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Original Investigation
Adalimumab as Steroid-Sparing Treatment of
Inflammatory-Stage Thyroid Eye Disease
Reed Ayabe, B.A.*, Dan B. Rootman, M.D.†, Catherine J. Hwang, M.D.†, Ami Ben-Artzi, M.D.‡, and
Robert Goldberg, M.D.†
*Division of Orbital and Ophthalmic Plastic Surgery, Jules Stein Eye Institute; †David Geffen School of Medicine; and
‡Department of Medicine, Division of Rheumatology, University of California, Los Angeles, U.S.A.
Purpose: Steroids are often used as medical therapy for
active thyroid eye disease (TED). While high-dose steroids
have been shown to be effective in reducing the severity of TED
symptoms, the side effects of steroids can be severe. As the
pathogenesis of TED is thought to involve the upregulation of
proinflammatory cytokines, including tumor necrosis factor-α
(TNF-α), it has been postulated that anti-TNF agents may be
used as steroid-sparing agents in the treatment of TED. This
retrospective study was conducted to examine the efficacy of
adalimumab, a subcutaneously administered TNF-α antagonist,
in treating the inflammatory symptoms of active TED.
Methods: All patients in the inflammatory phase of
TED who were treated with adalimumab at the Jules Stein
Eye Institute over a 2-year period were reviewed. Data
concerning visual acuity, optic nerve function, extraocular
motility restriction, binocular visual fields, and proptosis
were extracted from patient charts. Clinical photographs
from baseline and 3-month follow-up visits were reviewed by
masked orbital specialists. Each photograph was graded on the
severity of conjunctival injection, chemosis, eyelid erythema,
and eyelid edema on a scale from 1 to 4. An inflammatory
score was calculated as the sum of these 4 elements. Groups
were compared using paired t tests.
Results: Six of 10 patients showed a decrease in inflammatory
score while on adalimumab, whereas 3 showed an increase
and 1 stayed the same. One patient experienced a significant
complication (hospital admission for sepsis). Eight patients
received concomitant tapering steroids during the first 6 weeks
of therapy as the adalimumab reached maximum efficacy.
When data from all 10 subjects were analyzed together, there
was no significant change in inflammatory index after 3 months
of treatment with adalimumab. However, when the 5 patients
with a high baseline inflammatory index (>4) were considered
separately, there was a significant improvement (mean decrease
of 5.2 ± 2.7; p < 0.01) after adalimumab treatment. Four of 5
patients also reported a subjective improvement in symptoms
while on adalimumab.
Conclusions: This study suggests that adalimumab may
have a role in the treatment of active TED with prominent
inflammatory symptoms. The use of adalimumab and other
immunosuppressive agents in the treatment of TED may help
to mitigate some of the metabolic and psychiatric side effects of
pulsed steroid treatment. A future randomized controlled study
Accepted for publication March 28, 2014.
The authors have no financial or conflicts of interest to disclose.
Address correspondence and reprint requests to Daniel B. Rootman,
M.Sc., M.D., University of California Los Angeles, CA 12159. E-mail: dan.
[email protected]
DOI: 10.1097/IOP.0000000000000211
Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014
will be necessary to determine the efficacy of adalimumab as a
primary therapy for TED.
(Ophthal Plast Reconstr Surg 2014;30:415–419)
S
teroids are the current mainstay of medical therapy for
inflammatory-stage thyroid eye disease (TED).1 While highdose steroids can effectively reduce the severity of inflammatory
TED symptoms, the side effects of steroids can be severe and
include diabetes, cardiovascular disease, infection, hepatotoxicity, major depression, and psychosis.1 The rate of steroid-related
morbidity in the treatment of TED is reported to be as high as
6.5% and appears to correlate directly with steroid dosage.1,2
Potential targets for steroid-sparing agents have come
to light as more is learned about the complex pathogenesis of
TED. A 2003 study using reverse transcriptase– polymerase
chain reaction to quantify the expression of inflammatory
cytokines in orbital tissue specimens from patients with TED
found that TNF-α, interleukin-1β, interferon-γ, interleukin-6,
interleukin-8, and interleukin-10 transcription was increased.3
One of these cytokines, TNF-α, has garnered much attention
because of the use of anti-TNF-α agents in the treatment of
rheumatoid arthritis. The effectiveness of anti-TNF-α agents in
treating rheumatoid arthritis has led to their application in other
autoimmune diseases, including TED. A 2005 case report demonstrated that a patient with steroid-refractory TED responded
favorably to the anti-TNF-α agent infliximab, and a pilot study
the same year showed an overall reduction in inflammatory
symptoms using the recombinant anti-TNF-α agent etanercept
in 10 patients with new-onset TED.4,5
The newest of the commonly prescribed TNF-α inhibitors, adalimumab (Humira), is a fully human monoclonal
antibody whose main advantage is that it can be taken as a subcutaneous injection administered every other week (etanercept
is typically given twice per week and infliximab must be given
as an intravenous infusion). The Anti-TNF Research Study
Program of the Monoclonal Antibody Adalimumab trial in
2003 found that patients with rheumatoid arthritis treated with
adalimumab plus methotrexate were more likely to experience
a reduction in disease severity compared with patients treated
with methotrexate alone (67% vs. 14%).6 Further studies comparing adalimumab with etanercept and infliximab in patients
with rheumatoid arthritis have found no significant difference in
efficacy or adverse effect rates among the 3 agents.7–10
A 2011 study showed that the in vitro treatment of orbital
fat in patients with TED with adalimumab resulted in a decreased
expression of proinflammatory cytokines.11 However, to the best
of the authors’ knowledge, no study examining the clinical efficacy of adalimumab in the treatment of TED has been reported.
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Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014
R. Ayabe et al.
Here, the authors retrospectively examine the efficacy of adalimumab in 10 patients with active inflammatory TED.
MATERIALS AND METHODS
Subject Selection. Institutional approval for this review was obtained
from the University of California Los Angeles Institutional Review
Board, and all procedures were performed in accordance with the 1964
Declaration of Helsinki.
Patients at the Jules Stein Eye Institute’s TED clinic who were
treated with adalimumab within the past 2 years were selected from the
clinic’s electronic database. Criteria for inclusion included 1) diagnosis of
TED within 9 months of starting adalimumab therapy; 2) the presence of
at least 1 inflammatory symptom including chemosis, conjunctival injection, eyelid erythema, and eyelid edema (Table 1); 3) treatment with adalimumab for at least 10 weeks at a standard dosing of one 80 mg injection
followed by biweekly 40 mg injections; and 4) age from 18 to 75 years.
All injections were self-administered by patients after an instructional
session. Patients who received decompression surgery or orbital radiation during the treatment period were excluded. Patients on other biologic
agents, including certolizumab, rituximab, and ustekinumab, were also
excluded. Patients who were pregnant or lactating were also excluded.
Measures of Treatment Efficacy:
Inflammatory Composite Score. Photographs of 10 subjects, taken
from 6 standard angles at baseline and after 3 months of adalimumab
therapy, were graded in a randomized fashion by masked oculoplastics
specialists at the Jules Stein Eye Institute. A score of 0 to 4 was assigned
for each of 4 visible signs of inflammation: chemosis, conjunctival injection, eyelid erythema, and eyelid edema. An inflammatory composite
score (0 to 16) was calculated by summation.
Extraocular Movement Restriction. Horizontal and vertical extraocular
movement restriction was recorded as a score from 0 to −4 at each clinic
visit. These values were summed across the horizontal and vertical axes,
respectively, to provide 2 composite restricting scores. Values at baseline and after 3 months of adalimumab therapy were calculated.
Proptosis. The degree of proptosis at baseline and 3 months was graded
by Hertel exophthalmometry.
Subjective Improvement. Patients at each visit were prompted with
an open-ended question concerning their perception of improvement.
Statements of improved pain, diplopia, or swelling from each patient’s
3-month visit were recorded as subjective improvement.
TABLE 1. Criteria for active TED and signs of TED severity
Criteria for active
TED
Criteria for
severity of
inflammation
Hyper- or hypothyroidism associated with 1 or
more of the following inflammatory signs with
onset under 9 months prior to presentation:
Chemosis
Conjunctival injection
Eyelid edema
Eyelid erythema
Progressive restriction of extraocular movement
Progressive proptosis
Inflammatory composite score, each graded on
scale from 0 (absent) to 4 (severe) and the
score summed:
Chemosis
Conjunctival injection
Eyelid erythema
Eyelid edema
TED, thyroid eye disease.
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Data Analysis. A paired samples t test was performed to compare composite inflammatory scores, extraocular movement restriction, and proptosis at baseline and 3 months. A subgroup of 5 patients with baseline
inflammatory composite score >4 was also analyzed separately using a
paired samples t test.
RESULTS
Subject Baseline Characteristics. Of 10 patients who satisfied the inclusion criteria, 5 were men and 5 were women. The average age was
56.3 years. The average number of weeks subjects received concurrent
intravenous steroid treatment was 5. Most of these subjects had been
receiving steroids prior to starting treatment with adalimumab. None of
the patients were current smokers, and 1 had a distant history of smoking. Three of the patients had previous radioactive iodine ablation, 2 had
a previous thyroidectomy, and 3 were on concurrent antithyroid medications (Table 2).
Treatment Effect. After 3 months of adalimumab therapy, the inflammatory composite score was decreased for 6 patients, increased for 3
patients, and the same for 1 patient. Four patients reported a subjective
improvement in pain, swelling, or diplopia. The average reduction in inflammatory composite score was 2.2, but this reduction did not achieve
statistical significance (p = 0.09; Table 3). However, when the subset of
patients with a baseline inflammatory composite score >4 were analyzed
separately, there was a significant decrease in inflammatory composite
score after 3 months of adalimumab treatment (5.2 ± 2.7; p < 0.01; Table
3). All the 4 patients with documented subjective improvement were
part of this subset. Pre- and post-treatment photographs of the subset
of patients with high baseline inflammatory scores are shown in Figure.
There was no significant change in proptosis or extraocular
movement restriction between baseline and 3 months of treatment for
all 10 patients taken together, or for the subgroup of patients with high
baseline inflammatory composite score (Table 3).
Complications. One patient was admitted to the hospital for diarrhea
and sepsis while on adalimumab and intravenous steroids. All immunosuppressive therapy was held for a 3-week period until the patient had
fully recovered. Adalimumab therapy was then restarted and continued
at the standard dose as the patient was clinically stable and had reported
subjective improvement while on adalimumab. No other adverse events
including infusion-related reactions were reported by any of the patients.
DISCUSSION
To the authors’ knowledge, this is the first study of the clinical efficacy of adalimumab in treating active-stage TED. After 3
months of treatment with biweekly adalimumab injections, the
subset of patients with more severe baseline inflammation had
a significant reduction in inflammatory composite score, while
patients with less severe baseline inflammation did not experience a significant change in their inflammatory status. This suggests that patients with TED with severe inflammation may benefit
most from adalimumab therapy. These findings are in agreement
with those of a pilot study examining the efficacy of etanercept
treating active TED. In that study, patients’ clinical activity scores12
decreased by an average of 60% after 6 weeks of treatment.5 In this
study, the average decrease in inflammatory composite score was
44% overall and 66% in the subset with higher baseline inflammation. A calculation of clinical activity scores for each patient in
this study may have allowed for a more direct comparison to the
etanercept pilot study.5 However, they used an inflammatory composite score comprising the objective components of the clinical
activity scores in lieu of the actual clinical activity scores, because
these patients were not routinely screened for gaze-evoked orbital
pain and they find that caruncular edema can be a deceiving and
late sign of congestion in general.
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014
Steroid-Sparing Treatment of Thyroid Eye Disease
TABLE 2. Subjects’ baseline characteristics
Patient
Sex
Age
Duration
of Graves
disease
(months)
1
M
54
15
3
5
2
3
M
F
54
62
18
147
9
9
0
8
4
F
53
1
1
6
5
F
32
27
4
3
6
F
42
7
6
6
7
M
66
22
9
10
8
9
F
M
73
65
3
14
3
4
0
9
10
M
62
8
6
6
56
26.4
5
5
Average
Duration
of TED
(months)
Weeks on
concurrent
steroids
Dose and route of steroids
Methylprednisone 500 mg
intravenous weekly
—*
Methylprednisone 500 mg
intravenous weekly
Prednisone 50 mg per os daily
tapering by 10 mg each week
and 5 mg for sixth week
Methylprednisone 500 mg
intravenous weekly
Methylprednisone 400 mg
per os weekly
Methylprednisone 400 mg
per os weekly
—*
Methylprednisone 320 mg
per os weekly
Methylprednisone 500 mg
intravenous weekly
—
Smoking
Prior
RAI
Prior
thyroidectomy
Concurrent
antithyroid
medication
No
No
No
Yes
No
No
No‡
Yes†
No
Yes
No
No
No
No
No
No§
No
Yes†
No
No
No
No
No
Yes
No
No
Yes
No
Hx
No
No
Yes†
No
No
Yes
No
No
No
No
No
Of note, the subjects who received prior RAI or thyroidectomy either did not experience significant improvement in eye symptoms after the procedure or developed TED
after the procedure.
Hx, history of smoking; RAI, radioactive iodine; TED, thyroid eye disease.
*Did not receive prior steroid therapy due to steroid intolerance (patient 2, previous psychosis; patient 8, personal preference).
†RAI therapy did not affect the course of disease in these patients.
‡Received RAI shortly after the completion of adalimumab course.
§Patient with subclinical hyperthyroidism.
Patients receiving TNF-α inhibitors have been shown to
be at increased risk of infection, particularly when first beginning the therapy.10 Only 1 subject in this study experienced a
severe infection while on adalimumab, and it is possible that
other factors contributed to this, including concomitant steroid
treatment and multiple comorbidities. The treatment was otherwise tolerated well, even in patients who received an extended
course of adalimumab. Studies of adalimumab and other TNF-α
inhibitors in patients with rheumatoid arthritis suggest that they
are generally safe, and serious complications such as infection,
lupus-like reactions, immunogenicity, and demyelinating disorders are extremely rare.7–10
The greatest limitation of this study was lack of a control
group. For this reason, there was no way to definitively determine whether any of the subjects’ improvement was due to steroids, adalimumab, or a natural history of the disease. However,
the improvement for patients with inflammatory disease was
seen with tapering doses of steroids, suggesting an adalimumab
effect. Further, these patients were either unresponsive or intolerant of steroids, pointing toward a complementary role for
adalimumab in certain cases. A larger sample of active patients
with high inflammatory scores would have enabled the pairing
of these subjects to age- and gender-matched historical controls.
Unfortunately, patients often present late to this quaternary care
center and can be concurrently on steroid therapy, thus reducing their overall inflammatory presentation. The retrospective
study design also made it difficult to control for therapies used
to treat hyperthyroidism, including antithyroid medication, 134I
ablation, and total thyroidectomy. Studies have shown that these
measures may shorten the course of TED.13,14 The authors were
also unable to control for concomitant steroid dosages, although
most of the subjects were treated by pulsed methylprednisone at
300 to 500 mg weekly. One subject who was not treated with steroids due to a past episode of steroid-induced depression experienced significant improvement in inflammation and subjective
symptoms while on adalimumab. Finally, the authors were not
Patient photograph prior to (left) and after (right) 3 months of adalimumab treatment.
© 2014 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
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Ophthal Plast Reconstr Surg, Vol. 30, No. 5, 2014
R. Ayabe et al.
TABLE 3. Treatment effect
Individual patients
Baseline
Patient 1
1
Patient 2
1
Patient 3
4
Patient 4
3
Patient 5
5
Patient 6
7
Patient 7
7
Patient 8
11
Patient 9
9
Patient 10
4
All patients (n = 10)
Mean inflammatory
5.2
composite score
Mean horizontal EOM
−3.1
restriction
Mean vertical EOM
−3.6
restriction
Mean Hertel OD
23.5
Mean Hertel OS
23.9
Subset with baseline inflammatory score >4 (n = 5)
Mean inflammatory
7.8
composite score
Mean horizontal EOM
−4
restriction
Mean vertical EOM
−4
restriction
Mean Hertel OD
23.7
Mean Hertel OS
24.8
3 months
Change (3-month baseline)
Subjective improvement?
4
2
4
4
2
3
0
3
5
3
+3
+1
0
+1
−3
−4
−7
−8
−4
−1
3
−2.2 (−4.8–0.4)
No
No
No
No
Yes
Yes
No
Yes
Yes
No
p
0.09
−3
+0.1 (−1.1–1.39)
0.85
−4.6
−1 (−2.9–0.9)
0.27
23.7
23.9
+0.2 (−0.6–0.0)
+0.1 (−3.7–3.9)
2.6
−5.2 (−7.9–−2.5)
0.60
0.96
p
<0.01
−3.4
+0.6 (−2.1–3.3)
0.57
−3.6
+0.4 (−3.8–4.6)
0.83
23.8
24.8
+0.1 (−5.9–6.1)
0.0 (−4.8–4.8)
0.97
1.00
Subjects’ inflammatory scores were compared at baseline and after 3 months of adalimumab treatment using a paired samples t test. A statistically significant decrease
was noted in patients whose initial inflammatory composite score was >4.
EOM, extraocular muscle.
able to quantify subjective improvement, which may have been
useful in this analysis.
Steroids are known to be effective in reducing the inflammatory symptoms of active TED, with an average response rate to
intravenous steroids of 80% across numerous studies.1 However,
the relatively high dose of steroids required to reduce the symptoms of active TED is associated with significant morbidity.15 A
2012 trial of 3 doses of methylprednisolone sodium succinate
found that the highest dose (7.47 g weekly) was most effective,
but was also associated with the highest rate of major adverse
events, including diabetes, sepsis, psychosis, and major depression.2 There is ample evidence that patients with active inflammatory TED benefit more from steroid therapy than those with
less active or fibrotic disease.1 As this appears to be the same
group of patients that benefits most from adalimumab thearpy,
the authors believe that adalimumab may have a role as a steroidsparing agent for patients with TED.
In conclusion, this retrospective study suggests that adalimumab is of greatest benefit to patients with active TED associated with severe inflammatory signs. A randomized controlled
trial is necessary to more accurately determine the efficacy and
adverse effects of adalimumab and whether it can reduce the
steroid requirements for patients with active TED.
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