Intravitreal infliximab in refractory uveitis in Behcet's disease: A safety and efficacy clinical study

Abstract

Purpose:
To assess the safety and efficacy of intravitreal infliximab (1 mg/0.05 mL) in patients with refractory posterior uveitis in Behcet's disease.

Methods:
Twenty patients were included in this study. Best corrected visual acuity (BCVA), vitreous haze (graded 0-4), vasculitis, retinitis, and papillopathy (presence or absence) were assessed at baseline, Day 1 and Week 2, 4, 6, 8, 12, and 18. Optical coherence tomography (OCT) central foveal thickness, fluorescein angiography, and flash electroretinogram were done at baseline and 4, 12, and 18 weeks.

Results:
Mean baseline logMAR BCVA was 0.94 (20/160), had improved significantly by Week 2 to 0.6 (20/80) (P < 0.0001), and reached 0.36 (20/40) by Weeks 18 with three injections (P < 0.0001). Mean central foveal thickness OCT decreased significantly from baseline 361 μm to 180 μm at the end of follow-up (P < 0.0001). Profound decrease in mean vitreous haze gradings from two to 0.2 by the end follow-up (P < 0.05). There was a significant reduction in the number of patients with vasculitis (15 at baseline to 1 weeks at 18 weeks), retinitis (nine at baseline to none at 4 weeks), and papillitis (two at baseline to none at 4 weeks) (P < 0.05). No significant electrophysiological changes or ocular adverse inflammatory reactions were observed during the study period.

Conclusion:
Intravitreal infliximab appeared to be safe and effective in treating uveitis in Behcet's disease and should be considered as an alternative to systemic therapies.

Full text

INTRAVITREAL INFLIXIMAB
IN REFRACTORY UVEITIS IN
BEHCET’S DISEASE
A Safety and Efficacy Clinical Study
MOSTAFA M.E. HAMZA, MD,* TAMER A. MACKY, MD, FRCSED,* MOHAMED KARIM SIDKY, MD,*
GAAFAR RAGAB, MD,†MAHMOUD M. SOLIMAN, MD*
Purpose: To assess the safety and efficacy of intravitreal infliximab (1 mg/0.05 mL) in
patients with refractory posterior uveitis in Behcet’s disease.
Methods: Twenty patients were included in this study. Best corrected visual acuity
(BCVA), vitreous haze (graded 0–4), vasculitis, retinitis, and papillopathy (presence or
absence) were assessed at baseline, Day 1 and Week 2, 4, 6, 8, 12, and 18. Optical
coherence tomography (OCT) central foveal thickness, fluorescein angiography, and flash
electroretinogram were done at baseline and 4, 12, and 18 weeks.
Results: Mean baseline logMAR BCVA was 0.94 (20/160), had improved significantly by
Week 2 to 0.6 (20/80) (P,0.0001), and reached 0.36 (20/40) by Weeks 18 with three
injections (P,0.0001). Mean central foveal thickness OCT decreased significantly from
baseline 361 mm to 180 mm at the end of follow-up (P,0.0001). Profound decrease in
mean vitreous haze gradings from two to 0.2 by the end follow-up (P,0.05). There was
a significant reduction in the number of patients with vasculitis (15 at baseline to 1 weeks at
18 weeks), retinitis (nine at baseline to none at 4 weeks), and papillitis (two at baseline to
none at 4 weeks) (P,0.05). No significant electrophysiological changes or ocular adverse
inflammatory reactions were observed during the study period.
Conclusion: Intravitreal infliximab appeared to be safe and effective in treating uveitis in
Behcet’s disease and should be considered as an alternative to systemic therapies.
RETINA 36:2399–2408, 2016
Intravitreal injection of up to 2 mg of infliximab has
proved to be safe in animal models (rabbits and
primates).
1–6
These studies have shown no evidence
of intraocular inflammation or toxicity by clinical,
electrophysiological, and histopathological examina-
tionforupto90daysevenwiththreerepeated
monthly injections. However, the study conducted
by Rassi et al
5
was the only one to report the devel-
opment of severe intraocular inflammation in one eye
out of 12 rabbit eyes at 90 days following three intra-
vitreal injections (2 mg monthly). In addition, the
half-life of intravitreal infliximab was found to be
6.5 days to 8.5 days,
1,7
and it is also capable of pen-
etrating all retinal layers.
6
These animal study results
should have set the stage for a relatively safe use of
intravitreal infliximab in human eyes. Unfortunately,
clinical studies conducted on patients so far have
raised serious concerns about its safety and adverse
effects.
These clinical studies have shown various and incon-
sistent results in terms of the safety and efficacy of
intravitreal infliximab.
8–19
These studies were conducted
on patients with refractory as well as naive cases of age-
related macular degeneration choroidal neovasculariza-
tion,
8–10,16–18
diabetic macular edema,
11,12
central retinal
vein occlusion,
17
angiomatous malformations,
17
pseudo-
phakic macular edema,
13
and uveitis.
11,14,15
The doses
used ranged from 0.5 mg to 2 mg. Two studies have
monitored injected eyes with flash electroretinogram
From the Departments of *Ophthalmology, and †Internal
Medicine, Kasr El Aini Hospital, Cairo University, El-Manial,
Cairo, Egypt.
None of the authors have any financial/conflicting interests to
disclose.
ClinicalTrials.gov ID is: NCT02620618.
Reprint requests: Tamer A. Macky, MD, FRCSEd, 29th, 13th Street,
Apt. # 11, Maadi, Cairo 11431, Egypt; e-mail: tamermacky@gmail.com
2399

(ERG) with mild reversible changes at 3 months in one
study
9
(2 age-related macular degeneration eyes and two
diabetic macular edema eyes using 0.5 mg), whereas with
no changes in the other study (six age-related macular
degeneration eyes using 2 mg) at 6 months.
18
The initial study by Theodossiadis et al
8
in 2009 did
not report any intraocular inflammation in three pa-
tients receiving two intravitreal injections of 1 mg
and 2 mg for refractory age-related macular degener-
ation choroidal neovascularization with 7 months
follow-up period. Later several clinical studies have
reported severe intraocular inflammation following in-
travitreal injections of infliximab in nonuveitic pa-
tients.
9,10,12,13,16–18
This occurred with doses as low
as 0.5 mg, in 15% to 100% of patients, and usually
starts several weeks
3,4
after the intravitreal injections.
These collected data have initiated a call for cautious
use of intravitreal infliximab.
19,20
On the other hand, studies investigating intravitreal
infliximab in uveitis patients have shown improvement
in vision, reduction in central foveal thickness (CFT)
on optical coherence tomography (OCT), and reduc-
tion in inflammation with no reported adverse ef-
fects.
11,14,15
In our study, we have investigated the
safety and efficacy of three consecutive intravitreal
infliximab injections (1 mg/0.05 mL, 6 weeks apart)
in carefully selected group of patients with refractory
uveitis in Behcet’s disease.
Patients and Methods
Approval of the study was obtained from the
hospital’s ethical committee. The study design and
methodology followed the tenets of the Declaration
of Helsinki. All patients were provided with written
informed consent and received a thorough explanation
of the study design, aims, and the off-label use of
infliximab, its potential risks, and benefits. This is
a prospective noncomparative interventional clinical
study. The study was conducted on 20 eyes of 20
patients with refractory posterior uveitis in Behcet’s
disease who received three consecutive intravitreal in-
jections of infliximab (1 mg/0.05 mL) 6 weeks apart.
Inclusion Criteria
Refractory posterior uveitis in a systemically con-
trolled Behcet’s disease.
Behcet’s disease. Behcet’s disease was diagnosed
based on the criteria of the International Study
Group.
21
Disease classification was recorded in accor-
dance with the Standardization of Uveitis Nomencla-
ture Working Group criteria.
22
Posterior uveitis. Posterior uveitis is defined as
inflammation that predominantly affects the retina
and/or choroid with any of the following: focal,
multifocal, or diffuse chorioditis; retinitis; chorioreti-
nitis; retinochorioditis; vasculitis; or neuroretinitis
(papillitis).
22
In Behcet’s disease, it is mainly retinitis,
vasculitis, and papillitis.
21
Refractory cases. Refractory cases in this study are
those with ocular inflammations not responding to
“systemic”therapies. Patients with Behcet’s disease
who have received one or two conventional systemic
treatment modalities with adequate control of disease
systemically and no adequate ocular response in the
previous 3 months were included.
Conventional treatments. Conventional treatments
are systemic immunosuppressive drugs other than
infliximab and other tumor necrosis factor alpha
(TNFa) inhibitors.
Exclusion Criteria
1. Patients receiving or who had received systemic
infliximab or other TNFainhibitors,
2. Patients with uncontrolled systemic Behcet’s
disease,
3. Patients who received previous intravitreal steroids
(,6 months),
4. Patients with severe media opacity,
5. Patients with previous history of ocular surgery
other than cataract surgery, and
6. Cataract surgery within the previous 6 months.
Patients’Examination
A) Patients were subjected to the following initial
examinations:
1. Best corrected visual acuity (BCVA) measurements
on Snellen Charts to be converted to logMARs.
2. Slit-lamp examination of anterior segment inflam-
mation (iritis) and complications.
3. Measuring intraocular pressure (IOP) by Goldman
applanation tonometry.
4. Dilated fundus examination by indirect ophthalmo-
scope using +20 diopter lens for grading of vitreous
haze as follows: Grade 0: good view of nerve fiber
layer, Grade +1: clear optic nerve and vessels but
hazy nerve fiber layer, Grade +2: optic nerve and
vessels are hazy, Grade +3: view of optic nerve
only, and Grade +4: no optic nerve view.
23
5. Dilated slit-lamp biomicroscopy for the presence
or absence of vasculitis, retinitis, and papillopathy.
Vasculitis is diagnosed clinically by retinal blood
2400 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2016 VOLUME 36 NUMBER 12

vessels gliotic sheathing or occlusive vasculopathy
in the presence of inflammation, and with fluores-
cein angiography (FA) by vascular staining, leak-
age, or occlusion.
22
6. Patients also had the following at baseline: FA,
flash ERG, and CFT OCT (Stratus III OCT; Carl
Zeiss, Dublin, CA).
B) Follow-up clinical examinations were at Day 1,
andWeeks2,4,6,8,12and18.Eachfollow-upvisit
included: BCVA, slit-lamp examination, IOP,
dilated fundus examination with grading of vitreous
haze, and the presence or absence of vasculitis,
retinitis, or papillopathy. CFT OCT and flash ERG
were done at 4, 12, and 18 weeks. FA was done at
the discretion of the examiner and not at every
postinjection evaluation.
Drug Preparation
A vial containing 100 mg of commercially available
infliximab powder (Remicade; Janssen Pharmaceutica,
Buckinghamshire, United Kingdom) was reconstituted
with 5 mL of sterile water, and 0.05 mL of this
solution (1 mg of infliximab) was used for each patient
and placed in a tuberculin syringe using aseptic
techniques. The remaining syringes are kept in a sterile
package at 2°C to 8°C for 6 weeks.
24
The intravitreal
dose of infliximab used in this study is 1 mg/0.05 mL.
Animal studies have shown intravitreal infliximab in
doses up to 2 mg is safe
1–6
even with 3 monthly in-
jections.
5
Since clinical trial in nonuveitic eyes showed
severe intraocular inflammation with even a single low
dose of 0.5 mg
9
and the 1 mg dose was shown to be
effective in controlling uveitis in one study,
15
we
decided to use this dose 1 mg and avoid the 1.5 mg
and 2 mg doses that were reported for to effective as
well in uveitic eyes.
11,14
Injection Technique and Criteria for Reinjections
The eye was prepared in a standard fashion using
5% povidone-iodine, an eyelids speculum to stabilize
the eyelids, and the injection of 1 mg (0.05 mL) was
performed 3.5 mm to 4 mm posterior to the limbus,
through the inferotemporal pars plana with a 30-gauge
needle under topical anesthesia. After the injection,
retinal artery perfusion was checked, and patients were
instructed to administer topical antibiotics for 3 days.
All patients were given detailed postinjection instruc-
tions and asked to call promptly if any pain or
significant changes in vision occurred. Patients were
seen on follow-ups, and repeated injections were given
at 6-week intervals if reinjection criteria were met: 1)
no evidence of significant flash ERG changes, 2) no
evidence of adverse effects to the drug, and 3) signs of
anatomical and/or functional improvement during the
first 6 weeks.
Outcome Measures
Comparing the following baseline parameters to
each study visit:
1. Changes in mean BCVA in logMAR.
2. Changes in mean CFT by OCT.
3. Changes in the inflammatory parameters:
•Mean vitreous haze grading.
•Number of patients with retinitis, vasculitis, and
papillitis. Patients were either diagnosed with or
without retinitis; vasculitis or papillitis, any fea-
ture of it is considered as posterior uveitis.
4. Changes in mean flash ERG a- and b-wave ampli-
tudes and implicit times.
Systemic Therapy
The Department of Internal Medicine (Cairo Uni-
versity) systemic therapy protocol for patients with
Behcet’s disease and posterior uveitis (vasculitis, reti-
nitis, and papillitis) is a regimen adapted and modified
from the EULAR recommendations for the manage-
ment of Behcet’s disease.
25
We start with 0.5 g to 1 g
methylprednisolone as daily pulse therapy (intrave-
nous line) for three consecutive days, followed by oral
prednisolone 0.75 mg/kg to 1 mg/kg body weight for 4
weeks to be tapered gradually later on. Cyclophospha-
mide (in intravenous line, 500 mg/m
2
body surface
area) starts on Day 4 after the three consecutive daily
doses of methylprednisolone, to be repeated every
month or 6 months. After the initial 6 months, azathi-
oprine 2 mgkg
21
day
21
to 2.5 mgkg
21
day
21
or
cyclosporine 2 mgkg
21
day
21
to 5 mgkg
21
day
21
replaces cyclophosphamide. In aggressive and severe
cases or when an eye is still involved, infliximab infu-
sion is considered; however, in our study, those cases
were offered intravitreal infliximab.
Statistical Analysis
Data were statistically described in terms of mean ±
standard deviation, median and range, or frequencies
(number of cases) and percentages when appropriate.
Comparison of numerical variables between the study
groups was done using Freidman’s test with Conover
test for paired (matched) samples as post hoc multiple
two-group comparisons. For comparing categorical
data, Chi square (±2) and McNemar’s tests were per-
formed. Agreement was tested using kappa statistic.
Correlation between various variables was done using
INTRAVITREAL INFLIXIMAB FOR UVEITIS HAMZA ET AL 2401

Spearman rank correlation equation. Pvalues ,0.05
was considered statistically significant. All statistical
calculations were done using the computer program
SPSS (Statistical Package for the Social Science;
SPSS Inc, Chicago, IL) version 15 for Microsoft
Windows and Stats Direct statistical software version
2.7.2 for Microsoft Windows (StatsDirect Ltd,
Cheshire, United Kingdom).
Results
In this study, 20 eyes of 20 patients with refractory
posterior uveitis in Behcet’s disease were included.
Patients with ocular activities despite a systemically
controlled disease were referred to us from the Depart-
ment of Internal Medicine where those with posterior
uveitis were included in this study for intravitreal in-
jections. The patients included had their initial eye
examinations recorded following referral, with no
record of prior BCVA. Patients were then given three
consecutive intravitreal injections of infliximab (1 mg/
0.05 mL) 6 weeks apart, for 18 weeks in the 20 study
eyes.
Baseline demographics, ocular clinical finding, and
therapies are shown in Table 1. The patients’mean age
was 31.40 ± 3.45 years (range: 26 years–38 years),
with 19 male patients (95%). Eighteen patients had
history of previous ocular activities and two patients
had their first attacks of uveitis. All 20 patients had
bilateral involvement, of which 19 patients had unilat-
eral inflammation with no activities in the other eyes.
Only one patient had a bilateral inflammation, and
Table 1. Baseline Patients’Demographics; Ocular Clinical Findings (Both Eyes); and Topical and Systemic Treatments
Patient
Age,
Years Sex
BCVA in
logMAR
(Snellen)
Ocular Findings in Injected
Eyes
Topical
Treatment Systemic Treatment
Ocular Findings
in Noninjected
Eyes
Anterior
Segment
Posterior
Segment
1 28 M 1 (20/200) PS, No
activity
VH, VS, PP Timolol Prednisolone,
Azathioprine,
Cyclophosphamide
PS
2 26 M 1.77 (20/1,000) No activity VH, VS, R —Cyclophosphamide No activity
3 32 M 0.77 (20/100) No activity VH, VS —Cyclophosphamide No activity
4 31 M 1 (20/200) C&F VH, R Timolol,
Pred
Cyclophosphamide C&F, VH
5 29 M 0.77 (20/100) No activity VH, VS —Azathioprine,
Cyclophosphamide
No activity
6 34 M 1.77 (20/1,000) No activity VH, VS, R Timolol Prednisolone,
Cyclophosphamide
No activity
7 34 M 0.77 (20/100) C&F VH, R Timolol,
Pred
Cyclophosphamide No activity
8 34 M 1 (20/200) No activity VH, VS —Cyclophosphamide No activity
9 38 M 0.60 (20/80) No activity VH, VS —Prednisolone,
Azathioprine
No activity
10 32 M 1 (20/200) No activity VH, VS, R,
PP
—Cyclophosphamide No activity
11 28 M 0.77 (20/100) No activity VH, VS —Prednisolone,
Azathioprine
No activity
12 32 M 0.60 (20/80) C&F VH, R Pred Cyclophosphamide No activity
13 28 M 0.60 (20/80) No activity VH, VS —Cyclophosphamide No activity
14 28 M 0.77 (20/100) No activity VH, VS —Prednisolone PS, cataract
15 37 M 0.77 (20/100) C&F VH, VS Timolol,
Pred
Prednisolone,
Azathioprine
No activity
16 35 M 1.079 (20/250) No activity VH, R —Cyclophosphamide No activity
17 26 M 1 (20/200) No activity VH, VS, R —Prednisolone,
Azathioprine
No activity
18 33 F 1 (20/200) No activity VH, VS —Cyclophosphamide No activity
19 30 M 0.77 (20/100) C&F VH, R Pred Prednisolone,
Azathioprine
No activity
20 33 M 1 (20/200) No activity VH, VS —Prednisolone,
Cyclophosphamide
No activity
M, Male; F, Female; BCVA, Best Corrected Visual Acuity; C&F, Cells&Flare; PS, posterior synechae; VH, vitreous haze; VS, vasculitis;
PP, papillitis; R, Retinitis; Timolol, timolol maleate eye drops; Pred, Prednisone Acetate eye drops.
2402 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2016 VOLUME 36 NUMBER 12

intravitreal injection was given to the eye with the
worst vision and more severe posterior inflammation.
The other eye, of this bilateral case, had mainly ante-
rior involvement and was treated with topical steroids
with no intravitreal injections or change in systemic
therapies. All patients had FA done at baseline, and all
but three patients had FA done during the study visits.
Those three patients had mild systemic reaction with
the dye on the first injections.
Topical therapies
Five study eyes and one contralateral eye had mild
anterior iritis and were treated with topical prednisone
acetate eye drops. Five study eyes received topical
timolol maleate eye drops to control a slightly elevated
intraocular pressure (Table 1). These topical eye drops
were initiated with the initial examinations and were
not changed during the study period. The mean IOP
remained stable with no statistically significant differ-
ence in IOP before and after repeated injections
throughout the study period (Table 2).
Changes in mean BCVA and CFT OCT in the
study eyes. Baseline BCVA (mean logMAR 0.94 ±
0.32 [20/160]) improved significantly by Week 2
(mean logMAR 0.60 ± 0.18 [20/80], P,0.0001)
and continued to improve by Week 4 (mean logMAR
0.41 ± 0.18 [20/50], P,0.0001). There were no
statistically significant difference in BCVA between
Weeks 4, 6, and 8. BCVA worsened by Week 12
(mean logMAR 0.51 ± 0.23 [20/63], P= 0.0001)
then reimproved again by Week 18 (mean logMAR
0.36 ± 0.19 [20/40], P,0.0001) (Table 2, Figure 1).
The mean baseline CFT OCT (361 mm) improved
significantly by Week 4 to 239 mm(P,0.0001)
and continued to improve by Week 12 to 210 mm
(P,0.0001) and Week 18 to 180 mm(P,0.0001)
(Table 2, Figure 1).
Changes in mean vitreous haze grading in the
study eyes. There was a statistically significant improve-
ment in vitreous haze throughout the study, mean
vitreous haze grading decreased from two at baseline
to 0.2 at the end of follow-up (P,0.0001). Baseline
mean vitreous haze grading was two, improved signif-
icantly by Week 2 to 0.45, and continued to improve by
Week 4 to 0.2. The vitreous haze worsened at Weeks 6
and 12 to a mean grade of 0.35 and 0.4, respectively. It
then reimproved by Week 8 and 12 to a mean of 0.1
and 0.2, respectively, following reinjections (Table 2,
Figure 2).
Changes in rate of vasculitis, retinitis, and papill-
opathy in the study eyes. There was a statistically
significant reduction in the number of patients with
active vasculitis from 15 patients before injection to
only 1 patient at the end of follow-up (P,0.001).
Before injections, there were 15 patients with active
vasculitis, which continued to be reduced throughout
the study period to 11 patients at Week 2, and dra-
matic reduction to two patients at Week 4; then only
one patient had vasculitis at Week 12 till the end of
the study (Table 2, Figure 3). Preinjections, there
were nine patients with active retinitis that was sig-
nificantly (P,0.001) reduced to three patients at
Week 2, then none at Week 4 and for the rest the
study period (Table 1, Figure 3). Preinjection, there
were two patients with papillopathy, 1 patient at
Week 2, and none at Week 4 (P,0.001) till the
end of follow-up (Table 2, Figure 3).
Electroretinogram in the study eyes. There was no
statistically significant difference in flash ERG (sco-
topic and photopic b-wave amplitude and implicit
time) between baseline and 4, 12, or 18 weeks (Table
3, Figure 4).Figure 5 shows a patient’s FA and OCT
revealing clinical improvement inflammatory activity
during the study period which was observed in most
patients.
Table 2. Mean BCVA in logMAR (Snellen), CFT OCT, IOP, Vitreous Haze Grading, and Number of Patients With Retinitis,
Vasculitis, and Papillitis at Baseline and Each Study Visit
Mean Changes of the Different Parameters Through the Study Period
BCVA in logMAR
(Snellen) CFT OCT (mm) IOP (mmHg)
Vitreous Haze
Grading
No. Patients
Vasculitis Retinitis Papillitis
Baseline 0.94 (20/160) 361 14.30 2 15 9 2
Day 1 0.94 (20/160) 350 14.70 2 15 9 2
Week 2 0.60 (20/80) 290 15.20 0.45 11 3 1
Week 4 0.41 (20/50) 239 14.70 0.2 2 0 0
Week 6 0.44 (20/50) 220 14.10 0.35 2 0 0
Week 8 0.38 (20/50) 200 14.25 0.1 2 0 0
Week 12 0.51 (20/63) 210 13.80 0.4 1 0 0
Week 18 0.36 (20/40) 180 14.30 0.2 1 0 0
INTRAVITREAL INFLIXIMAB FOR UVEITIS HAMZA ET AL 2403

Subconjunctival hemorrhage was observed in four
patients after injection. No other complications were
detected (no endophthalmitis, retinal detachment, or
significant increase in IOP). There were no ocular or
extraocular side effects detected, and the used dose was
tolerated by all patients. There were no observed
immunological reactions detected after the injections
in any of the injected eyes. None of the patients
required any surgical interventions during the 18 weeks.
Discussion
Behcet’s disease is a multisystem inflammatory dis-
order characterized by recurrent orogenital ulcers and
recurrent ocular inflammation. It frequently involves
the joints, skin, central nervous system, and gastroin-
testinal tract. It is classified as a systemic vascultis that
can involve both the arteries and veins of almost any
body organ.
26,27
The etiology remains unknown. Ocu-
lar involvement in Behcet’s disease is common and
ranges from 30% to 70%. Ocular Behcet’s disease
usually presents with chronic relapsing panuveitis, ret-
initis, and retinal vascultis and has devastating effects
on vision.
26,28
Behcet’s disease is characteristically
a bilateral inflammation in about 80% of cases and
unilateral in 20%.
29–32
However in our study, all our
patients had bilateral involvement, but 19 patients had
“activity”(inflammation) in one eye only and only one
patient had bilateral activity. The other eye for that
patient with bilateral activity had a milder inflamma-
tion with mainly anterior segment involvement and
was treated with topical steroids with no intravitreal
injections or change in systemic therapies.
The TNFabelongs to a group of proinflammatory
cytokines produced by macrophages and T cells and
plays a key role in inflammation and apoptosis.
33
In
Fig. 1. Shows changes in the
mean BCVA in logMARs and
mean CFT OCT in microns
throughout the study. Mean BCVA
in logMARs at baseline = 0.94 ±
0.32 (20/160), Week 2 = 0.60 ±
0.18 (20/80), Week 4 = 0.41 ± 0.18
(20/50), Week 6 = 0.44 ± 0.17 (20/
50), Week 8 = 0.38 (20/50), Week
12 = 0.51 ± 0.23 (20/63), and
Week 18 = 0.36 ± 0.19 (20/40).
Fig. 2. Changes in the mean
grades in vitreous haze through-
out the study.
2404 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2016 VOLUME 36 NUMBER 12

the eye, TNFaappears to participate in the pathogen-
esis of various inflammatory disorders. Increased lev-
els of this cytokine have been found in the serum of
patients with active uveitis. TNFahas also been de-
tected in increased levels in eyes with a variety of
inflammatory conditions.
34
Infliximab is a chimeric
human immunoglobulin G1 (IG1) with a mouse vari-
able fragment having TNFaaffinity and neutralizing
capacity. The potent anti-inflammatory effects of in-
fliximab make them a valid alternative for the control
of noninfectious ocular inflammation, particularly
when standardized treatment protocols involving ste-
roids and antimetabolites have failed.
35–39
Farvardin et al
11
in 2010 used 1.5 mg intravitreal
infliximab in 10 eyes with noninfectious uveitis that
failed to respond to systemic treatment. They reported
significant visual improvement and significant reduc-
tion of CFT by OCT at 1 month. Later, Markomiche-
lakis et al
15
in 2012 used 1 mg of intravitreal
infliximab for refractory uveitis in Behcet’s disease
with significant improvement in vision, reduction in
CFT by OCT, and reduction in inflammation at 1
month. In their second study, Farvardin et al
14
in
2012 have reported the use of 1.5 mg intravitreal in-
fliximab in noninfectious uveitis with a 6-month
follow-up that showed recurrence after initial improve-
ment. None of these three studies have used repeated
injections and none used flash ERG to monitor retinal
toxicity of the intravitreal injection. On the other hand,
in nonuveitic eyes, two studies have used flash ERG to
monitor retinal toxicity following a single intravitreal
injection of infliximab.
9,18
To the best of our knowl-
edge, this is the first study to assess safety using flash
ERG and the efficacy of three consecutive intravitreal
injections (6 weeks apart) of infliximab for refractory
posterior uveitis in Behcet’s disease.
Safety of Intravitreal Infliximab
In our study, we found that intravitreal infliximab in
the described dose and frequency (1 mg/0.05 mL,
three injections/6 weeks) to be well tolerated by all
patients clinically and by electrophysiological assess-
ment. There were no statistically significant difference
in flash ERGs (scotopic and photopic b-wave ampli-
tude and implicit time) between baseline and the
different study visits up to 18 weeks. The electrophys-
iological results in this study match previous clini-
cal
9,18
and animal studies
1–6
for the same dose, which
confirms that intravitreal injection of infliximab in 1
mg or 2 mg is not toxic to the intraocular tissue espe-
cially the retina.
However, the main concern with the intravitreal use
of this drug remains to be the development of
intraocular immunogenic reaction. Although this reac-
tion is reported in a high percentage of eyes with
nonuveitic diseases,
8–10,12,13,16–18
yet it was not re-
ported by the three studies investigating intravitreal
infliximab for uveitis.
11,14,15
We did not observe clinically any increased intraoc-
ular inflammatory reactions in any of the injected eyes
during all study visits. Although, it is difficult to assess
an immunogenic reaction to the drug in already
inflamed eyes, yet we did not even observe changes
in the pattern of the inflammations in any of the study
eyes during the study visits compared with preinjection
status. None of our patients needed vitrectomy or
Fig. 3. Changes in the number
of patients with vasculitis, reti-
nitis, and papillitis throughout
the study period.
Table 3. Mean Flash ERG b-Wave Implicit Time
(milliseconds) and Amplitudes (Micrvolts) in Photopic and
Scotopic Conditions at Baseline, 4, 12, and 18 Weeks
b-Wave
Mean Photopic ERG Mean Scotopic ERG
Implicit
Time Amplitude
Implicit
Time Amplitude
Preinjection 36.20 18.34 37.90 26.93
Week 4 34.87 18.55 37.79 27.21
Week 12 36.49 17.92 38.01 26.98
Week 18 36.05 18.13 37.74 27.04
INTRAVITREAL INFLIXIMAB FOR UVEITIS HAMZA ET AL 2405

any surgical interventions in their eyes during the
study period, as previously reported after intravitreal
infliximab.
10,12,17
There were no other clinical ocular
or systemic adverse effects reported during the study;
however, we did not assess systemic human antichi-
meric antibodies.
Efficacy of Intravitreal Infliximab
In our study, the mean BCVA in logMAR (Snellen)
has significantly improved from a baseline mean of
0.94 (20/160) to 0.6 (20/80), 0.41 (20/50), 0.51 (20/
63), and 0.36 (20/40) at Weeks 2, 4, 12, and 18,
respectively (P,0.0001). There was no statistically
significant difference in BCVA between Weeks 4, 6,
and 8. However, BCVA worsened at Week 12 and
was significantly worse than Week 8 (P,0.0001)
which coincided with an increased mean vitreous
haze grading. BCVA also showed nonsignificant
deterioration between Weeks 4 and 6, again coincid-
ing with deteriorated vitreous haze grading. This may
be explained by the waning effect of the intravitreal
dose and is an indication for the need of shorter in-
tervals between injections. The changes in BCVA
corresponded to the changes in CFT by OCT. The
mean baseline CFT (361 mm) improved significantly
by Week 4 (239 mm, P,0.0001) and continued to
Fig. 4. Mean flash electro-
retinogram b-wave implicit time
(milliseconds) and amplitudes
(microvolts) in photopic and
scotopic conditions throughout
the study visits.
Fig. 5. Fluorescein angiogram for patient 9, preinjection (A) and 4 weeks after injection (B) showing reduced vasculitis and leakage (arrows) and
papillitis.
2406 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2016 VOLUME 36 NUMBER 12

improvebyWeek12(210mm, P,0.0001) and
Week 18 (180 mm, P,0.0001).
In this study, all parameters of intraocular inflam-
mation showed dramatic improvement during the
study period. We can see that the maximum drug
effect was reached at 4 weeks. Vitreous haze reached
its lowest rate at 4 weeks, and only two patients had
vasculitis, and no patients had retinitis or papillitis at 4
weeks. There was mild increase of vitreous haze
between 4 and 6 weeks, and between 8 and 12 weeks
with rapid control of activity after reinjections of the
second and third injections, respectively. The result of
our study confirms the favorable visual and anatomical
outcomes of intravitreal infliximab that were reported
by Farvardin et al
11,14
and Markomichelakis et al
15
on
eyes with uveitis. All previous three studies as well as
ours have shown significant control of intraocular
activities within weeks with significant improvement
of BCVA and reduction of macular edema by OCT.
To the best of our knowledge, our study is the
largesttodatetobereportedonthesafetyand
efficacy of intravitreal injections of infliximab in
patients with uveitis. We are also the first to use
repeated intravitreal injections and monitor such
uveitic eyes with flash ERG in addition to clinical
examination. Based on the results of our study and
previous clinical studies, intravitreal infliximab ap-
peared to be very effective in cases of posterior
noninfectious uveitis including Behcet’sdisease.The
intravitreal infliximab dose of 1 mg was well toler-
ated with no observed adverse effects clinically and
by flash ERG. However, these effects were temporary
and reinjections were needed perhaps at intervals
shorter than 6 weeks. We should, however, consider
the limits of this study; small in size, nonrandomized,
short duration, and an open label design. At this
stage, we still believe in the cautious use of this drug,
especially in nonuveitic eyes, until larger randomized
clinical trials with longer durations establish a better
understanding of the benefits versus the risks of using
intravitreal infliximab.
Key words: intravitreal, infliximab, uveitis, Behcets
disease.
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