MISS ZUZANA SIPKOVA (Orcid ID : 0000-0003-2398-4914)

Accepted Article
Article type : Original Article - UK, Europe

Title: Early use of steroid-sparing agents in the inactivation of moderate-to-severe

active thyroid eye disease; a step-down approach

Running title: Steroid-sparing agents in thyroid eye disease

Authors:

Zuzana Sipkova,1

Elizabeth A Insull,1

Joel David,2

Helen E Turner,3

Shay Keren,1

Jonathan H Norris1

1
Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust.
2
Rheumatology Department, Nuffield Orthopaedic Centre, Oxford University Hospitals NHS

Foundation Trust.
3
Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford University Hospitals

NHS Foundation Trust.

Corresponding author: Mr Jonathan H Norris; jonathan.norris@ouh.nhs.uk

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/cen.13834
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 Summary:
Accepted Article Objectives: The current first-line treatment for management of active thyroid eye disease

(TED) is high-dose intravenous corticosteroids, which have the potential for serious adverse

effects. Our aim was to evaluate the effect of steroid-sparing agents (SSAs) in patients with

moderate-to-severe active TED, using methotrexate as first-line.

Methods: Presented is a retrospective, four-year, single-centre, consecutive case series of

patients with moderate-to-severe TED treated using the Oxford protocol. Treatment

modality, disease activity and adverse effects are reported at presentation, 6- and 12-month

follow-up.

Results: 104 consecutive TED patients treated by the Oxford TED team were reviewed. 24

patients with moderate-to-severe active disease were identified (mean age 46.8 years;12

female) with a mean pre-treatment VISA inflammatory index score of 5.5/10 (SD=1.98;

range 1-9). Intra-venous methyl-prednisolone (IVMP) and an SSA was commenced in all

patients.

Mean total steroid dose was 2.72g (SD=1.4;1.0-6.9). 38% of patients (n=9) received ≤1.5g of

IVMP. Only two patients required >4.5g of IVMP equating to the EUGOGO treatment

protocol dose for this patient group. There was significant improvement in inflammatory

index score both at the intermediate review (mean score 2.7;SD=2.8;p<0.001; mean follow

up 25.2 weeks) and at one year or last follow up (mean score 1.4;SD=1.5;p<0.001; mean

follow up 48.0 weeks). No serious or long-term adverse effects were reported.

Conclusion: This study suggests that the initiation of an SSA, using methotrexate as first-

line, with limited adjuvant IVMP is an effective and safe treatment for moderate-to-severely

active TED, resulting in a significant reduction in both disease activity and total steroid load.

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 Keywords: Thyroid eye disease, methotrexate, steroid-sparing agents, methylprednisolone,
Accepted Article Graves’ orbitopathy

Conflict of interest: none

Introduction

Thyroid eye disease (TED) is the most common cause of orbital disease in adults and

causes significant morbidity in those with Graves’ disease.1 TED is an autoimmune condition

characterised by enlargement of orbital adipose tissues and extra-ocular eye muscles.

Clinical features are varied and may include a combination of proptosis, periocular soft

tissue swelling, pain, impaired extraocular motility, diplopia and visual impairment. These

features often negatively impact on psycho-social well-being.2

Management of TED is challenging and the optimal treatment regimen has yet to be

determined. Administration of glucocorticosteroids (GC) in the form of pulsed intravenous

methylprednisolone (IVMP) is the first-line recommended treatment based on the European

Group on Graves’ Orbitopathy (EUGOGO) guidelines, for patients with moderate-to-severe

active TED.3,4 This has proved the mainstay of treatment for many departments in the United

Kingdom (UK) for the last decade. However, chronic use of GC is associated with several

potential significant adverse effects, including: hypertension, infections, gastritis, diabetes,

osteoporosis, liver failure and death, and the risk of relapse of active disease following

steroid discontinuation.5,6 Numerous alternative treatments including immuno-suppressive

therapies and biologic agents have been proposed; however, the effectiveness of these

treatments is still widely debated in literature.7-10

The aim of this study was to evaluate the effect on disease activity of steroid sparing agents

(SSAs) as first-line therapy in patients with moderate-to-severely active thyroid eye disease

(TED).

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Accepted Article
Subjects and Methods

Study design and patients

We performed a retrospective consecutive audit review of medical records of 104 patients

who were treated by the Oxford multi-disciplinary thyroid eye disease (TED) team (OxTED)11

between 1st March 2013 and 31st August 2016. Patients with VISA inflammatory index score

of three or more (Table 1) were classified as having ‘active’ inflammation12,13 and were

included in the audit.

Treatment modality, disease activity and any adverse effects were reviewed at initial

presentation and at 6- and 12-month follow up after the commencement of treatment.

Treatment protocol

All patients presenting to the OxTED clinic with a VISA inflammatory index score of 3 or

more on the 10 point scale (Table 1) are routinely commenced on an SSA with adjunctive

IVMP, typically 500mg weekly for three doses (Figure 1). Methotrexate is our preferred first-

line SSA (if not contraindicated) and is initiated at the same time as IVMP infusions at a dose

of 20-25mg per week, orally or subcutaneously, along with folic acid supplementation.

Second and third-line SSAs (ciclosporin and azathioprine) are added if there is insufficient

clinical response or adverse effects or if methotrexate is contraindicated. Patients with good

response but with persistent active TED receive three further doses of IVMP over the

following three weeks.

To prevent steroid-induced gastritis, all patients are given omeprazole 20mg/day while

receiving IVMP treatment. Patients also receive bone protection with oral bisphosphonate,

alendronate and vitamin D3.

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 Evaluation before SSAs
Accepted Article
Pre-treatment investigations included blood tests (full blood count, liver and renal function

tests). Additional investigations were performed depending on the type of SSA used. Chest

X-ray was performed prior to starting treatment with methotrexate and thiopurine

methyltransferase (TPMT) enzyme activity with azathioprine. Hepatitis and HIV serology, B-

cell subsets and immunoglobulin electrophoresis is performed prior to rituximab. Full blood

count and liver function was monitored in all patients on methotrexate every two weeks for

the first three months and monthly thereafter.

Statistical analysis

The data was analysed using Microsoft Excel 2013 (Microsoft Corporation, Redmond, WA,

USA). Student’s t-test was used to compare pre- and post-treatment VISA inflammatory

index scores. Values of p<0.05 were considered to be statistically significant.

Results

104 cases of TED were reviewed and 24 patients (12 males, 12 females; mean age 46.8

years (range: 23-84 years)) were included in the audit. The baseline patient characteristics

are summarised in Table 2. All 24 patients received IVMP with mean cumulative dose of

2.72g (range: 1.0g-6.9g). 38% of patients (n=9) received 1.5g IVMP or less. Only two

patients required more than 4.5g of IVMP equating to the EUGOGO treatment protocol dose

for this patient group (Figure 2).4 The average number of doses was seven (range 3-18 total

doses). No patients received oral corticosteroids.

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 MTX was given either orally or subcutaneously in 23 (96%) patients as first-line SSA. One
Accepted Article patient received azathioprine due to chronic lung disease findings on chest X-ray (Figure 1).

Twenty patients started on 20mg weekly oral dose, four of whom were later increased to a

25mg weekly subcutaneous dose. The subcutaneous route of administration reduces

gastro-toxicity symptoms in some patients. Four patients received 25mg weekly

subcutaneous doses first-line. The average MTX treatment course was 13 months (range:

2-27 months). Eleven patients (42%) received a second SSA, ciclosporin in most cases

(Figure 1). A third agent, in addition to methotrexate and ciclosporin, was required in three

patients: Rituximab in two cases and Azathioprine in one. Methotrexate was continued in all

cases.

The mean pre-treatment VISA inflammatory index score was 5.5 out of 10 (range: 1-9)

(Figure 3). There was significant improvement in this score both at the intermediate review

(mean score 2.7; SD=2.8; p<0.001; mean follow up 25.2 weeks) and at last follow-up (mean

score 1.4; SD=1.5; p<0.001; mean follow up 48.0 weeks).

Four patients did not show adequate clinical improvement despite high dose IVMP and two

or more SSAs and required orbital decompression due to signs of dysthyroid optic

neuropathy. This included one patient who could not have MTX due to chronic lung disease

and second patient who stopped MTX after 3 months due to chronic cough.

No serious or long-term adverse effects were reported. Three (13%) patients stopped

methotrexate due to: deranged liver function tests, chronic cough or recurrent cystitis

(Figure 4), all of which resolved on cessation of the methotrexate. None of the patients

developed leucopenia.

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 Discussion
Accepted Article
Presented is a retrospective audit of the clinical outcomes of 24 consecutive patients with

moderate-to-severe active thyroid eye disease (TED) treated with steroid-sparing agents

(SSAs) as first-line therapy. Adjuvant intravenous methylprednisolone (IVMP) was

commenced simultaneously as bridge therapy due to slower onset of action of methotrexate

and other SSAs. Overall, our results illustrate a substantial reduction in total IVMP dose

required compared to standard dose recommended by EUGOGO4 (Figure 2) alongside a

significant improvement in the clinical activity of the disease based on VISA inflammatory

index score throughout follow-up (Figure 3). Using our treatment protocol, patients also

needed almost 50% fewer visits for intravenous therapy.

A large number of immunosuppressive therapies have been studied to minimise the

autoimmune inflammatory phase of the natural course of TED, but no consensus regarding

the optimal treatment has been reached.3 Since the 1950s, glucocorticoids (GC) have been

the most common immuno-suppressants used in treatment of active moderate-to-severe

TED. Several randomised-controlled trials and meta-analyses have proven their beneficial

effect with reported response rate of approximately 80% for intravenous GC and 50% with

oral GC.6 As a result, EUGOGO recommends intravenous methylprednisolone (IVMP) as

first-line treatment for moderate-to-severe active TED with starting dose of 0.5g once weekly

for 6 weeks followed by 0.25g once weekly for 6 weeks and optimal cumulative dose of 4.5-

5.0g.3,4 Although effective, the use of GC has numerous associated side effects, including

hypertension, infections, gastritis, diabetes, osteoporosis and psychosis.14 Acute liver

damage has been reported in approximately 1% of patients treated with IV GC, resulting in

fatal liver failure in a few cases.15,16

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 Several alternative pharmacological steroid-sparing immuno-suppressive agents, including
Accepted Article methotrexate (MTX),5,14,17 ciclosporin,7 and azathioprine8 have been studied.8 More recently,

rituximab has been shown to be effective at suppressing inflammation in TED and can be

considered a second-line therapeutic option in moderate-to-severe active TED.4,9,10,18

In the Oxford multi-disciplinary TED (OxTED) clinic we use a ‘step-down’ approach in

treatment of moderate-to-severe active TED, starting intensive combination therapy of an

SSA and IVMP in the early stages of disease and then tapering down once appropriate

clinical response is achieved. The aim is to modify natural disease progression early, thus

limiting its severity and reducing the requirement for rehabilitative surgery once inactive.

This type of regimen has been well studied in early management of rheumatoid arthritis. It

showed increased effectiveness without increase in adverse effects in comparison to the

step-up approach.19,20

We use methotrexate (MTX) as first-line SSA. It has been widely used as the preferred

treatment in several autoimmune conditions requiring long-term immunosuppression, such

as rheumatoid arthritis. It has anti-inflammatory and immunomodulatory properties when

administered at lower doses. By inhibiting dihydrofolate reductase enzyme, MTX leads to

enhanced extracellular release of adenosine, thus decreasing the production of inflammatory

cytokines.21 Its clinical usefulness has been previously demonstrated in treatment of non-

infectious orbital inflammatory disease in patients failing to respond to systemic GCs.14

A small number of retrospective studies have been published showing encouraging results

of MTX use as second-line TED treatment.5,14,17 Strianese et al. observed improvement in

extraocular motility and significant reduction in clinical activity scores (CAS) in 36 patients

with TED who had to stop GC due to side effects.5 A recent study by Rivera-Grana et al. of

14 TED patients with previous history of GC dependence found 64% of patients were able to

discontinue GCs completely while on MTX treatment without re-activation of TED. Similar to

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 our approach, higher doses of MTX were given with an average of 15mg/week orally and
Accepted Article 20mg/week subcutaneously.17

In patients with insufficient response to MTX alone, our practice is to add ciclosporin with or

without azathioprine. Ciclosporin has been shown to result in greater reduction in TED

activity score compared to oral GC alone and lower relapse rate after discontinuation of

steroid therapy.7 Despite a reduction in thyroid-associated antibodies in patients on

azathioprine, no difference in clinical findings was found compared to a control group.8

The comparable response rate for different disease-modifying agents in treatment of active

TED suggests that these are only effective if commenced early in the disease course. This

emphasises the importance of EUGOGO recommendations of early referral and treatment in

multi-disciplinary TED clinics.3,4

Overall, we found the use of SSAs was associated with good safety and tolerability. No

serious adverse effects were reported with any of the SSAs we used. A small number of

patients taking MTX noted mild, predominantly gastro-intestinal, side-effects such as

nausea. These improved on switching from oral to subcutaneous MTX and by administering

folic acid on a daily basis instead of weekly. One patient’s blood tests showed deranged

liver function, which normalised spontaneously after stopping MTX.

The limitations of this study arise from the retrospective nature of data collection which relies

on the quality of clinical records. Our sample size was moderate and the study was single-

centre. In addition to clinical markers of disease activity, it would have been useful to study

the serum TSH receptor antibody (TRAb) levels which have been reported to correlate well

with the clinical course of Graves’ disease.9 Although now routinely performed for all patients

seen in OxTED clinic, data on pre- and post-treatment TRAb levels was only available for a

small proportion of patients included in this study (Table 2).

We report on the effect of SSAs on disease activity as assessed by the VISA inflammatory

index score. Unfortunately, the retrospective nature of this study did not permit evaluation of

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 the treatment effect on the overall VISA severity score, which is a major limitation of our
Accepted Article study. Further evaluation of the treatment effect on the global VISA score, including ‘vision’,

‘strabismus’ and ‘appearance’ grading would be useful.

We recognise that the natural course of TED is improvement over time and further

prospective double-blinded controlled trials with larger sample size are needed to confirm

long-term MTX efficacy and safety in treatment of active moderate-to-severe TED.

Conclusion

Thyroid eye disease (TED) is an autoimmune disorder, although its pathogenesis is not

completely understood which is reflected in the relatively limited therapeutic options. Our

findings suggest that MTX is a well-tolerated, safe and effective first-line SSA for moderate-

to-severe active TED treatment, significantly reducing the total corticosteroid dose required.

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on management of GO. Eur J Endocrinol. 2008;158:273–285.

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 4. Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly GJ, Marcocci C et al. The
Accepted Article 2016 European Thyroid Association/European Group on Graves’ Orbitopathy

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 10. Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS.
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 17. Rivera-Grana E, Lin P, Suhler EB, Rosenbaum JT. Methotrexate as a corticosteroid-
Accepted Article sparing agent for thyroid eye disease. J Clin Exp Ophthalmol. 2015;6:422.

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 Figure and Table legends:
Accepted Article
Figure 1:

Flow chart of immunosuppressant agents received by patients

Figure 2:

Total intravenous methylprednisolone (IVMP) dose received by individual patients

Figure 3:

Mean VISA inflammatory index score at presentation, 6- and 12-month follow up. Error bars

represent 95% confidence intervals. Asterisks (*) represent statistically significant

improvement in VISA score compared to score at presentation, p<0.001.

Figure 4:

Adverse effects in patients taking methotrexate.

Table 1:

VISA inflammatory index score12,13

Table 2:

Summary of baseline patient characteristics

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 Table 1: VISA inflammatory index score12,13

Inflammatory index sign Score per worst

Accepted Article
eye/eyelid

Caruncular oedema 0-1

Chemosis 0-2

Conjunctival redness 0-1

Lid oedema 0-2

Retrobulbar ache 0-2

Diurnal variation 0-1

Total (10 maximum) 0-10

Table 2: Summary of baseline patient characteristics

Patient characteristic
Age Mean 46.8 years
Range 23-84 years
Male 12
Female 12
Smokers 9 (38%)
Thyroid status
Hyperthyroid 18 (75%)
Euthyroid 5 (21%)
Hypothyroid 1 (4%)

Duration of thyroid disease Mean 43.8 months

Duration of thyroid eye
disease
Pre-treatment TRAb level
(available in 13 patients)
*One patient included in the study had reactivation of thyroid eye disease, originally
diagnosed 36 years previously.
Median 13.5 months
Range 1 month – 36 years*
Mean 37 months
Median 12 months
Range 1 month – 36 years*
7.3 IU/L
Range 2.8 - >30 IU/L
(reference range 0-0.4 IU/L)

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Accepted Article
Accepted Article