Articles

Adalimumab for prevention of uveitic flare in patients with

inactive non-infectious uveitis controlled by corticosteroids
(VISUAL II): a multicentre, double-masked, randomised,
placebo-controlled phase 3 trial
Quan Dong Nguyen, Pauline T Merrill, Glenn J Jaffe, Andrew D Dick, Shree Kumar Kurup, John Sheppard, Ariel Schlaen, Carlos Pavesio, Luca Cimino,
Joachim Van Calster, Anne A Camez, Nisha V Kwatra, Alexandra P Song, Martina Kron, Samir Tari, Antoine P Brézin

Summary
Background Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation Published Online
and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term August 16, 2016
http://dx.doi.org/10.1016/
corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We S0140-6736(16)31339-3
aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by
See Online/Comment
systemic corticosteroids. http://dx.doi.org/10.1016/
S0140-6736(16)31327-7
Methods We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in Ocular Imaging Research and
21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≤18 years) with inactive, Reading Center (OIRRC),
Omaha, NE, USA
non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10–35 mg/day of prednisone were randomly
(Prof Q D Nguyen MD); Rush
assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous University Medical Center,
adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Chicago, IL, USA (P T Merrill MD);
Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of Duke University, Durham, NC,
USA (Prof G J Jaffe MD);
the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment
University of Bristol, Bristol Eye
allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing Hospital, Bristol, UK
new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous (Prof A D Dick MD); National
haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with Institute for Health Research
(NIHR) Biomedical Research
ClinicalTrials.gov, number NCT01124838.
Centre (Prof A D Dick),
Moorfields Eye Hospital and
Findings Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or University College London,
adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days Institute of Ophthalmology,
London, UK (C Pavesio MD);
(IQR 77–357) in the placebo group and 245 days (119–564) in the adalimumab group. Treatment failure occurred in
Wake Forest Baptist Medical
61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time Center, Winston-Salem, NC,
to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median USA (Prof S K Kurup MD); Lions
not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39–0·84; p=0·004). The 40th percentile for Medical Eye Bank of Eastern
Virginia, Eastern Virginia
time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No Medical School and Virginia Eye
patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies Consultants, Norfolk, VA, USA
were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious (J Sheppard MD); Austral
squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group University, Buenos Aires,
Argentina (A Schlaen MD);
and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), Arcispedale Santa Maria Nuova
and headache (17 [15%] patients in each group). IRCCS, Reggio Emilia RE, Italy
(L Cimino MD); University
Interpretation Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid Hospitals Leuven, Leuven,
Belgium (J Van Calster MD);
withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by AbbVie Deutschland,
systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between Ludwigshafen, Germany
groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this (A A Camez MD,
patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for Prof M Kron PhD); AbbVie,
North Chicago, IL, USA
adalimumab in patients with non-infectious uveitis. (N V Kwatra PhD, A P Song MD,
S Tari MD); and Université Paris
Funding AbbVie. Descartes, Hôpital Cochin, Paris,
France (Prof A P Brézin MD)

Introduction restrict their long-term use in the treatment of Correspondence to:

Dr Quan Dong Nguyen,
Uveitis and its associated complications account for intermediate, posterior, or panuveitic forms.4–6 Guidance Ocular Imaging Research and
roughly 10–15% of preventable blindness in developed from the Standardization of Uveitis Nomenclature Reading Center (OIRRC), Omaha,
countries.1–3 Corticosteroids are the mainstay of uveitis (SUN) working group supports the use of systemic NE 68198, USA
treatment, but ocular and systemic adverse effects corticosteroid-sparing drugs in patients on chronic quan.nguyen@unmc.edu

www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31339-3 1

 Articles
Research in context
Evidence before this study
We searched PubMed for articles published up to
March 20, 2016, in any language, for drugs or agents that have
been used for the treatment of non-infectious uveitis.
Our search terms were “non-infectious uveitis”, “anti-TNF”,
“immunosuppression”, and “biologics”. We identified various
publications on the use of anti-tumour necrosis factor (TNF)
agents in the treatment of various types of anterior,
intermediate, posterior, or panuveitic uveitis. Several
publications reported the effectiveness of anti-TNF drugs
(infliximab and adalimumab) in the treatment of uveitis. Some
of the diseases for which adalimumab is currently indicated,
such as juvenile idiopathic arthritis, ankylosing spondylitis, and
psoriatic arthritis can present with uveitis. There have been
reports of efficacy of adalimumab in paediatric patients with
juvenile idiopathic arthritis-associated or idiopathic uveitis.
A retrospective study in patients with refractory chronic uveitis
showed that adalimumab effectively controlled inflammation in
35% of patients refractory to previous treatment with infliximab
or etanercept. In a prospective open-label pilot study of
19 patients with various uveitic diagnoses, adalimumab
significantly reduced inflammation in 63% of patients with
complete resolution of cystoid macular oedema in 55% of eyes
after 1 year. A multicentre study of 131 patients with a mean age
of 27 years also showed that adalimumab significantly improved
anterior chamber and vitreous inflammation with the ability to
taper corticosteroids. In an open-label study of infliximab, 77%
of patients with refractory autoimmune uveitis achieved clinical
success by week 10. In the open-label uncontrolled RHAPSODY
study in patients with ankylosing spondylitis, adalimumab
decreased the rate of acute anterior uveitis flares by 51%. In a
prospective study, adalimumab reduced anterior chamber and
vitreous inflammation, improved visual acuity, and reduced the
corticosteroid burden in patients with refractory uveitis.
corticosteroid treatment with quiescent (inactive)
disease; the ability to achieve a reduction in corticosteroid
dose below a clinically meaningful threshold while
maintaining inactive disease is a key determinant of
treatment success.6 Few currently approved non-
corticosteroid immunomodulatory drugs for uveitis can
provide long-term control of the disease.7,8 Globally,
there is an unmet need that warrants pursuit of
additional effective treatments in steroid-dependent
patients with non-infectious uveitis who are at risk of
long-term corticosteroid side-effects.
Tumour necrosis factor α (TNFα) is a proinflammatory
cytokine produced by various cells, including
macrophages and neutrophils.9–12 Adalimumab (Humira;
AbbVie, North Chicago, IL, USA) is a recombinant
human immunoglobulin (IgG1) monoclonal antibody
that binds specifically to TNF and neutralises its
biological function.13 The safety and efficacy profile of
adalimumab spans more than 13 years for various
2 www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31339-3
The French Uveitis Network did a multicentre study of
160 patients with refractory uveitis treated with anti-TNFα
drugs (infliximab and adalimumab); the overall response rate
was 93% at 12 months. However, most of these publications are
case reports, case series, or open-label studies. An adequate, well
controlled study of the efficacy and safety of anti-TNF therapy is
absent in the present literature. Previous clinical trials that were
initiated to evaluate therapeutic potential for inactive,
non-infectious uveitis have either not achieved their primary
endpoint or were prematurely terminated for unknown reasons.
Added value of this study
VISUAL II is a multicentre, double-masked, randomised,
placebo-controlled phase 3 trial assessing the efficacy and
safety of adalimumab in patients with inactive non-infectious
intermediate, posterior, or panuveitis controlled by
corticosteroids. We did this study at 62 sites in 21 countries,
representative of the global diversity of the study population.
To our knowledge, this is the first study to have achieved its
prespecified primary endpoint (time to treatment failure) and
show promise in the treatment of inactive non-infectious
uveitis in patients dependent on chronic oral corticosteroids
(≥10 mg/day) to maintain disease inactivity.
Implications of all the available evidence
Adalimumab significantly lowered the risk of uveitic flare or
visual acuity loss in patients with steroid-dependent inactive,
non-infectious intermediate, posterior, or panuveitic uveitis.
No new safety signals were identified and the safety profile of
adalimumab was similar to that of other approved indications.
These findings suggest that adalimumab could be well
tolerated and offered as an effective treatment option for
patients with inactive, non-infectious uveitis who are at risk of
the long-term side-effects of corticosteroids.
inflammatory conditions, such as rheumatoid arthritis,
psoriasis, ankylosing spondylitis, Crohn’s disease,
ulcerative colitis, hidradenitis suppurativa, and juvenile
idiopathic arthritis.13 Several prospective studies,
including the VISUAL I clinical trial, have shown the
efficacy and safety of anti-TNF drugs (infliximab and
adalimumab) in the treatment of chronic and refractory
uveitis and in reducing corticosteroid use.14–19
Treatment of uveitis has two major goals: to achieve
quiescence in an eye with active intraocular
inflammation (the focus of the VISUAL I trial), and to
prevent recurrence of intraocular inflammation and
reduce side-effects of long-term corticosteroid use in
patients with a history of uveitic flare controlled by oral
corticosteroids (≥10 mg/day). We did the VISUAL II to
assess the efficacy and safety of adalimumab in
preventing reactivation of non-infectious intermediate,
posterior, and panuveitic uveitis controlled by
corticosteroids.

Methods
Study design and participants
We did this multicentre, double-masked, randomised,
placebo-controlled phase 3 trial at 62 study sites in
21 countries in the USA, Canada, Europe, Israel,
Australia, and Latin America.
Eligible patients were individuals aged 18 years and older
with inactive non-infectious intermediate, posterior, or
panuveitic uveitis. Key inclusion criteria were inactive
uveitis inactivity for at least 28 days before the baseline
visit, and use of 10–35 mg/day oral prednisone to maintain
inactive disease. We defined inactive uveitis as eyes without
active inflammatory chorioretinal or retinal vascular
lesions, an anterior chamber cell grade of 0·5+ or less
(SUN criteria; score range, 0–4+),20 or a vitreous haze grade
of 0·5+ or less (National Eye Institute criteria adapted by
SUN).20,21 To demonstrate corticosteroid dependency,
patients were required to have a documented history of
having at least one disease flare within 18 months of the
screening visit. Additionally, this flare should have
occurred during or up to a maximum of 28 days after
tapering off the oral corticosteroid therapy. We excluded
patients who were receiving more than one
immunosuppressive drug (not including corticosteroids)
within the last 28 days before the baseline visit; the dose of
the one concomitant drug had to be stable for at least
28 days before baseline and within the dose range
(appendix pp 6–12). Additional exclusion criteria were
corneal or lens opacity that precluded visualisation of the
fundus or that might have required cataract surgery during
the study, and isolated anterior or infectious uveitis or any
condition that would preclude safe participation in the
study or interfere with study assessments. The appendix
provides a complete list of inclusion and exclusion criteria.
The study protocol (appendix) was approved by the
responsible ethics committees and internal review boards
at each study site and the study was done in compliance
with the Declaration of Helsinki, Good Clinical Practice
guidelines, and applicable local regulations. All patients
provided written informed consent.
Randomisation and masking
Patients were randomly assigned (1:1), via an interactive
voice and web response system with a block size of four,
to receive adalimumab or placebo. Randomisation was
stratified by baseline immunosuppressant treatment. All
sponsor personnel with direct oversight of the conduct
and management of the study (with the exception of
those providing study treatments), investigators, study
site personnel, and patients were masked to treatment
allocation throughout the treatment period.
Procedures
Adalimumab and placebo were supplied in prefilled
syringes and administered subcutaneously. Patients in
the adalimumab group received an 80 mg baseline
loading dose followed by 40 mg doses every other week
www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31339-3
Articles
starting at week 1 for the duration of the study. Patients
received 10–35 mg/day of oral prednisone at baseline
and, from week 2, all patients underwent a mandatory
prednisone taper to 0 mg by week 19. The schedule of
study procedures is described in the appendix (p 15).
Presence or absence of inflammatory chorioretinal or
retinal vascular lesions was determined by dilated
indirect ophthalmoscopy. Anterior chamber cell counts
and cataracts were assessed with slit-lamp biomicroscopy
at every study visit; cell counts were graded according to
SUN criteria whereas cataracts were graded with the
Age-Related Eye Disease Study lens opacity grading
system.20,22 Vitreous haze was assessed with dilated
indirect ophthalmoscopy and graded with SUN-adapted
National Eye Institute criteria.20,21 Macular oedema was
assessed with optical coherence tomography (Stratus
optical coherence tomography [Carl Zeiss Meditec, Jena,
Germany], Cirrus high-definition optical coherence
tomography [Carl Zeiss Meditec, Jena, Germany], or
Spectralis [Heidelberg Engineering, Heidelberg,
Germany]; appendix pp 3–5).
Clinic visits were scheduled at screening; baseline; and
weeks 2, 4, and roughly every 4 weeks thereafter. Patients
were assessed until treatment failure was determined or
until treatment completion. The maximum duration of
treatment was 80 weeks or when the 106th treatment
failure occurred. Beginning at or after week 2 and at
every subsequent visit thereafter, treatment failure was See Online for appendix
determined if any of the following criteria were met in at
least one eye: new active, inflammatory chorioretinal or
inflammatory retinal vascular lesions (investigator-
determined by clinical examination or ancillary testing,
such as fluorescein angiography); worsening of best-
corrected visual acuity by 15 letters or more; a two-step
increase in anterior chamber cell grade; or a two-step
increase in vitreous haze grade relative to baseline.
Outcomes
The primary efficacy endpoint was time to treatment
failure. We assessed nine ranked secondary endpoints in
prespecified hierarchical order: (1) change in anterior
chamber cell grade in each eye; (2) change in vitreous
haze grade in each eye; (3) change in best-corrected visual
acuity (logMAR) in each eye; (4) time to optical coherence
tomographic evidence of macular oedema in at least one
eye; (5) percentage change in central retinal thickness
(as defined by centre point thickness) in each eye;
(6) change in National Eye Institute Visual Functioning
Questionnaire-25 (VFQ-25) composite score; (7) change in
VFQ-25 distance vision subscore; (8) change in VFQ-25
near vision subscore; and (9) change in VFQ-25 ocular
pain subscore. With the exception of the fourth ranked
endpoint, all ranked endpoints were analysed comparing
baseline with the final or early termination visit.
Adverse events were monitored throughout the study
and reported from the first dose of study drug until
70 days after the last dose of study drug or until patients
3
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were enrolled into a separate extension study. Serious assumptions were done with East5 (version 5.2.0.0).
adverse events were recorded from the time of informed A sample size of about 220 patients was needed to
consent. Adverse events were tabulated with the Medical achieve roughly 96 treatment failure events.
Dictionary for Regulatory Activities (version 17.0) and An independent data monitoring committee set up at
categorised by system organ class and preferred terms. the beginning of the trial independently monitored and
Adalimumab immunogenicity was assessed at multiple assessed data until the end of the study. At each
times throughout the study. committee meeting, the committee undertook a
comprehensive review and assessment of the cumulative
Statistical analysis safety data. The committee met roughly every 6 months,
We assumed an overall treatment failure rate of 30–35% or at a frequency determined by the members, to render
at 6 months, with an expected treatment effect their recommendation for study termination,
corresponding to an absolute difference of 15% between continuation, or amendment. The independent data
treatment failure rates in the adalimumab and placebo monitoring committee analyses were done by an external
groups. A conservative assumption was that treatment statistics vendor (Axio Research, Seattle, WA, USA) to
failures would begin to occur after 2 months because of enable the study sponsor to remain masked to the results
prednisone taper. A pooled dropout rate of 35% over of the study. The committee met eight times and did not
12 months was also assumed. On the basis of these identify any safety issues that would necessitate either a
assumptions, 84 to 107 treatment failures were sufficient temporary hold or an early termination of the study.
for a two-sided significance level of 5% in a log-rank test. Protocol deviations were monitored via assessment of
This calculation assumed 80% power and an average inclusion and exclusion criteria at study entry and
accrual rate of three patients per month in the first throughout the study. We analysed efficacy endpoints in
28 months and 16 patients per month thereafter. A series the intention-to-treat population, which comprised all
of calculations with different sample sizes using the patients randomly assigned to treatment.
event rate, recruitment rate, and dropout rate The primary endpoint of time to treatment failure was
compared between groups with a log-rank test; a
337 patients assessed for eligibility proportional hazards model with treatment as a factor
was fitted to estimate the hazard ratio (HR) and 95% CI.
As additional prespecified exploratory endpoints, time to
108 excluded
88 because of criteria violations
treatment failure due to each component of the primary
1 because of criteria violations endpoint was analysed similarly.
and other reasons Testing of ranked secondary endpoints was done
8 withdrew consent
11 for other reasons in hierarchical order and nominal p values for
between-group differences were provided. Changes in
anterior chamber cell grade, vitreous haze grade, best-
229 randomly assigned corrected visual acuity, and central retinal thickness were
compared between groups by ANOVA, with treatment as
a factor adjusted for clustered observations within a
114 assigned to receive placebo 115 assigned to receive adalimumab
patient—ie, a repeated-measures ANOVA was used to
114 received placebo 115 received adalimumab account for correlation between measurements from
both eyes of a patient. Analysis of central retinal thickness
used the optical coherence tomography machine type as
3 excluded from analysis
1 had incomplete efficacy source data an additional factor. Time to optical coherence
2 had general GCP compliance issues tomographic evidence of macular oedema on or after
week 2 was compared between groups with a log-rank
95 completed the study* 101 completed the study*
test, excluding patients with pre-existing macular
16 discontinued the study† 14 discontinued the study oedema at baseline. Changes in VFQ-25 composite score
7 had adverse events 10 had adverse events and subscores were compared between groups by
3 were lost to follow-up 2 withdrew
3 withdrew 2 for other reasons ANOVA, with treatment as a factor. For analysis of
3 because of lack of efficacy secondary variables, with the exception of time to optical
3 for other reasons
coherence tomographic evidence of macular oedema, we
imputed missing data with last observation carried
111 included in intention-to-treat 115 included in intention-to-treat forward.
analysis analysis
114 included in safety analysis 115 included in safety analysis
We did safety analysis in the safety population, which
comprised patients who received at least one dose of
study drug. Adverse events were presented as events per
Figure 1: Trial profile
GCP=Good Clinical Practice. *Patients who had treatment failure or reached 80 weeks of treatment without 100 patient-years to avoid confounding by between-group
treatment failure. †Some patients had more than one reason for discontinuation. differences in duration of exposure to study treatment.

4 www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31339-3

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All statistical tests were two sided at a significance level

Placebo group Adalimumab
of 0·05. Statistical analyses were done by the study (n=111) (n=115)
sponsor with SAS version 9.2. This trial is registered with
Sex
ClinicalTrials.gov, number NCT01124838.
Female 72 (65%) 66 (57%)
Male 39 (35%) 49 (43%)
Role of the funding source
Race
The funder of the study contributed to study design, and
White 93 (84%) 96 (83%)
participated in data collection, data analysis, and data
Black or African American 8 (7%) 6 (5%)
interpretation, and preparation and approval of the report
Asian 3 (3%) 3 (3%)
for publication. All authors had access to study data,
Other 5 (5%) 9 (8%)
reviewed and approved the final report, and take full
responsibility for the accuracy of the data and statistical Age (years)

analysis. The corresponding author had full access to all Mean (SD) 42·2 (14·0) 42·9 (12·9)

the data in the study and had final responsibility for the Range 20–79 18–75
decision to submit for publication. Type of uveitis
Intermediate 30 (27%) 17 (15%)
Results Posterior 34 (31%) 39 (34%)
Between Aug 10, 2010, and May 14, 2015, we randomly Panuveitis 46 (41%) 57 (50%)
assigned 229 patients to receive placebo (n=114) or Intermediate and posterior 1 (1%) 2 (2%)
adalimumab (n=115); 226 patients comprised the Diagnosis
intention-to-treat population (figure 1). 54 (24%) patients Idiopathic 40 (36%) 29 (25%)
had important reportable protocol deviations, including Birdshot choroidopathy 15 (14%) 15 (13%)
criteria violations; receipt of excluded concomitant Multifocal choroiditis and panuveitis 2 (2%) 5 (4%)
treatment; receipt of wrong treatment or incorrect dose Vogt-Koyanagi-Harada 25 (23%) 26 (23%)
of adalimumab, placebo, or prednisone; or development Sarcoid 14 (13%) 18 (16%)
of withdrawal criteria without being withdrawn (appendix Behçet’s 6 (5%) 10 (9%)
p 14). No patients received a treatment to which they Other 9 (8%) 12 (10%)
were not randomised for the entire period; therefore, all Affected eye
patients were analysed as allocated for both safety and Left 3 (3%) 2 (2%)
efficacy analyses. Baseline characteristics were similar Right 4 (4%) 1 (1%)
between groups; almost half of patients had panuveitic Both 104 (94%) 112 (97%)
uveitis (table 1). Mean patient age was 42·5 years Duration of uveitis (months)
(SD 13·4), and mean duration of uveitis was 66 months Mean (SD) 62·9 (67·7) 59·5 (64·5)
(61; table 1). Median follow-up time was 155 days Range 4–394 2–381
(IQR 77–357) in the placebo group and 245 days (119–564) Number of flares in past 12 months
in the adalimumab group. 0–1 46 (41%) 48 (42%)
We recorded an early and sustained separation of the 2 40 (36%) 43 (37%)
treatment failure curves between the adalimumab and ≥3 25 (23%) 24 (21%)
placebo groups (figure 2). Treatment failure occurred in Concomitant immunomodulators at baseline
61 (55%) of 111 patients in the placebo group compared
Azathioprine 11 (10%) 3 (3%)
with 45 (39%) of 115 patients in the adalimumab group.
Cyclosporine 11 (10%) 15 (13%)
Time to treatment failure was significantly improved in
Methotrexate 14 (13%) 19 (17%)
the adalimumab group compared with the placebo group
Mycophenolate mofetil 17 (15%) 17 (15%)
(43% risk reduction; median not estimated [>18 months;
more than half the adalimumab-treated patients did not Data are n (%), unless otherwise indicated.
have treatment failure] vs 8·3 months; HR 0·57, 95% CI
Table 1: Demographics and baseline characteristics
0·39–0·84; p=0·004; figure 2). The 40th percentile for
time to treatment failure was 4·8 months in the placebo
group and 10·2 months in the adalimumab group. adalimumab for all ranked secondary variables except
Patients given adalimumab met fewer treatment failure change from baseline in VFQ-25 near vision subscore
criteria than did those given placebo (figure 3). (table 2).
Hierarchical testing of the nine ranked secondary In exploratory analyses of the four prespecified reasons
variables was stopped after the first ranked endpoint for treatment failure, the largest between-group
because no statistically significant difference was shown difference in proportions of patients with treatment
between groups; p values provided for ranked secondary failure was shown for visual acuity (21% in the placebo
endpoints are exploratory in nature (table 2). Results group and 9% in the adalimumab group; figure 3). Time
were numerically, albeit non-significantly, in favour of to treatment failure due to visual acuity was significantly

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100 Placebo The incidence of adverse and serious adverse events

Adalimumab was similar between treatment groups (table 3). The
most frequently reported adverse events were injection-
80
site reactions and allergic reactions (table 3). Serious
Treatment failure (%)

Prednisone taper infections occurred at a similar rate between groups

60
HR 0·57, 95% CI 0·39–0·84; p=0·004 (table 3). One malignancy (non-serious squamous cell
carcinoma) was reported in the adalimumab group, and
40
one event and three events of latent tuberculosis were
reported in the placebo and adalimumab group,
20 respectively (table 3). No patients had opportunistic
infections (excluding oral candidiasis and tuberculosis),
0 active tuberculosis, lupus or lupus-like reactions, or
0 2 4 6 8 10 12 14 16 18 20
Time (months)
demyelinating disorders (table 3).
Number at risk
Placebo 111 89 66 50 41 33 26 21 19 17 0
Seven (6%) patients in the placebo group and ten (9%)
Adalimumab 115 105 82 67 58 51 42 37 34 30 0 patients in the adalimumab group discontinued study
drug due to adverse events. Adverse events leading to
Figure 2: Kaplan–Meier plot of treatment failure for any reason
patient discontinuation in the adalimumab group were a
HR=hazard ratio.
positive test for Mycobacterium tuberculosis complex
(n=4), pulmonary sarcoidosis (n=2), and bronchitis,
A neutropenia, hepatic stenosis, dermatitis, and worsened
50 Placebo
Adalimumab migraine (n=1 each). At baseline, 60 (27%) patients were
pseudophakic. Six (5%) patients in the placebo group and
40 two (2%) patients in the adalimumab groups, developed
Proportion of patients (%)

cataracts during the study. Overall, two (2%) patients in

30 the placebo group and one (1%) patient in the
adalimumab group had cataract surgery or YAG-laser
20 capsulotomy during the study, but did not withdraw. One
death due to aortic dissection and cardiac tamponade
was reported post-treatment in a patient in the
10
adalimumab group (table 3); the investigator deemed
these events as unrelated to study drug. Six (5%) patients
0 had anti-adalimumab antibodies during the study. Five
One Two Three Four
Number of reasons (83%) of these patients had treatment failure at weeks 13,
16, 16, 24, and 31 weeks, respectively; median time to
B
treatment failure was not estimable for patients with no
30
antibodies against adalimumab (n=109) because more
Reasons for treatment failure (%)

than half of these patients did not have treatment failure.

20
10
0 sustained separation of the adalimumab and placebo
Chorioretinal or retinal Anterior chamber cells Vitreous haze grade
vascular lesion
Figure 3: Causes of treatment failure
Number of reasons for treatment failure (A). Individual reasons for treatment failure (B).
improved in the adalimumab group compared with the
placebo group (67% risk reduction; figure 4). Time to
treatment failure due to new active inflammatory
chorioretinal or inflammatory retinal vascular lesions,
increases in anterior chamber cell grade, and increases
in vitreous haze grade did not differ significantly between
groups, but were numerically lower in the adalimumab
group (figure 4).
Discussion
Our findings show that adalimumab significantly
reduced the risk of uveitic flare or loss of visual acuity in
patients with inactive, non-infectious intermediate,
posterior, or panuveitic uveitis, as shown by an early and
Visual acuity
treatment failure curves. Median time to treatment
failure for adalimumab-treated patients, although not
estimable, was significantly longer than for placebo-
treated patients. Furthermore, patients given
adalimumab met fewer treatment failure criteria than
did those given placebo. Risk of treatment failure based
on logMAR best-corrected visual acuity was reduced by
roughly two-thirds in patients in the adalimumab group
compared with those in the placebo group. Rates of
treatment failure based on active inflammatory lesions,
anterior chamber cell grade, or vitreous haze were
numerically, albeit not significantly, lower in the
adalimumab group than in the placebo group.

6 www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31339-3

 Articles

Placebo group (n=111) Adalimumab group (n=115) Mean difference (95% CI) p value

n* Mean (SD) n* Mean (SD)

1 Change in anterior chamber cell grade

Left eye 110 0·57 (1·00) 115 0·41 (0·97) ·· ··
Right eye 110 0·53 (0·96) 115 0·40 (0·93) –0·14 (–0·37 to 0·08) 0·218†
2 Change in vitreous haze
Left eye 110 0·33 (0·73) 115 0·16 (0·60) ·· ··
Right eye 110 0·27 (0·61) 115 0·18 (0·60) –0·13 (–0·28 to 0·01) 0·070†
3 Change in logMAR best-corrected visual acuity
Left eye 110 0·06 (0·24) 115 0·01 (0·25) ·· ··
Right eye 110 0·02 (0·20) 115 –0·01 (0·17) –0·04 (–0·08 to 0·01) 0·096†
4 Time to optical coherence tomographic evidence 95 Median not estimable 90 Median not estimable HR 0·75 (0·34 to 1·69)‡ 0·491§
of macular oedema on or after week 2 (months)
5 Percentage change in central retinal thickness
Left eye 107 6·4% (20·7) 114 4·5% (29·8) ·· ··
Right eye 108 7·7% (28·9) 113 5·4% (34·8) –2·3 (–8·5 to 3·8) 0·451¶
6 Change in VFQ-25 total score 109 1·24 (10·7) 115 3·36 (11·7) 2·12 (–0·84 to 5·08) 0·16||
7 Change in VFQ-25 distance vision subscore 109 0·76 (16·3) 115 2·64 (17·2) 1·88 (–2·53 to 6·29) 0·40||
8 Change in VFQ-25 near vision subscore 109 3·98 (17·4) 115 3·88 (18·3) –0·10 (–4·81 to 4·61) 0·97||
9 Change in VFQ-25 ocular pain subscore 109 2·87 (17·2) 115 3·42 (21·3) 0·56 (–4·56 to 5·68) 0·83||

With the exception of endpoint 4 (time to optical coherence tomographic evidence of macular oedema), data represent change from baseline to final or early termination
visit. HR=hazard ratio. VFQ-25=Visual Functioning Questionnaire-25. *Number of patients with non-missing values. †From ANOVA, with treatment as a factor adjusted for
clustered observations. ‡HR of adalimumab versus placebo from proportional hazards regression with treatment as factor. §Log-rank test. ¶From ANOVA, with treatment
and type of optical coherence tomographic machine as factors adjusted for clustered observations. ||From ANOVA, with treatment as factor.

Table 2: Ranked secondary efficacy variables

Most of the measurable effect of adalimumab was on
the best-corrected visual acuity component of the primary
efficacy endpoint. Although the effect of adalimumab on
the other inflammatory components of the primary
endpoint was not significant, the improvement in best-
corrected visual acuity is likely to be through its effect on
multiple aspects of inflammation within the eye, some
of which might not have been included in the
multicomponent endpoint. The inflammatory mani-
festations in patients with vision loss that might partly
have been the cause of the loss were increases in anterior
chamber cell grade and vitreous haze grade (≥1), new
inflammatory or chorioretinal vascular lesions, retinal
thickening, and cataracts. The cross-sectional study by
Dick and colleagues,2 based on population insurance
data, provides supportive evidence that presence of
chronic low-grade inflammation in this population
worsens visual outcomes.
The efficacy results of the present trial were in accordance
with those of previous studies. In the multicentre, double-
masked, randomised controlled VISUAL I trial,19
adalimumab significantly reduced the risk of treatment
failure by 50% compared with placebo in patients with
active non-infectious uveitis. In both VISUAL I (active
disease) and VISUAL II (inactive disease), adalimumab
halved risk to failure and almost doubled time to failure. A
retrospective study23 in patients with refractory chronic
uveitis showed that adalimumab effectively controlled
inflammation in 35% of patients refractory to previous
treatment with infliximab or etanercept. In a prospective
open-label pilot study24 of 19 patients with various uveitic
diagnoses, adalimumab significantly reduced
inflammation in 63% of patients with complete resolution
of cystoid macular oedema in 55% of affected eyes after
1 year. In another non-comparative open-label prospective
study25 of 31 patients with refractory uveitis, 68% of patients
had a clinical response at 10 weeks and 39% had a
sustained response at 50 weeks. A multicentre prospective
study14 of 131 patients with a mean age of 27 years also
showed that adalimumab significantly improved anterior
chamber and vitreous inflammation with the ability to
taper corticosteroid use. The French Uveitis Network did a
multicentre observational study26 of 160 patients with
refractory uveitis treated with anti-TNFα drugs (infliximab
and adalimumab); the overall response rate was 93% at
12 months.
The low adalimumab immunogenicity in the present
study was within the range of rates reported in other
disease states.13 Moreover, the safety profile of adalimumab
in this study was similar to that in other approved
indications, for which the rates of adverse events, serious
adverse events, and discontinuations due to an adverse
event were similar in both adalimumab and placebo
groups,13 and no new safety signals were detected.27,28

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 Articles

A Vitreous haze B New lesions

100 Placebo
Adalimumab

80
Treatment failure (%)

60
HR 0·79, 95% CI 0·34–1·81; p=0·589 HR 0·55, 95% CI 0·26–1·15; p=0·105

40

20

C Anterior chamber cells D Best-corrected visual acuity

100

80
Treatment failure (%)

60 HR 0·70, 95% CI 0·42–1·18; p=0·180 HR 0·33, 95% CI 0·16–0·70; p=0·002

40

20

0
0 2 4 6 8 10 12 14 16 18 20 0 2 4 6 8 10 12 14 16 18 20
Time (months) Time (months)
Number at risk
Placebo 111 89 66 50 41 33 27 21 19 17 0 111 89 66 50 41 33 26 21 19 17 0
Adalimumab 115 105 82 67 58 51 42 37 34 3 0 115 105 82 67 58 51 42 37 34 3 0

Figure 4: Kaplan–Meier plot of treatment failure due to vitreous haze (A), new lesions (B), anterior chamber cells (C), or best-corrected visual acuity (D)
HR=hazard ratio.

Placebo group (n=114; Adalimumab group

been prematurely terminated for unknown reasons.29–31
71·0 person-years) (n=115; Thus, to our knowledge, VISUAL II is the first phase 3 trial
94·5 person-years) of a non-steroidal systemic drug in patients with quiescent
Any adverse event 642 (905) 831 (879) disease to have reached its prespecified primary endpoint
Adverse event leading to death* 0 2 (2·1) (time to treatment failure) and show promise in treatment
Serious adverse event 10 (14·1) 13 (13·8) of patients with inactive non-infectious uveitis controlled
Adverse event leading to discontinuation of study drug 7 (9·9) 11 (11·6) by chronic oral corticosteroids (≥10 mg/day).
Serious infectious adverse event 2 (2·8) 3 (3·2) Strengths of this study were the trial design, relatively
Injection-site reactions 16 (22·6) 36 (38·1) large study population, range of uveitis diagnoses, and
Malignancies† 0 1 (1·1) multicomponent primary endpoint. The composite
Opportunistic infections (excluding oral candidiasis and 0 0
primary endpoint assessed various facets of the disease,
tuberculosis) ranging from anterior to posterior segments of the eye,
Active tuberculosis 0 0 and facilitated detailed assessment of treatment response
Latent tuberculosis 1 (1·4) 3 (3·2) and efficacy, given that inflammation does not always
Demyelinating disease 0 0 manifest as one endpoint (eg, vitreous haze).
Lupus-like reaction 0 0 Furthermore, all patients had a mandatory corticosteroid
Allergic reactions (including angio-oedema, anaphylaxis) 8 (11·3) 5 (5·3) taper to zero, enabling assessment of the corticosteroid-
sparing effect of adalimumab.
Data in parentheses are events are per 100 person-years. *One death due to two fatal events of aortic dissection and There were limitations to the interpretation of the
cardiac tamponade (day 54 [18 days after last adalimumab dose]); these events were deemed not related to treatment.
†One event of non-serious squamous cell carcinoma (day 210, resolved on day 215; adalimumab treatment was not secondary endpoints given that the magnitude of the
interrupted). treatment effect was diluted because only a few patients
had treatment failure due to one of the four components.
Table 3: Adverse events (safety population)
Thus, the magnitude of mean change was small for these
endpoints. A floor effect could have been possible
Previous clinical trials that were done to evaluate the because most patients started with reasonably good
therapeutic potential for inactive, non-infectious uveitis visual acuity and minimum inflammation; detection of a
have either not achieved their primary endpoint or have change might have been particularly difficult because

8 www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31339-3


more than half of patients in the adalimumab group
never achieved treatment failure. Although range of
uveitis diagnoses was a strength of our study, it could
also be a potential limitation because no information was
provided about which disease groups (with their
recognised heterogeneity) were actually responsive to
therapy. Due to the difficulty in recruitment of patients in
a rare disease cohort with multiple competing studies, no
restriction on the number of recruiting sites was
imposed—an additional weakness. Furthermore, the
study was not statistically powered to analyse a differential
efficacy among the different causes of uveitis.
Studies or clinical trials intended for the treatment of
uveitis face various challenges. Uveitis is a heterogeneous
group of conditions characterised by intraocular
inflammation. Most uveitis syndromes are individually
rare, but for taxonomic and clinical convenience are
commonly clustered according to their anatomical
classification, despite the wide range of systemic and
clinical associations they represent. Another challenge
encountered in any uveitis trial is the scarcity of high-
quality outcome measures. Currently, vitreous haze
grade, as defined by Nussenblatt,32 is a surrogate endpoint
for disease activity that is accepted by the US Food and
Drug Administration for clinical trials. This score uses a
subjective ordinal scale of cloudiness of the vitreous
humour, but has substantial interobserver variability.
Our findings suggest that adalimumab could be a well
tolerated and effective treatment option for patients with
inactive, non-infectious intermediate, posterior, or
panuveitis who are at risk of the long-term side-effects of
corticosteroids. An open-label extension study
(NCT01148225) is ongoing to provide long-term safety data
for adalimumab in patients with non-infectious uveitis.
Contributors
QDN, PTM, SKK, JS, AS, CP, LC, JVC, and ADD participated in the
conduct of the study, including selection, treatment, and follow-up of
patients; data interpretation; and preparation and critical review of the
report. QDN, GJJ, and APB participated in the conception and study
design, analysis and interpretation of data, and preparation and critical
review of the report. AAC, NVK, APS, MK, and ST participated in the
analysis and interpretation of data, and the preparation and critical review
of the report. All authors provided a final review and approved
the manuscript.
Declaration of interests
AAC, MK, APS, NVK, and ST are AbbVie employees and all hold AbbVie
stock or options. QDN has served on the scientific advisory boards for
AbbVie, Santen, XOMA, Bausch & Lomb, and Genentech uveitis studies,
and chairs the steering committee for the VISUAL, EYEGUARD, and
SAKURA studies. APB has served on advisory boards and as a
consultant for AbbVie. GJJ has served as a consultant for AbbVie.
ADD has served on advisory boards for AbbVie. PTM has served on the
steering committee for the VISUAL studies and has served as consultant
for Santen. SKK has been an advisor or steering committee member for
AbbVie, Allergan, Bayer, Clearside, Regeneron, and Xoma. JS has been a
consultant for AbbVie, Alcon, Allergan, Aldeyra, Bausch & Lomb,
Clearside, EyeGate, Ocular Therapeutix, Tear Lab, Tear Science, Santen,
Shire; an investigator for Xoma, Bausch & Lomb, Lux Biosciences,
Eyegate, Alcon, Allergan, Clearside, Alimera, pSivida, Novartis, Shire,
Aldeyra; and has served on the steering committee for the VISUAL
studies. LC has been on advisory boards and served as a consultant for
AbbVie. CP has received a research grant from Alcon; has served as a
www.thelancet.com Published online August 16, 2016 http://dx.doi.org/10.1016/S0140-6736(16)31339-3
Articles
consultant for Xoma, Servier, and Santen; and has served on advisory
boards for Xoma, Servier, Santen, Alcon, and Bausch & Lomb. JVC has
served on advisory boards for AbbVie and MSD, and has served as a
consultant for MSD. AS declares no competing interests.
Acknowledgments
This study was funded by AbbVie. We thank Friederike Mackensen for her
contribution to the study conception and design, and data analysis and
interpretation. Dr Mackensen passed away during the development of the
manuscript. We thank Amin Kherani, Andrew Logan, Antonio Ciardella,
Justus Garweg, Chloe Gottlieb, David Scales, De Schryver, Eric Fortin,
Farzin Forooghian, G Pertile, Hiroshi Goto, Jennifer Thorne,
Kenichi Namba, Koh-Hei Sonoda, Koju Kamoi, Lourdes Arellanes-Garcia,
Lucia Kuffova, Lyndell Lim, Maria Pia Paroli, Marta Misiuk-Hojlo,
Masahiro Zako, Michal Kramer, Nicholas Beare, Nobuhisa Mizuki,
Noriyasu Hashida, Pablo Franco, René Cervantes-Castañeda,
Robert Wang, Rui Proença, Sanjay Kedhar, Sarju Patel, Sofia Androudi,
Talin Barisani-Asenbauer, Theresa Larson, Thomas Flynn, Thomas Ness,
Toshiaki Abe, Toshikatsu Kaburaki, and Yan Guex-Crosier for their
contribution and assistance for the study. Gaurav Patki (AbbVie,
North Chicago, IL, USA) provided medical writing assistance.
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