resistant Graves’ orbitopathy.
Opthal Plast Reconstr Surg 2014; 30: 162–67.

62 Yamamoto K, Goto H, Hirao K, et al. Longterm safety of
tocilizumab: results from 3 years of followup postmarketing
surveillance of 5573 patients with rheumatoid arthritis in Japan.
J Rheumatol 2015; 42: 1368–75.
63 Laurence DR. Clinical pharmacology, 3rd edn. London:
J & A Churchill, 1966.
64 Perros P, Zarkovic M, Azzolini C, et al. PREGO (presentation of
Graves’ orbitopathy) study: changes in referral patterns to European
Group On Graves’ Orbitopathy (EUGOGO) centres over the period
from 2000 to 2012. Br J Ophthalmol 2015; 99: 1531–35.
65 Terwee CB, Dekker FW, Mourits MP, et al. Interpretation and
validity of changes in scores on the Graves’ ophthalmopathy quality
of life questionnaire (GO-QoL) after different treatments.
Clin Endocrinol 2001; 54: 391–98.
www.thelancet.com/diabetes-endocrinology Published online June 23, 2016 http://dx.doi.org/10.1016/S2213-8587(16)30046-8
Review
66 Yang M, Wiersinga WM, Soeters MR, Mourits MP. What is the aim
of immunosuppressive treatment in patients with Graves’
orbitopathy? Ophthal Plast Reconstr Surg 2014; 30: 157–61.
67 Zhao SX, Tsui S, Cheung A, Douglas RS, Smith TJ, Banga JP.
Orbital fibrosis in a mouse model of Graves’ disease induced by
genetic immunization of thyrotropin receptor cDNA. J Endocrinol
2011; 210: 369–77.
68 Moshkelgosha S, So PW, Deasy N, Diaz-Cano S, Banga JP. Cutting
edge: retrobulbar inflammation, adipogenesis, and acute orbital
congestion in a preclinical female mouse model of Graves’
orbitopathy induced by thyrotropin receptor plasmid-in vivo
electroporation. Endocrinology 2013; 154: 3008–15.
9