Clinical Ophthalmology Dovepress

open access to scientific and medical research

Open Access Full Text Article

ORIGINAL RESEARCH

Real-World Efficacy and Safety of Mycophenolate

Mofetil in Active Moderate-to-Sight-Threatening
Thyroid Eye Disease

Nicole Quah Qin Xian 1 Purpose: There is no universal consensus on second-line agents for the treatment of
Ahmed Alnahrawy 2 moderate/severe to sight-threatening thyroid eye disease (TED) to maintain remission after
Rashmi Akshikar 2 first-line intravenous methylprednisolone (IVMP). This study investigates the efficacy and
Vickie Lee 2,3 safety of mycophenolate mofetil (MMF) in TED patients in a real-world setting and over
a longer period than previous randomized controlled trials.
1
Department of Stroke Medicine,
Methods: A retrospective cohort study of TED patients with active moderate/severe to
Charing Cross Hospital, Imperial College
Healthcare NHS Trust, London, UK; sight-threatening TED seen over a 4-year period. Data collected were visual acuity (VA),
2
Department of Ophthalmology, Clinical Activity Score (CAS), Gorman Diplopia scores, MMF dosing and side effects at 24,
Western Eye Hospital, Imperial College
Healthcare NHS Trust, London, UK; 52 and 78 weeks. Clinical efficacy was defined as an absence of relapse: no decline in best
3 corrected LogMAR VA, no need for further steroids, no increase in CAS of ≥2.
Department of Surgery & Cancer,
General Surgery, Faculty of Medicine, Results: Out of 23 patients, 20 patients were included in this study. 10% (2/20) stopped
Imperial College London, London, UK
MMF before 24 weeks. Median duration of MMF treatment was 76 weeks (1–140 weeks).
55% (11/20) had dysthyroid optic neuropathy (DON). In those with active moderate-severe
TED without DON, clinical efficacy was seen in 100% (8/8) at 24 weeks, 87.5% (7/8) at 52
weeks, and 83.3% (5/6) at 78 weeks, with CAS decreasing from a baseline of 2.78±1.99 to
0.50±0.58 at 24 weeks, 0.50±0.82 at 52 weeks and 1.00±1.30 at 78 weeks. In DON,
improvements were seen in 90% (9/10) at 24 weeks, 100% (7/7) at 52 weeks and 100%
(4/4) at 78 weeks, with significantly reduced CAS scores from 2.55±1.54 to 0.83±1.27, 1.00
±1.17 and 0.63±0.95 at 24, 52 and 78 weeks, respectively. Gorman score, VA and soft tissue
inflammation parameters also improved throughout. There were two significant side effects
over the treatment period.
Conclusion: MMF appears to be an effective and safe second-line immunosuppressive
agent. Further studies aimed at elucidating optimal dosing regimens and ideal treatment
duration will prove helpful.
Keywords: Graves orbitopathy, dysthyroid optic neuropathy, CellCept

Introduction
Thyroid Eye Disease (TED) is a disfiguring and occasionally sight-threatening
autoimmune orbital inflammation occurring predominantly in patients with
Correspondence: Vickie Lee Graves’ hyperthyroidism. About two thirds of TED patients have clinically mild
Department of Ophthalmology, Western disease that requires supportive measures1,2 including achievement of euthyroidism,
Eye Hospital, Imperial College Healthcare
NHS Trust, 153–173 Marylebone Road, smoking cessation, selenium supplementation and tear supplements.2 Those with
Marylebone, London, NW1 5QH, UK moderate-severe and sight-threatening disease usually benefit from timely immu­
Tel +44 20 3312 6666
Email [email protected] nosuppression of their eye disease to decrease the eventual disease burden and

Clinical Ophthalmology 2021:15 1921–1932 1921

© 2021 Quah Qin Xian et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/
terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing
the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
Quah Qin Xian et al Dovepress

prevent visual loss.3 Regardless of disease severity, it is Our inclusion criteria comprised patients aged >18
well known that TED inflicts significant psychological, years with moderate-severe TED who had received first-
occupational and financial burden.4 line IVMP treatment (using the EUGOGO protocol) over
Medical management of TED continues to pose a 12-week period and started on MMF during or soon after
a challenge for clinicians. Most patients with moderate- IVMP treatment. Patients were excluded if they had inade­
severe and sight-threatening dysthyroid optic neuropathy quate health records, with no documentation available
(DON) disease in the UK are treated in line with the between our proposed timepoints of 24 weeks, 52 weeks,
European Group of Graves’ Orbitopathy (EUGOGO) and 78 weeks after MMF initiation. As most of our
recommendations with a 12-week course of weekly intra­ patients started MMF after IVMP treatment, they had
venous methylprednisolone (IVMP) as a first-line treat­ already been pre-screened for immunosuppression.
ment for active moderate-severe TED, with higher All patients had at least one endocrine assessment by
initiation doses used for DON.3 However, around one an Endocrinologist, with optimization of thyroid status,
third of patients experience relapse after the first-line where appropriate. Hyperthyroidism was treated with
IVMP treatment.5 As TED is generally deemed a self- a titration or “block and replace” regimen, using carbima­
limiting condition that has an inflammatory duration of zole (CBZ) as first-line or propylthiouracil (PTU)
up to 12 to 18 months, there is a role for second-line as second-line; with thyroxine replacement added in the
consolidation treatment modalities including orbital radio­ “block and replace” model. Hypothyroid patients and post-
therapy or biological and non-biological immunosuppres­ thyroidectomy patients were treated with thyroxine repla­
sive agents.3 There is no general consensus surrounding cement as guided by their thyroid function.
the optimal consolidation treatment. We describe our All patients were assessed for TED severity and activ­
experience with mycophenolate mofetil (MMF) in our ity by a Consultant Ophthalmologist through documenta­
multidisciplinary thyroid eye (MDTED) clinics in an eth­ tion of their symptoms, orbital and ocular examination and
nically diverse patient cohort in London over a 4-year the Clinical Activity Score (CAS).6 Most of our patients
period. also underwent magnetic resonance imaging (MRI) to
assess the level of radiological inflammation. Those
Materials and Methods patients with TED of at least moderate severity, as deter­
Patients treated with MMF were identified through mined by their required first-line IVMP, were considered
a retrospective audit of our MDTED clinics at Imperial to have clinically active TED. The severity of the disease
College Healthcare NHS Trust. The MDTED was led by was graded according to the EUGOGO consensus
Consultant Ophthalmic and Oculoplastic Surgeon (VL) statement.3
and Immunosuppression Specialist (RA) and included con­ All of our TED patients who had received IVMP also
sultant ophthalmologists, endocrinologists and orthoptists received detailed counselling regarding whether to adopt
(for measurement of ocular motility). Data was collected a “treat and extend” approach after terminating IVMP
for all patients from the inception of the clinic in 2016. where second-line treatment was only started if there
Referrals for MMF treatment also came from two other were clinical signs of relapse, or to commence second-
associated MDTED clinics: Central Middlesex Hospital line treatment and/or orbital radiotherapy during their 12-
(CMH, 2011) and Charing Cross Hospital (CXH, 2017). week course of IVMP. Usually, most of our DON patients
The database used in this audit was directly populated and would progress to either orbital radiotherapy and/or MMF,
verified by a board round consensus of all the MDTED especially for those who required urgent orbital decom­
consultants working in the clinic. Additional clinical data pression during the early phase of their treatment. For
were collected from the electronic record systems; this those individuals with severe diplopia from restrictive
included clinic letters, biochemical and radiology results. myopathy or sight-threatening disease, we aimed to start
Database lock was on 1st May 2020, before the initiation MMF whilst they were still receiving their 12-week IVMP
of the analysis. This retrospective audit was registered and treatment.
approved by Imperial College Healthcare NHS Trust’s MMF regimens in our MDTED clinics usually com­
Audit Department (ref: OPH_029); data were anonymized prised an initiation phase (500 mg increasing up to 2 g),
and confidentiality was maintained throughout. This study followed by a maintenance phase (doses of ≥1.5 g), then
adhered to the tenets of the Declaration of Helsinki. a weaning phase (1 g tapered down to 750 mg then

1922 https://doi.org/10.2147/OPTH.S305717 Clinical Ophthalmology 2021:15

DovePress
Dovepress Quah Qin Xian et al

500 mg). The intention was to treat for 52 weeks, and we baseline measurements immediately prior to MMF admin­
generally aimed to initiate the treatment during the 12- istration were unavailable, the most recent available mea­
week IVMP course to allow MMF efficacy to coincide surement before MMF initiation was used. Blood pressure
with the termination of IVMP treatment. During the initia­ and biochemical parameters were monitored at baseline
tion phase, they had weekly full blood counts (FBC), and throughout treatment, including FBC, renal
fortnightly urea and electrolytes (U&Es) and liver function profile and electrolytes, liver function tests, and glycated
tests (LFTs) until dose stabilization, then the above tests hemoglobin (HbA1c).
monthly. The primary outcomes were measured at dates closest to
The following data were retrospectively collected for 24, 52 and 78 weeks after treatment initiation. Ophthalmic
each patient: gender, ethnicity, age at MMF initiation, parameters at these timepoints were compared to those mea­
smoking status, thyroid disease diagnosis, thyroid treat­ sured prior to MMF initiation. Clinical efficacy of MMF was
ments received prior to MMF initiation and after MMF defined as: an absence of relapse during the period of treat­
discontinuation, duration of thyroid disease and ophthal­ ment, with relapse was defined as (i) worsening of BCVA
mopathy, and previous treatments for thyroid disease and denoted by a LogMAR score of >0.2; (ii) requirement of
TED. Duration of thyroid disease was defined as the a further course of IVMP or oral steroids; (iii) increment in
period between clinical or biochemical thyroid function CAS score by ≥2; or iv) decision to increase in MMF dose
derangement and database lockdown. The onset of TED by ≥1 g following attempts at tapering.
was defined as the first onset of signs or symptoms or the Secondary outcomes included: side effects or clinically
first visit to an ophthalmology clinic where the diagnosis significant worsening of laboratory parameters during
was made. MMF treatment duration. A side effect is defined as any
Ophthalmic parameters recorded were CAS score, soft undesirable symptom or sign occurring after the start of
tissue involvement including pain and swelling, Gorman MMF treatment, regardless of its relation to MMF.
Score for diplopia, best corrected visual acuity (BCVA) in A significant side effect was defined as any medical occur­
the worst eye and Ishihara color vision. These parameters rence relating to MMF treatment which required hospital
were recorded at the first presentation to the eye clinic just admission or permanent MMF discontinuation. Significant
prior to MMF initiation, at 24 weeks, 52 weeks, 78 weeks, derangement in any of the blood measurements over the
or at point of MMF cessation, if stopped prior to 24 weeks. course of MMF treatment was considered a side effect.
Diplopia severity was evaluated using the Gorman scoring
system:7 no diplopia = 1, intermittent diplopia = 2, incon­
Statistical Analysis
stant or gaze-evoked diplopia = 3, continuous diplopia in
Continuous variables were expressed as the mean±stan­
the primary and reading position = 4. BCVA was con­
dard deviation (SD), with duration expressed as median
verted to LogMAR score equivalents.8 For patients with
(range). Categorical variables were expressed as frequency
visual acuity scores worse than 1.0 on LogMAR, we
and percentage of total population. Welch’s t-test was used
assigned a maximum value of 1.0 to the following acuities
to compare continuous variables for the population at the
of Counting Fingers (CF), Hand Motion (HM), Light
four defined timepoints. All statistical analyses were per­
Perception (LP), and No Light Perception (NPL). For
formed using the Data Analysis Toolkit on Microsoft
individuals with DON, color vision was recorded as the
Excel. Statistical significance is defined as p<0.05.
number of color vision plates correctly identified out of the
total number of plates tested, with fractions then converted
to decimals for comparison of color vision changes over Results
time, to give a maximum score of 1. Patient Demographics
Baseline laboratory measurements before MMF initia­ Twenty-three patients received MMF for TED treatment. 3
tion were recorded where available, of: Thyroid were excluded due to lack of documentation. 60% (12/20)
Stimulating Hormone (TSH), free tetraiodothyronine of our cohort were female, and the mean age was 50.9
(fT4), TSH-receptor antibodies (TRAbs), thyroid peroxi­ years (31–79 years, Table 1). 50% (10/20) were documen­
dase antibodies (TPOAbs), alanine aminotransferase ted to be of White ethnicity. 75% (15/20) of individuals
(ALT), prothrombin time (PT), serum creatinine and esti­ were either ex-smokers (70%, 14/20) or current smokers
mated Glomerular Filtration Rate (eGFR). In cases where (5%, 1/20).

Clinical Ophthalmology 2021:15 https://doi.org/10.2147/OPTH.S305717

1923
DovePress
Quah Qin Xian et al Dovepress

Table 1 Demographics and Baseline Characteristics of Our Cohort of 20 Individuals

n 20

Sex (male: female) 8:12

Median age, years (range) 50.9 (31–79)

Ethnicity White (Irish, British), % 10 (50)

Black, African, Caribbean, Black British, % 3 (15)
Asian or Asian British, % 3 (15)
Mixed, % 2 (10)
Other, % 2 (10)

Smoking status Never smoked, % 5 (25)

Ex-smoker, % 14 (70)
Current smoker, % 1 (5)

Median duration of Thyroid Disease, years (range) 2.9 (0.8–61.7)

Median duration of TED, years (range) 2.9 (0.8–23.3)

Thyroid Disease Graves’ hyperthyroidism, % 17 (85)

Hashitoxicosis, % 1 (5)
Euthyroid, % 1 (5)
Thyroid resistance, % 1 (5)
Hashimoto’s, % 0 (0)
Hypothyroidism, % 0 (0)

Thyroid Treatment before MMF Anti-thyroid treatmenta, % 13 (65)

Thyroid hormone replacement, % 4 (20)
No treatment, % 3 (15)

Previous Treatments IVMP for TED, % 20 (100)

Oral prednisolone for TED, % 4 (20)
Orbital radiotherapy, % 7 (35)
Optic nerve decompression, % 11 (55)
Radioactive iodine, % 3 (15)
Thyroidectomy, % 2 (10)

Individuals with DON diagnosis, n (%) 11 (55)

Biochemical and Immunological Characteristics before MMF TSH, mU/L (mean±SD) 5.5±15.5
fT4, pmol/L (mean±SD) 15.3±10.4
TRAbs positive, % 12 (60)
TPOAbs positive, % 0 (0)
ALT, U/L (mean±SD) 29.1±13.5b
PT, seconds (mean±SD) 12.5±1.4
Serum creatinine, µmol/L (mean±SD) 69.7±12.8
eGFR, mL/min/1.73 m2 (mean±SD) 84.8±10.9
Notes: aAnti-thyroid treatments include: Titration (Carbimazole or Propylthiouracil) or Block and Replace (Carbimazole/propylthiouracil and levothyroxine). b1 sample
excluded with ALT: 422 which had risen secondary to IVMP use. Decision was made to proceed with MMF initiation due to benefits outweighing risks.
Abbreviations: ALT, alanine aminotransferase; eGFR, estimated glomerular filtration rate; fT4, free tetraiodothyrodine; IVMP, iv methylprednisolone; MMF, mycophenolate
mofetil; PT, prothrombin time; TED, thyroid eye disease; TPOAbs, thyroid peroxidase antibodies; TRAbs, TSH-receptor antibodies; TSH, thyroid-stimulating hormone.

The median duration of thyroid disease and TED was block and replace regimen, whilst 20% (4/20) were on
2.9 years (0.8–61.7 years) and 2.9 years (0.8–23.3 years) thyroid hormone replacement therapy, and 15% (3/20)
respectively. 85% (17/20) had Graves’ disease with 60% did not require ongoing treatment. All individuals received
(12/20) TSH-receptor antibody positive. 65% (13/20) of IVMP as a first-line immunosuppression, with 20% (4/20)
individuals were on anti-thyroid treatment in a titration or also receiving oral steroids. 35% (7/20) had undergone

1924 https://doi.org/10.2147/OPTH.S305717 Clinical Ophthalmology 2021:15

DovePress
Dovepress Quah Qin Xian et al

Figure 1 Duration of mycophenolate mofetil treatment for 20 patients.

previous orbital radiotherapy, whilst 55% of individuals demographics of treatments received by each cohort at
(11/20) had undergone previous orbital decompression. each timepoint are depicted in Figure 2.
15% (3/20) had previously received radioactive iodine
(RAI) treatment and 10% (2/20) had undergone thyroidect­ Baseline Findings
omy. Prior to MMF initiation, 65% (13/20) of our patients In the 9 individuals with active moderate-severe TED
were euthyroid, with 25% (5/20) documented to be without DON, the mean CAS prior to MMF treatment
hyperthyroid, and 10% (2/20) hypothyroid at the point of was 2.78±1.99. At baseline, the most common ophthalmic
their first MDT visit. There were no biochemical results feature was soft tissue involvement (88.9%, 8/9), charac­
indicating renal dysfunction. One individual had slightly terized by pain (77.8, 7/9). The mean Gorman score was
deranged liver function tests secondary to IVMP use. 2.33±1.32. The mean BCVA score on the LogMAR chart
for the worst-affected eye was 0.13±0.19 (Table 2).
In the 11 individuals with DON, mean baseline CAS
Patient Responses to MMF was 2.55±1.54. Soft tissue involvement was the most
The median duration of MMF treatment at the point of common ophthalmic feature (90%, 9/10), with 88.9% (8/
database lockdown was 76 weeks (1–140 weeks) 9) individuals reporting pain. Mean Gorman score was
(Figure 1). 90% (18/20) had received MMF for at least 24 2.64±0.99; mean BCVA was 0.45±0.42 and mean color
weeks; 75% (15/20) for at least 52 weeks and 50% (10/20) vision score for those with DON was 0.79±0.37 (Table 2).
for at least 78 weeks. Two individuals received MMF for
less than 24 weeks (19 weeks, 1 week). At 24 weeks, 24 Weeks (18 Patients)
average MMF dose was 1722 mg, with 22.2% (4/18) of In those without DON (8 individuals; 7 ex-smokers, 1 non-
individuals receiving 1500 mg and 66.7% (12/18) receiving smoker), the mean CAS was 0.50±0.58. This was
2000 mg or more. At 52 weeks, mean dose was 1339 mg; a statistically significant improvement from the baseline
13% (2/15) were on 1500 mg and 40% (6/15) on 2000 mg. CAS of 2.78±1.99 (p=0.01). There was a general trend in
At 78 weeks, mean dose was 1472 mg, 30% (3/10) were on improvement in all other ophthalmic parameters. Overall,
1500 mg and 30% (3/10) were receiving 2000 mg or more. 100% (8/8) of individuals exhibited improvements when
At baseline, there were 9/20 (45%) individuals with assessed after 24 weeks of MMF treatment, with no
active moderate-severe TED without sight-threatening relapses (Table 3).
DON, and 11/20 (55%) with a DON diagnosis. By 24 In DON cases (10 individuals, 7 ex-smokers, 3 non-
weeks, individuals with DON comprised 10/18 (55.6%) smokers), the mean CAS was 0.83±1.27, a significant
of the cohort, whereas this dropped to 7/15 (46.7%) by 52 decrease from 2.55±1.54 baseline (p=0.004). Other
weeks and 4/10 (40%) by 78 weeks. The changing ophthalmic parameters were also improved, with 90% (9/

Clinical Ophthalmology 2021:15 https://doi.org/10.2147/OPTH.S305717

1925
DovePress
Quah Qin Xian et al Dovepress

Moderate-Severe TED Moderate-Severe TED Moderate-Severe TED Moderate-Severe TED

(9 Patients): (8 Patients): (8 Patients): (6 Patients):
+ 1 thyroidectomy
0/9 receiving oral steroids + 1 ORT course 0/8 receiving oral steroids Nil change 0/8 receiving oral steroids +1 further IVMP 0/6 receiving oral steroids
9/9 had received IVMP 0/8 received further IVMP 0/8 received further IVMP 1/6 received further IVMP
2/9 previous RAI 2/8 previous RAI 2/8 previous RAI 1/6 previous RAI
4/9 previous ORT 4/8 previous ORT 4/8 previous ORT 3/6 previous ORT
1/9 previous thyroidectomy 2/8 previous thyroidectomy 2/8 previous thyroidectomy 1/6 previous thyroidectomy
3/9 optic nerve decompressed 2/8 optic nerve decompressed 2/8 optic nerve decompressed 1/6 optic nerve decompressed

At baseline: By 24 weeks: By 52 weeks: By 78 weeks:

Sight-threatening DON Sight-threatening DON Sight-threatening DON Sight-threatening DON

(11 Patients): (10 Patients): (7 Patients): (4 Patients):
+ 1 further IVMP
+ 1 thyroidectomy + 1 optic nerve
4/11 receiving oral steroids + 2 ORT courses 0/10 receiving oral steroids 0/7 receiving oral steroids Nil change 0/4 receiving oral steroids
decompression
11/11 had received IVMP 0/10 received further IVMP 1/7 received further IVMP 1/4 received further IVMP
1/11 previous RAI 1/10 previous RAI 1/7 previous RAI 1/4 previous RAI
3/11 previous ORT 5/10 previous ORT 3/7 previous ORT 3/4 previous ORT
1/11 previous thyroidectomy 1/10 previous thyroidectomy 0/7 previous thyroidectomy 0/4 previous thyroidectomy
8/11 optic nerve decompressed 7/10 optic nerve decompressed 5/7 optic nerve decompressed 3/4 optic nerve decompressed

Figure 2 Flowchart demonstrating the treatments received by individuals with moderate-severe TED and those with DON at baseline, 24 weeks, 52 weeks and 78 weeks.

10) of individuals reporting improvements. One patient tried to wean patients off MMF in line with our regimen,
(10.0%) had worsened BCVA with an increase of 0.3 and 1 individual (16.7%) required a slower weaning off
LogMAR BCVA (Table 4). period with some increases in doses needed after a slight
relapse in soft tissue symptoms.
52 Weeks (15 Patients) For the remaining 4 individuals with DON (1 ex-
At 52 weeks, those without DON (8 individuals, 7 ex- smoker, 3 non-smokers), mean CAS was 0.63±0.95
smokers, 1 non-smoker) had a mean CAS of 0.50±0.82, which was significantly lower than baseline (p=0.006).
a statistical improvement from baseline CAS (p=0.016). All individuals experienced improvements in their
There was maintenance of the general trend in improve­ ophthalmic parameters, though 1 individual (25%)
ment of ophthalmic parameters compared to baseline and required a re-increase in MMF dose during the weaning
overall, 87.5% (7/8) individuals improved after 52 weeks process.
of MMF. 1 individual (12.5%) experienced a relapse due
to a decrement in BCVA >0.2 on LogMAR chart.
For individuals with DON (7 individuals, 4 ex-
Side Effects
We recorded side effects in 65% (13/20) of our cohort, but
smokers, 3 non-smokers), the mean CAS was 1.00±1.17
most of these were mild. 10% (2/20) met the criteria for
which was significantly decreased from baseline
a significant side effect related to MMF treatment
(p=0.016). All 7 patients (100%) reported improvements
(Table 5) – one being viral pneumonia requiring hospital
amongst their other ophthalmic parameters, although one
admission between the 24th and 52nd week and the other
(14.3%) individual experienced a relapse by our definition
being MMF discontinuation due to development of severe
during this same timeframe, due to provision of a further
gastrointestinal symptoms in the first 4 weeks in an indi­
IVMP course.
vidual who subsequently underwent bilateral orbital
decompression, as well as orbital radiotherapy for their
78 Weeks (10 Patients)
DON with eventual good outcome.
At 78 weeks, there were 6 individuals with moderate-
severe TED without DON (5 ex-smokers, 1 smoker).
Mean CAS was 1.00±1.30 compared to the baseline of Discussion
2.78±1.99 (p=0.101). Overall, a response occurred in As far as we are aware, there are few studies in the peer-
83.3% (5/6) of those individuals still receiving MMF at reviewed literature describing the use of MMF in a real-
78 weeks. This was the stage when our MDTED clinics world clinical setting for TED treatment. In a recent UK

1926 https://doi.org/10.2147/OPTH.S305717 Clinical Ophthalmology 2021:15

DovePress
Dovepress Quah Qin Xian et al

Table 2 Ophthalmic Assessments for Individuals with Moderate-Severe TED and Sight-Threatening DON at Baseline, 24 Weeks, 52
Weeks, 78 Weeks
Before MMF 24 Weeks 52 Weeks 78 Weeks

Individuals with Active Moderate-Severe TED without Sight-Threatening DON

n 9 8 8 6
CAS (mean±SD) 2.78±1.99a 0.50±0.58d 0.50±0.82g 1.00±1.30j
Soft tissue involvement, % 8/9 (88.9) 2/5 (40.0) 4/7 (57.1) 3/5 (60.0)
Pain, % 7/9 (77.8) 1/5 (20.0) 2/5 (40.0) 2/5 (40.0)
Gorman Score (mean±SD) 2.33±1.32b 0.63±0.50e 1.13±0.84h 1.83±1.30k
VA in worst eye (mean±SD) 0.13±0.19c 0.04±0.22f 0.11±0.27i 0.00±0.14l

Individuals with Sight-Threatening DON

n 11 10 7 4
CAS (mean±SD) 2.55±1.54m 0.83±1.27q 1.00±1.17u 0.63±0.95y
Soft tissue involvement, % 9/10 (90.0) 3/10 (30.0) 1/5 (20.0) 2/4 (50.0)
Pain, % 8/9 (88.9) 3/10 (30.0) 3/7 (42.9) 0/4 (0.0)
Gorman Score (mean±SD) 2.64±0.99n 1.50±1.22r 1.43±1.29v 1.75±1.53z
VA in worst eye (mean±SD) 0.45±0.42o 0.42±0.42s 0.40±0.45w 0.33±0.48aa
Color vision (mean±SD) 0.79±0.37p 0.94±0.16t 0.68±0.26x 0.98±0.03ab
Notes: aMean Clinical Activity Score at baseline for 9/9 individuals. bMean Gorman score at baseline for 9/9 individuals.cMean visual acuity at baseline for 9/9 individuals. dMean Clinical
Activity Score at 24 weeks for 4/8 individuals. eMean Gorman score at 24 weeks for 4/8 individuals. fMean visual acuity at 24 weeks for 8/8 individuals. gMean Clinical Activity Score at 52
weeks for 6/8 individuals. hMean Gorman score at 52 weeks for 6/8 individuals. iMean visual acuity at 52 weeks for 8/8 individuals. jMean Clinical Activity Score at 78 weeks for 5/6
individuals. kMean Gorman score at 78 weeks for 5/6 individuals. lMean visual acuity at 78 weeks for 5/6 individuals. mMean Clinical Activity Score at baseline for 9/11 individuals. nMean
Gorman score at baseline for 10/11 individuals. oMean visual acuity at baseline for 11/11 individuals. pColor vision score at baseline for 11/11 individuals. qMean Clinical Activity Score at
24 weeks for 9/10 individuals. rMean Gorman score at 24 weeks for 5/10 individuals. sMean visual acuity at 24 weeks for 10/10 individuals. tColor vision score at 24 weeks for 7/10
individuals. uMean Clinical Activity Score at 52 weeks for 6/7 individuals. vMean Gorman score at 52 weeks for 4/7 individuals. wMean visual acuity at 52 weeks for 7/7 individuals. xColor
vision score at 52 weeks for 5/7 individuals. yMean Clinical Activity Score at 78 weeks for 4/4 individuals. zMean Gorman score at 78 weeks for 3/4 individuals. aaMean visual acuity at 78
weeks for 4/4 individuals. abColor vision score at 78 weeks for 4/4 individuals.
Abbreviations: CAS, Clinical Activity Score; DON, dysthyroid optic neuropathy; MMF, mycophenolate mofetil; SD, standard deviation; TED, thyroid eye disease; VA, visual acuity.

survey of TED services, it was found that there was sig­ We found it difficult to wean half of our patients off MMF
nificant geographical variation in the accessibility even at 52 weeks as patients would complain of increased
of second-line immunosuppression.9 Despite the advent soft tissue swelling or pain upon dose reduction.
of the recently targeted TED treatment We found that the optimal duration of MMF treatment
Teprotumumab,2,10,11 due to its limited licensing and may lie between 24 and 78 weeks; this is similar to Ye
cost, there remains a distinct need for an effective and et al’s highly promising findings of a 91% response rate to
safe yet affordable second-line immunosuppression agent. MMF at 24 weeks,12 and higher than Kahaly et al’s figure
Although previous randomized controlled prospective stu­ of 71% response to mycophenolate sodium at 24 weeks.13
dies have investigated the role of mycophenolate in active Mycophenolate sodium (Myfortic) is an enteric-coated
moderate-severe TED,12,13 these studies specifically formulation of mycophenolate acid, whereas MMF
excluded individuals with sight-threatening DON,12,13 (Cellcept) is a pro-drug of mycophenolate acid with higher
recent second-line immunosuppression,12,13 and previous oral bioavailability, which may explain the increased
orbital decompression.12 In normal clinical practice, levels of clinical response observed with MMF over myco­
a combination of these modalities is used to control severe phenolate sodium.15 Of note, despite the current global
and sight-threatening disease, and our population demo­ pandemic of COVID-19 which has called for reviews
graphics reflect this. Our study examined the effects of over the necessity of existing immunosuppressive therapy,
MMF treatment in an ethnically diverse cohort for dura­ none of our patients terminated their MMF treatments.
tions of up to 18 months, whereas previous studies had Current literature reports that the most common side
a final follow-up at 9 months in cohorts with less severe effects of MMF include gastrointestinal16 or hematological
disease than ours. Our MMF cohort had a much higher disorders, and infections.13,17 Sore throat was the most
proportion of smokers and ex-smokers (75%) compared to common side effect and we had 2 cases of mild gastro­
all of the patients attending our MDTED clinics (43%).14 intestinal disturbance or hematological derangements

Clinical Ophthalmology 2021:15 https://doi.org/10.2147/OPTH.S305717

1927
DovePress
Quah Qin Xian et al Dovepress

Table 3 Ophthalmic Responses for Individuals with Moderate-Severe TED and Individuals with Sight-Threatening DON at 24 Weeks,
52 Weeks, 78 Weeks vs Baseline
24 Weeks 52 Weeks 78 Weeks

Individuals with Active Moderate-Severe TED without Sight-Threatening DON

Total n 8 8 6

CAS score available n, % 4/8 (50.0) 6/8 (75.0) 5/6 (83.3)

Improved, % 3/8 (37.5) 5/8 (62.5) 4/6 (66.7)
Stable, % 1/8 (12.5) 1/8 (12.5) 1/6 (16.7)
Deteriorated, % 0/8 (0.0) 0/8 (0.0) 0/6 (0.0)
Unknown, % 4/8 (50.0) 2/8 (25.0) 1/6 (16.7)

Soft tissue involvement n, % 2/5 (40.0) 4/7 (57.1) 3/5 (60.0)

Improved, % 3/8 (37.5) 3/8 (37.5) 2/6 (33.3)
Stable, % 2/8 (25.0) 3/8 (37.5) 2/6 (33.3)
Deteriorated, % 0/8 (0.0) 1/8 (12.5) 1/6 (16.7)
Unknown, % 3/8 (37.5) 1/8 (12.5) 1/6 (16.7)

Diplopia n, % 1/4 (25.0) 2/6 (33.3) 3/5 (60.0)

Improved, % 3/8 (37.5) 3/8 (37.5) 1/6 (16.7)
Stable, % 2/8 (25.0) 2/8 (25.0) 2/6 (33.3)
Deteriorated, % 1/8 (12.5) 1/8 (12.5) 2/6 (33.3)
Unknown, % 2/8 (25.0) 2/8 (25.0) 1/6 (16.7)

Pain n, % 1/5 (20.0) 2/5 (40.0) 2/5 (40.0)

Improved, % 3/8 (37.5) 3/8 (37.5) 2/6 (33.3)
Stable, % 2/8 (25.0) 2/8 (25.0) 3/6 (50.0)
Deteriorated, % 0/8 (0.0) 0/8 (0.0) 0/10 (0.0)
Unknown, % 3/8 (37.5) 3/8 (37.5) 1/6 (16.7)

Visual acuity in most affected eye n, % 8/8 (100.0) 8/8 (100.0) 5/6 (83.3)
Improved, % 5/8 (62.5) 5/8 (62.5) 2/6 (33.3)
Stable, % 2/8 (25.0) 2/8 (25.0) 3/6 (50.0)
Deteriorated, % 1/8 (12.5) 1/8 (12.5) 0/6 (0.0)
Unknown, % 0/8 (0.0) 0/8 (0.0) 1/6 (16.7)
Improvement in any Parameter n, % 8/8 (100.0) 7/8 (87.5) 5/6 (83.3)

Individuals with Sight-Threatening DON

Total n 10 7 4

CAS score available n, % 9/10 (90.0) 6/7 (85.7) 4/4 (100.0)

Improved, % 7/10 (70.0) 5/7 (71.4) 3/4 (75.0)
Stable, % 1/10 (10.0) 1/7 (14.3) 1/4 (25.0)
Deteriorated, % 0/10 (0.0) 0/7 (0.0) 0/4 (0.0)
Unknown, % 2/10 (20.0) 1/7 (14.3) 0/4 (0.0)

Soft tissue involvement n, % 3/10 (30.0) 1/5 (20.0) 2/4 (50.0)

Improved, % 6/10 (60.0) 3/7 (42.9) 3/4 (75.0)
Stable, % 4/10 (40.0) 2/7 (28.6) 0/4 (0.0)
Deteriorated, % 0/10 (0.0) 0/7 (0.0) 1/4 (25.0)
Unknown, % 0/10 (0.0) 2/7 (28.6) 0/4 (0.0)

Diplopia n, % 4/5 (80.0) 3/4 (75.0) 2/3 (66.7)

Improved, % 3/10 (30.0) 3/7 (42.9) 1/4 (25.0)
Stable, % 3/10 (30.0) 1/7 (14.3) 1/4 (25.0)
Deteriorated, % 1/10 (10.0) 1/7 (14.3) 1/4 (25.0)

(Continued)

1928 https://doi.org/10.2147/OPTH.S305717 Clinical Ophthalmology 2021:15

DovePress
Dovepress Quah Qin Xian et al

Table 3 (Continued).

24 Weeks 52 Weeks 78 Weeks

Unknown, % 3/10 (30.0) 2/7 (28.6) 1/4 (25.0)

Pain n, % 3/10 (30.0) 3/7 (42.9) 0/4 (0.0)

Improved, % 6/10 (60.0) 6/7 (85.7) 4/4 (100.0)
Stable, % 3/10 (30.0) 0/7 (0.0) 0/4 (0.0)
Deteriorated, % 0/10 (0.0) 0/7 (0.0) 0/4 (0.0)
Unknown, % 1/10 (10.0) 1/7 (14.3) 0/4 (0.0)

Visual acuity in most affected eye n, % 10/10 (100.0) 7/7 (100.0) 4/4 (100.0)
Improved, % 5/10 (50.0) 3/7 (42.9) 1/4 (25.0)
Stable, % 3/10 (30.0) 3/7 (42.9) 1/4 (25.0)
Deteriorated, % 2/10 (20.0) 1/7 (14.3) 1/4 (25.0)
Unknown, % 0/10 (0.0) 0/7 (0.0) 1/4 (25.0)

Color Vision score available n, % 7/10 (70.0) 5/7 (71.4) 4/4 (100.0)
Improved, % 2/10 (20.0) 2/7 (28.6) 0/4 (0.0)
Stable, % 4/10 (40.0) 2/7 (28.6) 3/4 (75.0)
Deteriorated, % 0/10 (0.0) 1/7 (14.3) 1/4 (25.0)
Unknown, % 4/10 (40.0) 2/7 (28.6) 0/4 (0.0)

Improvement in any Parameter n, % 9/10 (90.0) 7/7 (100.0) 4/4 (100.0)

Abbreviations: CAS, Clinical Activity Score; DON, dysthyroid optic neuropathy; TED, thyroid eye disease.

Table 4 Relapses in Those with Moderate-Severe TED and Sight-Threatening DON Occurring by 24 Weeks, 52 Weeks, 78 Weeks
24 Weeks 52 Weeks 78 Weeks

Individuals with Active Moderate-Severe TED without Sight-Threatening DON

Worse BCVA 0 1 0
Further IVMP Doses 0 0 0
Increase in CAS 0 0 0
Up-titration of MMF 0 0 1
Total Relapse, n (%) 0/8 (0.0) 1/8 (12.5) 1/6 (16.7)

Individuals with Sight-Threatening DON

Worse BCVA 1 0 0
Further IVMP Doses 0 1 0
Increase in CAS 0 0 0
Up-titration of MMF 0 0 1
Total Relapse, n (%) 1/10 (10.0%) 1/7 (14.3) 1/4 (25.0)
Abbreviations: BCVA, best corrected visual acuity; CAS, Clinical Activity Score; DON, dysthyroid optic neuropathy; IVMP, intravenous methylprednisolone; MMF,
mycophenolate mofetil; TED, thyroid eye disease.

within our cohort. Significant side effects occurred in 2 thus, these events may not necessarily have been directly
patients (viral pneumonia and GI upset), the latter of MMF-related. Our other MMF permanent cessation occur­
which resulted in permanent cessation. The viral pneumo­ ring before 24 weeks was due to a switch to ciclosporin at
nia required hospital admission and although MMF was 19 weeks. Overall, these findings suggest that the safety
temporarily suspended, it was not permanently discontin­ profile of MMF is comparable to the safety profile of oral
ued. Both these patients had several other comorbidities; and intravenous steroids18,19 and offers promising initial

Clinical Ophthalmology 2021:15 https://doi.org/10.2147/OPTH.S305717

1929
DovePress
Quah Qin Xian et al Dovepress

Table 5 Side Effects During Mycophenolate Mofetil Treatment for Our Cohort
Week

4 8 12 16 20 24 52 78 Post
78

Infection, total 2 1 0 1 0 0 7 1 0
Tonsillitisa 2 1 0 0 0 0 4 0 0
Chest infectionb 0 0 0 1 0 0 2 0 0
Viral labyrinthitis 0 0 0 0 0 0 1 0 0
Urinary tract infection 0 0 0 0 0 0 0 1 0

Gastrointestinal and
Hepatobiliary, total 3 0 0 0 1 0 2 1 0
Nausea 0 0 0 0 0 0 2 0 0
Mouth ulceration 1 0 0 0 0 0 0 0 0
Change in bowel habitc 0 0 0 0 1 0 0 1 0
Deranged LFTs 1 0 0 0 0 0 0 0 0
Other/unknown 1 0 0 0 0 0 0 0 0

Neurological, total 0 0 0 0 3 0 0 0 1
Headache 0 0 0 0 1 0 0 0 0
Limb weakness 0 0 0 0 1 0 0 0 0
Vasovagal syncope 0 0 0 0 0 0 0 0 1
Otherd 0 0 0 0 1 0 0 0 0

Respiratory, total 0 0 0 0 2 0 0 0 0
Shortness of breath 0 0 0 0 1 0 0 0 0
Worsening of asthma 0 0 0 0 1 0 0 0 0

Hematological, total 0 0 1 0 0 0 0 0 0
Leukopenia 0 0 1 0 0 0 0 0 0

General, total 2 1 0 2 2 0 1 0 1
Fatigue 0 1 0 1 0 0 0 0 0
Cramps 0 0 0 1 0 0 0 0 0
Cold intolerance 1 0 0 0 0 0 0 0 0
Insomnia 1 0 0 0 0 0 1 0 1
Hypertension 0 0 0 0 2 0 0 0 0

Other 0 0 0 0 1 0 0 0 1
Epistaxis 0 0 0 0 1 0 0 0 1
New skin lesion 0 0 0 0 0 0 0 0 0

Number of side effects 7 2 1 3 9 0 10 2 3

Number of hospitalizations 0 0 0 0 0 0 1 0 0

Number of discontinuations 1 0 0 0 0 0 0 0 0

Patients with side effects, % 13/20 (65%)

Patients with significant side effects, % 2/20 (10%)

Notes: Tonsillitis definition includes sore throat and throat infection. Chest infection includes bacterial pneumonia and viral pneumonia. cChange in bowel habit includes
a b

development of tarry stool and diarrhea. dOther neurological side effects include speech difficulty and numbness.

data demonstrating that MMF is safe to use for longer TED assessment recorded when they were monitored in
periods of up to 18 months. the immunosuppression clinic instead of the MTDTED
Our study is limited by its retrospective nature, small clinics (where more complete TED assessments were per­
patient numbers, and the empirical adjustment in dosing formed) once their inflammation was more quiescent and
regimen. Patients sometimes did not have a comprehensive their immunosuppression established. Guidance regarding

1930 https://doi.org/10.2147/OPTH.S305717 Clinical Ophthalmology 2021:15

DovePress
Dovepress Quah Qin Xian et al

optimal treatment duration may be helped by ongoing 3. Bartalena L, Baldeschi L, Dickinson A, et al. Consensus statement of
the European Group on Graves’ Orbitopathy (EUGOGO) on manage­
radiological MRI assessment of radiological measure­
ment of graves’ orbitopathy. Thyroid. 2008;18(3):333–346.
ments of orbital inflammation,20 as well as a more consis­ doi:10.1089/thy.2007.0315
tent use of validated TED quality of life instruments, such 4. Ponto K, Pitz S, Pfeiffer N, Hommel G, Weber M, Kahaly G. Quality
of life and occupational disability in endocrine orbitopathy. Dtsch
as the Graves’ ophthalmopathy quality of life question­
Arztebl Int. 2009. doi:10.3238/arztebl.2009.0283
naire (GOQOL).21 Additionally, combinations of treatment 5. Wiersinga WM. Graves’ orbitopathy: management of difficult cases.
modalities were used in some individuals due to the real- Indian J Endocrinol Metab. 2012;16(Suppl 2):S150–2. doi:10.4103/
2230-8210.104026
world setting of this study; thus, it is not possible to solely 6. Mourits M, Prummel M, Wiersinga W, Koornneef L. Clinical activity
attribute all long-term therapeutic effects to MMF alone. score as a guide in the management of patients with Graves’ ophthal­
We would recommend a long-term prospective study be mopathy. Clin Endocrinol (Oxf). 1997;47(1):9–14. doi:10.1046/
j.1365-2265.1997.2331047.x
performed on patients who do not receive oral predniso­ 7. Bahn R, Gorman C. Choice of therapy and criteria for assessing
lone nor orbital radiotherapy, to fully establish the thera­ treatment outcome in thyroid-associated ophthalmopathy.
Endocrinol Metab Clin North Am. 1987;16(2):391–407.
peutic effects of MMF.
doi:10.1016/s0889-8529(18)30485-7
In conclusion, MMF is an effective and safe second-line 8. Holladay JT. Proper method for calculating average visual acuity.
immunosuppressive drug for moderate-severe and sight- J Refract Surg. 1997;13(4):388–391. doi:10.3928/1081-597X-
19970701-16
threatening TED, but we found that a longer treatment period 9. Lee V, Avari P, Williams B, Perros P, Dayan C. A survey of current
of up to 72 weeks, and higher doses than that previously practices by the British Oculoplastic Surgery Society (BOPSS) and
established by randomized controlled studies, were needed. recommendations for delivering a sustainable multidisciplinary
approach to thyroid eye disease in the United Kingdom. Eye.
2019;34(9):1662–1671. doi:10.1038/s41433-019-0664-z
Acknowledgments 10. Smith T, Kahaly G, Ezra D, et al. Teprotumumab for
thyroid-associated ophthalmopathy. N Engl J Med. 2017;376
The authors would like to thank Bhavini Dixit for her (18):1748–1761. doi:10.1056/nejmoa1614949
invaluable support within the immunosuppression clinic; 11. Douglas R, Kahaly G, Patel A, et al. Teprotumumab for the treatment
of active thyroid eye disease. N Engl J Med. 2020;382(4):341–352.
and are grateful to the Imperial Open Access Fund for
doi:10.1056/nejmoa1910434
assistance with the open access cost of this publication. 12. Ye X, Bo X, Hu X, et al. Efficacy and safety of mycophenolate
mofetil in patients with active moderate-to-severe Graves’ orbitopa­
thy. Clin Endocrinol (Oxf). 2016;86(2):247–255. doi:10.1111/
Author Contributions cen.13170
All authors made a significant contribution to the work 13. Kahaly G, Riedl M, König J, et al. Mycophenolate plus methylpredni­
solone versus methylprednisolone alone in active, moderate-to-severe
reported, whether that is in the conception, study design, Graves’ orbitopathy (MINGO): a randomised, observer-masked, multi­
execution, acquisition of data, analysis and interpretation, centre trial. Lancet Diabetes Endocrinol. 2018;6(4):287–298.
or in all these areas; took part in drafting, revising or doi:10.1016/s2213-8587(18)30020-2
14. Kelada M, Avari P, Farag S, et al. Association of other autoimmune
critically reviewing the article; gave final approval of the diseases in thyroid eye disease. Front Endocrinol. 2021;12:116.
version to be published; have agreed on the journal to doi:10.3389/fendo.2021.644200
15. Staatz C, Tett S. Clinical pharmacokinetics and pharmacodynamics of
which the article has been submitted; and agree to be mycophenolate in solid organ transplant recipients. Clin
accountable for all aspects of the work. Pharmacokinet. 2007;46(1):13–58. doi:10.2165/00003088-
200746010-00002
16. Behrend M. Adverse gastrointestinal effects of mycophenolate
Funding mofetil. Drug Saf. 2001;24(9):645–663. doi:10.2165/00002018-
No funding was received for this study. 200124090-00002
17. Riedl M, Kuhn A, Krämer I, Kolbe E, Kahaly G. Prospective,
systematically recorded mycophenolate safety data in Graves’ orbito­
pathy. J Endocrinol Invest. 2016;39(6):687–694. doi:10.1007/
Disclosure s40618-016-0441-9
The authors report no conflicts of interest for this work. 18. Aktaran Ş, Akarsu E, Erbağci İ, Araz M, Okumuş S, Kartal M.
Comparison of intravenous methylprednisolone therapy vs. oral
methylprednisolone therapy in patients with Graves’ ophthalmopathy.
References Int J Clin Pract. 2006;61(1):45–51. doi:10.1111/j.1742-
1. Perros P, Cromble A, Kendall-Taylor P. Natural history of thyroid 1241.2006.01004.x
associated ophthalmopathy. Clin Endocrinol (Oxf). 1995;42(1):45–50. 19. Marcocci C. Comparison of the effectiveness and tolerability of
doi:10.1111/j.1365-2265.1995.tb02597.x intravenous or oral glucocorticoids associated with orbital radiother­
2. Genere N, Stan M. Current and emerging treatment strategies for apy in the management of severe Graves’ ophthalmopathy: Results of
Graves’ orbitopathy. Drugs. 2019;79(2):109–124. doi:10.1007/ a Prospective, Single-Blind, Randomized Study. J Clin Endocrinol
s40265-018-1045-9 Metab. 2001;86(8):3562–3567. doi:10.1210/jc.86.8.3562

Clinical Ophthalmology 2021:15 https://doi.org/10.2147/OPTH.S305717

1931
DovePress
Quah Qin Xian et al Dovepress

20. Feeney C, Lingam R, Lee V, Rahman F, Nagendran S. Non-EPI-DWI 21. Terwee C, Gerding M, Dekker F, Prummel M, Wiersinga W.
for detection, disease monitoring, and clinical decision-making in Development of a disease specific quality of life questionnaire for
thyroid eye disease. Am J Neuroradiol. 2020;41(8):1466–1472. patients with Graves’ ophthalmopathy: the GO-QOL. Br
doi:10.3174/ajnr.a6664 J Ophthalmol. 1998;82(7):773–779. doi:10.1136/bjo.82.7.773

Clinical Ophthalmology Dovepress

Publish your work in this journal
Clinical Ophthalmology is an international, peer-reviewed journal cover­ Central and CAS, and is the official journal of The Society of
ing all subspecialties within ophthalmology. Key topics include: Clinical Ophthalmology (SCO). The manuscript management system
Optometry; Visual science; Pharmacology and drug therapy in eye dis­ is completely online and includes a very quick and fair peer-review
eases; Basic Sciences; Primary and Secondary eye care; Patient Safety system, which is all easy to use. Visit http://www.dovepress.com/
and Quality of Care Improvements. This journal is indexed on PubMed testimonials.php to read real quotes from published authors.
Submit your manuscript here: https://www.dovepress.com/clinical-ophthalmology-journal

1932 DovePress Clinical Ophthalmology 2021:15