Introduction

Intraocular pressure (IOP) elevation in non-infectious uveitis is multifactorial and includes: chronic damage to trabecular meshwork, obstruction of trabecular meshwork by inflammatory material, angle closure with or without pupillary block, peripheral anterior synechiae, recovery from ciliary body shutdown with resolution of inflammation, steroid response, or a combination of several of these mechanisms.

Corticosteroids are essential medications in uveitis, with rapid and effective control of inflammation, but have an important ocular side-effect profile that includes IOP elevation. Corticosteroids alter protein turnover in trabecular meshwork, increase extracellular matrix protein deposition by inhibition of matrix metalloproteinases, and reorganize the cytoskeletal cellular network that ultimately leads to trabecular swelling and reduced trabecular outflow. The degree of IOP elevation is related to a patient’s individual susceptibility to corticosteroids, as well as the drug’s potency, ocular penetration, and route, frequency, and duration of administration. ^{, ,} Treating uveitis with corticosteroids results in IOP elevation in up to one-third of patients. Clinically important IOP elevation usually occurs after 2 to 6 weeks of treatment and typically returns to normal limits within 2 to 4 weeks after stopping corticosteroids. ^,

Difluprednate is a newer synthetic corticosteroid that has a 56-times greater receptor binding affinity than prednisolone acetate, a widely accepted standard topical corticosteroid for uveitis. ^, Topical difluprednate has superior intraocular penetration than prednisolone acetate, resulting in higher therapeutic concentrations in the posterior segment of the eye. Although topical difluprednate (Durezol, Alcon Laboratories) was FDA approved for the treatment of inflammation and pain associated with ocular surgery and anterior uveitis in the USA, several studies have reported clinically effective results with topical difluprednate alone for the management of uveitic, diabetic, and pseudophakic macular edema and for posterior segment inflammation such as for pars planitis and Vogt-Koyanagi-Harada disease. Topical difluprednate was also reported to have similar efficacy compared to sub-Tenon’s triamcinolone injection in reducing retinal thickness in patients with refractory diabetic macular edema. These data suggest that topical difluprednate may be a valuable adjunct to other treatment modalities in the management of uveitis other than anterior uveitis and in uveitic macular edema.

Difluprednate 0.05% eye drops have an advantage of less frequent use over prednisolone acetate with similar efficacy; ^, the four times a day regimen has been shown to be as effective as prednisolone acetate 1% eye drops, dosed eight times a day for the treatment of anterior uveitis, potentially increasing patient compliance to treatment.

The reported incidence of clinically important IOP elevation with difluprednate varies between studies. Furthermore, there is limited information on the incidence and risk factors associated with IOP elevation following difluprednate treatment in uveitis. Thus, this study aimed to evaluate potential risk factors associated with clinically important IOP elevation during difluprednate treatment in patients with uveitis.

Methods

Records of uveitis patients treated with topical difluprednate between 2014 and 2020 at the National Eye Institute were retrospectively reviewed under institutional review board-approved clinical research protocol. The study adhered to the tenets of the Declaration of Helsinki. All patients were seen in the uveitis clinic, provided written informed consent, and underwent a comprehensive eye examination. Demographic and clinical data were recorded at the time of initiation of treatment and at follow-up visits.

The main outcome measure was the incidence of a clinically important IOP elevation defined as having an IOP ≥21 mmHg and ≥10 mmHg increase from baseline at the same visit. Due to the retrospective nature of the study, having this clinically important IOP elevation at one visit constituted the incident event. To prevent potential correlation between eyes from the same individual one eye from each patient was included in the study. For patients who received difluprednate treatment for both eyes, one eye was randomly selected as the study eye. Eyes with a history of intravitreal dexamethasone (Ozurdex) implant in the past 1 year, fluocinolone (Retisert, Iluvien, Yutiq) implant in the past three years, and/or intravitreal triamcinolone acetonide or subtenon/periocular injection of corticosteroids within the past three months were excluded. Patients who had a change in their glaucoma medications during difluprednate treatment before development of clinically important IOP elevation and patients who had a history of glaucoma surgery were also excluded from the study. The classifications of uveitis and level of inflammation were based on the Standardization of Uveitis Nomenclature criteria. Retinal nerve fiber thickness was evaluated by optical coherence tomography (Zeiss Cirrus 5000, Carl Zeiss Meditec AG). Changes in dosing frequency of difluprednate and timing of follow-up schedules were made according to clinical response and at the discretion of the physician.

For statistical analyses, SPSS v.17.0 statistical software for Windows (SPSS Inc.) was used. For descriptive statistics, continuous variables were presented as means ± standard deviations or medians (ranges), and categorical variables presented as frequencies and proportions. Univariable (crude) and multivariable (adjusted) Cox proportional hazards models were used to identify statistically significant predictors of incident clinically important IOP elevation. Comparisons of continuous variables between two variables were performed by t test for normally distributed variables. If the variables were not normally distributed, Mann-Whitney U test was used for comparisons between two independent variables and Wilcoxon signed rank test was used for two dependent variables. A two-tailed P value of < .05 was considered statistically significant.

Results

Fifty-four eyes of 54 patients were included in the study. The mean age of patients was 40.4 ± 18.8 years (range 5-79). Nine of the patients (16.7%) were children (aged <18 years). The majority of patients were female ( N = 28; 51.9%). Uveitis was anterior in seven (13.0%), intermediate in 19 (35.2%), posterior in eight (14.8%), and panuveitis in 20 patients (37.0%). The mean duration of uveitis before difluprednate treatment was 34.0±40.9 months. The indications for difluprednate treatment were active anterior uveitis in 18 patients (33.3%), active anterior uveitis with cystoid macular edema (CME) in 12 patients (22.2%), active vitritis with CME in nine patients (16.7%), active vitritis in seven patients (13.0%), and CME alone in eight patients (14.8%). Difluprednate was used as monotherapy in 20 patients (37.0%), mostly in patients with anterior uveitis. In addition to topical difluprednate, 10 patients (18.5%) were taking concurrent oral steroids, nine patients (16.6%) were taking other immunomodulatory therapy, and 15 patients (27.8%) received both oral steroids and other immunomodulatory therapy. The mean dose of oral prednisone was 14.5±10.5 mg (range 1-40).

At the time of difluprednate initiation, the anterior chamber (AC) was quiet in 22 patients (40.7%). The AC cell grade was 0.5+ in 11 patients (20.4%), 1+ in 14 patients (25.9%), and 2+ or worse in seven patients (13.0%). The mean baseline IOP before difluprednate treatment was 14.6±3.6 mmHg (median 14, range 6-25). Fifteen patients (27.8%) were on topical glaucoma medications at baseline and the mean number of glaucoma medications was 0.63±1.1. The starting dose of difluprednate was two drops/day in 10 patients (18.5%), three drops/day in nine patients (16.7%), four drops/day in 33 patients (61.1%), and six drops/day in two patients (3.7%). The mean duration of difluprednate treatment was 11.3±9.9 weeks (range 1-44). The mean peak IOP during difluprednate treatment was 22.6±7.7 mmHg (median 20.5, range 10-48), which was significantly higher from baseline ( P < .001).

Clinically important IOP elevation (defined as having an IOP ≥21 mmHg together with ≥10 mmHg IOP rise from baseline at the same visit) was observed in 17 patients (31.5%). All patients in this cohort who had ≥10 mmHg rise in IOP from baseline also had an IOP reading ≥21 mmHg at the same visit. Three patients had an IOP of 21 to 25 mmHg at baseline: two of them developed ≥10 mmHg rise and were counted as having a clinically important IOP elevation. Among the remaining 51 patients who had an IOP <21 mmHg at baseline, 24 (47.1%) developed an IOP of ≥21 mmHg at some point during their difluprednate treatment. The mean time to clinically important IOP elevation was 7.4±4.8 weeks (median 6; range 3-19). Risk factor evaluation revealed that age <18 years and concurrent systemic corticosteroid use were the factors most associated with clinically important IOP elevation ( Table 1 ). Five of nine children (55.6%) and 12 of 45 adults (26.7%) developed clinically important IOP elevation. Children had an adjusted hazard ratio (aHR) of 7.85 (1.48-41.56) to develop clinically important IOP elevation compared with adults ( P = .02). There was no statistically significant difference in the mean baseline IOP, duration of uveitis, duration of difluprednate treatment, and time to development of clinically important IOP elevation between children and adults ( P = .65, P = .55, P = .19, and P = .47, respectively). Incident IOP ≥30 mmHg occurred in 7 patients (13.0%), in two children (22.2%) and in five adults (11.1%).

Table 1

Risk factors of clinically important IOP elevation with difluprednate in patients with non-infectious uveitis. *

		Crude			Adjusted ⁎⁎
Variable		Events/At Risk	Hazard Ratio (95% CI)	P	Hazard Ratio (95% CI)		P
Age group	Adult	12/45 (26.7%)	1		1
	Children	5/9 (55.6%)	1.98 (0.69 – 5.65)	.21	7.85 (1.48 – 41.56)		.02
Gender	Male	8/26 (30.8%)	1		1
	Female	9/28 (32.1%)	1.04 (0.40 – 2.69)	.94	1.32 (0.33 – 5.40)		.70
Uveitis category	Anterior	1/7 (14.3%)	1		1
	Intermediate	4/19 (21.1%)	1.26 (0.14 – 11.33)	.84	6.66 (0.21 – 216.44)		.29
	Posterior	3/8 (37.5%)	2.05 (0.21 – 19.76)	.54	5.74 (0.25 – 134.08)		.28
	Panuveitis	9/20 (45.0%)	2.42 (0.31 – 19.22)	.40	23.85 (0.82 – 692.45)		.07
Duration of uveitis history	<6 Months	7/20 (35.0%)	1		1
	6 Months to <2 Years	5/14 (35.7%)	0.94 (0.30 – 2.98)	.92	5.76 (0.36 – 91.76)		.22
	2 to <5 Years	2/8 (25.0%)	0.71 (0.15 – 3.41)	.66	3.58 (0.38 – 33.95)		.27
	5+ years	3/12 (25.0%)	0.46 (0.12 – 1.77)	.26	3.49 (0.18 – 68.42)		.41
Anterior chamber cell grade at baseline	Quiet	7/22 (31.8%)	1		1
	0.5+	4/11 (36.4%)	1.21 (0.35 – 4.16)	.76	3.24 (0.43 – 24.54)		.26
	1+	3/14 (21.4%)	0.85 (0.22 – 3.28)	.81	2.45 (0.30 – 19.78)		.40
	2+ or worse	3/7 (42.9%)	1.87 (0.48 – 7.28)	.36	1.09 (0.12 – 9.94)		.94
History of glaucoma/OHT	No	11/38 (28.9%)	1		1
	Yes	6/16 (37.5%)	1.23 (0.45 – 3.35)	.69	1.98 (0.55 – 7.12)		.30
Prior cataract surgery	No	15/42 (35.7%)	1		1
	Yes	2/12 (16.7%)	0.35 (0.08 – 1.52)	.16	0.10 (0.005 – 2.18)		.14
Difluprednate drops/day at baseline	2	2/10 (20.0%)	1		1
	3	3/9 (33.3%)	1.69 (0.28 – 10.18)	.57	0.48 (0.04 – 5.73)		.56
	4 or more ⁎⁎⁎	12/35 (34.3%)	2.50 (0.56 – 11.23)	.23	1.81 (0.29 – 11.33)		.52
Concurrent systemic steroid use	No	6/29 (20.7%)	1		1
	Yes	11/25 (44.0%)	2.56 (0.94 – 6.99)	.07	5.31 (1.18 – 24.00)		.03
Concurrent systemic immunosuppressive therapy/Biologics	No	10/30 (33.3%)	1		1
	Yes	7/24 (29.2%)	0.61 (0.23 – 1.60)	.31	0.30 (0.06 – 1.56)		.15

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