Download ARVO 2014 Annual Meeting Abstracts 283 Autoimmune Ocular

ARVO 2014 Annual Meeting Abstracts
283 Autoimmune Ocular Disease and Allergy
Monday, May 05, 2014 3:45 PM–5:30 PM
Exhibit/Poster Hall SA Poster Session
Program #/Board # Range: 2481–2520/C0001–C0040
Organizing Section: Immunology/Microbiology
Program Number: 2481 Poster Board Number: C0001
Presentation Time: 3:45 PM–5:30 PM
A model of allergic conjunctivitis in new zealand rabbits using
ragweed pollen
Paloma A. Marquez, Oscar Olvera, Yussett Contreras, Paulina
Melgarejo, Leopoldo M. Baiza-Duran, Jonathan Bonilla, Gabriela
Fregoso. pre-clinical, Laboratorios Sophia, Zapopan, Mexico.
Purpose: To develop a reproducible model of ocular allergy in new
zealand rabbits by assessing allergy clinical signs correlating IgE by
immunohistochemistry.
Methods: preclinical, prospective, longitudinal study. The study
subjects were 5 healthy male albino new zealand rabbits treated under
laboratory conditions and according to ARVO Statement for the
Use of Animals in Ophthalmic and Vision Research, these research
subjects were enumerated from 1 to 5 for its study. The allergen
used was ragweed pollen extract standardized high power (ambrosia
trifida). 100 mg were injected intraperitoneally three times during
the study on days 1, 8 and 15, on day 21 allergen challenge was
performed applying 400ug into the conjunctival sac.
The clinical review was performed by biomicroscopy and the
following signs of allergy were evaluated: conjunctival hyperemia,
eyelid edema, conjunctival edema and increased tear film, was
performed on days 0 (baseline ), 21 ( 20 minutes after allergen
challenge ), 22, 25 28 and 31; serum IgE levels were determined by
immunohistochemistry using ELISA Kit mybiosource, the blood
sample were taken on days 0, 8, 15, 21 (20 minutes after allergen
challenge ), 25, 28 and 31.
Results: On day 21 conjunctival hyperemia, eyelid edema,
conjunctival edema and increase in tear film were observed in a
moderate grade, on days 22, 25 and 28 these signs were mild and on
day 31 were absent. The mean concentration of serum IgE was 5.7pg/
ml baseline in subsequent measurements to the allergen challenge
showed a mean concentration of 8.2pg/ml, 7.4pg/ml, 7.1pg/ml and
6.6 pg / ml on day 21, 25, 28 and 31 respectively; being statistically
significant (p <0.05) compared with the baseline measurement on day
21.
Conclusions: In our model we found a relationship between clinical
signs of allergy and IgE mediated immune response, however did
not submit the severity reported in other allergic animal models
in efficacy studies. It will be necessary to modify the dose of
intraperitoneal sensitization in subsequent studies.
Commercial Relationships: Paloma A. Marquez, Laboratorios
Sophia (E); Oscar Olvera, Laboratorios Sophia (E); Yussett
Contreras, Laboratorios Sophia (E); Paulina Melgarejo,
Laboratorios Sophia (E); Leopoldo M. Baiza-Duran, Laboratorios
Sophia (E); Jonathan Bonilla, Laboratorios Sophia (E); Gabriela
Fregoso, Laboratorios Sophia (E)
Support: Laboratorios Sophia SA de CV
Program Number: 2482 Poster Board Number: C0002
Presentation Time: 3:45 PM–5:30 PM
The third generation of antihistamines: Assessment of Histamine
H1/H4 Receptor Antagonists in a Murine Model of Allergic
Conjunctivitis
Matt J. Chapin1, Laura Belen1, Andy Whitlock1, Jac Wijkmans2,
Tiffany van de Meer2, Mounir Andaloussi2, Rogier A. Smits2, Iwan de
Esch2, 3, Rob Leurs2, 3. 1ORA, Andover, MA; 2Griffin Discoveries BV,
Amsterdam, Netherlands; 3Medicinal Chemistry, Faculty of Exact
Sciences, VU University Amsterdam, Amsterdam, Netherlands.
Purpose: This study tested the hypothesis that drugs antagonizing
both the H1 and the H4 histamine receptors (H1R and H4R) may
provide superior relief for the signs and symptoms of allergic
conjunctivitis when compared to traditional allergy therapies.
Methods: The study employed a murine conjunctival allergen
challenge (CAC) model to test two structurally unrelated dual-action
H1R/H4R antagonists: GD134 and GD136, as well as selective
H4R antagonist GD135. Two positive comparators (olopatadine and
prednisolone) and a vehicle control were also tested. Test articles
were masked to investigators for the duration of the study. Animals
(female balb/c mice) were sensitized by injection with a short
ragweed allergen (SRW)/adjuvant mixture, and then challenged
with topical SRW 17 days later to confirm an allergic response. Nine
animals were randomly assigned to each of the 6 treatment groups.
Animals received topical applications of test agent on 3 consecutive
days, and then underwent CAC twice daily for 4 successive days;
test agents were also applied on these days. Mean group values
for hyperemia and squinting were compared with vehicle and with
baseline to determine test agent effects.
Results: Positive comparators reduced post-CAC hyperemia scores
relative to the vehicle controls; these reductions were significant
for prednisolone at challenge 1, 4, 6 and 8 (p <0.05). Both H1R/
H4R antagonists reduced hyperemia significantly (GD136, 3 of 4
challenges significant at p<0.05; GD134, 4 challenges significantly
lower at p<0.05). Selective H4R antagonist GD135 did not
significantly reduce hyperemia. Squinting scores exhibited a
progressive decline with each successive challenge, however only the
scores for olopatadine at challenge 8 were significantly reduced when
compared to controls (p<0.05).
Conclusions: Current antihistamine therapy for allergic conjunctivitis
focuses on antagonism of the H1R signaling pathway. Despite this,
recent studies have revealed not only a role for H4 receptors in
the etiology of itch, the hallmark symptom of ocular allergy, but
also identified the H4R as a new target to treat inflammation. Our
studies provide evidence that two of our test compounds, GD134
and GD136, may have potential efficacy in the treatment of allergic
conjunctivitis. Future studies, such as dose-ranging trials or studies in
humans will help to clarify their potential.
Commercial Relationships: Matt J. Chapin, Ora, Inc (E); Laura
Belen, Ora, Inc (E); Andy Whitlock, Ora, Inc (E); Jac Wijkmans,
Griffin Discoveries BV (E), Griffin Discoveries BV (P); Tiffany
van de Meer, Griffin Discoveries BV (E), Griffin Discoveries
BV (P); Mounir Andaloussi, Griffin Discoveries BV (E), Griffin
Discoveries BV (P); Rogier A. Smits, Griffin Discoveries BV (I),
Griffin Discoveries BV (P); Iwan de Esch, Griffin Discoveries BV
(I), Griffin Discoveries BV (P); Rob Leurs, Griffin Discoveries BV
(I), Griffin Discoveries BV (P)
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
Program Number: 2483 Poster Board Number: C0003
Presentation Time: 3:45 PM–5:30 PM
Automated Assessment of Conjunctival White Cell Infiltration by
Confocal Microscopy
Endri Angjeli, Colleen Heckley, Paul J. Gomes, Keith J. Lane. R&D,
Ora, Inc, Andover, MA.
Purpose: To develop an automated approach for the quantification of
inflammatory cell infiltration into the conjunctiva in the course of an
allergic inflammatory event.
Methods: The study examined allergen challenge responses in
subjects with a history of sensitivity to dust mites using a doublemasked, randomized, placebo-controlled protocol. Tears natural II
and Prednisolone Phosphate were used as placebo and active test
compounds. Entry criteria included both minimal response to allergen
challenge and maximal response to a saline (sham) challenge. Test
CAC was conducted following 5 days QID dosing of either placebo
or active. Evaluation criteria included (1) the number of white cells
within the vessel, (2) number of white cells on the vessel walls, and
(3) the number of cells in the tissue surrounding the vessel per unit
area, following a challenge. There were 13 subjects who completed
the study. An algorithm developed using Image J software was used
to quantify cells in images captured using an HRT II corneal module
confocal microscope. Images were captured immediately pre- and
post-challenge, and again at 16 hours post-challenge.
Results: Counts of cells for all 3 areas of interest were elevated
in placebo subjects compared to prednisolone-treated eyes; this
difference was statistically significant for cells apparently adhered
to the vessel walls at the 16 hour time point. Post-CAC time course
of these measures showed that this difference develops for many
hours following allergen challenge, demonstrating a chronic response
which was prevented by the topical steroid.
Conclusions: This study demonstrated that delayed time-points
such as the 16 hour post-CAC measure may be critical to the use of
automated methods going forward. Future efforts may employ time
course measures in which inflammation can be tracked from imaging
of white cells adhering to vessel walls to the process of diapedesis,
and subsequent dispersal of cells into surrounding tissues.
Commercial Relationships: Endri Angjeli, Ora, Inc (E); Colleen
Heckley, Ora, Inc (E); Paul J. Gomes, Ora, Inc (E); Keith J. Lane,
Ora, Inc (E)
Clinical Trial: NCT01730872
Program Number: 2484 Poster Board Number: C0004
Presentation Time: 3:45 PM–5:30 PM
Enhanced expression of conjunctival IL-9 co-localized with mast
cells in seasonal allergic conjunctivitis and its effect on mast cell
cytokine secretion via IL-9R
Amirah Mohd Zaki, Grazyna Galatowicz, Virginia L. Calder.
Department of Ocular Biology & Therapeutics, UCL Institute of
Opthalmology, London, United Kingdom.
Purpose: Mast cells (MC) are well known as the primary responders
in allergy, secreting pro-inflammatory mediators including cytokines
into the extracellular environment. IL-9 is a pro-inflammatory
cytokine that is associated with the immunopathogenesis of allergic
diseases including asthma. However, its role in allergic conjunctivitis
is still unknown. The aim of this study was to investigate conjunctival
expression of IL-9, and its role in cytokine secretion by mast cells.
Methods: Human anonymised conjunctival tissue biopsies (3μm)
were obtained from SAC donors (n=8, from all males; age: 18-65
years) at 8 hours’ post allergen challenge, and normal, non-inflamed,
conjunctival tissues from anonymised donors (n=8 from 3 males; age
31-57 years). Donor tissues were collected after obtaining informed
consent and Local Ethics approval in accordance with the Declaration
of Helsinki. Sequential tissue sections were stained for anti-human
IL-9 (Abcam), anti-human MC tryptase (AA1;DAKO) and primary
antibody was omitted as a negative control. Two independent,
masked observers enumerated positively stained cells per biopsy
area (at least three fields). To study the function of IL-9 in vitro, bone
marrow derived murine mouse mast cells (BMMCs) were exposed
to PMA/ionomycin, ionomycin alone or anti-IgE in the presence or
without anti-IL-9 or anti-IL-9R antibodies (R&D). Cytokine secretion
at 24, 48, 72, 96, and 120 hours was assayed using multiplex bead
arrays (Luminex).
Results: IL-9 expressing cells were detected mainly within the
subepithelial and stromal areas. There was a significant increase
in numbers of IL-9+ cells in SAC tissues (mean=10.25 ± 1.26)
compared to controls (mean= 25.00 ± 3.72; P<0.01). MC numbers
were increased in SAC tissues and co-localised with IL-9. IL-9 was
detected 24 hours’ post stimulation and reached its maximum at 48 hr
in response to PMA/ionomycin and anti-IgE and 96 hr in response to
ionomycin. Following neutralization of IL-9, secretion of IL-4, IL-5
and IL-13 was upregulated whereas these cytokine levels decreased
upon blocking IL-9R (P<0.05).
Conclusions: IL-9 expression within conjunctival tissues was
upregulated during challenge and is secreted by mast cells. In vitro
studies revealed that IL-9 affects IL-4, IL-5 and IL-13 secretion from
BMMC.
Commercial Relationships: Amirah Mohd Zaki, None; Grazyna
Galatowicz, None; Virginia L. Calder, None
Program Number: 2485 Poster Board Number: C0005
Presentation Time: 3:45 PM–5:30 PM
Dendritic Cell-produced IL-33 Links Microbial Pathogens to
Allergic Inflammation
De-Quan Li1, Zhitao Su1, 2, Jing Lin1, 3, Lili Zhang1, Cintia S. De
Paiva1, Stephen C. Pflugfelder1. 1Ocular Surface Center, Cullen Eye
Institute, Department of Ophthalmology, Baylor College of Medicine,
Houston, TX; 2School of Optometry and Ophthalmology, Wenzhou
Medical University, Wenzhou, China; 3Ophthalmology, Affiliated
Hospital of Qingdao University Medical College, Qingdao, China.
Purpose: Interleukin-33 (IL-33) has been identified as a novel proallergic cytokine that initiate Th2-dominant allergic inflammation.
Dendritic cells (DCs) are major innate immunity cells; however,
it is not clear whether DCs produce IL-33. This study identified
a novel mechanism by which DCs links microbial pathogens to
allergic inflammation via Toll-like receptor (TLR), NF-κB and IL-33
signaling pathway.
Methods: Mouse bone marrow derived DCs were treated with or
without microbial pathogens or recombinant mouse (rm) IL-33. The
mRNA expression was determined by reverse transcription and real
time PCR, and protein production was evaluated by ELISA, Western
blotting, immunofluorescent staining and flow cytometry.
Results: IL-33 mRNA and protein were found to be expressed by
DCs and largely induced by specific microbial pathogens, especially
lipopolysaccharide (LPS) and flagellin, the ligands to TLR4 and
TLR5 respectively. Using a mouse model of topical challenge by LPS
and flagellin, IL-33-producing DCs were observed in ocular mucosal
surface and the draining cervical lymph nodes. LPS and flagellin
were found to promote DC maturation with enhanced expression of
CD40, CD80, CD86 and MHC classs II. The increased expression
of MyD88, NF-κB1, NF-κB2 and RelA accompanied by NF-κB p65
activation with nuclear translocation was observed in DCs exposed to
flagellin. The IL-33 induction by flagellin was significantly blocked
by TLR5 antibody or NFκB activation inhibitor quinazoline. When
treated with rmIL-33, DCs were activated to express the increased
maturation markers CD40 and CD80, stimulated Th2 (IL-4, IL-5 and
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
IL-13) and inflammatory mediators (TNFα, IL-1β and CCL17), as
well as OX40L that enables amplification of Th2 cell differentiation.
This stimulatory effect of IL-33 in DCs was significantly blocked by
ST2 antibody or soluble ST2.
Conclusions: These findings demonstrate that DCs produce IL-33 via
TLR/NF-κB signaling pathways, suggesting a molecular mechanism
by which local allergic inflammatory response may be amplified by
DC-produced IL-33.
Commercial Relationships: De-Quan Li, None; Zhitao Su, None;
Jing Lin, None; Lili Zhang, None; Cintia S. De Paiva, None;
Stephen C. Pflugfelder, None
Support: National Institutes of Health grant EY11915 (SCP), an
unrestricted grant from Research to Prevent Blindness, the Oshman
Foundation and the William Stamps Farish Fund.
Program Number: 2486 Poster Board Number: C0006
Presentation Time: 3:45 PM–5:30 PM
Role of Chemokine C-C motif ligand 7 in Type I Hypersensitivity
Reactions in Murine Experimental Allergic Conjunctivitis
Chuan-Hui Kuo1, Andrea Collins1, Santa J. Ono1, 2. 1Allergy &
Immunology, Cincinnati Children’s Hospital, Cincinnati, OH;
2
University of Cincinnati, Cincinnati, OH.
Purpose: Molecules that are necessary for ocular hypersensitivity
reactions include the chemokine receptors CCR1 and CCR3;
chemokine C-C motif ligand 7 (CCL7) is a genetic target and ligand
for these receptors. Therefore, we hypothesized that CCL7 mediates
ocular hypersensitivity reactions and investigated CCL7’s necessity
in a murine model of IgE-mediated allergic conjunctivitis using wildtype (WT) and CCL7-deficient mice.
Methods: Allergic conjunctivitis was induced in WT and CCL7deficient mice. Mice were sensitized with OVA/alum intraperitoneally
and subjected to OVA-induced ocular anaphylaxis via eye drops.
Early-phase reactions including clinical symptoms, gene expressions
and pathological changes in the conjunctival tissue were evaluated.
Bone marrow–derived mast cells (BMMCs) from WT and CCL7deficient mice were sensitized and activated. β-hexosaminidase
activity was measured by incubating the supernatants with
p-nitrophenyl N-acetyl-β-D- glucosaminide.
Results: The early-phase clinical symptoms in the conjunctiva after
OVA challenge were significantly higher in OVA-sensitized than
in vehicle-sensitized WT mice, but this OVA-induced increase was
suppressed in CCL7-deficient mice. The mRNAs for FcεRIα and
the connective tissue-type mast cell proteases were detected in the
conjunctiva of both OVA-induced WT and CCL7-deficient mice.
Notably, in OVA-induced anaphylaxis, the number of conjunctival
mast cells was lower in CCL7-deficient than in WT mice, and
BMMCs from CCL7-deficient mice showed decreased degranulation
with IgE and antigen treatment compared with BMMCs from WT
mice.
Conclusions: Our results demonstrate that chemokine CCL7
deficiency suppressed OVA-induced ocular anaphylaxis, including
regulating mast cell recruitment in vivo and reducing FcεRI-mediated
mast cell activation in vitro. A better understanding of CCL7’s roles
in mediating ocular hypersensitivity reactions will provide insights
into mast cell function and novel treatments for allergic ocular
diseases.
Commercial Relationships: Chuan-Hui Kuo, None; Andrea
Collins, None; Santa J. Ono, None
Support: NIH R01-EY-019630-01
Program Number: 2487 Poster Board Number: C0007
Presentation Time: 3:45 PM–5:30 PM
Airborne Particulate Matter (PM2.5) and Prevalence of Allergic
Conjunctivitis in Japan
Tatsuya Mimura, Masao Matsubara. Department of Ophthalmology,
Tokyo Women’s Med Univ Med Ctr East, Arakawa-ku, Japan.
Purpose: Exposure to particulate matter less than 2.5 μm in
aerodynamic diameter (PM2.5) was associated with increasing
severity of asthma and respiratory symptoms; however, little is
known about the effect of PM2.5 with allergic conjunctivitis. The
purpose of this study is to examine the associations of PM2.5 on the
daily clinical visits for allergic conjunctivitis.
Methods: We conducted a time-series analysis of associations
between outpatient visits for allergic conjunctivitis and PM2.5
concentrations during May to July (non-pollen season) and August to
October 2012 (autumnal pollen season). Air pollution data including
PM2.5, oxidant, nitric oxide, nitrogen dioxide, nitrogen oxide,
carbon monoxide, methane, non-methane hydrocarbons, and total
hydrocarbons, and daily weather conditions (temperatures, wind
speed and humidity) were collected at a centrally located monitor
in Tokyo. We calculated weekly averages for the daily number of
outpatient visits and data of air pollution and weather conditions and
used the weekly average data for the analysis.
Results: The only significant association obtained was between
outpatient visits for allergic conjunctivitis and the concentration of
PM2.5 (r=0.62, p=0.0177) during May to July, while, no correlation
was found between the number of outpatients and any variables of
air conditions during August to November. Multivariate analysis also
showed that significant predictor of the number of outpatients was
the concentration of PM2.5 during May to July (odds ratio=9.05,
p=0.0463), while there were no significant predictors of the number
of outpatients during August to October. During May to July, PM2.5
was negatively correlated with humidity (r=-0.53, p=0.0499).
Conclusions: These results suggest a possible role for PM2.5 in the
development of allergic conjunctivitis during non-pollen season.
Moreover, the observed association between PM2.5 and allergic
conjunctivitis has a broad public health impact on allergic diseases.
Commercial Relationships: Tatsuya Mimura, None; Masao
Matsubara, None
Support: a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology of Japan.
Program Number: 2488 Poster Board Number: C0008
Presentation Time: 3:45 PM–5:30 PM
Phase 3 Study of Efficacy and Safety of Once-daily Olopatadine
Hydrochloride, 0.77% Ophthalmic Formulation in Patients With
Allergic Conjunctivitis Using the Ora Conjunctival Allergen
Challenge Model (Ora-CAC™*) (NCT01743027)
Eugene McLaurin1, Abhijit Narvekar2, Paul J. Gomes3. 1Total Eye
Care, P.A., Memphis, TN; 2Alcon Research Ltd, Fort Worth, TX; 3VP
Allergy, Ora Inc., Andover, MA.
Purpose: To assess the efficacy and safety of a new, once-daily
olopatadine 0.77% formulation compared with olopatadine
0.2%, olopatadine 0.1%, or vehicle for the treatment of allergic
conjunctivitis.
Methods: This multicenter, double-blind, parallel-group, vehicleand active-controlled study randomized patients with a history of
allergic conjunctivitis (N=345; ≥18 years) 2:2:2:1 to olopatadine
0.77% (n=98), olopatadine 0.2% (n=99), olopatadine 0.1% (n=99),
or vehicle (n=49). The primary endpoint was ocular itching (OI; at 3,
5 and 7 minutes post-CAC) at onset of action and 24-hours duration
of action for olopatadine 0.77% versus vehicle, and OI at 24-hours
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
duration of action for olopatadine 0.77% versus olopatadine 0.2% or
olopatadine 0.1%.
Results: Olopatadine 0.77% was superior (p<0.0001) to vehicle for
OI at all post-CAC time-points at onset and 24-hours duration of
action. Differences in means (olopatadine 0.77% – vehicle) were:
–1.53, –1.46, –1.17 (onset) and –1.29, –1.15, –0.89 (24 hours) for
olopatadine 0.77% at 3, 5 and 7 minutes post-CAC, respectively.
Olopatadine 0.77% was also superior to olopatadine 0.1% for the
treatment of OI at 24-hours duration of action at all post-CAC time
points, and superior to olopatadine 0.2% at 3 and 5 minutes postCAC (Table 1). There were no clinically relevant changes in safety
parameters from baseline across the treatment groups, and a review of
adverse events did not reveal any safety issues for olopatadine 0.77%.
Conclusions: Olopatadine 0.77% was superior to vehicle,
olopatadine 0.1% and olopatadine 0.2% with respect to reduction
of OI associated with allergic conjunctivitis 24 hours after dosing.
Olopatadine 0.77% had a safety profile comparable to olopatadine
0.1% and olopatadine 0.2%. The superior efficacy at 24 hours of
olopatadine 0.77% supports potential once-daily administration and
a longer duration of symptom relief compared with olopatadine 0.1%
and olopatadine 0.2%.
*Ora-CAC™ and Ora Calibra™ are trademarks of Ora, Inc. The Ora
Conjunctival Allergen Challenge Model and Ocular Itching Scale are
owned by Ora, Inc.
Commercial Relationships: Eugene McLaurin, Aciex (F), Acucela
(F), Alcon (F), Allergan (F), AstraZeneca (F), Bausch & Lomb (F),
Inotek Pharma (F), InSite Vision (F), Lexicon Pharma (F); Abhijit
Narvekar, Alcon Research Ltd (E); Paul J. Gomes, Ora, Inc. (E)
Support: Alcon Research
Clinical Trial: NCT01743027
Program Number: 2489 Poster Board Number: C0009
Presentation Time: 3:45 PM–5:30 PM
Frequency and severity of ocular allergy symptoms in Sydney
across seasons and their association with pollen levels
Sailesh Kolanu1, Blanka Golebiowski1, Connie Katelaris2, Pamela
Burton2, Isabelle Jalbert1. 1School of Optometry and Vision Science,
The University of New South Wales, Sydney, NSW, Australia;
2
Campbelltown Hospital, University of Western Sydney, Sydney,
NSW, Australia.
Purpose: Climate change can lead to an increase in levels and
allergenicity of environmental pollen, posing a risk of increase
in allergies. We measured the frequency and severity of ocular
symptoms and their association with pollen levels across seasons.
Methods: 632 university students and staff in Sydney were invited
to complete a self-administered online survey. Eye Allergy Patient
Impact Questionnaire (EAPIQ) and Aston University Allergy
Questionnaire (AUAQ) were completed in 2012 (spring1) and
2013 (autumn, winter and spring2). Burkard volumetric trap was
used for daily grass, weed, tree and total pollen counts. Frequency,
troublesomeness, severity of ocular symptoms (dryness, itchiness,
need to rub, burning, stinging, redness, watering, swelling/puffiness)
and AUAQ symptom severity score (0-21) were compared within
(one way ANOVA) and between seasons (repeated measures
ANOVA). Bonferroni corrected posthoc analysis was used.
Associations between pollen counts and symptoms were examined
using Spearman Correlation.
Results: 53 subjects completed all phases (age: 28±11 yrs, range
19-63). Tree, weed and total pollen counts were higher in spring
(37±20, 8±4, 61±26 n/m3 respectively) than in other seasons
(12±16, 2±2, 19±24 n/m3 respectively) (p<0.05). Grass pollen
levels remained constant in spring and autumn (13±7 n/m3) but
decreased to 0 in winter (p<0.001). Severity and troublesomeness of
dry eyes were higher in spring2 than in autumn (p<0.03). Severity
of burning eyes and red eyes were higher in spring2 than in autumn
(p<0.01). Symptom severity score was higher in spring2 than in
autumn or spring1 (p<0.01). Dry eyes (61-74%) and itchy/burning
eyes (50-59%) were reported as the most frequent symptoms in all
phases. Frequency and troublesomeness of dry eyes were higher
than that of red eyes, watery eyes or swollen/puffy eyes in all
seasons (p<0.05). Symptom severity score was correlated with grass
(ρ=0.32;p=0.005), weed (ρ=0.35;p=0.002), tree (ρ=0.35;p=0.002)
and total (ρ=0.33;p=0.03) pollen count during autumn and only weed
pollen count (ρ=0.3;p=0.01) during winter.
Conclusions: Mild ocular symptoms are frequent in Sydney
throughout the year and their severity was higher in spring than in
autumn. Further analyses including climatic variables and subject
behaviour are required in order to understand the relationship
between symptoms and pollen counts.
Commercial Relationships: Sailesh Kolanu, None; Blanka
Golebiowski, None; Connie Katelaris, None; Pamela Burton,
None; Isabelle Jalbert, None
Support: FRGP grant and UIPA scholarship, UNSW
Program Number: 2490 Poster Board Number: C0010
Presentation Time: 3:45 PM–5:30 PM
Evaluation of the Onset and Duration of Action of Topical
Cetirizine (AC-170 0. 24%) for the Prevention of Allergic
Conjunctivitis
Paul J. Gomes1, Yesha Raval1, Emily Schoemmell1, Donna L. Welch2.
1
Allergy, ORA, Andover, MA; 2Ora, Inc, Andover, MA.
Purpose: : In this phase 3, multicenter, vehicle-controlled, doubleblinded, randomized trial we evaluated the onset and duration of
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
action of topical cetirizine 0.24% using the conjunctival allergen
challenge model of allergic conjunctivitis.
Methods: The trial (NCT01881113) was conducted between June
and September of 2013, and enrolled a total of 101 subjects; this
number constituted the intent-to-treat and safety populations, while
the per-protocol population included 87 subjects. Qualified subjects
exhibited reproducible allergic responses to bilateral instillation
of allergen. Following randomization, they were challenged with
allergen on 2 separate visits, 15 minutes or 8 hours after receiving
bilateral instillation of test compound or vehicle. Primary efficacy
measures were ocular itching scores (at 3, 5, and 7 minutes postchallenge) and ocular hyperemia (at 7, 15, and 20 minutes postchallenge). Secondary endpoints included ciliary and episcleral
redness, chemosis, eyelid swelling, and ear/palate pruritis; each of
these were scored at 7, 15, and 20 minutes post challenge.
Results: For the primary endpoint of ocular itching, Cetirizine was
statistically superior to vehicle for the onset of action (challenge 15
minutes post-instillation; p < 0.0001) at all measured time points;
the drug was also statistically superior to vehicle 8 hours after
instillation (p < 0.0001). In a subgroup analysis, the drug exhibited
highest efficacy in those subjects with the most severe baseline
itch scores. Cetirizine was superior to vehicle for all secondary
endpoints, including all measures of hyperemia. Of particular note,
drug treatments were statistically superior to vehicle for prevention of
eyelid swelling and ear/palate pruritis at all measured time points (p<
0.001), suggesting a unique spectrum of efficacy. The study drug was
safe and well tolerated; no subjects withdrew from the study due to
any adverse event.
Conclusions: Cetirizine is one of the most commonly used oral
agents for treatment of allergic rhinitis, but its re-formulation for
topical use in treatment of allergic conjunctivitis is novel. This study
demonstrates the efficacy of the drug for prevention of ocular itching
associated with allergic conjunctivitis, and also establishes its unique
spectrum of action against other allergic symptoms.
Commercial Relationships: Paul J. Gomes, Ora, Inc (E); Yesha
Raval, Ora, Inc (E); Emily Schoemmell, Ora, Inc (E); Donna L.
Welch, Ora, Inc (E)
Support: Supported by Aciex Therapeutics, Inc.
Clinical Trial: NCT01881113
Program Number: 2491 Poster Board Number: C0011
Presentation Time: 3:45 PM–5:30 PM
Allergic conjunctivitis: a national cross-sectional study
Angela Castegnaro1, Federico Piliego1, Daniela Lazzarini1, Alvise La
Gloria Valerio1, Paolo Mattana2, Iva A. Fregona1, Andrea Leonardi1.
1
Neuroscience, Ophthalmology Unit, University of Padua, Padova,
Italy; 2Medical Service, Alfa Wassermann, Bologna, Italy.
Purpose: Ocular allergy is one of the most common ocular problems
in daily practice affecting 20% of the general population. A crosssectional study was conducted during the spring-summer of 2012 to
evaluate clinical aspects and therapeutic approach of ocular allergy in
Italy.
Methods: A total of 3685 patients affected by ocular allergy were
enrolled by 304 ophthalmology centers across different geographic
regions in Italy. A structured questionnaire was administered to
record demographic data, family history, co-morbidities, allergy
test results, trigger factors, number of episodes of ocular allergy
in the last year. Nine signs and symptoms were scored according
the severity, frequency and duration. Patients were divide into 6
clinical forms: SAC, PAC, VKC, AKC, GPC and contact blepharoconjunctivitis (CBC). Medical treatment in the last year was recorded
by drug classes.
Results: Out of 3685 records, 3545 were assessable. The mean age
of enrolled patients was 38±19 years (56% female). SAC (55% of
patients) and AKC (7%) were equally distributed among the different
age groups, while PAC (18%) increased with age and VKC (8%) was
more frequent under age of 16. GPC (4%) was more frequent in the
group 16-30 year of age. CBC (7%) was more frequent over 45. In
the entire population of patients, itching and redness were reported
in 94% and 85%, respectively, lid skin involvement in 22% of cases
and keratitis in 11%. However, only 35% of patients underwent to
an allergy diagnostic evaluation, with positive results in 40% of
cases. 68% of the patients reported 1-5 episodes of conjunctivitis in
the last year, 6% >10 episodes/year. Considering the entire patients
population, over the counter decongestants/ antihistamines were
used in 43%, corticosteroids in 41%, topical antihistamines in 29%,
systemic antihistamines in 27%, mast cell stabilizers in 15% and
antibiotics in 6% of cases. In the SAC group, 26% used systemic
antihistamines, 31% topical antihistamines and 44% over the counter
decongestants/antihistamines. Corticosteroids were used in 67% of
GPC, 55% of VKC, 53% of AKC, 47% of CBC, in 43% of PAC and
28% of SAC.
Conclusions: This survey, based on a simple questionnaire,
has provided extremely useful information regarding clinical
characteristics, risk factors and treatment options of a large cohort of
patients affected by different forms of ocular allergy and stimulates
further studies on the clinical evolution and management of these
diseases.
Commercial Relationships: Angela Castegnaro, None; Federico
Piliego, None; Daniela Lazzarini, None; Alvise La Gloria Valerio,
None; Paolo Mattana, None; Iva A. Fregona, None; Andrea
Leonardi, None
Program Number: 2492 Poster Board Number: C0012
Presentation Time: 3:45 PM–5:30 PM
Retrospective study to evaluate the efficacy on vernal keratoconjunctivitis (VKC) of 2% Ectoine versus 0.05% ketotifen
eye-drops
Pia Allegri1, Giuseppina Marrazzo2, Chiara Ciurlo1, Antonio
Mastromarino1, Silvia Autuori1, Ugo Murialdo1. 1Eye inflammatory
department, Allergic Conjunctivitis Outpatients Department of
Rapallo Hospital, Genoa, Italy; 2R&D Alfa Intes, Casoria, Italy.
Purpose: Ectoine is a strong water structure-forming solute. It exerts
cell-protective, anti-inflammatory and anti-allergic activity. VKC is
a rare, severe, challenging seasonal eye-allergic childhood disease
managed in our referral hospital center. We underwent a retrospective
case series review to evaluate and compare, when administered in
pre-allergic and allergic period, the efficacy of this solution versus
0.05% Ketotifen eye drops (Ketoftil®) on signs and symptoms of
VKC
Methods: We evaluated records from 64 male pediatric subjects
(mean age 8.5 y ± 2 months) and divided it into two groups of
patients treated three times a-day with Ectoine 2% (Group A)
and patients treated with 0.05% Ketotifen eye drops (Group B).
The included patients were evaluated from February 2013 until
November 2013 on three visits (at the beginning of treatment, 3
(±10 days) months later and 6 (±20 days) months).Main criteria
of statistical evaluation were for VKC slit-lamp signs: Focal or
diffuse conjunctival hyperemia; BUT; Modified Oxford scale; VKC
grading (modified Bonini scale); and for VKC signs: VAS scale
grading ( ocular pain, itching, tearing, photophobia and foreign body
sensation); Quick questionnaire on tolerance of the formulation. We
compared the previous year treatment and evaluated the beginning of
Cyclosporine eye drops treatment compared to the previous season
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
and the different Cyclosporine dosages (0.25%-0.5%-1%-2%) used
before
Results: When evaluating symptoms and signs of VKC patients, both
groups showed a significant improvement (p<0.0001) from baseline
and at three and six months after treatment. Althought we found a
significant difference (p<0.0001) between the two treatments on the
tolerability at each time point. Furthermore both drugs delayed the
beginning of treatment with Cyclosporine eye drops and reduced the
concentration dosage.
Conclusions: Our case series review allowed us to establish that
both topic treatments with 2% Ectoine as well as 0.05% Ketotifen
are effective in improving signs and symptoms of VKC and to delay
the adjuvant treatment with Cyclosporin. Therefore, we can conclude
that Ectoine (a natural compound without any side effects) can be
considered, in efficacy, equal to Ketotifen and is better tolerated
by pediatric patients. Further studies with the inclusion of a bigger
number of subjects are required.
Commercial Relationships: Pia Allegri, None; Giuseppina
Marrazzo, Alfa Intes (E); Chiara Ciurlo, None; Antonio
Mastromarino, None; Silvia Autuori, None; Ugo Murialdo, None
Program Number: 2493 Poster Board Number: C0013
Presentation Time: 3:45 PM–5:30 PM
Suppression of experimental autoimmune uveitis (EAU) and
recovery from uveitis correlate with expansion of regulatory B
cells (Breg)
Chengrong Yu, Ivy M. Dambuza, Sung-Hye Kim, Rashid M. Mahdi,
Charles Egwuagu. Laboratory Immunology, National Eye Inst/NIH,
Bethesda, MD.
Purpose: Regulatory B cells (Bregs), characterized by expression
of the immunoregulatory cytokine IL-10, have been implicated in
the suppression of excessive inflammatory responses that lead to
inflammatory and autoimmune mediated diseases (Ann Rev Imm
30:221, 2012). However, it is not clear whether it has a role in
suppressing intraocular inflammation and/or the maintenance of
ocular immune privilege. In this study, we have therefore examined
whether the suppression of experimental autoimmune uveitis (EAU)
or recovery from EAU correlates with expansion of Bregs.
Methods: Autoimmune uveitis was induced by active immunization
with IRBP (interphotoreceptor retinoid-binding protein in CFA
(Complete Freund’s adjuvant) in C57BL/6J mice. Disease
progression was monitored by clinical grading of EAU by
fundoscopy and histology. To characterize B cell populations
recruited into the spleen and draining lymph-nodes at the peak of the
disease (day 21 post-immunization) or during the recovery phase of
EAU (day 28 post-immunization) single cell suspensions from these
tissues were stained with anti-CD3, CB4, CD19, CD1d, CD5, CD21,
CD23, IgM, and IgD and analyzed by multicolor flow cytometry.
Cells were also stimulated with LPS/PMA/Ionomycin for 5 hour and
intracellular IL-10 was measured FACS. Naïve CD19+ B cells were
sorted and then activated by anti-CD40 antibody or LPS for IL-10
detection by RT-PCR and intracellular cytokine staining.
Results: We show that total number of B cells were significantly
increased in spleen and draining lymph nodes during EAU. We
further show that the major regulatory B cell population at day
21 post immunization were CD1dhi CD5hi IL-10-producing B
cells. Interestingly, we found that there were twice as many IL10-producing B cells (5.4%) than IL-10-producing T cells (2.4%),
suggesting that Breg may play a role during the recovery phase of the
disease.
Conclusions: We show here for the first time that Breg are
expanded during autoimmune uveitis and may play important role
in suppressing intraocular inflammation and in the maintenance of
ocular immune privilege.
Commercial Relationships: Chengrong Yu, None; Ivy M.
Dambuza, None; Sung-Hye Kim, None; Rashid M. Mahdi, None;
Charles Egwuagu, None
Program Number: 2494 Poster Board Number: C0014
Presentation Time: 3:45 PM–5:30 PM
Immunosuppressive function of exosomes isolated from
circulating blood of the mice with experimental autoimmune
uveitis (EAU)
Guomin Jiang, Amir R. Hajrasouliha, Yunsong Wang, Henry J.
Kaplan, Hui Shao. Department of Ophthalmology, University of
Louisville, Louisville, KY.
Purpose: To determine whether exosomes isolated from the sera of
EAU mice contain uveitogenic interphotoreceptor petinoid binding
protein (IRBP), and whether these IRBP-containing exosomes are
immunogenic or tolerogenic.
Methods: EAU was induced in C57BL/6 (B6) mice by immunization
with IRBP1-20 peptides emulsified with complete Freund’s adjuvant.
Exosomes were extracted from the sera of naïve and diseased mice
by ultra-speed centrifuge. The presence of IRBP in the exosomes
was examined by western blot using anti-IRBP Ab. IRBP-specific T
cell responses after incubation with IRBP containing exosomes were
tested by T cell proliferation assay. The severity of EAU treated with
or without IRBP-containing exosomes was evaluated by histology.
Results: Exosomes from the sera of EAU mice expressed
significantly high level of IRBP compared to those from naïve mice.
These IRBP containing exosomes inhibited the proliferation of
uveitogenic T cells in vitro and suppressed the uveitis induced by
IRBP-specific T cells in vivo.
Conclusions: IRBP-containing exosomes was detected in the
peripheral blood, which might deliver immunosuppressive signals
to autoimmune T cells and might be used as a novel therapy for
autoimmune uveitis.
Commercial Relationships: Guomin Jiang, None; Amir R.
Hajrasouliha, None; Yunsong Wang, None; Henry J. Kaplan,
None; Hui Shao, None
Support: NEI/NIH grant EY12974 (HS), RPB Lew R Wasserman
Merit Award (HS), Commonwealth of Kentucky Research Challenge
Trust Fund (HK). IRIG grant of university of Louisville (GJ). Fight
for Sight (GJ)
Program Number: 2495 Poster Board Number: C0015
Presentation Time: 3:45 PM–5:30 PM
Intravitreal leukocytes change plasma cell membrane expression
pattern in spontaneous recurrent uveitis
Cornelia A. Deeg1, Nina B. Burkhardt1, Roxane L. Degroote1,
Barbara Amann1, Marius Ueffing2, 3, Stefanie M. Hauck2. 1Department
of Veterinary Sciences, LMU Munich, Munich, Germany; 2Helmholtz
Center Munich, Research Unit for Protein Scienceute for Animal
Physiology, Munich, Germany; 3Centre for Ophthalmology,
University of Tübingen, Institute for Ophthalmic Research, Tübingen,
Germany.
Purpose: Horses frequently (10%) develop spontaneous recurrent
uveitis (ERU), an autoimmune mediated disease. Pathophysiology is
driven by lymphocytes that enter the inner eye through outer bloodretinal barrier and destroy retinal proteins. In order to understand
differences in cell surface phenotype of peripheral blood derived
lymphocytes and intraocular lymphocytes, we chose a differential
proteomics approach, determining plasma cell surface protein
phenotypes in healthy and diseased cells.
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
Methods: Peripheral blood derived lymphocytes (PBL) were
separated from horses with spontaneous equine recurrent uveitis,
that were presented to Equine Clinic of LMU Munich for therapeutic
vitrectomy. Intraocular lymphocytes (VL) were separated from
vitreous obtained during pars plana surgery. Amount of PBL used
in experiments was adjusted to total amount of cells obtained from
intraocular surgery (around 1 x 104 cells) for comparison of protein
expression. Cell surface proteins were covalently labeled with biotin,
affinity purified and released by PNGase F. Detection, identification
and quantification of respective proteins was carried out with label
free mass spectrometry.
Results: Our approach resulted in clear identification of 206
proteins in PBL and 212 proteins in VL preparation of plasma
cell membrane proteins. Of these, 196 proteins were identified in
both fractions. Overall, eight proteins were ≥ 5 fold enriched in
immune cells separated from vitreous. In contrast, 14 proteins were
enriched in PBL fraction (factor ≥ 5). Interestingly, upregulated
proteins in VL comprise activated sushi domain containing 2,
matrix metallopeptidase 25 and leukocyte cell adhesion molecule.
Downregulated candidates were semaphorin 4D, atlastin GTPase 3,
interferon (alpha, beta and omega) receptor 1 and Fas.
Conclusions: Cell surface analysis of ERU effector cells was suited
to generate a cell surface proteome profile and to detect specific
changes in intraocular lymphocytes of ERU cases. This will help
to understand inflammation associated changes in a spontaneous
autoimmune disease.
Commercial Relationships: Cornelia A. Deeg, None; Nina B.
Burkhardt, None; Roxane L. Degroote, None; Barbara Amann,
None; Marius Ueffing, None; Stefanie M. Hauck, None
Support: DFG DE 719/4-1
Program Number: 2496 Poster Board Number: C0016
Presentation Time: 3:45 PM–5:30 PM
Complete Freunds Adjuvant can protect from Retinal
Autoimmunity by an Interleukin-10 dependent mechanism
Rafael S. Grajewski, Rebecca Scholz, Deniz Hos, Claus Cursiefen,
Ludwig M. Heindl. Department of Ophthalmology, University of
Cologne, Cologne, Germany.
Purpose: Complete Freunds Adjuvant (CFA) is an oily emulsion
with mycobacterial components that is used as an adjuvant to induce
antigen-specific autoimmunity, such as experimental autoimmune
uveitis (EAU). Our previous work demonstrated that CFA is also
capable of non-specific activation of regulatory T cells (Treg). The
purpose of the present study was to analyze the immunoregulatory
properties of CFA in EAU.
Methods: Wild-type (WT) and IL-10 knockout (KO) C57Bl/6 mice
were pre-treated by subcutaneous injection of CFA or Incomplete
Freunds Adjuvant (IFA) seven days before induction of EAU by
immunization with IRBP peptide 1-20 emulsified in CFA and with
Pertussis-Toxin (PTX). EAU scores (scale ranging in severity from
0= no disease to 4 = complete retinal destruction) and associated
immunological responses (delayed type hypersensitivity, DTH) were
examined.
Results: Pre-treatment with CFA in WT mice (CFA/WT) significantly
reduced incidence (p=0.049) and severity (p=0.005) of EAU
compared to IFA pre-treatment (IFA/WT). Conversely, pre-treatment
of KO mice with CFA (CFA/KO) did not alter incidence and severity
of EAU, when compared to IFA pre-treatment of KO mice (IFA/
KO). Comparably, the DTH response was significantly lower in the
CFA/WT than in the IFA/WT group (p=0.016) and not significantly
different in the CFA/KO versus the IFA/KO group. EAU scores and
incidence, as well as DTH were not statistically different between the
control groups of the two mouse strains (IFA/WT versus IFA/KO).
Conclusions: Although CFA is needed to induce EAU, it partially
also has immunosuppressive properties that may be utilized, when it
is administered before immunization with antigen. This effect seems
to represent an active immunosuppressive mechanism rather than
being due to passive exhaustion of effector mechanisms, because it is
dependent on the presence of IL-10.
Commercial Relationships: Rafael S. Grajewski, None; Rebecca
Scholz, None; Deniz Hos, None; Claus Cursiefen, None; Ludwig
M. Heindl, None
Support: German Research Foundation: DFG GR 2647/4-1
Program Number: 2497 Poster Board Number: C0017
Presentation Time: 3:45 PM–5:30 PM
Altering the gut microbiota ameliorates experimental
autoimmune uveitis
Yukiko Nakamura1, Christina Metea1, Henry Gruner1, Mark Asquith3,
Stephen R. Planck1, 2, James T. Rosenbaum1, 2, Phoebe Lin1. 1Casey
Eye Institute, Oregon Health & Science University, Portland, OR;
2
Ophthalmology, Devers Eye Institute, Portland, Oregon, Portland,
OR; 3Rheumatology, Oregon Health and Science University,
Portland, OR.
Purpose: The gut microbiota appear to be important in the regulation
of a number of immune-mediated diseases including multiple
sclerosis, diabetes mellitus, and inflammatory bowel disease, but the
relationship between the gut microbiome and autoimmune uveitis
has not yet been determined. The objective of this study was to
investigate whether altering the gut microbiota with broad-spectrum
antibiotics affects the severity of experimental autoimmune uveitis
(EAU).
Methods: Interphotoreceptor binding protein (IRBP) peptide 161-180
was used to induce uveitis in B10.RIII mice. Mice were treated with
oral or intraperitoneal (ip) antibiotics (1 mg/mL each of ampicillin,
neomycin sulfate, and metronidazole, 0.5 mg/mL of vancomycin)
starting 1 week prior to antigen challenge. Eyes, spleen, cervical
and mesenteric lymph nodes (CLN, MLN), and lamina propia
lymphocytes (LPL) were collected on day 20-21. We performed
clinical and histological grading of eyes, as well as flow cytometry
analysis for quantifying regulatory T-cell (Treg) populations.
Results: A smaller proportion of antibiotic-fed animals had clinical
EAU scores ≥ 2.5 compared with water-fed animals (7.7% vs 46.1%,
p=0.048, OR=9.0) (Fig. 1a). The histopathological EAU scores
followed a similar trend with 22.2% eyes in the antibiotic-fed group
compared to 76.9% eyes in the water-fed group developing a score
≥ 2.5 (p=0.011, OR=11.67, Fig. 1b). No significant difference in
scores was found between ip antibiotic compared to ip control groups
(clinical: 33% vs. 44.4%, p=0.625, OR=0.629; histopathological:
50% vs 75%, p=0.302, OR=0.33). There were higher proportions of
Treg (CD4+, FoxP3+) cells in the CLN, MLN, spleen, and LPL of
oral antibiotic-fed mice compared to water-fed mice.
Conclusions: Our results suggest that alteration of the gut microbiota
by oral antibiotic administration modulates the development of EAU.
Further investigation of the Treg populations associated with the
gut microbial change will be warranted to determine the underlying
mechanism.
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
Commercial Relationships: Gerhild Wildner, None; Andrea
Huber, None; Maria Diedrichs-Möhring, None
Fig. 1. Altering the gut microbiota ameliorates EAU in B10.RIII
mice.(A) Clinical scores at peak inflammation (day 13-14) in 3
experiments (n=4-5, each experiment)(B) Histological scores at the
end of the experiment (day 20-21) in 2 experiments (n=4-5, each
experiment).
Commercial Relationships: Yukiko Nakamura, None; Christina
Metea, None; Henry Gruner, None; Mark Asquith, None; Stephen
R. Planck, None; James T. Rosenbaum, None; Phoebe Lin, None
Program Number: 2498 Poster Board Number: C0018
Presentation Time: 3:45 PM–5:30 PM
Therapy of relapsing-remitting experimental uveitis in rats by
oral tolerance induction
Gerhild Wildner, Andrea Huber, Maria Diedrichs-Möhring.
Ophthalmology, Clinic of the University of Munich LMU, Munich,
Germany.
Purpose: Antigen-specific tolerance induction would be a desired
therapy for uveitis patients. Our relapsing-remitting EAU rat
model, induced by immunization with IRBP peptide R14 offers
the possibility to test the effect of oral tolerance induction on the
prevention of relapses. We tested several peptides with sequences
overlapping the amino acid sequence of R14 for preventing uveitis,
and different doses of R14 for therapy. High dose of oral antigen
should cause clonal deletion, low dose induce regulatory T cells, thus
a combination of both, deleting autoreactive T cells and induce Tregs
should be most effective.
Methods: Lewis rats were immunized with R14-CFA to induce EAU.
Oral tolerance was induced prior to immunization (prophylaxis) with
200mg peptide 3x every other day before immunization, or from onset
of EAU to termination to prevent relapses (therapy). For prophylaxis
we also fed peptides overlapping the sequence of R14. Therapeutic
feeding was performed with 200mg R14 during EAU, 3x2mg R14
followed by 200mg or 3x2mg R14 only after onset of EAU. Control
groups received PBS only. Mesenteric LN cells were tested for
surface markers, cytokines and Foxp3 expression.
Results: Only preventive feeding of R14 and R16, but not of
overlapping peptides suppressed EAU. R14 was more tolerogenic
than R16 and also prevented relapses (EAU score PBS group: 2.4;
R14-fed: 0.56; R16-fed: 1.25). Therapeutic feeding with R14 had no
effect on the primary course of EAU, but reduced relapses to 19%
of eyes and 23% of rats compared to 50% and 69% relapses in the
control group). High-dose feeding (2mg) only had no effect, and
2mg+200mg feeding was less effective (23% relapses (eyes) vs. 31%
of rats) than low-dose feeding only. After in vitro-stimulation with
R14 TCRab+/CD4+ T cells increased in all R14-fed groups, while
TCRab+/CD4+/CD8+ cells and IL-10-producing TCRab and TCRgd
cells decreased. Less than 1% of the mLN T cells produced IL-17
or IFN-g, and less than 3% IL-10. Foxp3-expressing TCRab cells
slightly increased to 1.4% in the 200mg fed group only.
Conclusions: Therapeutic feeding of R14 was highly effective
in preventing relapses, making oral tolerance a useful therapy for
relapsing-remitting uveitis. High- and low dose combination did not
improve tolerance. There was no clear association with any of the
analyzed mLN populations and successful oral tolerance induction.
Program Number: 2499 Poster Board Number: C0019
Presentation Time: 3:45 PM–5:30 PM
Spontaneous ocular autoimmunity in mice expressing a
transgenic T cell receptor specific for a retinal autoantigen
Reiko Horai, Phyllis B. Silver, Jun Chen, Carlos Zárate-Bladés, Wai
Po Chong, Ru Zhou, Yingyos Jittayasothorn, Sonia Nguyen, ChiChao Chan, Rachel R. Caspi. Laboratory of Immunology, NEI, NIH,
Bethesda, MD.
Purpose: The EAU model, induced by immunization of mice with
the retinal protein IRBP or its peptides, has been very useful to study
basic mechanisms of ocular inflammation. However, it is inadequate
for some types of studies, due to the need for active immunization
in the context of strong bacterial adjuvants. To understand the
pathogenesis of uveitis under more physiological settings, we
generated transgenic mice that express a retina-specific T cell
receptor (TCR).
Methods: Transgenic constructs incorporating the IRBP161-180specific TCR α and β chains under CD2 or MHC class I promoters,
respectively, were co-injected into embryos of EAU-susceptible B10.
RIII mice. IRBP-specific T cells were detected with an Ag-MHC
class II-Ig dimer. Ocular pathology was evaluated by fundoscopy and
histology.
Results: Three lines of IRBP TCR Tg mice (R161H, M, L) were
established that express different levels of the transgenic TCR
and show different proportions of IRBP-specific CD4+ T cells in
their peripheral repertoire. Importantly, two of the lines, R161H
and R161M, rapidly developed spontaneous uveitis, reaching
100% incidence by 2 and 3 months of age, respectively, whereas
the third line, R161L, appeared “poised” and only developed
appreciable disease upon immune perturbation by microbial stimuli.
Susceptibility roughly paralleled expression of the transgenic
TCR. Peripheral IRBP-specific CD4+ T cells displayed a naïve
phenotype, whereas T cells infiltrating uveitic eyes mostly showed
an effector/memory phenotype, and included Th1, Th17 as well as T
regulatory (Treg) cells. Retina-specific Treg cells appeared to have
been peripherally converted rather than thymically derived. T cells
from R161 mice responded to IRBP and transferred uveitis to naïve
recipients, providing a source of retina-specific T cells for a variety
of basic studies. Examples that will be presented include the role
of commensal microbiota in uveitogenic T cell priming, as well as
effector cytokines and regulatory mechanisms in uveitis.
Conclusions: R161 lines of transgenic mice provide a new and
valuable model of spontaneous autoimmune uveitis that allows to
study natural triggers and basic mechanisms involved in breakdown
of immune homeostasis in the eye. This model may also be useful for
the development of therapeutic strategies for uveitis.
Commercial Relationships: Reiko Horai, None; Phyllis B. Silver,
None; Jun Chen, None; Carlos Zárate-Bladés, None; Wai Po
Chong, None; Ru Zhou, None; Yingyos Jittayasothorn, None;
Sonia Nguyen, None; Chi-Chao Chan, None; Rachel R. Caspi,
None
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
Program Number: 2500 Poster Board Number: C0020
Presentation Time: 3:45 PM–5:30 PM
Characterising the role of lipoprotein-associated phospholipase
A2 (Lp-PLA2) in experimental autoimmune uveoretinitis (EAU)
Gemma Beers1, Joanne Boldison2, David A. Copland1, Peter S.
Adamson3, Lindsay B. Nicholson1, 2, Andrew D. Dick1, 2. 1Academic
unit of Ophthalmology, University of Bristol, Bristol, United
Kingdom; 2School of Cellular and Molecular Medicine, University
of Bristol, Bristol, United Kingdom; 3Ophthalmology Discovery
Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom.
Purpose: Macrophage activation can be regulated via hydrolysis
of oxidised low density lipoproteins (oxLDL) by Lp-PLA2. This
produces lysophosphatidylcholine and non-esterified fatty acids
that up-regulate expression of chemokines and adhesion molecules,
induce macrophage migration and promote pro-inflammatory
cytokine release. Inhibition of this enzyme may therefore perturb
macrophage function and attenuate inflammation. We utilised
Lp-PLA2 knockout (KO) mice to determine the effect of LpPLA2 depletion in autoimmune retinal inflammation, employing a
murine model of autoimmune uveitis, EAU, in which macrophages
are central to progression and expression of disease. Uveitis is a
prominent cause of visual impairment, found commonly in the
working age population. As such, research into the underlying
mechanisms of the disease and development of new treatment
options is important to overcome the medical, social and financial
implications associated with this pathology.
Methods: C57BL/6 Lp-PLA2 KO mice, heterozygotes (HET)
and wild type (WT) controls were immunized to induce EAU by
subcutaneous injection of RBP-3 (IRBP)1-20 peptide in Complete
Freund’s adjuvant, plus intra-peritoneal (IP) injection of heat
inactivated pertussis toxin. Clinical disease was monitored by Topical
Endoscopic Fundus imaging (TEFI). Mice were sacrificed on day 26
post immunisation, infiltrating leukocytes were quantified by flow
cytometry and histological disease severity was assessed.
Results: Lp-PLA2 KO mice showed substantially fewer infiltrating
CD45+ cells compared to both WT and HET controls, which
correlated with a lower disease score by TEFI and histology. In
addition to a reduction in the absolute number of infiltrating cells
in the retina, KO mice also exhibited an altered ratio of leukocyte
populations compared to HET and WT controls. An apparent
reduction in the number of CD4+ infiltrating cells in Lp-PLA2 KO
retina may indicate an effect on T cell priming and subsequent tissue
infiltration in these animals.
Conclusions: Lp-PLA2 KO mice, immunised to induce EAU
experienced decreased macrophage infiltration and less clinical
disease. The observation of suppressed clinical and histological
disease score and number of infiltrating cells infers a reduction in
both activation and migration of inflammatory cells via depletion of
Lp-PLA2.
Commercial Relationships: Gemma Beers, None; Joanne
Boldison, None; David A. Copland, None; Peter S. Adamson,
GlaxoSmithKline (E); Lindsay B. Nicholson, None; Andrew D.
Dick, None
Support: Biotechnology and Biological Sciences Research Council
(BBSRC) and GlaxoSmithKline (GSK)
Program Number: 2501 Poster Board Number: C0021
Presentation Time: 3:45 PM–5:30 PM
P2X7 Deficiency Protects Against Experimental Autoimmune
Uveitis
Simon R. Taylor1, 2, Shenzhen Tempest-Roe1, Emily Shao1, 2, John
McDaid1. 1Immunology & Inflammation, Imperial College London,
London, United Kingdom; 2Ophthalmology, Royal Surrey County
Hospital, Guildford, United Kingdom.
Purpose: The immune system is designed to discriminate between
self and non-self, but also to detect foreign antigens in the context of
‘danger’. It has been suggested that ATP provides such a stimulus,
acting via the purinergic P2X7 receptor, and that pathological
stimulation of the P2X7 receptor may be involved in the development
of autoimmune disease. We therefore explored the impact of P2X7
deficiency on the development of Experimental Autoimmune Uveitis
(EAU) in mice, to whether this receptor may be a viable therapeutic
target.
Methods: EAU was induced in two strains of P2X7-/- mice
(which were both generated on a C57BL/6 background) and
in C57BL/6 control animals, using 500 mg IRBP peptide 1-20
(GPTHLFQPSLVLDMAKVLLD) in PBS emulsified in CFA.
Additional adjuvant of 1.5 mg Bordetella pertussis toxin was injected
into the peritoneal cavity. Procedures were performed under a Home
Office License in accordance with the regulations of the United
Kingdom Animal (Scientific Procedures) Act (1986). Animals were
monitored using topical endoscopic fundal imaging and culled at day
28, when histological examination of eyes was undertaken.
Results: P2X7 deficiency protected against the development of EAU,
with disease scores being significantly lower in both strains of genetargeted animals compared to control animals (Figure 1). There were
also differences in disease scores between the two strains of genetargeted animals, with Pfizer P2X7-/- showing lower disease activity
scores than GlaxoSmithKline P2X7-/- animals.
Conclusions: P2X7 deficiency protects against the development
of EAU in mice and may represent a viable therapeutic target for
ocular inflammatory disease. Intra-strain differences may reflect the
differences in gene targeting approaches and selective deletion (or
failure of deletion) of splice variants.
Figure 1: Representative images taken at day 21 post-inducationof
EAU in wild-type C57BL/6 animals (A,B); GSK P2X7ko animals
(C,D); Pfizer P2X7ko animals (E,F).
Commercial Relationships: Simon R. Taylor, None; Shenzhen
Tempest-Roe, GlaxoSmithKline (F); Emily Shao, None; John
McDaid, None
Support: NIHR CDF-2011-04-051; BBSRC BB/K501037/1
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
Program Number: 2502 Poster Board Number: C0022
Presentation Time: 3:45 PM–5:30 PM
A role for the Syk-CARD9 pathway in the pathogenesis of
autoimmune uveitis
Ellen J. Lee1, 3, Brieanna Brown3, 1, Emily Vance3, 1, Maya Lewinsohn3,
Phyllis B. Silver4, Rachel R. Caspi4, Holly L. Rosenzweig2, 1.
1
Ophthalmology, Oregon Health & Science University, Portland, OR;
2
Molecular Microbiology & Immunology, Oregon Health & Science
University, Portland, OR; 3Veterans Affairs Medical Center, Portland,
OR; 4Laboratory of Immunology, NEI/NIH, Bethesda, MD.
Purpose: While the role of adaptive T cell responses in uveitis has
been extensively studied, we know little of the innate signals that
precede and contribute to autoreactive T cell activation and disease.
We, therefore, investigated the C-type lectin receptors (CLRs) in the
T cell-dependent uveitis model, experimental autoimmune uveitis
(EAU).
Methods: EAU was induced in Card9 knockout (KO) mice and
C57BL/6J congenic wild-type (WT) controls by immunization with
interphotoreceptor retinoid-binding protein (IRBP). Pathway-focused
gene expression changes were quantified by real-time PCR-based
multiplex arrays at d10 post-immunization. At d21, uveitis was
assessed by fundus imaging and histopathology. Flow cytometry was
used to quantify cellular infiltrate of eyes and antigen-specific CD4+
T cell effector responses from IRBP-stimulated splenocytes. The
Syk inhibitor, piceatannol (5mg/kg x 4 i.p. injections), versus vehicle
control was evaluated in WT mice (n=6/treatment).
Results: Multiplex array analysis of isolated neuroretina revealed
early induction of genes involved in fungal and mycobacterial host
defense responses, including Dectin-1, Dectin-2, and Mincle, which
comprise a subgroup of CLRs that transduce signals through Syk and
CARD9. Card9 expression was essential for induction of “fungalassociated” transcriptional response and contributed functionally
to EAU, as CARD9 KO mice were resistant to EAU. Card9
deficiency significantly impaired EAU development, as assessed
by clinical fundus and histopathologic grading (WT=2.5±0.34 vs.
KO=0.28±0.11, p<0.001), as well as by reduced leukocyte infiltration
into the vitreous (WT=159±41 vs. KO=4±2, p<0.0001). Flow
cytometry of whole eyes revealed marked reduction of CD4+ T
cells, neutrophils and monocyte-macrophages. Card9 expression was
essential for induction of IRBP-specific T cell effector responses, as
KO mice demonstrated greater than 2-fold reduction in frequency
of both Th1 and Th17 cells. The resistance of CARD9 KO mice to
EAU was reproduced in WT mice by pharmacologic inhibition of the
upstream kinase Syk, further underscoring the importance of the SykCARD9 pathway in orchestration of EAU.
Conclusions: Our studies uncover a role for the Syk-CARD9
pathway in induction of uveitogenic T cell responses and autoimmune
uveitis and implicate CLRs as important players in uveitis. These
pathways could constitute new targets for treatment of ocular
inflammatory disease.
Commercial Relationships: Ellen J. Lee, None; Brieanna Brown,
None; Emily Vance, None; Maya Lewinsohn, None; Phyllis B.
Silver, None; Rachel R. Caspi, None; Holly L. Rosenzweig, None
Support: NEI/NIH grant EY019020, Research to Prevent Blindness
Foundation, NEI Intramural support EY000184-30
Program Number: 2503 Poster Board Number: C0023
Presentation Time: 3:45 PM–5:30 PM
Characterization of the Role of IRF-8 in the Retina During
Autoimmune Uveitis
Sung-Hye Kim, Chengrong Yu, Charles Egwuagu. Lab of
Immunology, NEI, Bethesda, MD.
Purpose: Interferon Regulatory Factor (IRF)-8 is required for the
development, maturation and expression of anti-microbial defenses
of myeloid cells and regulates CFH expression in retinal microglial
cells. However, IRF-8-dependent network contains several genes
that enhance susceptibility to infection while others confer complete
protection against parasitic diseases such as cerebral malaria. We
recently showed that retinal cells constitutively express low levels of
IRF-8 and its expression increased significantly in the retina during
intraocular inflammation. However, the functional significance of
IRF-8 expression in retina remains unclear. In this study, we have
generated mice with targeted deletion of IRF-8 in the retina to
investigate the function of IRF-8 during intraocular inflammation.
Methods: We generated two IRF-8 conditional knockout mouse
strains by breeding IRF-8 floxed mice (IRF-8 fl/fl) (kind gift from
Herbert Morse, NIH) with mice expressing Cre under direction of
the α-Cre promoter (α-CRE) or the Rx promoter (Rx). Experimental
autoimmune uveitis (EAU) was induced by active immunization
with IRBP/CFA. Disease severity was characterized by fundoscopy,
optical coherence tomography (OCT), histology and FACS. Visual
function was assessed by electroradiography (ERG).
Results: The WT mice developed severe EAU characterized
by massive infiltration of inflammatory cells into the retina,
photoreceptor cell loss, focal retinitis, retinal vasculitis and multifocal
choroiditis, In contrast, the two IRF-8 KO mouse strains developed
very mild EAU, suggesting that IRF-8 deletion conferred protection
against EAU. However, visual function tests reveal alterations in dark
and light adapted ERG in both IRF-8 KO mouse strains.
Conclusions: Our data confirm the pleiotropic effects of IRF-8
in different tissues and suggests that IRF-8 expression may have
double-edged effects in the retina. On the one hand, IRF-8 induces
transcription of CFH gene and may thus confer protection against
age-related macular degeneration (AMD). On the other hand, the
reduced inflammation in the IRF-8 KO mice suggest that IRF-8 may
promote inflammatory responses in the retina and that therapeutic
targeting of IRF-8 may be used to alleviate uveitis.
Commercial Relationships: Sung-Hye Kim, None; Chengrong Yu,
None; Charles Egwuagu, None
Program Number: 2504 Poster Board Number: C0024
Presentation Time: 3:45 PM–5:30 PM
The role of peripheral dendritic cells in immune activation in
anterior uveitis
Conor Murphy1, Micheal O’Rourke1, 2, Mary Connolly2, Cheryl
Sweeney2, Ursula Fearon2. 1Ophthalmology, RCSI, Dublin, Ireland;
2
Department of Rheumatology, University College Dublin, Dublin,
Ireland.
Purpose: Pathogens, such as microbial components express pathogen
associated molecular pathogens. These can interact with innate
pattern recognition receptors via toll like receptors (TLRs) on antigen
presenting cells (APCs). TLRs play a critical role linking innate
and adaptive immunity promoting the maturation of APCs through
the production of pro-inflammatory cytokines and the up-regulation
of co-stimulatory molecules. This interaction also allows APCs to
become efficient in the presentation of specific antigens to naïve T
cells initiating adaptive immunity. It is evident that these processes
can be altered by a class of small non-coding RNAs or microRNA
(miR) which exert their biological function through suppression
of their target genes, abnormal expression of which has been
demonstrated in chronic inflammatory diseases.
Methods: Peripheral blood mononuclear cells were isolated from
active AU patients and healthy controls (n=5). CD14+ monocytes
(purity >97%) isolated by positive selection using magnetic bead
separation were differentiated into imDCs by culturing for 7 days
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
with IL-4 and GM-CSF and matured in media for 24 hours. The
effects of TLR activation and pro-inflammatory stimuli were
examined by culturing moDC with Pam3CSK4 (1μg/ml), Poly I:C
(25μg/ml), LPS (1μg/ml), IL-1β (10ng/ml) and TNFα (10ng/ml).
Cell surface expression of CD83 (maturity) and CD86 (activation)
on DC were quantified by flow cytometry. Cytokine analysis was
performed on supernatant by ELISA. Total RNA from the mature DC
was isolated using the miRneasy isolation kit. Quantification of miR
expression was analyzed by real-time PCR, using miRNA-let-7a as
an endogenous control.
Results: CD83 and CD86 expression on AU DC was increased
in response to all agonists compared to basal, most notably for
TLR3 and IL1b. A significant increase in CD83 mean fluorescent
intensity (MFI) in response to IL1b was demonstrated in AU moDC
compared to HC (p=0.05). This was paralled by an increase in IL12
(p=0.05) and IL23 expression in cultured supernatants. Furthermore,
expression of miR155 was also increased in response to Poly I:C,
LPS and Il1b in AU DC.
Conclusions: These results support peripheral activation of DC by
TLR3 and Il1b in AU patients suggesting a possible role in AU.
Altered miR155 expression in DC from AU patients suggests that this
miR may contribute to the pathogenesis of AU by mediating TLR3
activated pro-inflammatory pathways.
Commercial Relationships: Conor Murphy, None; Micheal
O’Rourke, None; Mary Connolly, None; Cheryl Sweeney, None;
Ursula Fearon, None
Program Number: 2505 Poster Board Number: C0025
Presentation Time: 3:45 PM–5:30 PM
Distinct Patterns of Fundus Autofluorescence in Paraneoplastic
and Non-Paraneoplastic Forms of Autoimmune Retinopathy
Responding to Systemic Immunosuppressive Therapy
Sarwar Zahid1, 2, Melisa Nika2, Amani Al-Tarouti2, Kari E. Branham2,
John R. Heckenlively2, Thiran Jayasundera2. 1Henry Ford Hospital,
Detroit, MI; 2Kellogg Eye Center, Ann Arbor, MI.
Purpose: To describe distinct patterns of fundus autofluorescence
(FAF) in patients with paraneoplastic (pAIR) and non-paraneoplastic
autoimmune retinopathy (npAIR) who demonstrate a clinical
response to systemic immunosuppression.
Methods: A retrospective study was conducted of 35 patients
with AIR, who met the following diagnostic criteria: 1) presented
with sudden adult-onset rapidly progressive visual disturbance; 2)
exhibited abnormal full-field ERG (ffERG) parameters; 3) antiretinal antibody positivity, including anti-recoverin. Clinical data
focused on FAF findings in patients who exhibited objective clinical
improvement after immunosuppressive treatment as detected by a
25% improvement in quantified Goldmann visual fields (GVF) or
visual acuity (VA) during follow-up.
Results: Twenty-four patients with npAIR and 11 patients with pAIR
exhibited improvement after immunosuppressive treatment during
follow-up. Sixteen patients had FAF imaging available. Fourteen of
these patients exhibited a ring of parafoveal hyperfluorescence; 2 of
these patients had hyperfluorescence outside the vascular arcades
as well. Two patients exhibited central foveal hyperfluorescence,
while 4 patients exhibited peripheral hypofluorescence outside and
along the vascular arcades suggestive of retinal pigment epithelium
(RPE) atrophy. Three patients exhibited peripapillary atrophy with
surrounding hyperfluorescence. FAF findings were symmetric in each
eye irrespective of interocular differences in GVF areas or VA in each
patient.
Conclusions: Patients with suspected AIR that exhibit improved
visual function with treatment constitute an ideal group in which
to investigate the presence of FAF signatures in this heterogeneous
disease. We confirm that FAF changes seen in retinal dystrophies,
such as concentric rings of parafoveal hyperfluorescence and central
foveal hyperfluorescence, are also present in patients with AIR.
Commercial Relationships: Sarwar Zahid, None; Melisa Nika,
None; Amani Al-Tarouti, None; Kari E. Branham, None; John R.
Heckenlively, None; Thiran Jayasundera, None
Program Number: 2506 Poster Board Number: C0026
Presentation Time: 3:45 PM–5:30 PM
Malignancy Presenting After Immunomodulatory Therapy for
Presumed Non-Paraneoplastic Autoimmune Retinopathy
Heena Patel, Janet L. Davis. Bascom Palmer Eye Institute/UMH,
Miami, FL.
Purpose: To describe 3 patients who developed malignancies during
treatment with immunomodulatory therapy for presumed nonparaneoplastic autoimmune retinopathy (npAIR) despite negative
oncologic work-ups prior to therapy.
Methods: Review of clinical records of 3 patients with autoimmune
retinopathy who developed malignancies during treatment.
Results: Patients were a 73-year-old woman and two 72 and 63 year
old men. Patient #1 presented with bilateral decreased vision and
anti-CNS antibodies. The amplitudes of the ERG were moderately
reduced in both eyes for rods and cones. MRI brain, lumbar puncture,
vitreous cytology, CT scan of chest, abdomen, and pelvis, whole body
gallium scan, SPECT scan, and bone marrow biopsy were negative
for malignancy. She was treated with IV methylprednisolone,
followed by oral prednisone. Eight months later she received 2
doses of IVIG. Biopsy of a submandibular lymph node 17 months
following initial consult revealed small cell carcinoma of unknown
origin. Patient #2 presented with nyctalopia and ERG showed absent
rod responses, mixed rod and cone, and some slightly reduced
cone response. Serum antibodies reacted with an unknown 40kDa
protein. Oncologic work-up included CT chest, abdomen, and pelvis,
PET scan, and dermatologic exam. Patient was treated with IVIG
initially for 2 doses and 3 months later with immunosuppressants.
Two months after starting azathioprine and cyclosporine, a cervical
lymph node biopsy revealed large cell neuroendocrine carcinoma
with an unknown primary. Patient #3 presented with and unexplained
peripheral visual field defect and a nearly extinguished ERG in the
right eye and markedly reduced ERG in the left eye. Anti-retinal
antibodies were not detected. Initial oncologic work-up included CT
chest, abdomen, and pelvis. Patient was treated with azathioprine,
and 9 months later was diagnosed with colon adenocarcinoma
following colonoscopy due to enlarged lymph nodes seen on PET
scan. PET scan was performed after patient presented with new onset
diaphragmatic paralysis.
Conclusions: Suspected npAIR patients should have a
thorough work-up for a malignancy prior to the initiation of
immunomodulatory therapy. If treatment with an immunomodulatory
agent is recommended, the patient should be informed of the inability
to completely exclude occult malignancy and that treatment may
unmask an underlying tumor as the immune system is suppressed.
Commercial Relationships: Heena Patel, None; Janet L. Davis,
None
Program Number: 2507 Poster Board Number: C0027
Presentation Time: 3:45 PM–5:30 PM
Tattoo-Associated Uveitis
Trucian A. Ostheimer, Bryn Burkholder, Theresa G. Leung, Nicholas
J. Butler, James P. Dunn, Jennifer E. Thorne. Ophthalmology, Johns
Hopkins, Baltimore, MD.
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
Purpose: To describe the clinical presentation of bilateral uveitis
with coincident onset of raised and indurated tattooed skin in a case
series of six patients.
Methods: Six consecutive patients with coincident bilateral
uveitis and cutaneous tattoo induration were evaluated at a tertiary
ophthalmologic facility over the course of approximately one year.
All subjects underwent complete ophthalmic examination and a
focused systemic medical workup including serologic testing and
imaging studies to rule out syphilis and sarcoidosis. Additional testing
for specific uveitic etiologies was performed on a case-by-case basis.
Two participants underwent biopsy of their tattoos. The patients’
clinical courses and responses to treatment over a follow-up period of
one to twelve months are reported. Main outcome measures included
degree of intraocular inflammation, ocular complications, visual
acuity, clinically observable tattooed skin changes, and biopsy results.
Results: Patient ages at the time of presentation ranged from 20
to 42 years of age. Five patients are African-American and one
patient is Caucasian. Initial best-corrected visual acuity varied
from 20/20 to 20/400. Four patients were diagnosed with bilateral
non-granulomatous anterior uveitis; three with chronic and one with
recurrent disease. The remaining two patients were diagnosed with
bilateral chronic granulomatous panuveitis. The most significant
ocular complications included uveitic glaucoma, iris bombe, severe
cystoid macular edema, and a neurosensory retinal detachment. All
patients had multiple tattoos, some of which were multicolored, but
only areas of skin containing black pigment were affected. Biopsies
of raised and indurated tattoos were performed in two patients
and demonstrated non-caseating granulomatous inflammation
surrounding tattoo ink in the dermis. The skin changes resolved in
all patients, with a faster response noted in those treated with highdose oral prednisone for intraocular inflammation. Three patients
subsequently experienced recurrent flares of intraocular inflammation
in conjunction with the recurrence of raised and indurated tattoos.
Conclusions: These cases may represent a subset of patients with
previously undiagnosed sarcoidosis, in whom tattooing may have
incited a simultaneous inflammation of the eyes and tattooed skin.
Commercial Relationships: Trucian A. Ostheimer, None; Bryn
Burkholder, None; Theresa G. Leung, None; Nicholas J. Butler,
None; James P. Dunn, None; Jennifer E. Thorne, AbbVie (C),
Allergan (F), Gilead (C), NEI (F), NIAID (F), RPB (F), Xoma (C)
Program Number: 2508 Poster Board Number: C0028
Presentation Time: 3:45 PM–5:30 PM
Cataract surgery with or without primary lens implantation in
children with chronic uveitis
Damien Guindolet1, 2, Pascal Dureau2, Catherine Edelson2, Amandine
Barjol2, Céline Terrada3, Georges Caputo2, Phuc Lehoang1, Bahram
Bodaghi1. 1Hôpital Pitié-Salpétrière, Paris, France; 2Fondation
Ophtalmologique Adolphe de Rothschild, Paris, France; 3Hôpital
Saint Louis, Paris, France.
Purpose: To evaluate the management of cataract in children with
uveitis and compare the visual outcome with or without primary lens
implantation.
Methods: Retrospective study performed between 2007 and 2012
on children with chronic uveitis who underwent a cataract surgery,
with primary posterior chamber IOL implantation with a foldable
hydrophobic acrylic IOL or left aphakic.
Results: The study included 20 eyes of 16 patients (9 Juvenile
Idiopathic Arthritis). The mean age at surgery was 8.63 years (5.6813.97) in 14 implanted eyes and 6.08 years (4.11-11.28; p=0.03) in 6
eyes which remained aphakic. The mean postoperative follow-up was
36.44 months (8.72-69.57). All patients except one were treated with
methotrexate. Four patients (5 eyes) in the implanted group and 2
patients (2 eyes) in the apahakic group were additionally treated with
TNF-alpha blockers.
In the implanted and the aphakic groups, the preoperative mean
BCVA was 1.11 logMAR (0.40-2.30) and 1.78 logMAR (0.70-2.30),
respectively and the postoperative mean BCVA was 0.48 logMAR
(0-3; p=0.02) and 0.47 logMAR (0-2.6; p=0.047), respectively.
The baseline oral corticosteroids dosage in the implanted group and
in the aphakic group was 8.14mg/d (0-30) and 6.17mg/d (0-15),
respectively. It was increased to 27.9mg/d (0-55) and 25.83mg/d
(15-40), respectively during the perioeprative period and tapered to
7.54mg/d (0-50) and 2.08mg/d (0-2.50), respectively at the end of the
follow-up.
Postoperative complications in the implanted group were posterior
synachiae (5), posterior capsule opacification (1), cellular
proliferation (8), cells on IOL (2), Elschnig pearls (5), secondary
ocular hypertension (4), macular edema (5), retinal detachment (1). In
the aphakic group complications were choroidal detachment (1) and
intravitreal hemorrhage (2).
Conclusions: Pediatric cataract surgery in chronic uveitis with
primary posterior chamber hydrophobic IOL implantation is possible
and leads to a good and prompt visual rehabilitation. It requests a
powerful anti-inflammatory management with immunosuppressive
drugs. Nevertheless, JIA children below 6 years of age or those with
severe uveitis or a previous failure of implantation in the opposite eye
should remain aphakic.
Commercial Relationships: Damien Guindolet, None; Pascal
Dureau, None; Catherine Edelson, None; Amandine Barjol, None;
Céline Terrada, None; Georges Caputo, None; Phuc Lehoang,
None; Bahram Bodaghi, None
Program Number: 2509 Poster Board Number: C0029
Presentation Time: 3:45 PM–5:30 PM
Clinical characteristics of autoimmune neuro-retinopathy
(AINR)
Eric Sollenberger1, Rebecca S. Epstein1, Grazyna Adamus2,
Alessandro Iannaccone1. 1Ophthalmology/Hamilton Eye Institute,
University of Tennessee Health Science Center, Memphis, TN;
2
Ocular Immunology Lab, Oregon Health & Science University,
Portland, OR.
Purpose: To illustrate the clinical and functional presentation of a
retrospective case series of 57 patients with AINR.
Methods: Age, onset modality, symptoms at onset, fundus features,
Goldmann visual fields (GVF), flash electroretinogram (ERGs) and
pattern-reversal visual evoked potentials (PVEPs) were reviewed.
Anti-retinal and anti-optic nerve autoantibody (AAb) testing through
western blots and immunohistochemistry (IHC) was performed in a
diagnostic setting to confirm the suspicion of AINR.
Results: Average patient age at first exam was 50±16.2 yo (SD)
and as early as 4 yo. Patients were 63% female. Mean age of onset
was 46.3±16.3 yo (SD). In most cases, onset was acute or subacute.
Patients presented with as many as 6 anti-retinal and/or anti-optic
nerve AAbs. Symptoms of night blindness (82%), decreased visual
acuity (77%), photophobia (68%), and photopsia (49%) were
common in AINR. On fundus exam, Papillary and juxtapapillary
pigmentation and/or atrophy, disc elevation and/or hyperemia,
temporal atrophy, and cupping were seen 93% of cases. Macular
changes (epiretinal membrane, RPE changes, and focal macular
atrophy) were common (85%). Peripheral punched-out retinal lesions
(61%), bone spicule-like deposits (59%) and vascular attenuation,
alongside vasculitic changes and sheathings (61%), were also
frequently observed. PVEP delays were found in 87% of cases, also
with 20/20 acuity. ERG abnormalities were found in 95% of the
tested subjects. The most common findings were photopic ERGs
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
delays (86%) and reduced amplitude (75%). Inter-ocular asymmetry
seen by PVEP (85%), ERG (77%) and GVF (62%) criteria was
another characteristic of AINR. All but one patient had asymmetry on
at least one of these tests, while 56% had asymmetry in both PVEP
and ERG. Combining PVEP and ERG data, we found that 90% of the
tested patients had simultaneous retinal and optic nerve involvement.
Conclusions: AINR patients present with recognizable clinical and
functional findings. Our findings indicate that the proportion of
cases with simultaneous involvement of the retina and of the optic
nerve, whether at the retinal ganglion cell (RGC)/ retinal nerve fiber
layer (RNFL) and/or retrobulbar level, in patients with autoimmune
retinopathy – hence, actually affected with AINR – is even higher
than what we recently reported in a large, multi-center case series of
patients (Adamus et al. J Ophthalmic Inflamm Infect 2011;1:111-21).
Commercial Relationships: Eric Sollenberger, None; Rebecca S.
Epstein, None; Grazyna Adamus, None; Alessandro Iannaccone,
None
Support: Research to Prevent Blindness, Inc. New York, NY
(Physician Scientist Award to AI and unrestricted grant to UTHSC
Ophthalmology/Hamilton Eye Institute) and NIDDK Short-Term
Research Training Grant DK-7405-29 (ES)
Program Number: 2510 Poster Board Number: C0030
Presentation Time: 3:45 PM–5:30 PM
Autoimmune retinopathy in patients with birdshot
retinochoroidopathy (BSRC) who are in remission
Homaira A. Hossain, C Stephen Foster. Ophthalmology,
Massachusetts Eye Research and Surgery Institution, Cambridge,
MA.
Purpose: To investigate the continued deterioration of vision in
patients with BSRC who are in remission from active uveitis.
Methods: We identified four patients who demonstrated continued
deterioration in visual function despite long-term remission from
active BSRC as evinced by absence of inflammation on clinical
ophthalmoscopic examination and fluorescein angiogram. This visual
decline resembled that of autoimmune retinopathy, with painless loss
of vision and decline in visual acuity, abnormal electroretinography,
and defects on visual field testing. Sera were tested for anti-retinal
and anti-optic nerve antibodies by Western blot analysis.
Results: The four patients included two males and two females,
with an average age of 60.3 years (ranging from 54 to 68 years).
All patients were HLA-A29 positive. Three patients were treated
with a minimum of two years of immunomodulatory therapy (IMT).
One patient was treated with IMT for five months, after which it
was discontinued due to medication side effects. She subsequently
underwent bilateral fluocinolone acetonide intravitreal implants.
At the time of serum testing, all four patients demonstrated
absence of inflammation on clinical ophthalmoscopic examination
and fluorescein angiogram. Two patients demonstrated visual
decline as evinced by both visual field testing (SITA-SWAP) and
electroretinography (decreased amplitude and/or increased implicit
time on 30 Hz flicker). One patient demonstrated visual decline in
electroretinography testing only, and one patient demonstrated visual
decline in visual field testing only. The serum of all four patients
demonstrated positivity for anti-retinal antibodies. The serum of
three out of four patients demonstrated positivity for anti-optic nerve
antibodies.
Conclusions: The presence of anti-retinal and anti-optic nerve
antibodies in patients who have achieved long-term remission
of BSRC after prolonged treatment suggests that continued
deterioration has occurred because of autoimmune retinopathy.
Patients with BSRC who present with visual decline but show no
active inflammation on clinical ophthalmoscopic examination and
fluorescein angiogram may benefit from autoantibody screening. For
these patients, further treatment with IMT may be indicated due to the
presence of autoantibodies implicated in the continued deterioration
of visual function.
Commercial Relationships: Homaira A. Hossain, None; C
Stephen Foster, None
Program Number: 2511 Poster Board Number: C0031
Presentation Time: 3:45 PM–5:30 PM
VASCULAR ENDOTHELIAL GROWTH FACTOR IN TEARS
OF SYSTEMIC SCLEROSIS PATIENTS
Aniko Rentka. Department of Ophthalmology, University of
Debrecen, Debrecen, Hungary.
Purpose: Several cytokins, adhesion molecules and growth factors
play key role in inflammatory processes of the eye. Quantitative
changes of these factors are measurable of serum. In many cases
changes in these patiens’ tears is presented. The essential role of
vascular endothelial growth factor (VEGF) in the immunpathology
of systemic sclerosis (SSc) is confirmed in blood serum previously.
However, there have been no any other investigations according to
VEGF level determination in tears of SSc patients. To determine
VEGF and total protein levels in tears of SSc patients. We also aimed
to define tear secretion velocity in these patients and correlated the
levels with clinical signs and symptoms.
Methods: Tear samples were collected from 43 SSc patients and 27
healthy controls using capillary micropipette, first without, then with
stimulation. Tear collecting time was measured during tear secretion.
Diluted samples were stored in polypropylene tubes at -80 °C until
assessment. Total protein values were determined using the BCA
Microplate method, and then VEGF levels were measured with R&D
immunoassay kit. The protocol that was used in this study was in full
compliance with good clinical practices, the Declaration of Helsinki
(1996), and the guidelines of the Medical and Health Science Centre
of the University of Debrecen.
Results: Patients’ average tear secretion velocity was 4.53 ml/min
(1.5-25.6). The average total protein value was 6.9 mg/ml (1.8-12.3) in
case of basal tear secretion and 6.26 mg/ml
(2.3-16.5) in tears collected after stimulation. In tears collected
without stimulation the average VEGF level was 4.95 pg/ml (3.518.06) and 4.69 pg/ml (2.66-6.44) with stimulation. We measured 4.13
mg/ml (1.0-14.1) total protein and 6.15 pg/μl (3.84-12.3) VEGF level
in tears of healthy controls.
Conclusions: In patients with keratoconjunctivitis sicca, the most
frequent ocular sign of SSc, tear secretion velocity was 67% of the
controls’. Total protein values in patients were 42% higher than in
healthy controls, it may mean that total protein production or since
SSc patients have a decreased tear secretion velocity. The protein
concentration is only increased because of the smaller tear volume.
Though VEGF in tears of SSc patients is decreased with 20%, and
did not change upon stimulation, it can be explained also with the
decreased tear secretion of patients.
Commercial Relationships: Aniko Rentka, None
Program Number: 2512 Poster Board Number: C0032
Presentation Time: 3:45 PM–5:30 PM
Intraocular rubella virus antibody detection as a diagnostic tool
for atypical forms of Fuchs uveitis
Aymeric Bouillot1, Audrey Fel1, Valerie Touitou1, Phuc Lehoang1,
Flore Rozenberg2, Bahram Bodaghi1. 1Ophthalmology, DHU
ViewMaintain, Pitie Salpetriere Hospital, Paris, France; 2Virology,
Saint Vincent de Paul Hospital, Paris, France.
Purpose: To analyze the clinical profile and prognosis of rubella
virus-associated uveitis.
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
Methods: All patients managed between January 2009 and August
2013 for an atypical form of Fuchs uveitis were included in this
study. Clinical features for these patients were assessed. An extensive
work-up of anterior or intermediate uveitis was performed in
all cases. An anterior chamber tap was performed for molecular
detection of herpesviruses and intraocular anti-rubella virus antibody
synthesis. Treatment was adapted to the results of ocular fluids
analysis.
Results: The series included 27 patients (M/F : 14/13) with a proven
diagnosis of rubella virus-associated uveitis. The mean age was 39.6
years (23-67). All patients had an intraocular antibody production
against rubella virus with a Goldmann-Witmer coefficient > 3. Only
7 patients (23%) fulfilled the classical criteria of Fuchs cyclitis
with stellar keratic precipitates, heterochromia/iris atrophy, cataract
and vitritis. 15 patients (48%) had a posterior subcapsular cataract
requiring surgery. Mean laser flare meter values were 13.8 ph/ms. 18
patients (58%) had vitritis. Uveitis was bilateral in 4 patients (15%)
and 10 patients (32%) had an uncontrolled IOP requiring filtering
surgery.
Conclusions: For most of these patients, intraocular rubella virus
antibody production allowed the final diagnosis of Fuchs uveitis
despite incomplete clinical criteria. Intraocular rubella virus detection
can help to establish the diagnosis of atypical forms of Fuchs cyclitis.
This avoids unnecessary additional tests and prescription of local
or systemic corticosteroids. Secondary glaucoma remains a major
complication and needs an appropriate management in order to avoid
a poor visual outcome.
Commercial Relationships: Aymeric Bouillot, None; Audrey
Fel, None; Valerie Touitou, None; Phuc Lehoang, None; Flore
Rozenberg, None; Bahram Bodaghi, None
Program Number: 2513 Poster Board Number: C0033
Presentation Time: 3:45 PM–5:30 PM
Scleritis in Australia: Disease Associations and Ocular
Complications
Julie L. Morrison1, Ethan Nguyen3, 4, Jessica Brennan1, Richard
Stawell2, Lyndell L. Lim1, 2, Peter J. McCluskey4. 1Centre for Eye
Research Australia, University of Melbourne, East Melbourne, VIC,
Australia; 2Royal Victorian Eye and Ear Hospital, East Melbourne,
VIC, Australia; 3Sydney Eye Hospital, Sydney, NSW, Australia;
4
Save Sight Institute, Sydney Medical School University of Sydney,
Sydney, NSW, Australia.
Purpose: Scleritis is a rare ocular inflammatory condition which has
the potential for significant visual loss. This retrospective review
looks at the demographics, clinical features and complications
associated with infectious and non-infectious scleritis in an Australian
population.
Methods: Retrospective chart review of 90 patients with scleritis
from three Australian tertiary referral centers from 1988 to 2013.
Data collected included type of scleritis, demographics, ocular
complications, associated systemic disease and treatments.
Results: The mean age of onset was 50 years of age (range 8 to
85). Females accounted for 62% of presentations and had an earlier
mean age of onset (46 vs. 57, p=0.01).Nine of the 90 subjects had
infectious scleritis (tuberculosis n=3, herpes zoster ophthalmicus
n=2, other n=4). Of the non-infectious scleritis, the commonest
form was diffuse (45%), followed by nodular (23%), necrotising
(16%) and posterior (16%). The majority of cases (75%) were
unilateral, with diffuse scleritis being more likely to be bilateral than
other types (39%,p=0.008). Forty percent were found to have an
associated systemic disease, with diffuse anterior scleritis the most
likely to be associated with systemic disease than any other type of
scleritis (45%). The most commonly associated systemic disease
was rheumatoid arthritis (RA, n=9, 29%), followed by Wegener’s
granulomatosis (n=5, 16%). Those with RA were more likely to
have bilateral involvement (56%, p=0.037). Necrotising disease was
more likely than non-necrotising disease to have associated corneal
involvement (p=0.019), cataract (p=0019) and keratitis (p=0.032).
Those with posterior involvement were more likely to have reduced
visual acuity (p=0.010), due to its higher association with uveal
effusion (p=0.012), macular edema (p=0.028) and retinal detachment
(p<0.001).
Conclusions: This is the first study to categorize an Australian
population of scleritis patients. Consistent with previous studies,
we found females were more likely to suffer from scleritis and
present at a younger age. Necrotizing scleritis or scleritis with
posterior involvement were more likely to be associated with
ocular complications. A higher proportion of posterior scleritis was
identified compared to previous studies.
Commercial Relationships: Julie L. Morrison, None; Ethan
Nguyen, None; Jessica Brennan, None; Richard Stawell, None;
Lyndell L. Lim, None; Peter J. McCluskey, None
Program Number: 2514 Poster Board Number: C0034
Presentation Time: 3:45 PM–5:30 PM
Assessment of Inflammatory Cytokines in Aqueous Humour of
Patients with Sarcoidosis
Kyungmin Lee1, 2, Abhishek R. Payal1, 3, Jamie Metzinger1, Reena
Rasheed1, Ninani Kombo1, Pranav Patel1, Homaira A. Hossain1,
C Stephen Foster1, 4. 1Massachusetts Eye Research and Surgery
Institution, Cambridge, MA; 2Retina Center, HanGil Eye Hospital,
Incheon, Republic of Korea; 3Scheie Eye Institute, University of
Pennsylvania, Philadelphia, PA; 4Harvard Medical School, Boston,
MA.
Purpose: To compare the concentrations of 20 cytokines from T
helper (Th) pathways (Th1, Th2, and Th17) in aqueous humour of
patients with sarcoid uveitis (active or in remission) to normal eyes.
Methods: Single center, prospective, observational case control
study. Aqueous samples were collected from 7 eyes with sarcoid
uveitis (SU group), and 8 normal eyes (control group). Quantitative
multiplex sandwich ELISA-based microarray assay was used to
quantify 20 cytokines: interleukin (IL)-1b, IL-2, IL-4, IL-5, IL-6,
IL-10, IL-12p70, IL-13, IL-17, IL-17f, IL-21, IL-22, IL-23, IL-28a,
macrophage inflammatory protein-3α (MIP-3α), transforming growth
factor-β1 (TGF-β), interferon-γ (IFN-γ), granulocyte macrophage
colony-stimulating factor (GM-CSF), tumor necrosis factor-α
(TNF-α) and tumor necrosis factor-β (TNF-β). Cytokine levels from
patients were compared with normal controls.
Results: The aqueous levels of IL-2 (10.6 pg/ml: 1.5-40.5, p: 0.024)
and TNF-α (98.5 pg/ml: 4.2-542.6, p: 0.0093) were significantly
higher in the sarcoidosis group compared with the control group. The
aqueous levels of IL-2, IL-6, IL-21, IL-23, and GM-CSF were higher
in the active uveitis patients compared to the inactive group. TNF-α
was higher in the remission patients.
Conclusions: Multiplex immunoassay of 20 cytokines in patients
with sarcoid associated uveitis revealed that IL-2 and TNF- α were
concentrated in the aqueous fluid. We confirm that IL-21 and IL-23
levels were elevated and correlated with disease activity, suggesting
Th17 cells play an important role in autoimmune disease and uveitis.
Commercial Relationships: Kyungmin Lee, None; Abhishek
R. Payal, None; Jamie Metzinger, None; Reena Rasheed, None;
Ninani Kombo, None; Pranav Patel, None; Homaira A. Hossain,
None; C Stephen Foster, None
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
Program Number: 2515 Poster Board Number: C0035
Presentation Time: 3:45 PM–5:30 PM
Long-Term Drug-Free Remission and Visual Outcomes in
Sympathetic Ophthalmia
Abhishek R. Payal1, 2, C Stephen Foster2, 3. 1Scheie Eye Institute,
University of Pennsylvania, Philadelphia, PA; 2Massachusetts Eye
Research and Surgery Institution, Cambridge, MA; 3Harvard Medical
School, Boston, MA.
Purpose: Sympathetic ophthalmia (SO) has an unpredictable
but often chronic course requiring prolonged corticosteroid or
immunosuppressive therapy (IST) or a combination of both. The
therapy itself may result in additional complications in the remaining
good eye. We assessed corticosteroid and IST free long-term
remission in the treatment of patients with sympathetic ophthalmia.
Methods: Retrospective case series of 19 patients with sympathetic
ophthalmia treated with corticosteroids and immunosuppressive
therapy with a step-ladder protocol practiced at this center between
March 2005-October 2013. Primary outcomes were five-year and
two-year remission rates with and without corticosteroids and
immunosuppressive therapy; and visual acuity.
Results: Nineteen patients (10 females, 9 males) with sympathetic
ophthalmia, meeting inclusion criteria were identified for review.
Patients were in the age range of 16.1-94.95 years (median age
58.56 years). Median follow-up was 7.10 years (mean, 6.41; range,
2.5 to 8.63 years). All patients achieved remission, thirteen of them
for 2 years or more. Three (15.78%) of the 19 patients maintained
remission off all immunosuppressive therapy and corticosteroids
for more than 5 years with vision of 20/25 or better in the
sympathizing eye. Thirteen patients (68.42%) were in remission on
immunosuppressive therapy or corticosteroids or in combination
therapy. Eleven patients (57.9%) maintained visual acuity of 20/40 or
better at the end of follow up.
Conclusions: Even with a devastating and possibly lifelong
disease like sympathetic ophthalmia, long-term remission off all
immunosuppressive therapy and corticosteroids, perhaps even cure,
is possible. It is worthwhile to consider immunosuppressive therapy
early in the management of sympathetic ophthalmia for better
outcomes. Studies with longer follow-up might provide additional
evidence to support this.
Commercial Relationships: Abhishek R. Payal, None; C Stephen
Foster, None
Program Number: 2516 Poster Board Number: C0036
Presentation Time: 3:45 PM–5:30 PM
Duration of Immunomodulator Therapy and Uveitic Relapse
David Mostafavi, Michael Chang, Vicente Diaz, John Mauro, Sanjay
Kedhar, Michael Samson. New York Eye and Ear Infirmary, New
York, NY.
Purpose: To evaluate the relationship of length of time on
immunomodulator therapy (IMT) and relapse of uveitis upon IMT
discontinuation.
Methods: 1100 charts were reviewed at New York Eye and Ear
Infirmary from the years 2004-2006. Inclusion criteria included
patients who were on Methotrexate or Cellcept for at least 1 year and
had a minimum 3 year follow-up period once the medication was
discontinued. Three groups were formed: those who were on IMT for
1-2 years, 2-3 years, and greater than 3 years. The first 30 patients
who met the inclusion criterion were included in each group. The
length of time from IMT discontinuation to relapse was noted.
Results: About half of the patients in the 1-2 year IMT group
eventually had a relapse. There was no statistically difference
between the 2-3 year and 3 year or greater IMT group.
Conclusions: This pilot study suggests that patients should be treated
for a minimum of two years with IMT to minimize the risk of uveitic
relapse in the future.
Commercial Relationships: David Mostafavi, None; Michael
Chang, None; Vicente Diaz, None; John Mauro, None; Sanjay
Kedhar, None; Michael Samson, None
Program Number: 2517 Poster Board Number: C0037
Presentation Time: 3:45 PM–5:30 PM
Autoimmune Retinopathy Treated with the Fluocinolone
Acetonide Intravitreal Implant After Intolerance to Systemic
Immunosuppression
David A. DiLoreto, Zoë Williams, Yousuf M. Khalifa. Ophthalmology,
Flaum Eye Institute, U Rochester Med Ctr, Rochester, NY.
Purpose: To report outcomes of two cases of autoimmune
retinopathy (AIR), one cancer associated retinopathy (CAR) and one
non-paraneoplastic autoimmune retinopathy (npAIR), treated locally
with the fluocinolone acetonide intravitreal implant (Retisert) due to
intolerance to systemic immunosuppression
Methods: Case reports.
Results: Case 1. A 64 year old male with CAR secondary to poorly
differentiated carcinoma of the lung (confirmed with markedly
diminished full-field ERG and anti-retinal autoantibody testing
positive for antibodies against 30-kDA (carbonic anhydrase II),
36-kDa (GAPDH), 40-kDa (aldolase), 45-kDa (arrestin) and 62-kDa
proteins) was treated with a sustained release intravitreal steroid
implant (fluocinolone acetonide 0.59mg (Retisert)) after progressive
vision loss despite intravenous immunoglobulin therapy. He was
unable to tolerate systemic immunosuppression with mycophenolate
mofetil due to leucopenia and developed multiple adverse side effects
from high dose prednisone. His vision was successfully stabilized
with a sustained release intravitreal fluocinolone acetonide implant
alone for 6 months prior to his death. Case 2. An 87 year old male
with a 10-year history of chronic bilateral uveitis, severe arteriolar
attenuation and bilateral visual field constriction was diagnosed with
npAIR (antiretinal antibody testing pending) after work-up failed to
reveal cancer. Optical coherence tomography scan revealed diffuse
thinning of the retina with limited sparing of the inner segment/
outer segment junction in the central macula. He had been treated
previously with topical and subtenon’s steroids with limited response.
Intravitreal steroid injections stablilized the disease for limited
duration. Treatment with mycophenolate mofetil was not tolerated
and he deferred trial of other immunosuppressive agents. Bilateral
intravitreal fluocinolone acetonide implants were used to stabilize his
disease at 20/150 in both eyes with more than one year of follow-up.
Conclusions: Local ocular treatment with steroids is an option
in patients with autoimmune retinopathy when systemic
immunosuppresion fails or is not tolerated. We report the first use of
intravitreal steroids in sustained release form to treat autoimmune
retinopathy without concomitant use of systemic immunosuppression.
Commercial Relationships: David A. DiLoreto, None; Zoë
Williams, None; Yousuf M. Khalifa, Alcon (R), Bausch & Lomb
(R)
Support: Research to Prevent Blindness
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
Program Number: 2518 Poster Board Number: C0038
Presentation Time: 3:45 PM–5:30 PM
Uveitis Reactivation in Children Treated with Tumor Necrosis
Factor-α Inhibitors
Michael Lewen3, Monte Mills1, Melissa Lerman2. 1Division
of Ophthalmology, The Children’s Hospital of Philadelphia,
Philadelphia, PA; 2Division of Rheumatology, The Children’s
Hospital of Philadelphia, Philadelphia, PA; 3University of
Pennsylvania Health System, Philadelphia, PA.
Purpose: To evaluate reactivation of pediatric uveitis following
treatment with TNF-alpha inhibition (anti-TNFα).
Methods: We retrospectively assessed children (≤18 years) with
non-infectious uveitis who achieved quiescence while receiving
anti-TNFα at The Children’s Hospital of Philadelphia (January,
2000-July, 2012). Reactivation was defined as redevelopment of
“active” uveitis. Kaplan-Meier (KM) methods were used to calculate
the rates of reactivation while still on treatment (primary outcome)
and following complete discontinuation of anti-TNFα (secondary
outcome). Variables were evaluated for their association with failure
(reactivation).
Results: Of the 136 children and adolescents treated for uveitis,
39 met criteria for assessment of the primary, and 19 met criteria
for assessment of the secondary outcome. Almost two thirds of
subjects were female, almost half carried systemic diagnoses of
Juvenile Idiopathic Arthritis, and the majority were treated with
infliximab. The KM estimated proportion who failed within 12
months was 27.8% (95% confidence interval [95% CI]: 15.9-45.8%).
The estimated probability of failure within 12 months was higher
following discontinuation of anti-TNFα (63.8% [95% CI: 38.987.7%]) relative to before discontinuation (21.6% [95% CI: 10.840.2%]). Amongst those who discontinued anti-TNFα, the likelihood
of failure was significantly lower for those treated with infliximab
(vs. adalimumab) (Hazard Ratio [HR] 0.07, 95% CI: 0.01-0.46).
Older age at onset of ocular disease was associated with a significant
increase in the hazard of failure (HR 1.32, 95% CI: 1.03-1.69). The
duration of remission-on-medication did not significantly affect the
likelihood of failure.
Conclusions: The durability of the response to anti-TNFα is limited
in those children who remain on drug following achievement of
uveitis quiescence. It is poorly sustained in those who discontinue
anti-TNFα - with the majority having uveitis reactivation. These
data suggest that infliximab results in a more durable remission-offmedication than does adalimumab. Results from this small cohort did
not support the notion that maintenance of remission-on-medication
for a longer duration decreases the likelihood of later reactivation.
Commercial Relationships: Michael Lewen, None; Monte Mills,
None; Melissa Lerman, None
Program Number: 2519 Poster Board Number: C0039
Presentation Time: 3:45 PM–5:30 PM
: Use of Intravenous pulses of cyclophosphamide treatment in the
control of severe ocular inflammatory disease
Roberto Dalli1, Miguel Pedroza-Seres1, 2, Vanessa Valderrama2.
1
Uveitis and Ocular Immunology, Retina Clinic, Guadalajara,
Mexico; 2Uveitis and Ocular Immunology, Institute Of
Ophthalmology Conde de Valenciana, Mexico city, Mexico.
Purpose: The goal of this Study was the evaluation of Intravenous
pulses of cyclophosphamide in the control of severe ocular
inflammatory disease.
Methods: A total of 20 patients were included in this study. All the
patients received Intravenous pulses of cyclophosphamide (10-15 mg/
kg). Review of systems and a complete ophthalmologic exam were
made in each patient. The severity of their disease was considered in
order to treat them with intravenous cyclophosphamide.
Results: From a total of 20 patients, 14 (70%) were female and 6
(30%) were male. The average age of patients was 51.35 ± 22.22
years old. Ocular findings were necrotizing scleritis (30%), followed
by nodular scleritis (10%), difuse scleritis (10%) and others as retinal
vasculitis, mucous membrane pemphigoid, rheumatoid arthritis.
The average number of pulses of cyclophosphamide were 3.5 ± 2.5.
All patients were treated with oral steroids.
Ninety percent of patients showed improvement in the course of the
disease.
Seventy per cent of patients had systemic disease, granulomatosis
with polyangeitis, (Wegener’s disease) was seen in 35%, ocular
cicatrizial pemphigoid (10%), tubercoulosis disease (10%),
rheumatoid arthritis (5%) and miscellaneous (5, 5%).
The ocular manifestation in patients was primarily the scleritis.
Conclusions: Use of intravenous pulses of cyclophosphamide in
acute ocular inflammatory disease is effective and safe. It should
be considerer in any patient with a potential blinding inflammatory
disease
Commercial Relationships: Roberto Dalli, None; Miguel PedrozaSeres, None; Vanessa Valderrama, None
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].
ARVO 2014 Annual Meeting Abstracts
Program Number: 2520 Poster Board Number: C0040
Presentation Time: 3:45 PM–5:30 PM
Combination of Rituximab and Intravenous Immunoglobulin for
Recalcitrant Ocular
Cicatricial Pemphigoid
Asima Bajwa, Pranav Patel, Judit Z. Baffi, Ninani C. Kombo,
Homaira A. Hossain, Kyungmin Lee, C Stephen Foster.
Massachusetts Eye Research and Surgery Institution, Cambridge,
MA.
Purpose: To analyze the clinical course of patients with recalcitrant
Ocular Cicatricial Pemphigoid (OCP) treated with Rituximab (RTX)
and intravenous immunoglobulin (IV-Ig)
Methods: A non comparative retrospective case series of 12
immunohistopathologically proven OCP patients who failed
conventional immunosuppressive therapy. All patients received
a combination of RTX and IV-Ig according to the protocol and a
minimum follow up of 6 months. The main outcome measures were
blindness (best corrected visual acuity BCVA 20/200 or worse),
control of inflammation and Foster OCP staging.
RTX + IV-Ig Treatment Protocols:
1) RTX: Dose 375mg/m2 once weekly for 8 consecutive weeks, then
monthly for the subsequent 4 months, total of 12 infusions during a
period of 6 months.
2) IV-Ig: Dose 2g/kg/cycle. Total dose was divided into 3 equal parts
on 3 consecutive days. The patients were given one cycle of IV-Ig
prior to the initiation of RTX and then monthly until the B cell count
returned to normal. Thereafter, IV-Ig was continued at 6, 8, 10, 12, 14
and 16 weeks. The last cycle was given at 16 week interval.
Results: Twelve OCP patients (24 eyes), 7 female and 5 male, with
a median age of 58 years (range 40–70 years) were included. The
duration of the disease varied from 2-168 months (median 24). Total
follow-up period was between 6-108 months (median 18 months. All
but 5 patients received the above RTX+IV-Ig protocol (median 12.5
infusions). Five patients with aggressive disease (2 were monocular,
and 1 relapsed after being in remission for a year) received additional
RTX infusions. Of these 1 eventually failed therapy. The duration of
RTX infusions was 4-19 months (median 12months).
None of the eyes became blind at the end of follow up. Eight patients
(66.6%) were in remission after 3-12 months (median 6months). Of
these 8 patients, 6 achieved remission off therapy while 2 (16.6%)
had resolving inflammation with continuation of therapy. Two
patients failed (16.6%).
Before and after therapy, OCP staging remained stable throughout the
study period.
Conclusions: Combination of RTX and IV-Ig is effective in
preventing blindness and arresting disease progression in patients
with recalcitrant OCP.
Commercial Relationships: Asima Bajwa, None; Pranav Patel,
None; Judit Z. Baffi, None; Ninani C. Kombo, None; Homaira A.
Hossain, None; Kyungmin Lee, None; C Stephen Foster, None
©2014, Copyright by the Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Go to iovs.org to access the version of record. For permission
to reproduce any abstract, contact the ARVO Office at [email protected].