Role of methotrexate in thyroid-related orbitopathy

Avi Rubinov, MD,* Hila Zommer, MD,† Helya Aghazadeh, MD,† Ezekiel Weis, MD, MPH*,†
ABSTRACT ● RÉSUMÉ
Objective: To report the experience of a tertiary care orbital service in treating severe active thyroid related orbitopathy with
methotrexate (MTX) managed by the Ophthalmologist.
Design: Retrospective consecutive case series.
Participants: Nineteen consecutive patients (5 males and 14 females) with severe active thyroid related orbitopathy.
Methods: Severe active thyroid orbitopathy patients with partial or no response to intravenous glucocorticoids were treated with
MTX and observed for inflammatory scale reduction and treatment complications.
Results: Nineteen consecutive patients (5 males and 14 females) with severe active thyroid related orbitopathy were evaluated.
Mean follow-up time was 1206 days (standard deviation (SD) 576). Months passed from beginning of TRO symptoms to initiation
of MTX therapy showed a mean of 12 (SD 9). After the initiation of MTX 91% of eyes demonstrated a clinically significant
improvement to a VISA inflammatory scale of o3 within a mean of 189 days (SD 119); A subset of patients (29%) demonstrated a
rapid response, reaching a VISA inflammatory score of o3 within 90 days. One patient (5%) discontinued the medication
secondary to an adverse event (elevated liver enzymes) which normalized after discontinuation of MTX. During the follow up
period 12 patients (63%) have ended their MTX treatment due to TRO inactivity; One patient (8%) developed a recurrence of
inflammation after discontinuing MTX which resolved with the re-initiation of MTX treatment. Adjunctive treatments including
glucocorticoids and/or external beam radiotherapy were administered to 21% of patients.
Conclusion: Our experience suggests that methotrexate managed by an Ophthalmologist is a safe and effective treatment for
severe active thyroid related orbitopathy.

Objet : Présenter les résultats de l’administration du méthotrexate (MTX) dans le traitement de l’orbitopathie dysthyroïdienne (OD)
sévère et active prise en charge par l’ophtalmologiste d’un centre de soins tertiaires.
Nature : Étude rétrospective d’une série de cas consécutifs.
Participants : Dix-neuf patients consécutifs (5 hommes et 14 femmes) présentant une OD sévère et active.
Méthodes : Des patients atteints d’une OD sévère et active chez qui l’administration de glucocorticoïdes intraveineux avait eu un
effet partiel ou nul ont reçu le MTX et ont fait l’objet d’une surveillance de l’inflammation et des complications du traitement.
Résultats : Dix-neuf patients consécutifs (5 hommes et 14 femmes) présentant une OD sévère et active ont été évalués. Le suivi
moyen était de 1206 jours (écart-type [é.-t.] : 576). Le délai moyen entre l’apparition des symptômes d’OD et le traitement par le
MTX était de 12 mois (é.-t. : 9). Après la mise en route du traitement par le MTX, 91 % des yeux ont manifesté une amélioration
cliniquement significative se traduisant par un score o 3 à l’échelle VISA, dans un délai moyen de 189 jours (é.-t. : 119). Un sous-
groupe de patients (29 %) ont eu une réponse rapide et obtenu un score o 3 à l’échelle VISA en l’espace de 90 jours. Un patient
(5 %) a abandonné le traitement en raison d’un effet indésirable (élévation du taux des enzymes hépatiques) qui a disparu après
l’arrêt de l’administration du MTX. Au cours du suivi, 12 patients (63 %) ont mis fin à leur traitement par le MTX en raison d’une
inactivité de l’OD. Il s’est produit un cas (8 %) de récurrence de l’inflammation après l’arrêt de l’administration du MTX, laquelle a
disparu à la reprise du traitement par le MTX. Parmi les traitements d’appoint, citons les glucocorticoïdes et/ou la radiothérapie
externe, qui ont été administrés à 21 % des patients.
Conclusion : Selon notre expérience, l’administration du méthotrexate par un ophtalmologiste est une option thérapeutique sûre et
efficace de l’orbitopathie dysthyroïdienne sévère et active.

Thyroid-related orbitopathy (TRO) is a multifactorial auto-
immune disease affecting the ocular tissues in 40% of
patients with autoimmune hyperthyroidism.1 TRO has an
incidence of 16 female and 3 male cases per 100 000 person-
years,2 with an approximate prevalence of 0.25% and no
significant ethnic predilection.3 The autoimmune orbital
disease is believed to be initiated by the activation of
inflammatory cells in the orbit, activating a cascade that
results in the deposition of glycosaminoglycans and the
development of secondary edema.4 Enlargement of the
extraocular muscles in this phase, particularly the medial
rectus, can put the patient at risk of developing dysthyroid
optic neuropathy.5,6 Subsequently, the disease progresses into
an inactive/noninflammatory phase characterized by fibrosis
and adipogenesis.7–9 Patients with TRO may experience
edema, eyelid retraction, ocular surface irritation, diplopia,
cosmetic disfigurement, and irreversible visual loss due to
permanent corneal changes and dysthyroid optic neuropathy.
Current treatments for the inflammatory/active phase of
TRO include immunosuppressive therapy with glucocor-
ticoids, steroid-sparing agents, and radiation therapy.
Glucocorticoids currently are the first-line treatment in
most centres. In a meta-analysis of 25 articles performed
by Bartalena et al. “favorable effects” with the use of
glucocorticoids were noted in a majority of, but not all,
patients (63%–77%).10,11 In addition to an incomplete
response rate, many concerns remain about the use of
glucocorticoids due to potential serious adverse events and

& 2018 Published by Elsevier Inc on behalf of the

Canadian Ophthalmological Society.
http://dx.doi.org/10.1016/j.jcjo.2017.07.009
ISSN 0008-4182/18

34 CAN J OPHTHALMOL — VOL. 53, NO. 1, FEBRUARY 2018

 Methotrexate in thyroid-related orbitopathy—Rubinov et al.

the need for long term dosing due to prolonged disease factors for worsening TRO, including older age, male
activity and significant recurrence rates after discontinua- sex, smoking, or a rapid onset of orbitopathy19
tion.11,12 Both intravenous and oral glucocorticoid treat-
ments carry a significant risk for the development of Because of the expected delay in the onset of action of
adverse events over time. Kahaly et al. have reported MTX, all of our patients received another cycle of intra-
adverse events in 51% of patients receiving oral glucoste- venous steroids at the time of initiating MTX, unless they
roids and in 17% receiving intravenous glucocorticoids were currently taking oral steroids prescribed by the
after 12 weeks of treatment.13 Recurrence of TRO is referring physician. If they were on long-term oral steroids,
common after withdrawal of glucocorticoid treatment, and these were tapered over approximately 6 weeks. Partic-
often several cycles of therapy are needed to achieve ipants with contraindications to MTX, those under
adequate control over the disease process. In recent years, 18 years of age, women interested in conceiving, and
the search for newer drugs with better safety profiles and those who received MTX for non-TRO orbital inflamma-
long-term treatment tolerability has shown promising tory diseases were excluded.
results with several agents.14–16 The main outcome parameter of this study was the
Methotrexate (MTX) is an antimetabolite that inhibits decrease in the VISA inflammatory score to o3 during
folic acid synthesis, which is required for DNA manu- MTX treatment. This was selected as the main outcome
facturing and cell growth. MTX effects include reduction because congestion is a significant issue in patients with
in cell proliferation, T-cell apoptosis, altering cytokine severe TRO in the noninflammatory phase, making the
production, and humoral responses.17 In high doses,
MTX is used as a chemotherapeutic agent for different Table 1—Patient data showing different parameters surveyed
forms of cancer; in lower doses, it is used for long-term during the study
treatment of several autoimmune diseases, such as rheu- Maximal Days from
matoid arthritis, inflammatory bowel disease, and Wege- Patient OD/ Age, VISA Score Dose of Start until
No. OS years Pretreatment MTX, mg VISA o3 Comments
ner’s granulomatosis.15
1 OD 73 5 15 224 ❻
Published data on the use of MTX for treating orbital OS 5 224 ❻
inflammation in the setting of TRO are limited to 2 case 2 OD 47 6 10 423 ❷
OS 6 423 ❷
series, which described a total of 39 cases of TRO.15,16 3 OD 85 0 20 —
The purpose of this study is to report our experience with OS 6 231
treating severe active TRO with MTX prescribed and 4 OD 67 7 22.5 434
OS 4 105
managed by an ophthalmologist. 5 OD 62 5 17.5 — ❸
OS 4 67 ❶
6 OD 66 6 17.5 105
OS 6 105
MATERIALS AND METHODS 7 OD 60 4 20 78 ❶❷❹❺
OS 4 78 ❶❷❹❺
This is a retrospective consecutive case series of 8 OD 71 5 22.5 266 ❹
19 patients (5 males and 14 females) with severe active OS 5 266 ❹
TRO treated between 2009 and 2016. The study was 9 OD 50 3 22.5 364
OS 3 364
approved by the Health Research Ethics Board of Alberta. 10 OD 71 3 17.5 182
Disease activity/inflammation and progression were OS 3 182
— ❹
assessed using the VISA inflammatory score.18 The 11 OD
OS
54 1
5
20
189 ❹
inflammatory score calculation was performed by a single 12 OD 66 4 15 42 ❶
ophthalmologist (E.W.) during the physical examination. OS 6 42 ❶
13 OD 72 3 15 70 ❶
This report includes a consecutive case series of all OS 3 70 ❶
patients with TRO treated with MTX in our orbital service 14 OD 47 4 15 88 ❶
OS 4 88 ❶
between 2009 and 2016. All patients with severe active 15 OD 66 0 20 —
orbitopathy were first treated with at least one cycle of OS 5 144
intravenous solumedrol (1 g every 48 hours for 3 doses). In 16 OD 51 6 20 — ❸
OS 6 — ❸
cases of minimal, temporary, or no response to intravenous 17 OD 43 0 17.5 —
solumedrol, MTX treatment was offered in 3 settings: OS 3 68 ❶
18 OD 68 4 17.5 230
OS 4 230
1. Very active cases of active TRO, with at least one eye 19 OD 53 3 15 242 ❺
scoring ≥5 on the VISA inflammatory scale OS 3 242 ❺
2. Cases of active TRO with at least one eye ≥3 on the VISA ❶ VISA score went down to zero after less than 90 days.
❷
(VISA classification system) inflammatory scale and dys- IV steroids while on methotrexate (MTX).
❸ Decompression while on MTX because of dysthyroid optic neuropathy.
thyroid optic neuropathy ❹ External beam radiotherapy during MTX treatment.
3. Cases of active TRO with at least one eye ≥3 on the ❺ Elevated liver function tests.
❻ Reactivation after MTX withdrawal.
VISA inflammatory scale with at least 2 out of 4 risk

CAN J OPHTHALMOL — VOL. 53, NO. 1, FEBRUARY 2018 35

Methotrexate in thyroid-related orbitopathy—Rubinov et al.
Adjuvant an-inflammatory modalies used
during Methotrexate treatment
5%
5%
No modalies, N=15
11%
External beam radiotherapy, N=2
IV steroids, N=1
External beam radiotherapy+IV
steroids, N=1
79%
N= Number of paents
Fig. 1 — Percentage of concomitant anti-inflammatory modal-
ities used during methotrexate treatment.
assessment of changes in the inflammatory scale in the
range of 1–2 less valid. Tolerance of MTX, adverse events
related to its use, and other modalities used to control
inflammation during treatment were also recorded.
Pretreatment laboratory investigations included a com-
plete blood count; liver function tests (including alanine
aminotransferase, aspartate aminotransferase, alkaline
phosphatase, and bilirubin); kidney function tests (includ-
ing creatinine and urea); serum electrolytes comprising
potassium; and erythrocyte sedimentation rate, hepatitis B
and C serology, and hepatitis B immune status. Pretreat-
ment imaging included a chest x-ray.
After screening, patients were started on MTX using a
fixed protocol. Patients received 10 mg oral tablets once a
week for 4 weeks, followed by 15 mg once a week. Five
milligrams of folic acid was given daily, except for the day
of MTX administration. Adjustments in dosing were made
based on changes in the inflammatory VISA score and side
effects 3 months after starting the treatment. Patients were
given a standing order for monthly follow-up laboratory
examinations, which comprised a complete blood count,
liver function tests, kidney function tests, serum electro-
lytes, and erythrocyte sedimentation rate.
RESULTS
This study included 19 patients with TRO (Table 1)
with a mean age of 61.6 years (SD 11.1), and a 73%
female ratio (14 women). Twelve patients showed sym-
metric disease, 4 patients had bilateral asymmetric TRO,
and 3 patients had unilateral inflammatory disease with a
VISA inflammatory score of zero in one eye. The maximal
MTX dose given was 22.5 mg weekly, with the mean
being 17.8 mg (SD 3.2). The mean follow-up time was
1206 days (SD 576). Duration of TRO before beginning
MTX treatment was a mean of 12 months (SD 8).
Thirty-four eyes had a VISA score ≥3 on the start date
of MTX treatment. The inflammatory scale dropped to
o3 in 31 of these eyes (91%) within a mean follow-up
time of 189 days (SD 119). Twenty-nine percent of
36 CAN J OPHTHALMOL — VOL. 53, NO. 1, FEBRUARY 2018
patients (6 patients, 10 eyes) showed a rapid response to
treatment, reaching a VISA score o3 in less than 90 days.
Two of our patients (10%) had elevated results of liver
function tests while on MTX therapy. One of them
discontinued treatment, and the other patient’s treatment
dose was lowered. These measures led to normalized liver
function tests in both patients; therefore, MTX was
discontinued because of mild temporary adverse events
in 5% of our patients. Two of our patients (10%) required
decompression surgery because of the development of
dysthyroid optic neuropathy while on MTX therapy.
Adjunctive anti-inflammatory modalities were used in
4 patients (21%) while on MTX therapy. Out-of-protocol
pulse intravenous steroids were administered in 1 patient
and external beam radiotherapy in 2 patients; 1 patient
received both modalities (Fig. 1).
During the follow-up period, 12 patients (63%) ended
MTX treatment because of inactivity and stability of their
TRO. One of these patients (8%) showed signs of
reactivation after withdrawing MTX treatment. After
restarting MTX, the patient’s TRO became inactive; the
patient later successfully discontinued MTX without signs
of TRO reactivation.
DISCUSSION
TRO passes through different stages, with the first
being the active inflammatory stage, showing continuous
worsening of symptoms and inflammation. Stages of
steady improvement in the inflammatory signs and
symptoms follow until, ultimately, no further changes
occur, and the TRO is regarded as stable and inactive.4
Immunomodulatory therapy is used during the active
phase of TRO to lower the inflammation and symptoma-
tology and to decrease the occurrence of severe
complications.
In contrast to prior research that has demonstrated a
63%–77% partial response rate to glucorticoids,10 our
Response to treatmant with Methotrexate
9%
VISA inflammatory score lowered
to less than 3, N=31
Decompression due to severe
inflammaon and compressive
opc neuropathy, N=3
N=Number of eyes
91%
Fig. 2 — The effect of methotrexate on lowering inflammation
in active thyroid-related eye disease. Percentage of conco-
mitant anti-inflammatory modalities used during methotrex-
ate treatment.
 Methotrexate in thyroid-related orbitopathy—Rubinov et al.
current data show that 91% of eyes that showed a VISA
inflammatory score ≥3 (31 out of 34 eyes) demonstrated a
reduction in score to o3 during treatment with MTX
(Fig. 2). The reduction in VISA inflammatory score with
MTX occurred within a mean of approximately 6 months
(mean of 189 days [SD 119]). A subgroup of 6 patients
(10 eyes, 29%) showed a rapid response to treatment and
reached a VISA inflammatory score o3 in less than
3 months (90 days). Similar to our results, Strianese
et al. demonstrated a response rate of 94% in reducing
the Clinical Activity Score20 to o3 utilizing MTX in 36
patients with active TRO over 1 year.15
Long-term use of glucocorticoids can lead to complica-
tions such as hypertension, Cushing syndrome, diabetes,
osteoporosis, and, in rare cases, acute hepatitis.21,22 The
percentage of adverse events is considerably higher with
the use of oral (51%) and intravenous (17%) glucocorti-
coids after 12 weeks of treatment.13 A longer-term study
assessing oral glucocorticoids for a 20-week course of
100 mg/day in a group of 19 patients with active TRO
demonstrated side effects in 84% and major complications
in 11%, including severe hypertension and psychic dis-
orders.23 In contrast, elevated liver enzymes, fatigue, and
nausea have been reported to be the most common side
effects with MTX, usually occurring within 3 months of
treatment.24–26 Several of our patients did report minor
gastrointestinal upset, but only 5% (1 patient) needed to
discontinue the medication because of hepatic toxicity,
which normalized after discontinuation. No major com-
plications were noted. The excellent safety profile of MTX
prescribed and managed by an ophthalmologist (the
primary treating physician) theoretically reduces delays in
the initiation of MTX and dose adjustments, eliminates
issues and risks related to communication failures between
different practitioners, and reduces costs to the medical
system. Strianese et al. also reported minimal side effects
or complications with MTX, with no reported side effects
after 1 year of continuous treatment with MTX in patients
with active TRO.15
In addition, a temporary response to glucocorticoids
is frequently seen.11,12 Bartalena et al. showed that
after administering intravenous glucocorticoids in differ-
ent doses for 12 weeks, 21%–40% of their patients with
active TRO showed signs of relapsing orbitopathy
12 weeks after ending glucocorticoid treatment.27
Because of the prolonged course of the disease, there is
a need for a drug with a better safety profile to allow long-
term use—especially in severe cases. In our study, 12
patients (63%) completed MTX treatment after reaching
disease stability and inactivity within the follow-up period
assessed in this study, but one of these patients (8%)
developed reactivation of TRO after discontinuing
approximately 1 year of MTX therapy. After reinstitution
of MTX, the disease became inactive; after 2 years, MTX
was discontinued, and the patient reached a stable
inactive state.
CAN J OPHTHALMOL — VOL. 53, NO. 1, FEBRUARY 2018
The primary weakness of this study is the lack of a
control group to account for the natural history of the
disease. Yet, careful evaluation of natural history data does
provide some information on historical controls. Data on
the natural history of TRO measured by modern activity
scores are scarce,28,29 with data collected predominantly
on patients with mild to moderate TRO because observing
patients with severe disease is not thought to be safe or
ethical by most clinicians. The activity period of TRO is
usually referenced in the literature from Rundle’s curve,
stating that the active phase of TRO lasts between 0.5 and
1.5 years.30 Previous natural history reports30–32 did not
describe the full extent of disease activity and typically
reported serial measurements of isolated features of TRO
before the development of standardized activity scores.
With the advent of activity scores, it is now well
recognized that although TRO does show this biphasic
behaviour, the time axis of Rundle’s curve shows marked
individual variation and can take from a few months to
more than 5 years in the more severe cases to reach an
inactive phase.15 Perros et al. reviewed the natural history
of TRO patients.28,29 They found that 64% of patients
improved over time without treatment, and the vast
majority of those who improved showed signs of improve-
ment at 2 months. They also demonstrated that a small
proportion (14%) of patients with severe TRO do not
improve over time but rather continue to progress (mean
follow-up 12 months) and thus require immunosuppres-
sive treatment to enter the nonprogressive inactive phase.
Our patient cohort represented a progressive and active set
of patients with a mean length of TRO symptoms of 12
months at the time of initiating MTX. Furthermore, they
presented with severe levels of activity based on the
inflammatory scale. It is therefore unlikely that our cohort
was similar to the subset of patients who showed signs of
improvement at 2 months and continued to improve
spontaneously; instead, our patients likely represent
the severely progressive group that did not transition
to the inactive phase without immunosuppression
treatment.28,29
The strengths of this study are its assessment of MTX in
a group of patients who had failed IV steroids and had
severe inflammation scores and/or multiple risk factors for
progression. These patients are well recognized by experi-
enced ophthalmologists and in the literature as being very
difficult to treat.19 The weaknesses of this study include
the absence of a control group that did not take MTX and
the use of neoadjuvant and adjuvant treatments that were
given to many patients, typically before being referred to
our tertiary care orbit clinic. These limitations prevent
us from presenting the independent effect of
MTX. However, this study is still valid and is externally
valid in describing the outcomes of this cohort of
patients who were prescribed MTX in the real-world
setting of complicated patients referred to a tertiary orbit
service.
37
Methotrexate in thyroid-related orbitopathy—Rubinov et al.
CONCLUSIONS
In this cohort of patients with severe active TRO who
were prescribed MTX by their treating ophthalmologist,
29% experienced a rapid reduction of their inflammatory
score to o3 within 90 days; 91% achieved an inflamma-
tory score o3 within a mean of 189 days (SD 119); and
only 5% experienced side effects requiring discontinuation
of the medication (with a return to normal liver function).
No major side effects were noted. Our experience suggests
that MTX, prescribed by an ophthalmologist, is a safe
steroid-sparing agent for long-term use in the treatment of
TRO-associated inflammation. Because of confounding
factors inherent to a case series that includes neoadjuvant
and adjuvant treatments other than MTX, a controlled
study evaluating the efficacy of MTX is needed to further
validate its independent value.
REFERENCES
1. Burch HB, Wartofsky L. Graves’ ophthalmopathy: current concepts
regarding pathogenesis and management. Endocr Rev. 1993;14:
747-93.
2. Bartley GB, Fatourechi V, Kadrmas EF, et al. The incidence of
Graves’ ophthalmopathy in Olmsted County, Minnesota. Am J
Ophthalmol. 1995;120:511-7.
3. Lazarus JH. Epidemiology of Graves’ orbitopathy (GO) and
relationship with thyroid disease. Best Pract Res Clin Endocrinol
Metab. 2012;26:273-9.
4. Maheshwari R, Weis E. Thyroid associated orbitopathy. Indian J
Ophthalmol. 2012;60:87.
5. Weis E, Heran MKS, Jhamb A, et al. Quantitative computed
tomographic predictors of compressive optic neuropathy in patients
with thyroid orbitopathy: a volumetric analysis. Ophthalmology.
2012;119:2174-8.
6. Weis E, Heran MKS, Jhamb A, et al. Clinical and soft-tissue
computed tomographic predictors of dysthyroid optic neuropathy:
refinement of the constellation of findings at presentation. Arch
Ophthalmol (Chicago, Ill 1960). 2011;129:1332-6.
7. Feldon SE, Lee CP, Muramatsu SK, Weiner JM. Quantitative
computed tomography of Graves’ ophthalmopathy. Extraocular
muscle and orbital fat in development of optic neuropathy. Arch
Ophthalmol (Chicago, Ill 1960). 1985;103:213-5.
8. Nunery WR, Nunery CW, Martin RT, Truong TV, Osborn DR.
The risk of diplopia following orbital floor and medial wall
decompression in subtypes of ophthalmic Graves’ disease. Ophthal
Plast Reconstr Surg. 1997;13:153-60.
9. Smith TJ, Hoa N. Immunoglobulins from patients with graves’
disease induce hyaluronan synthesis in their orbital fibroblasts
through the self-antigen, insulin-like growth factor-I receptor. J Clin
Endocrinol Metab. 2004;89:5076-80.
10. Bartalena L, Pinchera A, Marcocci C. Management of Graves’
ophthalmopathy: reality and perspectives 1. Endocr Rev. 2000;21:
168-99.
11. Bartalena L, Marcocci C, Tanda L, Pinchera A. Management of
thyroid eye disease. Eur J Nucl Med Mol Imaging. 2002;29(Suppl 2):
S458-S465.
12. Krassas GE, Heufelder AE. Immunosuppressive therapy in patients
with thyroid eye disease: an overview of current concepts. Eur J
Endocrinol. 2001;144:311-8.
13. Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single
blind trial of intravenous versus oral steroid monotherapy in graves’
orbitopathy. J Clin Endocrinol Metab. 2005;90:5234-40.
14. Minakaran N, Ezra DG. Rituximab for thyroid-associated oph-
thalmopathy. Cochrane Database Syst Rev 2013:5: CD009226.
15. Strianese D, Iuliano A, Ferrara M, et al. Methotrexate for the
treatment of thyroid eye disease. J Ophthalmol. 2014;2014:128903.
38 CAN J OPHTHALMOL — VOL. 53, NO. 1, FEBRUARY 2018
16. Smith JR, Rosenbaum JT. A role for methotrexate in the manage-
ment of non-infectious orbital inflammatory disease. Br J Ophthal-
mol. 2001;85:1220-4.
17. Wessels JAM, Huizinga TWJ, Guchelaar H-J. Recent insights in the
pharmacological actions of methotrexate in the treatment of
rheumatoid arthritis. Rheumatology (Oxford). 2008;47:249-55.
18. Dolman PJ, Rootman J. VISA classification for Graves orbitopathy.
Ophthal Plast Reconstr Surg. 2006;22:319-24.
19. Dolman P, Rootman J. Predictors of disease severity in thyroid-
related orbitopathy (chapter 18). In: Orbital disease. Present status
and future challenges. 2005, CRC press, Taylor and Francis group,
Boca Raton, FL, pages 203-209.
20. Mourits M, Prummel M, Wiersinga W, Koornneef L. Clinical
activity score as a guide in the management of patients with Graves’
ophthalmopathy. Clin Endocrinol. 1997;47:9-14.
21. Le Moli R, Baldeschi L, Saeed P, Regensburg N, Mourits MP,
Wiersinga WM. Determinants of liver damage associated with
intravenous methylprednisolone pulse therapy in Graves’ ophthalm-
opathy. Thyroid. 2007;17:357-62.
22. Bartalena L, Marcocci C, Tanda ML, et al. An update on medical
management of Graves’ ophthalmopathy. J Endocrinol Invest.
2005;28:469-78.
23. Kahaly G, Pitz S, Muller-Forell W, Hommel G. Randomized trial of
intravenous immunoglobulins versus prednisolone in Graves’ oph-
thalmopathy. Clin Exp Immunol. 1996;106:197-202.
24. Kaplan-Messas A, Barkana Y, Avni I, Neumann R. Methotrexate as
a first-line corticosteroid-sparing therapy in a cohort of uveitis and
scleritis. Ocul Immunol Inflamm. 2003;11:131-9.
25. van Ede AE, Laan RF, Blom HJ, De Abreu RA, van de Putte LB.
Methotrexate in rheumatoid arthritis: an update with focus on
mechanisms involved in toxicity. Semin Arthritis Rheum. 1998;27:
277-92.
26. Samson CM, Waheed N, Baltatzis S, Foster CS. Methotrexate
therapy for chronic noninfectious uveitis: analysis of a case series of
160 patients. Ophthalmology. 2001;108:1134-9.
27. Bartalena L, Krassas GE, Wiersinga W, et al. Efficacy and safety of
three different cumulative doses of intravenous methylprednisolone
for moderate to severe and active Graves’ orbitopathy. J Clin
Endocrinol Metab. 2012;97:4454-63.
28. Perros P, Cromble AL, Kendall-taylor P. Natural history of thyroid
associated ophthalmopathy. Clin Endocrinol. 1995;42:45-50.
29. Perros P, Kendall-Taylor P. Natural history of thyroid eye disease.
Thyroid. 1998;8:423-5.
30. Hales IB, Rundle FF. Ocular changes in Graves’ disease. Q J Med.
1960;29:113-26.
31. Hamilton HE, Schultz RO, de Gowin EL, et al. The endocrine
eye lesion in hyperthyroidism. AMA Arch Intern Med. 1960;
105:675.
32. Streeten DHP, Anderson GH, Reed GF, Woo P. Prevalence, natural
history and surgical treatment of exophthalmos. Clin Endocrinol
(Oxf). 1987;27:125-33.
Footnotes and Disclosure:
The authors have no proprietary or commercial interest in any
materials discussed in this article.
From the *Division of Ophthalmology, Department of Surgery,
Faculty of Medicine, University of Calgary, Calgary, Alta;
†Department of Ophthalmology, Faculty of Medicine and
Dentistry, University of Alberta, Edmonton, Alta.
Originally received Dec. 11, 2016. Final revision Jun. 26, 2017.
Accepted Jul. 4, 2017.
Correspondence to Ezekiel Weis, Eye Clinic, Rocky View
General Hospital 7007—14th Street SW, Calgary, Alta.
T2V1P9; ezekiel_weis@post.harvard.edu