Outcomes of Changing Immunosuppressive

Therapy after Treatment Failure in Patients

with Noninfectious Uveitis
Lavnish Joshi, MD, FRCOphth,
1,2
Lazha Talat, MBChB, MPH,
1,2
Satish Yaganti, MBBS, MSc,
3
Sartaj Sandhu, MBBS,
4
Simon R. J. Taylor, PhD, FRCOphth,
3,5
Denis Wakeeld, MD, FRCPA,
6
Peter McCluskey, MD, FRANZCO,
4
Susan Lightman, PhD, FRCOphth
1,2
Purpose: To evaluate the outcomes of changing immunosuppressive therapy for noninfectious uveitis after failure.
Design: Retrospective cohort study.
Participants: Patients with noninfectious uveitis managed at 2 tertiary uveitis clinics in the United Kingdom
and Australia.
Methods: Participants with a history of using immunosuppressive therapy were identied in clinics, and
notes were reviewed by doctors trained in uveitis therapy. Each treatment episode/course (starting or changing a
therapy) was identied, and demographic details, clinical characteristics, drug used (second-line immunosup-
pressive agent [ISA] or biologicals), and drug doses were obtained.
Main Outcome Measures: For each treatment episode, the reasons for changing therapy, corticosteroid-
sparing effects, and control of inammation were determined.
Results: A total of 147 patients were identied who underwent 309 different treatment episodes. Fifty-ve
percent of patients eventually required a change in treatment after their rst treatment episode/course. Forty-
ve episodes involved switching from one ISA to another, with 50% to 100% of these patients achieving
success (prednisolone 10 mg and sustained control) with the new ISA. A combination of ISAs were used in 53
episodes, with success being achieved in 50% to 71% of these patients. Biological agents were used in 45
episodes, the most common one being iniximab, which achieved success in 80% of patients.
Conclusions: Our data suggest that control of inammation can be achieved after switching or combining
ISAs. Ophthalmology 2014;121:1119-1124 2014 by the American Academy of Ophthalmology.
Supplemental material is available at www.aaojournal.org.
Systemic corticosteroids are the mainstay of treatment for
uveitis resistant to local therapy, bilateral disease, and the
more severe forms of uveitis. In some patients, corticoste-
roids are unable to control inammation at a dose of 10 mg/
day, or preferably 7.5 mg/day or less,
1
whereas in others the
side effects of long-term treatment are severe and limit the
duration of therapy. These patients require additional
immunosuppressive agents (ISAs) to control their disease
and to minimize the corticosteroid dose they require.
1
Such
nonbiologic ISAs include T-cell inhibitors (cyclosporine A
[CSA] and tacrolimus), antimetabolites (azathioprine
[AZA], methotrexate [MTX], and mycophenolate mofetil
[MMF]), and alkylating agents (cyclophosphamide and
chlorambucil); ISAs have been reported to become ineffec-
tive in up to 17% of patients within the rst year.
2e6
An
expert uveitis panel published a comprehensive set of
guidelines on the use of ISAs, but there is no consensus on
whether to change ISAs or add a biologic in such patients.
There are a limited number of reports describing the out-
comes of switching or adding an ISA after failure of an ISA.
7
The objectives of this study were to determine the
outcome of individual immunosuppressive therapies (both
ISAs and biologicals) in producing a corticosteroid-sparing
effect after treatment has failed (because of side effects or
ineffectiveness) with a previous agent(s) in a large cohort of
patients.
Methods
A retrospective review of the clinical records of all patients who
attended the uveitis clinics of Susan Lightman at Moorelds Eye
Hospital (London, UK) and Peter McCluskey at St. Vincents
clinic (Sydney, Australia) for the management of noninfectious
uveitis from January 2010 to August 2012 was undertaken. Ethical
approval was obtained from the Moorelds Eye Hospital research
board under the program of research on causes of visual loss in
uveitis (LIGS 10201).
Data Collection, Follow-Up, and Outcome Measures
Patients who were currently using or had previously used immu-
nosuppressive drugs or biologics were identied. Patient medical
records were reviewed, and information from each treatment
episode/course (dened as starting or changing an ISA or biologic)
was collected. The following information was collected: age; sex;
1119 2014 by the American Academy of Ophthalmology ISSN 0161-6420/14/$ - see front matter
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.ophtha.2013.11.032
uveitis subtype; any associated medical condition (e.g., sarcoid-
osis); duration of disease and follow-up; prednisolone dose and
disease activity (based on the Standardization of Uveitis Nomen-
clature workshop grading system)
8
at the start of treatment episode;
baseline and nal best-corrected visual acuity (VA); any decrease/
gain in best-corrected VA by 2 Early Treatment Diabetic Reti-
nopathy Study (ETDRS) lines due to inammation; ocular com-
plications; maximum dose of ISA; reasons for changing treatment;
and corticosteroid-sparing effect of ISA or biologics (dened as
time to reach a prednisolone dose 7.5 or 10 mg with maintained
inactivity spanning at least 28 days).
5
Patients were followed up
until their last recorded visit to the clinic. Visual acuity was
recorded using Snellen VA charts and converted to approximate
ETDRS scores, which are more intuitively interpretable than
logarithm of the minimum angle of resolution units.
9
Other
associated features of uveitis were documented, such as increased
vitritis, new-onset macular edema, vasculitis, or optic neuropathy/
swelling.
The denition of remission was based on the clinicians eval-
uation of the patient, noting that the treatment could be reduced or
stopped because there was no disease activity for at least 6 months
after starting the agent; this denition also included no relapse
within 6 months after stopping the agent. Ineffectiveness was based
on the clinicians impression that a change in therapy was needed
because the agent failed to improve inammation or recurrent re-
lapses occurred while on the treatment regimen.
Statistical Analyses
All data were entered into a Microsoft Excel 2007 spreadsheet
(Microsoft Corp., Redmond, WA) and analyzed using the Excel
PivotTable function and GraphPad Prism v5.01 (GraphPad Soft-
ware, La Jolla, CA).
Results
The demographics and uveitis phenotypes of the patients are
detailed in Table 1. We identied a total of 147 patients who
underwent a total of 309 different treatment episodes; 30 episodes
were a reduction of treatment (reducing from a combination of
therapies to a single therapy), 56 episodes were a switch from one
systemic therapy to another, 87 episodes were an increase in
treatment (increasing from a single therapy to a combination of
therapies), and 9 episodes were due to the reintroduction of a
treatment that had been stopped. A total of 127 episodes involved
the use of a single agent as the rst treatment episode.
Continuation and Change of Treatment
Figure 1 shows that 55% of patients eventually required a change
in treatment after their rst treatment episode/course. Some patients
subsequently underwent up to 8 treatment courses/episodes,
highlighting that is difcult to achieve remission in these patients
with a single course of treatment.
Visual Acuity Changes across Treatment Courses
Figure 2 shows the last recorded ETDRS-equivalent VA in all eyes
for each consecutive treatment course and reveals a decline in VA
after consecutive treatment courses. There may be a trend for
patients to lose vision with increasing courses of treatment.
However, up to 22% of patients gained 2 or more ETDRS lines
of VA after treatment (Fig 3). The causes of visual loss are
shown in Table 2.
Effectiveness of Single Immunosuppressive Agents
after Failure of Other Agents in Comparison with
Their Use as Initial Agents
Of the 127 treatment episodes involving the use of a single agent
during the rst treatment episode, MMF (44%) was the most
commonly used initial agent, followed by CSA (25%), AZA
(16%), MTX (13%), and alkylating agents (2%). The mean doses
used for each of these initial ISAs are summarized in Table 3
(available at www.aaojournal.org). However, these agents failed
(stopped because of ineffectiveness or side effects) in 40% to
75% of patients (Table 4), with the highest proportion for those
given CSA. Remission (stopping treatment because of
maintained inactivity) was not achieved in many patients, but a
greater proportion of patients taking AZA managed to achieve
this (35%). A greater proportion of patients taking AZA had
systemic disease and a longer duration of disease and posterior
uveitis than those taking the other ISAs (Table 1). A statistical
comparison of baseline factors between ISAs was not possible
because it would violate the rule of independent samples
(because some patients may have multiple ISAs).
Of the 56 episodes that involved switching from one therapy to
another, 45 involved switching from one ISA to another, whereas
the other 9 involved switching between biological agents or
switching an agent in an ISA combination regimen. Table 3
(available at www.aaojournal.org) shows the summary and
outcomes of ISAs used after the failure of other ISAs, comparing
them with ISAs used as initial therapy. The most commonly
used ISAs after ISA failure were MTX (18 episodes) and MMF
Table 1. Baseline Characteristics of All Patients and First Treatment Episode for Commonly Used Immunosuppressive Agents
Characteristic
All Patients
(n [ 147)
Initial Agent Used (No. of Episodes)
MTX (n 16) AZA (n 20) MMF (n 56) CSA (n 32)
Age (yrs), median (range) 37 (5e75) 31 (10e59) 37 (20e64) 42 (5e75) 33 (17e54)
Female sex (%) 55 69 40 43 34
Site of inammation (%)
Anterior uveitis 16 54 10.5 5.5 10
Intermediate uveitis 20 13 10.5 32 13
Posterior uveitis 64 33 79 62.5 77
Systemic disease 53 63 95 38 63
Duration of disease (mos), median (range) 31 (0e528) 38 (0e156) 74 (0e364) 46 (0e249) 20 (0e95)
Ocular complications (%) 67 63 60 73 69
AZA azathioprine; CSA cyclosporine A; MMF mycophenolate mofetil; MTX methotrexate.
Ophthalmology Volume 121, Number 5, May 2014
1120
(16 episodes), with success (prednisolone dose 10 mg/day) still
being possible in 63% and 64%, respectively. Furthermore, a
gain in vision (2 ETDRS lines) was still possible in 33% of
patients switching to MTX and 44% of patients switching to
MMF. This suggests that these agents can still be effective in
controlling disease, even if they are used after other ISAs have
failed. However, some of these patients still went on to have
disease relapse, and a decline in vision (2 ETDRS lines due to
disease relapse) at any point was still experienced in 31% to
100% of patients after they switched to an ISA, highlighting that
long-term inactivity is difcult to achieve.
Commonly Used Immunosuppressive Agent
Combinations and Outcomes
Of the 87 episodes in which a combination of drugs was used, ISA
combinations were used in 53 courses, and 34 courses used bio-
logical agents along with another ISA.
The most commonly used ISA combinations are summarized in
Table 5. These included AZA CSA (14 episodes), CSA MMF
(20 episodes), and CSA MTX (4 episodes). Success at a
prednisolone dose of 10 mg/day was achieved in 50% to 71%
of these patients; a gain in VA (2 ETDRS lines) was achieved
in 21% to 30% of patients. However, 21% to 31% of these
patients also experienced subsequent disease relapses with a
decline in vision (2 ETDRS lines) at any point after these ISA
combinations were used. These ISA combinations were stopped
in up to 50% of patients because of ineffectiveness and in up to
29% because of side effects.
During these episodes, the mean (standard deviation) doses for
MMF, MTX, AZA, and CSA were 1.9 g/day (0.5), 17 mg/week
(6.7), 155 mg/day (81), and 303 mg/day (158), respectively.
Commonly Used Biological Agents and Outcomes
Biological agents were used in a total of 45 episodes. The out-
comes of the most commonly used biological agents are summa-
rized in Table 6. These included iniximab (30 episodes) and
adalimumab (8 episodes). The main reason for using a biological
agent was ineffectiveness of other ISAs in 94%. These biological
agents were able to achieve high success rates, but patients still
experienced a decline in vision (2 ETDRS lines) because of
inammation at any point while receiving these therapies.
Iniximab was stopped in 17% of patients because of
ineffectiveness, whereas adalimumab was stopped in 63% for the
same reason.
Discussion
This study demonstrates that a large proportion (60%) of
patients with uveitis undergo more than 1 change in their
Figure 2. Visual acuity (VA) changes across consecutive treatment courses
(based on nal VA for each course). Approximate Early Treatment Dia-
betic Retinopathy Study (ETDRS) letter score. SEM standard error of
mean.
Figure 3. Proportion of patients gaining approximately 2 Early Treat-
ment Diabetic Retinopathy Study (ETDRS) visual acuity lines across
consecutive treatment courses. SEM standard error of mean.
Figure 1. Continuation and change of therapy across consecutive treat-
ment courses. Asterisk indicates proportion of total cohort studied. Bars
indicate treatment status (stopped because of remission, changed, contin-
uation) for each course. Numbers within bars indicate the proportion of
patients in each treatment course and their treatment status.
Table 2. Causes of Visual Loss
Causes of Visual Loss Patients (n [ 147)
Cataract 33%
Glaucoma 14%
Ischemia/artery occlusion/vein occlusion 15%
Epiretinal membrane/macular hole 10%
Neovascular membrane 6%
CME/vitritis 40%
CME cystoid macular edema.
Joshi et al

Outcomes of Changing Immunosuppression in Uveitis
1121
immunosuppressive treatment with ISAs or biological
agents with time. Subsequent changes in treatment can be
effective, including switching to another ISA after failure of
one or adding another ISA to the treatment regimen. Bio-
logical agents were not frequently used, largely because of
the difculty in obtaining patient funding, but iniximab
had a good rate of success. There seems to be a trend in a
reduction in vision across consecutive treatment courses, but
a gain in vision is still possible in 12% to 22% of patients
after changing ISAs.
The use of any antimetabolites after the failure of other
immunosuppressive regimens led to success (prednisolone
10 mg/day) in 48% to 60% of cases. The use of CSA after
failure of other regimens also led to success in some cases.
Using a combination of ISAs was also useful and,
depending on the combination used, led to success in 50%
to 71% of cases. It is possible that a combination of agents
with a different mechanism of action could have a syner-
gistic effect in controlling inammation.
The effectiveness of ISA combinations in uveitis has not
been widely reported in the literature, but this strategy is used
by uveitis specialists. Menezo et al
10
reported that 32% of
their patients required the addition of a third agent
(prednisolone and 2 ISAs). In the Systemic
Immunosuppressive Therapy for Eye Diseases (SITE)
cohort study, the proportion of patients requiring a third
agent was 16%, 17%, 9%, and 19% in the MTX, CSA,
AZA, and MMF groups, respectively.
2e5
The efcacy and tolerance of combination strategies have
been evaluated in only a few studies. One of the earliest
studies found that a combination of steroids, MTX, and CSA
(5 mg/kg/day) was able to achieve total and lasting remis-
sion in all 32 patients with endogenous noninfectious
uveitis, with the only side effect being hirsutism in 2 cases.
11
They suggested that the combination therapy was able to
achieve control of inammation with lower doses of each
agent than monotherapy would allow, thus reducing the
toxicity of each individual agent. More recently, Kiss et al
12
reported that several strategies, including the use of CSA
and MMF, were able to preserve visual function in patients
with birdshot retinochoroidopathy. A previous report of
patients with the same condition found no difference in the
rate of visual loss between untreated patients and patients
treated with a single second-line ISA.
13
Sobrin et al
7
had to
add CSA to MMF in 9 of 85 patients (11%) with ocular
inammatory disease who failed MTX, and all these
patients having persistent inammation despite the addition
of a second agent.
The success in controlling ocular inammation after
switching from one ISA to another has not been widely
reported. Sobrin et al
7
found that switching to MMF after
MTX failure or intolerance is effective in controlling
inammation in 55% of patients with uveitis/scleritis. In
the SITE cohort study, patients switching from T-cell
inhibitors to MTX were 3 times more likely to gain
control of inammation than patients using MTX for the
rst time, but the prior use of other ISAs was not
associated with signicantly different rates of treatment
success.
2
This suggests that patients who have failed other
agents may still respond to MTX. This is in contrast to
our ndings because a lower proportion of patients
achieved success (50%) when switched to MTX in
comparison with when it was used as the initial agent. In
our study, switching to MMF achieved success in a
greater proportion of patients than when it was used as the
initial agent, which is again in contrast with the SITE
cohort.
4
It is possible that the higher MMF dose used in
patients who had previously failed ISAs contributed to
this difference. Our study did not use the maximum doses
of MMF and MTX given by the Uveitis Expert Panel
guidelines
1
because increasing doses beyond the average
doses used in our study led to increased side effects with
a limited increase in efcacy. In patients switching to
AZA, those previously taking other antimetabolites or T-
cell inhibitors tended to respond to AZA less often than
patients not previously taking these drugs,
3
which is in
contrast to our ndings, suggesting that AZA was able to
achieve control (inactivity at prednisolone 10 mg) in a
similar proportion of patients when used as an initial
agent or when switching to it after other agents (Table 3,
available at www.aaojournal.org). The prior use of other
Table 4. Reasons for Discontinuation of Initial Immunosuppres-
sive Agent
Initial Agent
Not
Stopped (%)
Reason for Discontinuation (%)
Ineffective
Side
Effects Remission Unknown
MMF (n 56) 23 50 7 18 2
MTX (n 16) 31 56 0 13 0
AZA (n 20) 20 35 5 35 5
CSA (n 32) 13 66 9 9 3
ALK (n 2) 0 50 0 50 0
ALK alkylating agents; AZA azathioprine; CSA cyclosporine A;
MMF mycophenolate mofetil; MTX methotrexate.
Table 5. Outcomes of Commonly Used Combination Agents
Agents Used
Success (%) VA Changes (%) Reason for Discontinuation (%)
Prednisolone 10 mg Prednisolone 7.5 mg Gain 2 Lines Loss 2 Lines Ineffective Side Effects Remission
AZA CSA (n 14) 71 29 21 21 29 29 36
CSA MMF (n 20) 65 25 30 35 50 15 10
CSA MTX (n 4) 50 0 0 25 50 25 25
ALK alkylating agents; AZA azathioprine; CSA cyclosporine A; MMF mycophenolate mofetil; MTX methotrexate; VA visual acuity.
Ophthalmology Volume 121, Number 5, May 2014
1122
ISAs in patients switching to CSA was not associated with
differences in subsequent treatment success compared with
those patients using CSA for the rst time in the SITE
cohort.
5
The denition of success used in our study was similar to
that used by the SITE cohort study. During their sensitivity
analysis, the authors found that not having such a stringent
denition of success (i.e., success to be sustained) also
resulted in a larger proportion of patients achieving success
on the basis of this denition. However, their analyses found
that for some ISAs, 83% of patients who achieved control
would subsequently have had a relapse by the next visit,
2
suggesting that many patients relapse just after achieving
control of inammation or corticosteroid-sparing goals.
Local and topical steroids were increased for many of the
patients in our study, without systemic steroids being
increased. Indications included an increase in anterior
chamber cell activity (topical steroids) and the presence of
cystoid macular edema (CME) and vitritis (local steroids).
In the SITE cohort study, patients may have achieved
quiescence if there was no cellular activity and prednisolone
doses 10 mg, but there is no indication of whether these
patients required an increase in local steroids to treat CME.
If there were such patients, did they truly achieve sustained
control of inammation? Thus, such patients would actu-
ally overestimate the benets of treatment effect. Whether
CME is a measure of disease activity is a matter of debate.
Cystoid macular edema certainly can be treated in a similar
way as ocular cellular activity through the increase of oral
corticosteroids,
14-16
which may actually lead to a more rapid
decrease of CME than with periocular steroid injections.
17
However, the SUN group regards CME as a structural
complication of uveitis,
8
rather than a measure of active
disease. The basis of this assumption shares common
ground with the explanation for the presence of anterior
chamber are in chronic uveitis. The presence of CME
and anterior chamber are is due to vascular damage from
the inammatory process, and both may be long-standing,
if not permanent; thus, both are believed to be a marker of
past inammation but not a sign of active inammation.
18,19
Study Limitations
The limitations of our study include its retrospective nature,
which can lead to imprecise and nonstandardized data
collection from assessment at irregular intervals and differ-
ential follow-up. Treatment bias may have existed because
treatment was not randomized or administered in a standard
manner.
The SITE cohort study did not report VA outcomes,
which can be difcult to report in a standardized manner.
Several approaches can be taken. In studies in which the
follow-up time is variable, the proportion with a particular
threshold VA at presentation and rates of VA events
during follow-up (e.g., falling below a specied threshold
because of disease activity) can be reported,
8,20
which is
the method we adopted in our study. However, this can be
problematic because a decline in VA may not be a direct
result of the current ISA regimen that a patient is re-
ceiving. For example, a cataract may develop in a patient
receiving a particular ISA, but although this ISA may have
achieved sustained control for this patient and the decline
may not be due to disease activity, any improvement in
VA caused by the ISA regimen would be limited by the
cataract.
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Agent Used
Success (%) VA Changes (%) Reason for Discontinuation (%)
Prednisolone
10 mg
Prednisolone
7.5 mg Gain 2 Lines Loss 2 Lines Ineffective Side Effects Remission Unknown
Iniximab (n 30) 80 60 17 20 17 13 23 7
Adalimumab (n 8) 88 75 25 50 63 0 0 0
VA visual acuity.
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Footnotes and Financial Disclosures
Originally received: June 11, 2013.
Final revision: November 16, 2013.
Accepted: November 18, 2013.
Available online: January 14, 2014. Manuscript no. 2013-933.
1
Moorelds Eye Hospital, London, United Kingdom.
2
UCL Institute of Ophthalmology, London, United Kingdom.
3
Royal Surrey County Hospital, Guildford, United Kingdom.
4
Save Sight Institute, Sydney Eye Hospital, Sydney, Australia.
5
Faculty of Medicine, Imperial College London, Hammersmith Hospital,
London, United Kingdom.
6
School of Medical Sciences, University of New South Wales, Kensington,
New South Wales, Australia.
Financial Disclosure(s):
The author(s) have made the following disclosure(s): S.R.J.T. has board
membership with Allergan and has received nancial support for the
development of educational presentations by Allergan. S.L. has board
membership with Allergan and GlaxoSmithKline.
Funding:
L.J. and S.R.J.T. were supported by the UK National Institute of Health
Research. S.L. has received consultancy fees from PAREXEL International
Corp., Bayer, and Zeiss, and received payment for lectures and develop-
ment of educational materials from Allergan.
Correspondence:
Susan Lightman, PhD, FRCOphth, UCL Institute of Ophthalmology, 11-43
Bath Street, London, EC1V 9EL. E-mail: s.lightman@ucl.ac.uk.
Ophthalmology Volume 121, Number 5, May 2014
1124