Multicenter Study of Intravitreal Dexamethasone Implant in Noninfectious Uveitis: Indications, Outcomes, and Reinjection Frequency ˜ O, ROBERT L. JOHNSTON, QURESH MOHAMMED, JAVIER ZARRANZ-VENTURA, ESTER CARREN ADAM H. ROSS, CARL BARKER, ALEX FONOLLOSA, JOSEBA ARTARAZ, LAURA PELEGRIN, ALFREDO ADAN, RICHARD W. LEE, ANDREW D. DICK, AND AHMED SALLAM
PURPOSE:

To identify clinical outcomes and treatment patterns of intravitreal dexamethasone implant (Ozurdex; Allergan, Inc) in noninfectious uveitis in the clinical setting.
DESIGN: Multicenter retrospective cohort study.
METHODS: Eighty-two eyes (63 patients) receiving 142 implant injections over 35 months were included. Treatment indication, uveitis diagnosis, visual acuity, intraocular pressure, vitreous haze score, central retinal thickness by optical coherence tomography, phakic status, number of injections, time to reinjection, systemic treatments, and complications data were collected. Time to visual acuity and vitreous haze score improvement as per the Standardization of Uveitis Nomenclature guidelines were also determined.
RESULTS: The probability of visual acuity improvement (‡0.3 logarithm of the minimal angle of resolution units improvement) was 39% at 1 month, 49% at 3 months, 52% at 6 months, and 58% at 12 months. Eyes with baseline vitritis (vitreous haze score ‡D0.5, n [ 45) had a probability of vitreous haze score improvement (2-step decrease or change from D0.5 to 0) at 2 weeks of 41%, at 1 month 63%, at 3 months 73%, at 6 months 79%, and at 12 months 88%. In eyes that completed 12-month follow-up (n [ 54), 40.7% underwent 2 injections (mean time to second injection of 6.6 ± 1.9 months) and 11.2% required ‡3 injections (mean time to third injection of 11 ± 1.5 months).

Supplemental Material available at AJO.com. Accepted for publication Sep 2, 2014. From Bristol Eye Hospital, Bristol, United Kingdom (J.Z.-V., E.C., A.H.R., C.B., R.W.L., A.D.D.); Gloucestershire Hospitals National Health Service Trust, Cheltenham, United Kingdom (J.Z.-V., R.L.J., Q.M., A.S.); Hospital Universitario de Cruces, Bilbao, Spain (A.F., J.A.); Institut Clı´nic d9 Oftalmologia (ICOF), Hospital Clı´nic, Barcelona, Spain (J.Z.-V., L.P., A.A.); National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust and University College London Institute of Ophthalmology, London, United Kingdom (R.W.L., A.D.D.); and University Hospitals Bristol National Health Service, Foundation Trust, and University of Bristol, Bristol, United Kingdom (R.W.L., A.D.D.). Inquiries to Javier Zarranz-Ventura, Bristol Eye Hospital, Lower Maudlin St, Bristol BS1 5LA, United Kingdom; e-mail: jzarranz@ hotmail.com 0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2014.09.003

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CONCLUSIONS:

Dexamethasone implant use in uveitis provides favorable visual acuity and vitreous haze score outcomes but requires repeated injections, an important consideration when choosing intraocular treatment as a route to controlling uveitis. (Am J Ophthalmol 2014;-:-–-. Ó 2014 by Elsevier Inc. All rights reserved.)

A

S UNCONTROLLED INTRAOCULAR INFLAMMATION

results in cumulative damage to the retina, there is consensus that long-term maintained control of uveitis is critical for preserving vision.1 Sustained-release intraocular implants have been developed in recent years to provide maintained delivery of different types of steroids to the posterior segment.2–4 Whereas some of the first steroid implants required a major surgical procedure for their placement in the vitreous cavity,5 the technological advances in pharmacotherapy have made possible the development of new injectable devices that can be easily administered in an office-based setting.6,7 Currently commercially available devices are classified into 2 types: inert shells, which slowly release drug; and bioerodible polymers.2 Among the latter is included the dexamethasone implant (Ozurdex; Allergan, Inc, Irvine, California, USA), which is a bioerodible device composed of a mix of polylactic acid and polyglycolic acid polymers that releases 0.7 mg of preservative-free dexamethasone for up to 6 months.8 Its safety and efficacy has been confirmed in clinical trials for the management of a variety of retinal diseases, such as macular edema related to retinal vein occlusions or diabetes.9–11 The use of the dexamethasone implant for uveitis was evaluated in the HURON (cHronic Uveitis evaluation of the intRavitreal dexamethasONe implant) trial.12 This study demonstrated that a single injection led to adequate control of intraocular inflammation and good visual outcomes for up to 6 months in noninfectious intermediate and posterior uveitis. However, given the strict entry criteria under trial conditions, it is unclear whether these outcomes reflect the routine use of this implant in uveitis units in real-world situations, in which treatment is driven by wider indications, for longer follow-up periods, when repeat injections are required. The criteria for determining

ELSEVIER INC. ALL

RIGHTS RESERVED.

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intraocular steroid treatment in uveitis have yet to reach consensus on where it sits in the pathway of care outside the clinical trial setting; therefore, larger study cohort outcomes have the opportunity to inform this consensus over and above the short single-center series currently reported.13–15 With this in mind, we established a collaborative project between 4 specialized uveitis units in the United Kingdom and Spain to ascertain the clinical characteristics, demographics, and clinical outcomes, as well as complications and reinjection frequency, of intravitreal dexamethasone implant in noninfectious uveitis in routine clinical practice.

ysis for eyes with low VA was undertaken by substituting counting fingers and hand movement with 2.0 and 2.3 logarithm of the minimal angle of resolution (logMAR), respectively.16 Vitreous haze score was measured using a standardized scale in conformance with Standardization of Uveitis Nomenclature guidelines.17 Central retinal thickness was determined by OCT imaging, using 1 of 2 different devices depending on the study center (Cirrus HD OCT; Carl Zeiss Meditec, Dublin, California, USA and Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany). In patients for whom data were not available for a particular visit or who had been lost to follow-up, no missing value substitutions were performed.
STATISTICAL METHODS:

METHODS CLINICAL DATA WERE RETROSPECTIVELY COLLECTED FROM

4 specialized uveitis clinics, 2 in the United Kingdom (Bristol Eye Hospital, University Hospitals Bristol National Health Service Foundation Trust, Bristol; and Gloucestershire Hospitals National Health Service Foundation Trust, Cheltenham) and 2 in Spain (Hospital Universitario de Cruces, Bilbao; and Institut Clı´nic d9 Oftalmologı´a [ICOF] at Hospital Clinic, Barcelona). A comprehensive data spreadsheet was provided to each study center and was completed within the predetermined timeframe by the end of August 2013, collecting data from injections performed between October 26, 2010 and July 4, 2013. Patient identifiers were removed to make data anonymous, and on this basis an ethics committee at Gloucestershire Hospitals National Health Service Foundation Trust determined that formal ethics approval was not required. Data from individual centers were collated and merged to a centralized database for analysis purposes. This study was conducted in accordance with the tenets of the Declaration of Helsinki. Analysis was restricted to eyes undergoing intravitreal dexamethasone implant injection for noninfectious uveitis, with clinical indications of vitritis or uveitic cystoid macular edema (CME) or both.
CLINICAL DATA:

Data collected included age; sex; laterality; indication; uveitis anatomic classification; phenotypic diagnosis; previous local treatments; previous and current systemic treatments; surgical details; number of injections; complications; and visual acuity (VA), intraocular pressure (IOP), central retinal thickness assessed by optical coherence tomography (OCT), and vitreous haze score at baseline and at 1, 3, 6, and 12 months post injection of the first intravitreal dexamethasone implant.


DATA SOURCES/MEASUREMENTS:

As data were gathered from routine clinical settings, visual acuity was determined as the best VA with habitual correction or pinhole rather than best-corrected refracted VA at all time points. Anal-

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Probabilities of events occurring after intravitreal dexamethasone implant injection are presented as survival curves using the Kaplan-Meier method.18 Snellen VA was converted to logMAR equivalents for the purposes of statistical analysis. Improvement in VA and vitreous haze score was defined as per the Standardization of Uveitis Nomenclature guidelines as halving _0.3 logMAR unit change) and 2-step of the visual angle (> decrease or change from þ0.5 to 0 in vitreous haze score, respectively.19 Subgroup analysis was performed in eyes with vitritis and eyes with CME. Descriptive frequency statistics and the x2 test were used to assess qualitative variables. Normality of quantitative variables was examined using histograms. The paired t test was used to compare pre- and posttreatment mean changes when variables were normally distributed, and the Wilcoxon test was used in cases where nonparametric tests were required. A P value of less than .05 was considered statistically significant. All statistical analysis was performed using Excel and SPSS 15.0 software (SPSS Inc, Chicago, Illinois, USA). Kaplan-Meier survival analysis curves were constructed using MedCalc 13.3 software (MedCalc Software, Ostend, Belgium).

RESULTS
DEMOGRAPHICS, INDICATIONS, AND UVEITIS TYPE OF STUDY EYES: Data were received for 146 intravitreal dexa-

methasone implant injections performed in 85 eyes over a 35-month period (October 2010–August 2013) (Supplemental Figure 1, available at AJO.com). Three of these eyes were excluded from analysis owing to different indications than noninfectious uveitis (1 eye had hypotonous maculopathy, 1 had CME following a previously treated toxoplasma chorioretinitis, 1 had CME following penetrating eye injury). A total of 142 intravitreal dexamethasone implant injections performed in 82 eyes of 63 patients with noninfectious uveitis were analyzed, with 30.1% of patients receiving bilateral injections (19/63). Patient demographics, indications, uveitis anatomic classification, phenotypic diagnosis, and current and previous

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treatments of study eyes are detailed in Table 1. The most common indication for treatment was CME (60.9%, 50/ 82), followed by vitritis (25.6%, 23/82), then combined CME and vitritis (10.9%, 9/82). The most frequent anatomic locations were intermediate uveitis (37.8%, 31/ 82), posterior uveitis (23.1%, 19/82), and panuveitis (21.9%, 18/82), and most frequent phenotypic diagnoses were nondifferentiated (54.8%, 45/82), birdshot chorioretinopathy (14.6%, 12/82), sarcoidosis (7.3%, 6/82), and multiple sclerosis (7.3%, 6/82). The mean time from diagnosis to the first injection was 67.8 6 65.2 months (median ¼ 48 months, interquartile range 49). Excluding patients with juvenile idiopathic arthritis (as they are commonly diagnosed in childhood with prolonged follow-up), the mean time from diagnosis to first injection was 58.4 6 51.6 months (median ¼ 48, IQR ¼ 51.5).
CURRENT SYSTEMIC TREATMENT, PREVIOUS LOCAL TREATMENTS, AND PHAKIC STATUS: At the time of the

first injection, 53.9% of patients (34/63) were on systemic treatment, which included 14.3% (9/63) on prednisolone, 9.5% (6/63) on 1 second-line immunomodulatory therapy, and 30.1% (19/63) on a combined regimen of prednisolone and immunomodulatory therapy as dual therapy in 20.6% (13/63) and as triple therapy in 9.5% (6/63) (Table 1). Previous local treatments with periocular and intravitreal therapies were used in 63.4% of eyes (52/82), with 37.8% treated with prior periocular steroids (31/82), 56.0% with intravitreal triamcinolone (46/82), and 19.5% with intravitreal anti–vascular endothelial growth factor (VEGF) drugs (16/82). Regarding the phakic status, 51.2% of the eyes were pseudophakic (42/82), 42.6% were phakic (35/ 82), and 6.1% were aphakic (5/82). Previous pars plana vitrectomy had been undertaken in 32.9% of included eyes (27/82) to facilitate uveitis control.
VISUAL ACUITY, VITREOUS HAZE, AND CENTRAL RETINAL THICKNESS OUTCOMES: VA (mean 6 standard

deviation [SD]) was 0.68 6 0.4 (median ¼ 0.5) logMAR at baseline, 0.59 6 0.4 (0.5) 2 weeks post injection, 0.49 6 0.4 (0.4) at 1 month, 0.49 6 0.5 (0.4) at 3 months, 0.60 6 0.5 (0.4) at 6 months, and 0.52 6 0.5 (0.4) at 12 months (P < .01 at all time points) (Table 2). The probability of visual acuity improvement as per the Standardization of Uveitis Nomenclature guidelines (improvement > _0.3 logMAR units) was 17% at 2 weeks, 39% at 1 month, 49% at 3 months, and 52% at 6 months, which was maintained at 12 months (58%) (Figure 1). The median time to visual acuity improvement was 6 months (95% confidence interval [CI] ¼ 5.34–7.79). Restricting the analysis to include only eyes with vitritis _þ0.5, n ¼ 39 eyes), the at baseline (vitreous haze score > probability of achieving vitreous haze score improvement as per the Standardization of Uveitis Nomenclature guidelines (2-step improvement or change from þ0.5 to 0) was 41% at 2 weeks, 63% at 1 month, 73% at 3 months, 79%

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at 6 months, and 88% at 12 months (Figure 2). The median time to vitreous haze score improvement was 1 month (95% CI ¼ 0.6–1.3). In the cohort of eyes with CME (n ¼ 59 eyes), the mean central retinal thickness was 469 6 193 mm (mean 6 SD) at baseline, improving to 326 6 81 at 2 weeks, 267 6 74 at 1 month, 318 6 149 at 3 months, 366 6 140 at 6 months, and 355 6 160 at 12 months (P < .001 at all time points) (Supplemental Table 1, available at AJO.com). These results, together with corresponding visual acuity measures at each time point, are shown in Supplemental Figure 2 (available at AJO.com).
INTRAOCULAR PRESSURE OUTCOMES:

Mean IOP at baseline was 14.1 6 4 mm Hg (mean 6 SD) and increased to 18.0 6 8 mm Hg at 2 weeks (P < .001), 18.0 6 7 mm Hg at 1 month (P < .001), 15.9 6 5 mm Hg at 3 months (P ¼ .01), 14.4 6 4 mm Hg at 6 months (P ¼ .62), and 14.6 6 4 mm Hg at 12 months (P ¼ .43) (Table 2). At 1 month, _21 mm Hg was 32%, the probability of having an IOP > > _25 mm Hg was 19%, and > _35 mm Hg was 7%, and at 3 months these probabilities were 41%, 23%, and 7%, respectively (Figure 3, Left). Regarding changes in IOP from baseline, at 1 month the probability of IOP increase > _5 mm Hg was 46%, > _10 mm Hg was 23%, and > _15 mm Hg was 12%. These probabilities increased to 53%, 30%, and 13% at 3 months, respectively (Figure 3, Right).
REINJECTION FREQUENCY AND NUMBER OF INJECTIONS: The overall mean number of injections was 1.7 6

0.8 (mean 6 SD) with a median of 1 injection over a mean follow-up of 15.4 6 9 months (median ¼ 13). A single injection was performed in 52.4% (43/82) of eyes, 29.3% (24/82) required 2 injections, and 18.2% (15/82) _3 injections. The probability of having a second required > injection at 6 months was 26%, increasing to 47% at 9 months and 51% at 12 months, with a median time to second injection of 10 months (95% CI ¼ 6.3–13.6) (Figure 4, Left). Among eyes that were injected twice, the probability of having the second injection by 6 months _3 injections the probabilwas 43%, and among those with > ity of having the third injection by 12 months was 43% (Figure 4, Right). Restricting the analysis to eyes that completed 12 months of follow-up (54/82 eyes, 65.9%; 28 eyes [34.1%] did not complete 12 months of follow-up), the mean number of injections was 1.64 6 0.7 (median ¼ 2) (Supplemental Table 2, available at AJO.com). In this subgroup, 40.7% (22/54) of eyes required a second injection, which was performed on average 6.6 6 1.9 months after the first injection (median ¼ 6); and in the 9.3% (5/54) of eyes that required a third injection, this was done on average 11.0 6 1.5 months (median ¼ 11.5) after the first implant (Supplemental Figure 3, available at AJO.com). Only 1 eye required a fourth injection within 12 months (1.9%). For patients who completed 12 months of follow-up,

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4 TABLE 1. Baseline Characteristics of Study Patients and Eyes Treated With the Intravitreal Dexamethasone Implant in Noninfectious Uveitis

Age, mean 6 SD (median, IQR) Sex, % female (female:male) N eyes (patients) Indications (%)

Total

Bristol Eye Hospital, Bristol, UK

Gloucestershire NHS Trust, Cheltenham, UK

Hospital de Cruces, Bilbao, Spain

Hospital Clinic, Barcelona, Spain

47.4 6 17.2 (50.5, IQR 26)

51.2 6 15.7 (53, IQR 22)

40 6 16.9 (37, IQR 28)

47.9 6 21.6 (52, IQR 29.5)

48.2 6 16.1 (48, IQR 24.5)

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74.1% (2.8:1) 82 (63) 1. CME (61%) 2. Vitritis (28%) 3. CME þ vitritis (11%) Uveitis anatomic classification 1. Intermediate uveitis (37.8%) (%) 2. Posterior uveitis (23.1%) 3. Panuveitis (21.9%) 4. Anterior chronic uveitis (13.4%) 5. Acute anterior uveitis (2.4%) 6. Retinal vasculitis (1.2%) Phenotypic diagnosis (%) 1. Nondifferentiated (54.8%) 2. Birdshot (14.6%) 3. Sarcoidosis (7.3%) 4. Multiple sclerosis (7.3%) 5. Juvenile arthritis (6.1%) 6. Ankylosing spondylitis (2.4%) 7. HLA-B27 uveitis (2.4%) 8. IRVAN (2.4%) 9. Sympathetic ophthalmia (1.2%) 10. Behc¸et disease (1.2%) Systemic therapies (%) 53.9% (34/63) -Prednisolone 14.3% -1 second-line agent 9.5% 20.6% -2 double therapya 9.5% -3 Triple therapyb

60% (1.5:1) 15 (10) 1. CME (66.7%) 2. Vitritis (20%) 3. CME þ vitritis (13.3%) 1. Intermediate uveitis (46.6%) 2. Posterior uveitis (40%) 3. Panuveitis (13.3%)

100% (9:0) 10 (9) 1. Vitritis (40%) 2. CME þ vitritis (40%) 3. CME (20%) 1. Intermediate uveitis (70%) 2. Panuveitis (30%)

75% (3:1) 15 (12) 1. CME (80%) 2. CME þ vitritis (13.4%) 3. Vitritis (6.6%) 1. Anterior chronic uveitis (46.7%) 2. Panuveitis (13.3%) 3. Intermediate uveitis (20%) 4. Intermediate uveitis (20%)

1. Nondifferentiated (60.0%) 2. Birdshot (26.6%) 3. HLA-B27 uveitis (13.3%)

1. Nondifferentiated (90%) 2. Juvenile arthritis (10%)

1. Nondifferentiated (66.6%) 2. Sarcoidosis (20%) 3. Juvenile arthritis (6.7%) 4. Birdshot (6.7%)

50% 20% 0% 20% 10%

44.4% 22.2% 0% 22.2% 0%

58.3% 8.3% 8.3% 41.7% 0%

71.8% (2.5:1) 42 (32) 1. CME (61.9%) 2. Vitritis (35.7%) 3. CME þ vitritis (2.4%) 1. Intermediate uveitis (33.3%) 2. Panuveitis (26.2%) 3. Posterior uveitis (23.8%) 4. Anterior chronic uveitis (9.5%) 5. Acute anterior uveitis (4.7%) 6. Retinal vasculitis (2.3%) 1. Nondifferentiated (40.4%) 2. Birdshot (16.6%) 3. Multiple sclerosis (14.3%) 4. Sarcoidosis (7.1%) 5. Juvenile arthritis (7.1%) 6. Ankylosing spondylitis (4.7%) 7. IRVAN (4.7%) 8. Sympathetic ophthalmia (2.3%) 9. Behc¸et disease (2.3%) 56.2% 12.5% 15.6% 18.7% 9.4%

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Continued on next page

CME ¼ cystoid macular edema; IQR ¼ interquartile range; IRVAN ¼ idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis; MTX ¼ methotrexate; UK ¼ United Kingdom. Double therapy: steroids þ second-line agent. b Triple therapy: steroids þ second-line agents 32.

Previous local therapies (%) -Periocular steroids -Intravitreal steroids -Anti-VEGF

a

59.5% (25/42) 45.2% (19/42) 61.9% (26/42) 26.1% (11/42) 60% (9/15) 40% (6/15) 26.6% (4/15) 20% (3/15) 90% (9/10) 50% (5/10) 70% (7/10) 0% (0/10) 60% (9/15) 6.6% (1/15) 60% (9/15) 13.3% (2/15)

1. Adalimumab (29.4%) 2. MTX (23.5%) 3.Mycophenolate (11.7%) 4. Cyclosporine (11.7%) 5. Azathioprine (5.8%) 6. Beta-interferon (5.8%) 7. Abatacept (5.8%) 8. Golimumab (5.8%) 1. MTX (71.4%) 2. Adalimumab (28.6%) 1.Mycophenolate (100%) 1.Mycophenolate (50%) 2. Adalimumab (25%) 3. Tacrolimus (25%)

1. MTX (31%) 2. Adalimumab (20.6%) 3.Mycophenolate (20.6%) 4. Cyclosporine (6.9%) 5. Tacrolimus (6.9%) 6. Azathioprine (3.4%) 7. Beta-interferon (3.4%) 8. Abatacept (3.4%) 9. Golimumab (3.4%) 63.4% (52/82) 37.8% (31/82) 56% (46/82) 19.5% (16/82) Immunomodulatory therapy (%)

Hospital Clinic, Barcelona, Spain Hospital de Cruces, Bilbao, Spain Gloucestershire NHS Trust, Cheltenham, UK Bristol Eye Hospital, Bristol, UK Total

TABLE 1. Baseline Characteristics of Study Patients and Eyes Treated With the Intravitreal Dexamethasone Implant in Noninfectious Uveitis (Continued )

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no significant differences were observed between eyes treated for vitritis or uveitic CME in the mean number of injections (1.76 6 0.7 vs 1.65 6 0.7, P ¼ .54), percentage of eyes requiring 2 injections (53.5% vs 39.0%, P ¼ .19), or mean time to second injection (6.73 vs 6.71 months, P ¼ .97). Among eyes with CME, a trend was observed for higher mean number of injections when concomitant vitritis was present (2.14 vs 1.56, P ¼ .06), without significant differences in mean visual acuity (0.50 6 0.6 logMAR vs 0.55 6 0.5 logMAR, P ¼ .81) or mean central retinal thickness (229 6 29 mm vs 272 6 76 mm, P ¼ .23) at month 1, or at month 12 (0.51 6 0.5 logMAR vs 0.72 6 0.6 logMAR, P ¼ .36; and 343 6 147 mm vs 418.8 6 222 mm, P ¼ .30, respectively).
SYSTEMIC TREATMENT:

The probability of dose reduc_5 mg of prednisolone or tion, defined as reduction in > any decrease in second-line immunomodulatory therapy dose for patients on systemic treatment at baseline (n ¼ 34, 53.9%), was 36% at 1 month, increasing to 42% at 3 months and 46% at 6 months, and peaking at 62% at 12 months (Supplemental Figure 4, available at AJO. com). Standardization of Uveitis Nomenclature criteria definition for dose reduction (oral prednisolone temic steroid discontinuation was 8% at 1 and 3 months, increasing to 11% at 6 months and 36% at 12 months.


ADVERSE EFFECTS AND COMPLICATIONS:

The most _21 mm Hg) in frequent adverse effect was raised IOP (> 40.2% of the eyes (33/82), requiring ocular hypotensive treatment in 39% (32/82) and glaucoma surgery in 2.4% of study eyes (2/82). The percentage of pseudophakic patients increased from 51.2% (42/82) at baseline to 56.1% (46/82) at final follow-up. Among the 142 injections there were 3 cases of vitreous hemorrhage (2.1%, 3/142), 3 cases of hypotony (2 in vitrectomized eyes) (2.1%, 3/142), 2 cases of implant dislocation into the anterior chamber (1 in aphakic eyes, 1 in pseudophakic eyes with iris-claw intraocular lens) (1.4%, 2/142), and 1 case of endophthalmitis (0.7%, 1/142). No cases of retinal detachment were observed.

DISCUSSION THIS STUDY DEMONSTRATES THAT THE USE OF INTRAVI-

treal dexamethasone implant, outside the criteria requested for HURON trial inclusion, can achieve adequate control of vitreous haze and macular edema with significant improvement in vision in eyes with noninfectious uveitis. This multicenter cohort also highlights that in the clinical setting the main indication for implant

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CRT ¼ central retinal thickness; IOP ¼ intraocular pressure; IQR ¼ interquartile range; VA ¼ visual acuity; VHS ¼ vitreous haze score. Number of eyes (% at each time point). a

VA, logMAR Mean 6 SD (median, IQR) 0.68 6 0.47 (0.5, IQR 0.4) 0.59 6 0.49 (0.5, IQR 0.6) 0.49 6 0.47 (0.4, IQR 0.4) 0.49 6 0.50 (0.4, IQR 0.6) 0.60 6 0.5 (0.4, IQR 0.4) 0.52 6 0.53 (0.4, IQR 0.575) IOP, mm Hg Mean 6 SD (median, IQR) 14.1 6 4.0 (14, IQR 5) 18.0 6 8.1 (17, IQR 5.75) 18.0 6 7.6 (17, IQR 7.25) 15.9 6 5.4 (16, IQR 5) 14.3 6 4.2 (14, IQR 5.5) 14.6 6 4.2 (15, IQR 6) VHS 0 37 (48.6%)a 47 (68.1%) 55 (85.9%) 52 (74.2%) 43 (72.8%) 42 (79.2%) þ0.5 9 (11.8%) 10 (14.4%) 5 (7.8%) 9 (12.8%) 8 (13.5%) 5 (9.4%) þ1 18 (23.6%) 9 (13%) 3 (4.6%) 5 (7.1%) 4 (6.7%) 5 (9.4%) þ2 9 (11.8%) 3 (4.3%) 1 (1.5%) 3 (4.2%) 3 (5%) 0 (0%) þ3 2 (2.6%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) þ4 1 (1.3%) 0 (0%) 0 (0%) 1 (1.4%) 1 (1.6%) 1 (1.8%) CRT, mm Mean 6 SD (median, IQR) 462 6 190 (436, IQR 245) 327 6 97 (312, IQR 124) 274 6 89 (260, IQR 76) 324 6 150 (278, IQR 87) 366 6 158 (311, IQR 173) 335 6 153 (277, IQR 145) (Total n ¼ 82) (n ¼ 80) (n ¼ 71) (n ¼ 66) (n ¼ 75) (n ¼ 61) (n ¼ 54)

12 Months 6 Months 3 Months 1 Month 2 Weeks Baseline All Study Eyes

TABLE 2. Clinical Outcomes of Intravitreal Dexamethasone Implant in Noninfectious Uveitis at Different Time Points

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use was CME in eyes with quiescent or minimal vitritis (as defined by vitreous haze score _þ1.5, whereas in our series only 47.5% (39/82) of the _þ0.5) at baseline eyes had vitritis (vitreous haze score > _þ1.5. and only 14.6% (12/82) had vitreous haze score > Therefore, in this cohort most of our study eyes exhibited mild vitritis cases (vitreous haze score

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FIGURE 1. Kaplan-Meier survival analysis of time to visual acuity improvement with the intravitreal dexamethasone implant in noninfectious uveitis eyes as per the Standardization of Uveitis Nomenclature criteria, defined as eyes with halving of the visual angle from baseline visual acuity. (Dotted lines [ 95% confidence intervals; formula [ median time to visual acuity improvement in months, CI [ confidence intervals; bottom right [ time points, 2w [ 2 weeks, 1m [ 1 month, 3m [ 3 months, 6m [ 6 months, 12m [ 12 months; n [ total number of eyes at each time point).

FIGURE 2. Kaplan-Meier survival analysis of time to vitreous haze score improvement with the intravitreal dexamethasone implant in noninfectious uveitis eyes as per the Standardization of Uveitis Nomenclature criteria, defined as improvement in ‡2 vitreous haze score units or change from D0.5 baseline vitreous haze score to 0. (Dotted lines [ 95% confidence intervals; formula [ median time to vitreous haze score improvement in months, CI [ confidence intervals; bottom right [ time points, 2w [ 2 weeks, 1m [ 1 month, 3m [ 3 months, 6m [ 6 months, 12m [ 12 months; n [ total number of eyes at each time point).

logMAR, equivalent to halving of visual angle as per Standardization of Uveitis Nomenclature guidelines) was 42% at 1 and 3 months (6 and 12 weeks, respectively) and 38% at 6 months (26 weeks). These figures are consistent with our current data, especially considering the following: first, our cohort had worse VA at baseline and therefore more potential to gain; second, our cohort’s main treatment indication was for CME and any improvement in CME presented opportunity to reveal a more significant visual gain; and third, the proportion of eyes with a good baseline vision (>70 letters, was 63% at 1 month, 73% at 3 months, 79% at 6 months, and 88% at 12 months, respectively. In the HURON trial, 47% of eyes had a vitreous haze score of 0 at 8 weeks, which increased to 51.5% (34/66) when analysis was restricted to eyes with no inflammation in the anterior chamber.12

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FIGURE 3. Kaplan-Meier survival analysis of time to raised intraocular pressure and intraocular pressure change within 12 months after intravitreal dexamethasone implant injection in noninfectious uveitis eyes (in months). (Left) Time to different levels of raised intraocular pressure in months (dotted line [ intraocular pressure ‡21 mm Hg, solid line [ intraocular pressure ‡25 mm Hg, dashed line [ intraocular pressure ‡35 mm Hg). (Right) Time to different levels of intraocular pressure change in months (dotted line [ intraocular pressure change ‡5 mm Hg, solid line [ intraocular pressure change ‡10 mm Hg, dashed line [ intraocular pressure change ‡15 mm Hg).

FIGURE 4. Kaplan-Meier survival analysis of time to repeat intravitreal dexamethasone implant injections after first implant injection in noninfectious uveitis eyes. (Left) Time to second injection including all study eyes (n [ 82 eyes) (dotted lines [ 95% confidence intervals; formula [ median time to second injection, CI [ confidence intervals; bottom right [ time points, 6m [ 6 months, 9m [ 9 months, 12m [ 12 months, 15m [ 15 months, 30m [ 30 months; n [ total number of eyes at each time point). (Right) Subgroup analysis by eyes with ‡2 injections and ‡3 injections. Time to second injection in eyes with ‡2 injections (solid line) and time to third injection in eyes ‡3 injections (dotted line) in months.

However, comparisons should not be made directly with HURON, given the differences in indications for treatment and starting mean vitreous haze scores between the 2 patient cohorts. In the clinical setting, a recent study to assess the effect of repeat injections reported that 58% of eyes had a vitreous haze score of 0 at baseline (22/38), similar to our 48.6% (37/80). In their series, they noted greater success (compared with HURON), with improvement in 83% of eyes at 1 month, which was maintained at 85% at 6 months; but the effect subsided, with only 53% at 12 months showing improvement even with repeat injections. Overall the figures are consistent with our data (85.9%, 72.8%, and 79.2%, respectively, Table 2). Of note, these results, in contrast with the HURON trial, are in patients in whom the main indication was CME. The baseline central retinal thickness was higher in our series than in the HURON trial (462 vs 344 mm), which is 8

perhaps not surprising given the differences in the indication for treatment between the 2 cohorts. The extent of central retinal thickness decrease was significantly greater in our series at 1 month (194 mm) and 3 months (137 mm) than in the HURON trial at 2 months (99 mm), and further reduced thickness at the 6-month analysis (116 mm in our cohort vs 50 mm in the trial). In subsequent subgroup analysis, restricted to eyes with CME at baseline, visual acuity improved as central retinal thickness improved (reduced thickness) over the initial 3 months, after which VA was maintained despite central retinal thickness continuing to increase again up to 6 months. At this time, eyes with relapsing CME were reinjected and the pattern repeated, as represented in Supplemental Figure 2 (available at AJO.com). There are only a few published studies assessing the effect of the dexamethasone implant in uveitic CME. In a short follow-up, single-center cohort study of uveitic CME in

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vitrectomized eyes (n ¼ 17, baseline central retinal thickness ¼ 461 mm), the central retinal thickness reduction was 184 mm at 1 month, 112 at 3 months, and 67 at 6 months, and our results are consistent with these findings and corroborate the published similar pharmacokinetic profile of the implant between vitrectomized and nonvitrectomized eyes.13,21 Another single-center cohort report that compared dexamethasone implant vs fluocinolone acetonide implant in uveitis also supports our findings, and in the patients treated with the dexamethasone implant (n ¼ 11, baseline central retinal thickness ¼ 379 mm), central retinal thickness reduction was 100 mm at 1 month, 64 mm at 6 months, and 37.4 mm at 12 months.14 Finally, the previously cited recent single-center report in the clinical setting (n ¼ 38, baseline central retinal thickness ¼ 453 mm) showed data consistent with our results at 1 and 6 months (263 and 127 mm), with a slightly less marked effect in central retinal thickness with repeat injections.15 The percentage of eyes with raised IOP in our study was higher than in the HURON trial at all time points analyzed, and also a higher proportion of eyes required IOP-lowering treatment. The probability of moderate _25 mm Hg) in our series was 12% at IOP elevation (> 2 weeks, increasing to 20% at 1 month compared to the HURON report of 7% at 3 and 6 weeks. At 1 month the _35 mm Hg) was 7% in our probability of very high IOP (> series compared to the 4% reported in the HURON trial. In HURON the percentage of eyes requiring IOPlowering medication throughout the 6-month follow-up period was at most 23%, whereas in our series 36.5% of eyes (30/82) required treatment within 6 months, and up to 42.5% if the analysis is restricted to eyes with 12month follow-up (23/54). However, although these differences in IOP and requirement of IOP-lowering treatment could be explained at least in part by the longer followup period and the use of repeat dexamethasone implants in our study, our results show increased incidence compared to those reported in a clinical setting study with repeat injections and a median follow-up of 13 months. In this _21 mm Hg) was observed in 7.8% series,15 raised IOP (> _25 mm Hg) of eyes (3/38) and moderate IOP elevation (> was observed in only 2.4% of the study eyes (1/38) at 2 months, much less than our estimate of 20% at 1 month (15/76). Regarding the effect of repeat injections, in our series raised IOP was observed in 45.2% of eyes (19/42) with 1 injection compared to 35% of eyes (14/40) with > _2 injections, without significant differences between these

groups (P ¼ .34). Consistently, there were no differences in the percentage of eyes that required IOP-lowering treatment (45.2%, 19/42 vs 32.5%, 13/40; P ¼ .23). However, although we have not found differences between these groups we do think that specific studies should be directed to address this important issue. The current results should be interpreted with caution, as differences in the study cohorts may explain the differential in raised IOP rates observed between studies. For example, our real-world study cohort did not exclude glaucoma patients (n ¼ 8, 9.7%), as these patients also require steroid treatment to control their inflammation. Despite these limitations, the results observed are better than the intraocular pressure rates reported for intravitreal triamcinolone.22 Where we _10 mm Hg of 23% at found a probability of IOP rise > 1 month and 30% at 3 months, Kok and associates reported 43.1% of eyes (28/65) for the same IOP elevation with intravitreal triamcinolone in a similar uveitis series. This study overall has a number of limitations. First, data were retrospectively collected with a risk of missing data. Second, the variable follow-up may have affected the estimates for time to repeat reinjections. Third, as the study was multicenter, cases were collected from 4 different specialized units with potential of different patient demographics and clinician-guided indications for treatment and retreatment criteria, which may have introduced bias. The data, however, were collected using a standardized form and the results have been similar among the study centers. Fourth, selection bias may have occurred, since cases included in this study were collected in specialized uveitis units and may not reflect those seen in a standard general ophthalmology practice. Finally, potential confounding factors such as concomitant pathology or cataracts were not specifically excluded (as would be in a trial setting). In summary, the outcomes of this observational multicenter cohort analysis support that the use of the dexamethasone implant will provide positive clinical outcomes in the treatment of noninfectious uveitis eyes as either a single therapy or co-adjuvant to systemic treatment. Our results also demonstrate that the outcomes and increase in adverse events (IOP) with the use of the implant in routine clinical care (albeit with varying indications for treatment) differ significantly from the HURON clinical trial. These data also provide an estimate of the reinjection frequency and time to repeat injections in a clinical setting.

ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Financial Disclosures: Javier Zarranz-Ventura has received travel grants from Allergan and is a member of the Allergan European Retina Panel; Robert L. Johnston has served as consultant for Novartis, Bayer, Alimera Science, and Alcon, and has received grants and given lectures for Novartis; Quresh Mohammed has been on advisory boards for Novartis, Alcon, Allergan, and Bayer, and has received grants and has given lectures for Alcon, Novartis, and Allergan; Adam H. Ross has served as consultant and lecturer for Bayer and Novartis; Alex Fonollosa has been a board member for Allergan; Alfredo Adan has been on advisory boards for Abbvie and Novartis; Richard W. Lee has served as consultant for Roche-Genentech and has been on advisory boards for EMD Sorono; Andrew D. Dick has been on advisory boards for Novartis, Abbvie, LuxBio, Qchips, Exonate, and Sanofi; has received grants from Novartis, Varleigh Ltd, and Glaxo-Smith-Kline; and has given lectures for Genentech; Ahmed Sallam has been on advisory boards for Novartis, Alcon, and Allergan; has received grants from Allergan; and has received travel grants from DORC. Javier Zarranz-Ventura is a grant recipient of the Spanish Retina

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& Vitreous Society (Sociedad Espan˜ola de Retina y Vı´treo, SERV, Santiago de Compostela, Spain). This work was partly supported by the National Institute for Health Research Biomedical Research Centre based at Moorfields Eye Hospital National Health Service Foundation Trust and University College London Institute of Ophthalmology (London, UK). The views expressed are those of the authors (Richard W. Lee, Andrew D. Dick) and not necessarily those of the National Health Service, the National Institutes for Health Research, or the Department of Health. Contributions of authors: conception and design (J.Z.-V., E.C., R.L.J., A.D.D., A.S.), literature search (J.Z.-V., A.S.), data collection (J.Z.-V., E.C., C.B., A.F., L.P.), statistical expertise (J.Z.-V.), analysis and interpretation (J.Z.-V., R.L.J., A.D.D., A.S.), writing the article (J.Z.-V.), critical revision of the manuscript (J.Z.-V., R.L.J., A.D.D., A.S.), final approval of the manuscript (J.Z.-V., E.C., R.L.J., Q.M., A.H.R., C.B., A.F., J.A., L.P., A.A., R.W.L., A.D.D., A.S.).

REFERENCES 1. Nguyen QD, Callanan D, Dugel P, Godfrey DG, Goldstein DA, Wilensky JT. Treating chronic noninfectious posterior segment uveitis: the impact of cumulative damage. Proceedings of an expert panel roundtable discussion. Retina 2006;26(Suppl 8):1–16. 2. de Smet MD. Corticosteroid intravitreal implants. Dev Ophthalmol 2012;51:122–133. 3. Christoforidis JB, Chang S, Jiang A, Wang J, Cebulla CM. Intravitreal devices for the treatment of vitreous inflammation. Mediators Inflamm 2012;2012:126463. 4. Wang J, Jiang A, Joshi M, Christoforidis J. Drug delivery implants in the treatment of vitreous inflammation. Mediators Inflamm 2013;2013:780634. 5. Jaffe GJ, Ben-Nun J, Guo H, Dunn JP, Ashton P. Fluocinolone acetonide sustained drug delivery device to treat severe uveitis. Ophthalmology 2000;107(11):2024–2033. 6. Kane FE, Burdan J, Cutino A, Green KE. Iluvien: a new sustained delivery technology for posterior eye disease. Expert Opin Drug Delivery 2008;5(9):1039–1046. 7. London NJ, Chiang A, Haller JA. The dexamethasone drug delivery system: indications and evidence. Adv Ther 2011; 28(5):351–366. 8. Chang-Lin JE, Attar M, Acheampong AA, et al. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci 2011;52(1):80–86. 9. Haller JA, Bandello F, Belfort R Jr, et al. Randomized, shamcontrolled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117(6):1134–1146.e3. 10. Haller JA, Bandello F, Belfort R Jr, et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011;118(12): 2453–2460. 11. Boyer DS, Faber D, Gupta S, et al. Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina 2011;31(5):915–923.

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12. Lowder C, Belfort R Jr, Lightman S, et al. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129(5):545–553. 13. Adan A, Pelegrin L, Rey A, et al. Dexamethasone intravitreal implant for treatment of uveitic persistent cystoid macular edema in vitrectomized patients. Retina 2013;33(7):1435–1440. 14. Arcinue CA, Ceron OM, Foster CS. A comparison between the fluocinolone acetonide (Retisert) and dexamethasone (Ozurdex) intravitreal implants in uveitis. J Ocul Pharmacol Ther 2013;29(5):501–507. 15. Tomkins-Netzer O, Taylor SR, Bar A, et al. Treatment with repeat dexamethasone implants results in long-term disease control in eyes with noninfectious uveitis. Ophthalmology 2014;121(8):1649–1654. 16. Lange C, Feltgen N, Junker B, Schulze-Bonsel K, Bach M. Resolving the clinical acuity categories ‘‘hand motion’’ and ‘‘counting fingers’’ using the Freiburg Visual Acuity Test (FrACT). Graefes Arch Clin Exp Ophthalmol 2009;247(1): 137–142. 17. Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology 1985;92(4):467–471. 18. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–481. 19. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 140(3):509–516. 20. Cao JH, Mulvalhill M, Zhang L, Joondeph BC, Dacey MS. Dexamethasone intravitreal implant in the treatment of persistent uveitic macular edema in the absence of active inflammation. Ophthalmology 2014; http://dx.doi.org/10. 1016/j.ophtha.2014.04.012. 21. Chang-Lin JE, Burke JA, Peng Q, et al. Pharmacokinetics of a sustained-release dexamethasone intravitreal implant in vitrectomized and nonvitrectomized eyes. Invest Ophthalmol Vis Sci 2011;52(7):4605–4609. 22. Kok H, Lau C, Maycock N, McCluskey P, Lightman S. Outcome of intravitreal triamcinolone in uveitis. Ophthalmology 2005;112(11):1916. e1–7.

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Biosketch Javier Zarranz-Ventura, MD, PhD, FEBO, currently works as Vitreo-Retinal surgeon in Institut Clı´nic d9 Oftalmologia (ICOF) at Hospital Clı´nic, Barcelona, Spain. Dr Zarranz-Ventura obtained his MD, his PhD, and underwent his Specialist Training at Clı´nica Universidad de Navarra, Pamplona, Spain. He underwent a Fellowship in Medical Retina and Uveitis at Moorfields Eye Hospital, London, United Kingdom and 2 Fellowships in Vitreo-Retinal surgery at Gloucestershire Hospitals National Health Service Trust and Bristol Eye Hospital, United Kingdom.

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SUPPLEMENTAL FIGURE 2. Relationship between visual acuity and central retinal thickness measured by optical coherence tomography at different time points in noninfectious uveitis eyes treated with the intravitreal dexamethasone implant.

SUPPLEMENTAL FIGURE 1. Consolidated Standards of Reporting Trials–style diagram showing the patients and eyes treated with the intravitreal dexamethasone implant for noninfectious uveitis included in the study.

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SUPPLEMENTAL FIGURE 4. Subgroup analysis of patients on systemic treatment at baseline treated with the intravitreal dexamethasone implant for noninfectious uveitis. Time to systemic treatment dose reduction defined as reduction in ‡5 mg of prednisolone or any decrease in second line immunomodulatory therapy dose (solid line) and time to systemic steroid discontinuation (dotted line).

SUPPLEMENTAL FIGURE 3. Subgroup analysis by number of intravitreal dexamethasone injections and time to reinjection in noninfectious uveitis eyes with 12 months follow-up, overall and disclosed by treatment indication. (Top) Percentage of eyes receiving each number of injections, disclosed by all eyes (dark gray) and subgroup analysis of eyes with vitritis (light gray) and cystoid macular edema (CME) (black). (Bottom) Time to second and third injection, disclosed by all eyes (dark gray) and subgroup analysis of eyes with vitritis (light gray) and cystoid macular edema (black).

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10.e4 _0.5) and by Cystoid Macular Edema Indication at Baseline in Eyes Treated With the Intravitreal SUPPLEMENTAL TABLE 1. Subgroup Analysis by Vitritis (Vitreous Haze Score > Dexamethasone Implant in Noninfectious Uveitis

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Only Vitritis Eyes

Baseline

2 Weeks

1 Month

3 Months

6 Months

12 Months

VHS 0 þ0.5 þ1 þ2 þ3 þ4 (Total n ¼ 39)

0 (0%)a 9 (23%) 18 (46%) 9 (23%) 2 (5%) 1 (3%) (n ¼ 39)

16 (42%) 10 (26%) 9 (24%) 3 (8%) 0 (0%) 0 (0%) (n ¼ 38)

23 (72%) 5 (16%) 3 (9%) 1 (3%) 0 (0%) 0 (0%) (n ¼ 32)

18 (50%) 9 (25%) 5 (14%) 3 (8%) 0 (0%) 1 (3%) (n ¼ 36)

17 (55%) 7 (23%) 4 (13%) 2 (6%) 0 (0%) 1 (3%) (n ¼ 31)

19 (66%) 4 (14%) 5 (17%) 0 (0%) 0 (0%) 1 (3%) (n ¼ 29)

Only CME Eyes

Baseline

2 Weeks

1 Month

3 Months

6 Months

12 Months

CRT Mean 6 SD (median, IQR) (Total n ¼ 59)

469 6 193 (436, IQR 221) (n ¼ 58)

326 6 81 (319, IQR 107) (n ¼ 44)

267 6 74 (262, IQR 69) (n ¼ 66)

318 6 149 (280, IQR 76) (n ¼ 48)

366 6 140 (315, IQR 139) (n ¼ 44)

355 6 160 (290, IQR 166) (n ¼ 38)

CME ¼ cystoid macular edema; CRT ¼ central retinal thickness; IQR ¼ interquartile range; VHS ¼ vitreous haze score. Number of eyes (% at each time point).

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SUPPLEMENTAL TABLE 2. Subgroup Analysis of Eyes Treated With the Intravitreal Dexamethasone Implant in Noninfectious Uveitis That Completed 12-Month Follow-up Period Eyes That Completed 12-Month Follow-up

Mean number of injections, mean 6 SD (median, IQR) Time to 2nd injection, mean 6 SD (median, IQR) Time to 3rd injection, mean 6 SD (median, IQR) Number of injections (% eyes) X1 X2 > _X3 N (eyes)

Total

Bristol Eye Hospital, Bristol, UK

Gloucestershire NHS Trust, Cheltenham, UK

Hospital de Cruces, Bilbao, Spain

Hospital Clinic, Barcelona, Spain

1.6 6 0.7 (2, IQR 1)

2.1 6 0.9 (2, IQR 0.5)

1.7 6 0.4 (2, IQR 0.5)

1.6 6 1.0 (1, IQR 1.5)

1.5 6 0.6 (1, IQR 1)

6.6 6 1.9 (6, IQR 3.25)

5.5 6 0.8 (6, IQR 0.75)

7.4 6 2.0 (7, IQR 3)

6.0 6 1.4 (6, IQR 1)

6.9 6 2.1 (7, IQR 3.5)

11 6 1.5 (11, IQR 1)

9.5 6 2.1 (9.5, IQR 0.75)

–

12.0 6 0.0 (12, IQR 0)

11.5 6 0.7 (11.5, IQR 0.5)

48.1%a 40.7% 11.2% 54

25% 50% 25% 8

28.6% 71.4% – 7

66.7% 0% 33.3% 6

54.5% 39.4% 6.1% 33

IQR ¼ interquartile range; UK ¼ United Kingdom. % of eyes per number of injections at each center.

a

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