ORIGINAL ARTICLE

E n d o c r i n e C a r e

A Prospective, Randomized Trial of Intravenous

Glucocorticoids Therapy With Different Protocols for
Patients With Graves’ Ophthalmopathy

Wei Zhu,* Lei Ye,* Liyun Shen,* Qin Jiao, Fengjiao Huang, Rulai Han,
Xiaofang Zhang, Shu Wang, Weiqing Wang, and Guang Ning
Shanghai Key Laboratory for Endocrine Tumors (W.Z., L.Y., L.S., F.H., R.H., X.Z., S.W., W.W., G.N.),
Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and
Metabolic Diseases and Shanghai E-institute for Endocrinology, Ruijin Hospital, Shanghai Jiaotong
University, School of Medicine, Shanghai 200025, P. R. China; Department of Ophthalmology (Q.J.),
Ruijin Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200025, P. R. China; and
Laboratory for Endocrine and Metabolic Diseases of Institute of Health Science (G.N.), Shanghai
JiaoTong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese
Academy of Sciences, Shanghai 200025, P. R. China

Background: For patients with active moderate-to-severe Graves’ ophthalmopathy (GO), a course
of 4.5 g iv glucocorticoids (GCs) is the recommended therapy. The weekly protocol is preferred
because of the potential safety concerns with the daily protocol. However, evidence for the su-
periority of different administration protocols is lacking.

Methods: We conducted a prospective, randomized trial to compare the efficacy and safety of two
protocols of iv 4.5 g methylprednisolone in a total of 80 patients in our institute. The patients were
randomized to receive iv methylprednisolone weekly or daily. The response rate (a composite
response endpoint including lid width, soft tissue involvement, proptosis, intraocular pressure,
Clinical Activity Score [CAS], diplopia, and visual acuity) was evaluated as the primary outcome, and
adverse effects were recorded at each visit. GO-associated serum cytokines were measured.

Results: We found a significantly greater response rate for the weekly protocol vs the daily protocol
at the 12th week (76.92 vs 41.03%; P ⫽ .0025) and a similar response rate at the fourth week. Seven
patients on the daily protocol worsened when tapering iv methylprednisolone to oral prednisone
in the fourth week. Patients in both groups showed significant CAS response, and at the 12th week,
patients on the weekly protocol showed a nonsignificant trend toward greater CAS response.
Weekly protocol showed significant prolonged retreatment-free survival. Severe side effects were
only observed in two cases, both of which were on the daily protocol. Furthermore, we observed
sustained decreased levels of serum CXCL10 in the 12th week compared to the baseline level (P ⫽
.0009) in the patients on the weekly protocol.

Conclusions: The weekly protocol of iv methylprednisolone therapy is more efficient and safer than
the daily protocol for patients with active moderate-to-severe GO. (J Clin Endocrinol Metab 99:
1999 –2007, 2014)

pproximately 3–5% of patients with Graves’ oph- medical intervention (1). These interventions include
A thalmopathy (GO) have severe diseases with the
potential of losing their sight and requiring optimized
management of hyperthyroidism, measures to relieve local
symptoms, immunosuppressive therapies for active mod-

ISSN Print 0021-972X ISSN Online 1945-7197 * W.Z., L.Y., and L.S. contributed equally to this work.
Printed in U.S.A. Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMD,
Copyright © 2014 by the Endocrine Society bone mineral density; CAS, Clinical Activity Score; DM, diabetes mellitus; GC, glucocor-
Received October 27, 2013. Accepted February 20, 2014. ticoid; GO, Graves’ ophthalmopathy; IFG, impaired fasting glucose; IGT, impaired glucose
First Published Online February 28, 2014 tolerance; RCT, randomized controlled trial; TRAb, TSH receptor antibody.

doi: 10.1210/jc.2013-3919 J Clin Endocrinol Metab, June 2014, 99(6):1999 –2007 jcem.endojournals.org 1999

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2000 Zhu et al IV GC Therapy for Graves’ Ophthalmopathy J Clin Endocrinol Metab, June 2014, 99(6):1999 –2007

erate and severe GO, and rehabilitative surgery for inac- Table 1. Inclusion and Exclusion Criteria
tive patients (2). The nonsurgical approaches are gluco-
corticoids (GCs) and orbital radiotherapy. The reported 2 Thyroid dysfunction
3 Proptosis
response rate to orbital radiotherapy in open trials is ap- 4 Optic nerve involvement
proximately 60% (3). Although tolerated, orbital radio- 5 Extraocular muscle involvement
therapy is associated with transient exacerbation of ocular 6 Exclude cases with ophthalmological signs caused by
other diseases
symptoms, theoretical concerns about carcinogenesis in 7 Moderate to severe patients defined by EUGOGO
younger patients, and retinal microvascular abnormali- 8 CAS ⱖ3/7
ties, especially in patients with hypertensive or diabetic 9 Normal heart, liver and kidney function
retinopathy (4, 5). Patients should meet either criterion 1 plus at least one of criteria 2 to
GC therapy can be administered through oral, retrob- 5, or criterion 2 plus at least one of 3 to 5 together with 6 to 9 to be
included in the study.
ulbar, or subconjunctival and iv routes. Oral GC showed
a favorable response in 33– 63% of patients with active protocol for 4.5 g iv GC. This study was designed to ad-
moderate-to-severe GO (6, 7). Retrobulbar or subcon- dress this question.
junctival GC therapy is less effective than oral GCs (8).
Evidence from randomized controlled trials (RCTs) has
suggested that iv GC is more effective than oral GC, either Patients and Methods
as monotherapy (77 vs 51%; P ⬍ .01) (6) or combined
with orbital radiotherapy (87.8 vs 63.4%; P ⬍ .02) (6). Patients
All eligible patients diagnosed as having active moderate-to-
Intravenous GC is more efficient at controlling local in-
severe GO from 2010 to 2012 in our hospital were included in
flammation because the Clinical Activity Score (CAS) was this study. The diagnosis was based on the EUGOGO consensus
significantly lower based on the comparison of iv GC to (9). None of the patients received any immunosuppressive ther-
oral GC (6, 7). Moreover, iv GC was associated with less apy or radiotherapy in the previous 3 months. The detailed in-
adverse events than oral GC (17 vs 51% for monotherapy; clusion and exclusion criteria was addressed as in Table 1. The
board of medical ethics of Ruijin Hospital approved the study,
56.1 vs 85.4% for combined therapy with orbital radio- and all patients gave their written informed consent.
therapy) (6, 7). Therefore, the European Group on GO Patients were randomized to receive 4.5 g methylpred-
(EUGOGO) published a consensus statement in 2008 and nisolone for 12 weeks as recommended (13) or 4 weeks as pre-
suggested iv GC as the first-line treatment for active mod- viously reported (13). The weekly protocol was as follows: 0.5 g
weekly for 6 weeks, followed by 0.25 g weekly for 6 weeks. The
erate-to-severe GO (9).
daily protocol was as follows: 0.5 g daily for 3 consecutive days
Even when treated with iv GC, liver failure occurred in per week for 2 weeks, followed by 0.25 g daily for 3 consecutive
0.8% of GO patients, especially those with cumulative days per week for another 2 weeks and by tapering oral pred-
doses over 8 g of methylprednisolone (10). Most studies nisone. A total of 80 eligible patients were randomly assigned
therefore recommend a course of 4.5 g iv methylpred- following a restricted randomization scheme: computer random
number generator, a block size of six, and an allocation ratio of
nisolone. However, RCT studies are required to determine
one-to-one. Sealed envelopes were applied for allocation con-
the optimal dosage and administration protocol. The most cealment. Two patients left the study before the fourth week—
recently published study addressed the optimal doses of iv one because of impaired liver function and the other because of
GC and found that a 7.47-g dose provided short-term intractable hiccups. Intention-to-treat analysis was applied, in-
cluding all eligible enrolled patients.
advantages over 4.98-g and 2.25-g doses (overall ophthal-
Table 2 summarizes the baseline clinical characteristics in the
mic improvement was 52, 35, and 28%, respectively), but two groups. Patients on the weekly protocol had longer duration
with slightly greater toxicity for GO patients (11). The of eye symptoms (13.63 ⫾ 16.52 vs 6.41 ⫾ 4.90 months; P ⫽ .01)
authors thereafter recommended an intermediate-dose and marginally lower levels of TSH receptor antibody (TRAb)
regimen for most cases with active moderate-to-severe (3.81 [1.62–9.91] vs 9.75 [3.45–27.14]; P ⫽ .05) compared to
patients on the daily protocol. In addition, there was no signif-
GO (11).
icant difference between the two groups.
There are mainly two protocols for iv GC therapy for
GO patients: one is on a daily basis, and the other on a Ophthalmic assessment and outcome evaluation
weekly basis. Although liver damage was associated with Overall ophthalmic assessment was performed before ther-
daily GC therapy, the dosage was 1 g per day and more apy and in the fourth and 12th weeks after therapy. Eye exam-
than 8.45 g in total (12, 13). With the exception of sight- inations were performed by a single ophthalmologist (Q.J.).
Proptosis, eyelid width, diplopia, intraocular pressure, visual
threatening GO, daily administration of GC was not pre- acuity, and CAS were recorded by using the modified EUGOGO
ferred (13). However, no solid evidence has been reported patient form (9). The seven-point CAS (spontaneous retrobulbar
to compare the efficacy and safety of the daily vs weekly pain, pain on attempted eye movements, conjunctival hyper-

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doi: 10.1210/jc.2013-3919 jcem.endojournals.org 2001

Table 2. Baseline Characteristics of the Patients

12-Week Protocol 4-Week Protocol P Value
n 39 41
Age, y 45.30 ⫾ 11.2 48.23 ⫾ 8.88 .21
Gender (females) 24 (61.54) 22 (53.66) .51
Weight, kg 64.56 ⫾ 9.90 66.62 ⫾ 12.11 .43
BMI, kg/m2 23.59 ⫾ 3.35 23.97 ⫾ 4.92 .66
Systolic blood pressure, mm Hg 124.95 ⫾ 24.79 122.3 ⫾ 17.28 .59
Diastolic blood pressure, mm Hg 76.40 ⫾ 13.37 76.38 ⫾ 10.58 .99
Smoking history .39
Current smoker 5 (13.51) 8 (21.62)
Ex-smoker 5 (13.51) 9 (24.32)
Passive smoker 19 (51.35) 13 (35.14)
Never smoker 8 (21.62) 7 (18.92)
History of thyroid disease
Graves’ hyperthyroidism 33 (84.62) 32 (91.43) .27
Primary hypothyroidism 2 (5.13) 0 .49
Hashimotos’ thyroiditis 0 0
Previous antithyroid treatments
Antithyroid drugs 28 (71.79) 33 (80.48) .44
Radioiodine 4 (10.26) 8 (19.51) .35
Thyroidectomy 1 (2.56) 0 .49
Current thyroid treatments
None 15 (38.46) 8 (21.62) .13
Levothyroxine only 3 (7.69) 6 (16.21) .31
Tapzole only 6 (15.38) 14 (37.83) .06
Propylthiouracil only 1 (2.56) 1 (2.7) 1
Levothyroxine and tapazole 8 (20.51) 8 (21.62) 1
Levothyroxine and propylthiouracil 5 (13.51) 0 .06
Duration of eye symptoms, mo 13.63 ⫾ 16.52 6.41 ⫾ 4.90 .01
Serum TSH (0.35– 4.95), ␮IU/mLa 0.41 (0.01–1.45) 0.07 (0.01–2.13) .37
Free T3 (2.62– 6.49), pmol/La 4.42 (4.07–5.15) 4.58 (4.04 –5.47) .17
Free T4 (9.01–19.047), pmol/La 13.43 (11.73–15.55) 14.88 (11.9 –16.57) .47
TRAb (⬍1.75), U/La 3.81 (1.62–9.91) 9.75 (3.45–27.14) .05
TPOAb (⬍5.61), IU/La 72.21 (0.52–363.6) 21.07 (0.76 – 402.9) .83
Lid edema .22
None 0 0
Mild 23 (58.97) 17 (41.46)
Moderate 14 (35.9) 22 (53.66)
Severe 2 (5.13) 1 (2.44)
Lid erythema 2 (5.13) 4 (10.26) .67
Conjunctival hyperemia .19
None 4 (10.26) 3 (7.5)
Suspicious 5 (12.82) 1 (2.5)
Hyperemia 30 (76.92) 36 (90)
Chemosis 21 (53.85) 27 (69.23) .16
Caruncle swelling 21 (53.85) 27 (67.5) .25
Proptosis, mm 22.06 ⫾ 3.17 21.66 ⫾ 3.34 .59
Eyelid width, mm 10.91 ⫾ 2.04 10.8 ⫾ 2.11 .81
Diplopia (Gorman score) .39
Absent 11 (28.2) 12 (30.77)
Intermittent 6 (15.38) 10 (23.08)
Inconstant 15 (38.46) 9 (23.08)
Constant 7 (17.95) 10 (23.08)
CAS 4 (3–5) 4 (4 –5) .46
Intraocular pressure, mm Hg 19.23 ⫾ 4.15 17.63 ⫾ 4.02 .09
Visual acuity 0.91 ⫾ 0.27 0.96 ⫾ 0.38 .48
Abbreviations: BMI, body mass index; TPOAb, thyroid peroxidase autoantibodies.. Data are expressed as mean ⫾ SD, number (percentage), or
median (interquartile interval). The values were calculated from the mean value of the two eyes.
a
Numbers in parentheses represent normal ranges.

emia, eyelid redness, chemosis, swelling of the caruncle, swell- 3, severe [NOSPECS 4 – 6, including eye muscle involvement/
ing of the eyelids) and the NOSPECS score (1, mild/absent corneal involvement or sight loss]) were evaluated as previously
[NOSPECS 0 –1, including lid retraction or lid lag]; 2, moderate reported (14, 15). A Hertel exophthalmometer (Keeler Instru-
[NOSPECS 2–3, including periorbital edema and proptosis]; or ments Inc) was used for the measurement of proptosis, and the

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2002 Zhu et al IV GC Therapy for Graves’ Ophthalmopathy J Clin Endocrinol Metab, June 2014, 99(6):1999 –2007

upper limit of normal Chinese subjects in our study was 18.6 mm
(16). TRAb was measured using commercially available electro-
chemiluminescence assays based on the M22 monoclonal anti-
body, with a normal range ⬍1.75 U/L.
The primary outcome was overall response. “Responsive”
was defined as at least three of the following outcome measures:
1) reduction in lid width by at least 3 mm; 2) reduction in any of
the class 2 NOSPECS signs by at least two grades; 3) reduction
in proptosis by at least 2 mm; 4) reduction in intraocular pressure
by at least 2 mm Hg; 5) improvement in CAS by at least two
points; 6) improvement in diplopia (disappearance or degrade in
degree); and 7) improvement in visual acuity by 1 Snellen line.
“Deterioration” of each parameter was defined as follows: 1)
increase in lid width by at least 3 mm; 2) increase in any of the
class 2 NOSPECS signs by at least two grades; 3) increase in
proptosis by at least 2 mm; 4) increase in intraocular pressure by
at least 2 mm Hg; 5) increase in CAS by at least two points; 6)
increase in diplopia (new onset or upgrade in degree); and 7)
decrease in visual acuity by 1 Snellen line. “Unchanged” was
defined as no change or changes smaller than previously defined
in any of the mentioned parameters.
The second outcome was a change in CAS, adverse events,
and retreatment.
Adverse effects
Body weight, blood pressure, blood glucose, blood lipid, liver
function, ion concentration, and bone mineral density (BMD)
were assessed to monitor treatment-associated weight gain, de-
creased BMD or osteoporosis, hypertension, impaired fasting
glucose (IFG)/impaired glucose tolerance (IGT)/diabetes melli-
tus (DM), hyperlipidemia, impaired liver function, hypokalemia,
and hyperuricemia. Dual-energy x-ray absorptiometry (GE-Lu-
nar Prodigy; GE Healthcare) was used to measure BMD (grams
per square centimeter) in the lumbar spine, femoral neck, and hip
of all subjects. Adverse events occurring in the fourth and 12th

Table 3. Ophthalmological Evaluation at Baseline, Fourth Week, and 12th Week

12-Week Protocol 4-Week Protocol P Value
P (Between
Baseline 4 Wk 12 Wk P Value Baseline 4 Wk 12 Wk Value Protocols)
CAS 4 (3–5) 2 (2–3) 2 (1– 4) .0001 a
4 (4 –5) 3 (2– 4) 3 (2– 4) ⬍.0001a .82c
Improved 25 (64.1%) 25 (64.1%) ⬍.0001b 25 (60.9%) 21 (51.22%) .0001b .4d
Unchanged 14 (36.9%) 13 (33.33%) 16 (39%) 17 (41.46%) .82e
Deteriorated 0 1 (2.56%) 0 3 (7.32%)
Proptosis (mean) 22.06 ⫾ 3.17 21.08 ⫾ 3.04 20.81 ⫾ 3.01 ⬍.0001a 21.66 ⫾ 3.34 21.14 ⫾ 3.07 21.56 ⫾ 3.51 .47a
Improved 11 (28.21%) 11 (28.21%) ⬍.0001b 7 (17.07%) 10 (24.39%) .91b .29c
Unchanged 28 (71.79%) 27 (69.23%) 32 (78.05%) 23 (56.10%) .056d
Deteriorated 0 (0%) 1 (2.56%) 2 (4.88%) 8 (19.51%) .45e
Lid width (mean) 10.91 ⫾ 2.04 10.26 ⫾ 1.57 10.43 ⫾ 1.57 .03a 10.8 ⫾ 2.11 10.59 ⫾ 2.00 10.54 ⫾ 1.84 .65a
Improved 4 (10.26%) 6 (15.38%) .07b 0 (0%) 4 (9.76%) .56b .06c
Unchanged 34 (87.18%) 33 (84.62%) 41 (100%) 36 (87.8%) .51d
Deteriorated 1 (2.56%) 0 (0%) 0 (0%) 1 (2.44%) .01e
Diplopia (Gorman)
Absent 11 (28.21%) 11 (28.21%) 11 (28.21%) .43a 12 (30.77%) 18 (43.9%) 15 (37.5%) .57a .03c
Intermittent 6 (15.38%) 10 (25.64%) 13 (33.33%) .09b 10 (23.08%) 9 (21.95%) 8 (20%) .85b .06d
Inconstant 15 (38.46%) 9 (23.08%) 6 (15.38%) 9 (23.08%) 7 (17.07%) 7 (17.5%) .003e
Constant 7 (17.95%) 9 (23.08%) 8 (20.51%) 10 (23.08%) 7 (17.07%) 10 (25%)
Improved 11 (28.21%) 17 (43.59%) 9 (21.95%) 9 (21.95%)
Unchanged 19 (48.72%) 14 (36.9%) 30 (73.17%) 25 (60.97%)
Deteriorated 9 (23.08%) 8 (20.51%) 2 (4.88%) 7 (17.07%)
Intraocular pressure 19.23 ⫾ 4.15 18.51 ⫾ 4.45 17.66 ⫾ 4.04 .17a 17.63 ⫾ 4.02 18.13 ⫾ 3.97 17.73 ⫾ 4.61 .58a
(mean)
Improved 12 (30.77%) 22 (56.41%) .01b 6 (14.63%) 10 (24.39%) .91b .07c
Unchanged 23 (58.97%) 13 (33.33%) 24 (58.54%) 20 (48.78%) .01d
Deteriorated 4 (10.26%) 4 (10.26%) 11 (26.83%) 11 (26.83%) .0004e
Visual acuity (mean) 0.91 ⫾ 0.27 1.02 ⫾ 0.30 1.11 ⫾ 0.29 .007a 0.96 ⫾ 0.38 1.11 ⫾ 0.48 0.98 ⫾ 0.32 .12a
Improved 16 (45.71%) 22 (56.41%) .0002b 21 (60%) 12 (30.77%) .82b .09c
Unchanged 18 (51.43%) 9 (23.08%) 10 (28.57%) 18 (46.15%) .049d
Deteriorated 1 (2.86%) 8 (20.51%) 4 (11.43%) 9 (23.08%) .55e
Lid edema
None 0 2 (5.13%) 4 (19.53%) .41a 0 1 (2.5%) 1 (2.56%) .12a
Mild 23 (58.97%) 28 (71.79%) 29 (76.32%) .056b 17 (41.46%) 24 (60%) 24 (61.54%) .07b
Moderate 14 (35.9%) 9 (23.08%) 5 (13.16%) 22 (53.66%) 15 (37.5%) 14 (35.90%)
Severe 2 (5.13%) 0 0 1 (2.44) 0 0
Improved 0 3 (7.69%) 1 (2.44%) 1 (2.44%) 1c
Unchanged 39 (100%) 36 (92.31%) 40 (97.56%) 40 (97.56%) .35d
Deteriorated 0 0 0 0 .35e
Conjunctival
hyperemia
None 4 (10.26%) 12 (30.77%) 18 (47.37%) .03a 3 (7.5%) 15 (37.5%) 11 (28.21%) .002a .12c
Suspicious 5 (12.82%) 8 (20.51%) 7 (18.42%) .0003b 1 (2.5%) 3 (7.5%) 2 (5.13%) .04b .62d
Hyperemia 30 (76.92%) 19 (48.72%) 13 (34.21%) 36 (90%) 22 (55%) 26 (66.67%) 1e
Improved 6 (15.38%) 12 (30.77%) 13 (31.71%) 10 (24.39%)
Unchanged 33 (84.62%) 27 (69.23%) 26 (63.41%) 30 (73.17%)
Deteriorated 0 0 2 (4.89%) 1 (2.44%)
Response (⬎ ⫽ 3) 22 (56.41%) 30 (76.92%) 23 (56.1%) 16 (41.03%) 1c, .0025d, .14e

P values: a baseline vs fourth week; b baseline vs 12th week; c fourth week between the two groups; d 12th week between the two groups; e end
of iv therapy between the two groups.

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doi: 10.1210/jc.2013-3919
weeks without self-reported history and being detected as nor-
mal at baseline were evaluated as follows: 1) body weight in-
creased by 0.5, 1, 2, and 3 kg in the fourth and 12th weeks
compared to baseline; 2) BMD of L2–L4, femoral neck, and total
hip is represented by T score, and osteoporosis is defined as either
one of three T scores ⱕ⫺2.5 and ⫺2.5 ⬍ T ⬍ ⫺1.0 as bone loss
according to World Health Organization criteria; 3) develop-
ment of the following: IFG, defined as 6.1 mmol/L ⱕ fasting
glucose ⬍7 mmol/L and 2 hours ⬍7.8 mmol/L; IGT, fasting
glucose ⬍7 mmol/L and 7.8 mmol/L ⱕ2 hours ⬍11.1 mmol/L;
DM, defined as a fasting glucose ⱖ7 mmol/L or 2 hours ⱖ11.1
mmol/L; 4) development of hypertension, defined as systolic
blood pressure ⱖ140 mm Hg or diastolic blood pressure ⱖ90
mm Hg; 5) development of hyperkalemia, defined as serum po-
tassium ⬍3.5 mmol/L; 6) development of hyperuricemia, de-
fined as serum uric acid ⬎420 ␮mol/L (for men) or ⬎ 360 ␮mol/L
(for women); 7) development of liver function impairment, de-
fined as alanine aminotransferase (ALT) or aspartate amino-
transferase (AST) ⬎40 U/L and ALT or AST ⬎100 U/L (2.5-fold
of the upper normal limits); and 8) development of hyperlipid-
emia as evaluated according to Adult Treatment Panel III: total
cholesterol ⱖ6.22 mmol/L, triglycerides ⬎2.26 mmol/L, low-
density lipoprotein ⬎4.14 mmol/L, and high-density lipoprotein
⬍1 mmol/L.
Measurement of serum IL-4, IL-6, IL-12, IL-13, and
CXCL10 cytokines
Known GO-associated serum cytokines (IL-4, IL-6, IL-13,
and CXCL10) were measured to explore the serum response to
Figure 1. Improvement in the fourth and 12th weeks in response rate (A and B), diplopia (C and D), and intraocular pressure (E and F) in the two
treatment groups. IOP, intraocular pressure.
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jcem.endojournals.org 2003
different iv methylprednisolone protocols. Serum was processed
from whole blood and stored at ⫺80°C until analyzed. Cytokine
analyses were run in duplicate using Procarta Cytokine kit Hu-
man 39-plex (Panomics) according to the manufacturer’s pro-
tocols. Briefly, antibody magnetic beads were hybridized with 25
␮L antigen standards and patient serum, followed by the addi-
tion of 25 ␮L premixed detection antibodies and streptavidin-
conjugated phycoerythrin (Panomics). The plate was read on a
Luminex Instrument (Luminex 100; Millipore). Serum cytokine
levels were calculated by plotting the expected concentration of
the 131 standards against the median fluorescence intensity gen-
erated by each standard (R2 ⬎0.98; % coefficient of variation of
replicates ⬍15%).
Statistical analysis
Continuous variables are expressed as the mean ⫾ SD or
median (interquartile intervals, 25–75%ile); categorical vari-
ables are expressed as frequency and percentage. Values of serum
free T3, free T4, TSH, TRAb, thyroid peroxidase antibody, and
thyroglobulin antibody are shown as median (25th to 75th per-
centile) of the original values and log10 normal transformed be-
fore statistical analysis.
For each patient, the mean value of the two eyes was presented
for each ophthalmological parameter. Student’s t test was used
to compare the two groups in continuous variables, and a Mann-
Whitney U test was used for comparing CAS. ␹2 test or Fisher’s
exact test was used for comparing proportions. Retreatment-free
percentage was depicted with Kaplan-Meier survival curves, and
the log-rank (Mantel-Cox) test was used to compare the per-
2004 Zhu et al IV GC Therapy for Graves’ Ophthalmopathy J Clin Endocrinol Metab, June 2014, 99(6):1999 –2007

centage of the two groups. Hazard ratio and its 95% confidence
interval were computed using Mantel-Haenszel method. All
analyses were performed with Statistical Analysis System (SAS)
software for Windows, version 8.1 (SAS Institute Inc) and Prism
5 for Windows, version 5.01 (GraphPad Software Inc).

Results
Patient response
In the 12th week, patients on the weekly protocol
showed a significantly higher response rate than those on
the daily protocol (76.92 vs 41.03%; P ⫽ .0025) (Table 3
and Figure 1). Both groups showed similar response rates
in the fourth week (56.41 vs 56.10%). The response rate
of the patients on the daily protocol dropped from
56.10% in the fourth week to 41.03% in the 12th week.
Patients showed similar CAS response to both proto-
cols in the fourth week, whereas in the 12th week, patients
on the weekly protocol showed a trend of better CAS re-
sponse than patients on the daily protocol, although this
difference was not significant: 64.1 vs 51.22% improved,
33.33 vs 41.46% unchanged, and 2.56 vs 7.32% deteri-
Figure 2. A, Kaplan-Meier survival curves of retreatment-free survival
orated. Specifically, conjunctival hyperemia was signifi- for patients in the two treatment groups. B, Time of retreatment
cantly improved in both groups, and we observed a trend decision.
of greater response to the weekly protocol (Table 3).
Interestingly, the weekly protocol improved diplopia, treatment, showed impaired liver function (liver enzymes
intraocular pressure, and visual acuity compared to the more than three times the upper limit) but with no history
daily protocol at all time points, either significantly or of liver disease. One patient (age, 47 y; male) developed
marginally. In addition, patients on the weekly protocol intractable hiccups in the third week of treatment and was
showed improved lid width at the end of iv methylpred- incapable of handling daily life. Both patients were on the
nisolone therapy (P ⫽ .01) and marginally improved prop- daily protocol and recovered after the methylprednisolone
tosis in the 12th week (P ⫽ .056). (Table 3 and Figure 1). treatment was discontinued. Apart from these two cases,
no other severe adverse effects were recorded. Weight gain
Retreatment and hypokalemia were the most common adverse events.
A total of three patients on the weekly protocol and 12 Thirty-six of 79 patients (46.1%) gained body weight over
patients on the daily protocol underwent a second run of 0.5 kg, and 14 of 78 (17.9%) gained over 3 kg by the end
therapy in 6 months, including seven cases on iv methyl- of iv methylprednisolone therapy. There were no signifi-
prednisolone, two cases on oral prednisone, two cases on cant differences between the two groups (Table 4).
surgery therapy, one on orbital betamethasone injection,
and one case on iv methylprednisolone plus immunosup- Sustained decreased serum CXCL10 for patients on
pressive therapy. Kaplan-Meier survival curves and log- the weekly protocol
rank (Mantel-Cox) test found significantly prolonged re- The nadir of the serum cytokine level mostly occurred
treatment-free survival for patients on the weekly protocol when the iv methylprednisolone was discontinued (Sup-
(P ⫽ .01) (Figure 2A). The detailed retreat time was shown plemental Figure 1). For patients on the weekly protocol,
in Figure 2B. The median time (interquartile range) to we found significant lower levels of serum CXCL10 in the
failure was 4.0 (3.25– 4.88) vs 4.5 (4.5–5.0) months for 12th week compared to baseline (P ⫽ .0306), with values
the daily and weekly protocol, respectively. in the fourth week being between the 12th week and base-
The hazard ratio was 3.729 (95% confidence interval, line values. For patients on the daily protocol, we detected
1.334 –10.42; P ⫽ .012) for patients on the daily protocol. a marginally significant increase in CXCL10 in the fourth
week (P ⫽ .0489), whereas there was no difference in the
Adverse events 12th week. Serum IL-4 and IL-13 showed similar trends
One patient (age, 44 y; female), who was hepatitis B but no statistical significance. Serum IL-6 was not
virus and hepatitis C virus negative in the second week of detected.

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doi: 10.1210/jc.2013-3919 jcem.endojournals.org 2005

Table 4. Treatment-Associated Adverse Effects in the Fourth, Eighth, and 12th Weeks
Weekly Protocol (n ⴝ 39) Daily Protocol (n ⴝ 39)

4th Week 8th Week 12th Week 4th Week 8th Week 12th Week P Value
Weight gain, kg
0.5 0 1 1 2 1 1 .68
1 6 3 5 6 5 7
2 3 5 5 2 5 4
3 2 4 6 4 8 4
BMD
Bone loss 0 1 0 0
Osteoporosis 0 0 0 0
Hypertension 1 2 0 1 1 1 1
Glucose regulation
IFG 1 1 0 1 0 0
IGT 1 2 2 3 3 3 1
DM 1 0 2 1 0 0 .49
Lipids, mmol/L
TC ⱖ6.22 4 2 4 7 3 2 .42
TG ⬎2.26 4 1 5 3 2 2 .24
LDL ⬎4.14 3 1 3 5 1 3 1
HDL ⬍1 0 1 1 0 0 0 1
Liver function, U/L
ALT ⬎40 1 2 0 4 0 2 .49
ALT ⬎100 0 1 0 1 0 0
AST ⬎40 0 1 0 1 0 1 1
AST ⬎100 0 0 0 0 0 0
Hypokalemia 5 5 11 4 7 7 .56
Hyperuricemia 0 1 1 2 0 0 .49
Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; TC, total cholesterol; TG, triglyceride. P value comparing the events
occurring in the 12th week between the two groups was calculated using Fisher’s exact test.

Discussion nisolone for both protocols. Although both strategies

showed efficacy, the weekly protocol showed greater ef-
We performed a prospective study to compare the efficacy ficacy and safety in the 12th week without compromising
and safety of 4.5 g iv methylprednisolone in the daily and
efficacy in the fourth week.
weekly protocol. We found a significantly greater re-
Other important findings of this study were as follows.
sponse rate and prolonged retreatment-free survival, less
First, seven patients showed worse eye symptoms, and
severe toxicity, and decreased serum CXCL10 for patients
four patients with improved CAS relapsed on the daily
on the weekly protocol.
protocol once the iv methylprednisolone was switched to
For active moderate-to-severe GO, a course of iv 4.5 g
oral prednisone. This is another piece of evidence that iv
methylprednisolone within 12 weeks has been recom-
methylprednisolone is more efficient than oral prednisone
mended (13). The weekly protocol is preferred because of
in controlling local inflammation (6, 7). This suggested
the potential safety issues associated with the daily pro-
tocol. However, serious adverse events only occurred in sustained and less severe features of the GO-related im-
patients receiving daily and/or alternate single doses that mune imbalance. A fixed dosage in a longer duration of
were higher than 0.5 g (13). Previous studies have shown pulse iv methylprednisolone therapy might lead to a better
that the daily administration of 0.5 g methylprednisolone response. Second, patients on the weekly protocol showed
alone or combined with orbital irradiation was effective greater improvement of diplopia, intraocular pressure,
for both dysthyroid optic neuropathy and moderately se- and visual acuity at multiple time points, suggesting that
vere GO (17, 18). However, no head-to-head RCT study weekly therapy is superior to daily therapy in terms of
has investigated the efficacy and safety of daily vs weekly disease severity. Third, a significant number of GO pa-
iv GC therapy in treating moderate-to-severe GO. The tients experienced recurrent diseases or failure of iv meth-
current study was designed to address this important ques- ylprednisolone therapy. Therefore, the need for retreat-
tion. A total of 4.5 g methylprednisolone was adminis- ment is another criterion to evaluate treatment efficacy. In
tered on a daily basis within 4 weeks and on a weekly base our cohort, we found significantly fewer retreatment
within 12 weeks. The efficacy and safety of iv methylpred- events and prolonged retreatment-free survival for pa-
nisolone was evaluated at the end of iv methylpred- tients on the weekly protocol. Fourth, we measured serum

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2006 Zhu et al IV GC Therapy for Graves’ Ophthalmopathy J Clin Endocrinol Metab, June 2014, 99(6):1999 –2007

cytokines as a marker of local orbital inflammation (19, longed protocol for iv methylprednisolone, eg, biweekly
20) and observed a more sustained decrease of CXCL10 in therapy, is worth evaluating for the treatment of active
patients on the weekly protocol. Serum CXCL10 was el- moderate-to-severe GO patients.
evated during the active inflammatory phase of GO and
decreased when the disease became inactive (21). Further-
more, thyrocyte, orbital fibroblast, and preadipocyte pro- Acknowledgments
duced CXCL10 when treated with interferon␥ (22). The
Address all correspondence and requests for reprints to: Profes-
more sustained decrease in serum CXCL10 for the weekly
sor Guang Ning, PhD, MD, Shanghai Institute of Endocrine and
protocol might partially explain the better response in this
Metabolic Diseases, Department of Endocrine and Metabolic
group. IL-6 was another cytokine that was associated with
Diseases, Ruijin Hospital, 197 Ruijin Er Road, Shanghai
GO activities (19). Serum IL-6 was not detected in our 200025, China. E-mail: gning@sibs.ac.cn.
study, which might be due to different methodology from This work was supported by grants from the Science and
previous reports. Technology Commission of Shanghai Municipality (11DJ1400200
The calculated morbidity and mortality of GO patients and 13QH1402000).
treated with iv GC were 6.5% and 0.6%, respectively (13). Clinical Trial Registration No.: NCT01969019.
The most common severe side effect is hepatotoxicity. Disclosure Summary: The authors have nothing to declare.
Other severe adverse effects included cardiovascular risk
(23). In our study, we recorded two severe adverse events:
impaired liver function, and intractable hiccups. No car- References
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