|Year : 2020 | Volume
| Issue : 2 | Page : 611-616
Difluprednate 0.05% vs prednisolone acetate 1% for treatment of endogenous anterior uveitis
Amin F Ellakwa1, Ahmed I Basiony1, Dalia M Yousef2
1 Department of Ophthalmology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Ophthalmology, Faculty of Medicine, Zagazig University, Sharkia, Zagazig, Egypt
|Date of Submission||30-Oct-2019|
|Date of Decision||21-Dec-2019|
|Date of Acceptance||30-Dec-2019|
|Date of Web Publication||27-Jun-2020|
Dalia M Yousef
Meet Ghamr, Dakahlia
Source of Support: None, Conflict of Interest: None
The aim was to compare topical difluprednate 0.05% vs prednisolone acetate 1% in the management of acute anterior uveitis (AAU) regarding their efficacy and safety.
Patients and methods
A prospective clinical trial was conducted on two parallel groups comprising 48 patients who attended the Shebin El-Kom Ophthalmology Outpatient Clinic. All were diagnosed with AAU. Patients in the first group received difluprednate 0.05% eye drops four times daily, whereas patients of the second group received prednisolone acetate 1% eight times per day for 2 weeks. The 14-day treatment period was followed by 14-day tapering dose period. The observation was continued until day 35.
At day 14, there was no significant difference between the two studied groups regarding anterior chamber cell grading, as all cases were detected to have grade 0 in both groups. Complete clearing of anterior chamber cells at day 3 were seen in eight eyes (8/24; 33.3%) in both groups (P = 0.2). Intraocular pressure change was higher among the prednisolone group at seventh day (P = 0.2) and 14th day (P = 0.03) compared with the difluprednate group, except at day 3, where intraocular pressure change was the same in both groups. The mean IOP values in both groups remained less than 21 mmHg throughout the study.
Difluprednate 0.05% four times daily is well tolerated and safe compared with prednisolone acetate 1% eight times daily for the treatment of endogenous AU. Difluprednate exhibits better bioavailability, strong efficacy, and low incidence of adverse effects.
Keywords: acute anterior uveitis, difluprednate, endogenous anterior uveitis, intraocular pressure, prednisolone acetate, uveitis
|How to cite this article:|
Ellakwa AF, Basiony AI, Yousef DM. Difluprednate 0.05% vs prednisolone acetate 1% for treatment of endogenous anterior uveitis. Menoufia Med J 2020;33:611-6
|How to cite this URL:|
Ellakwa AF, Basiony AI, Yousef DM. Difluprednate 0.05% vs prednisolone acetate 1% for treatment of endogenous anterior uveitis. Menoufia Med J [serial online] 2020 [cited 2020 Jul 14];33:611-6. Available from: http://www.mmj.eg.net/text.asp?2020/33/2/611/287782
| Introduction|| |
Uveitis is a group of inflammatory diseases affecting the eye. It is a major cause of blindness globally, with a prevalence of 38–114.5 per 100,000 populations. Uveitis can occur at any age, but it has a tendency to affects the working-age group (between 20 and 50 years), thus having a high socioeconomic effect,.
Anterior uveitis (AU) is an inflammation of the uveal tract, which includes iritis, iridocyclitis, and anterior cyclitis. Acute anterior uveitis (AAU) is considered the most common form of uveitis, accounting for ∼90% of all cases. Endogenous AU is not directly caused by an infectious pathogen,,.
In uveitis, there is a breakdown of the blood-aqueous barrier, allowing the influx of protein from the plasma. This produces a Tyndall effect, usually referred to as flare. Flare can be observed during the acute phase of uveitis, owing to increased concentration of immunoglobulins and plasma albumin in the aqueous humor.
Vision-threatening complications of acute uveitis include cystoid macular edema, cataract, glaucoma, band keratopathy, synechiae formation, pupillary membrane, epiretinal membrane, ciliary fibrosis, vitreous opacification, and optic nerve edema. Repeated episodes of uveitis, when untreated or undertreated, may lead to vision impairment; thus, timely treatment is critical.
Corticosteroids are considered the mainstay of treatment of all types of uveitis. AU is treated to control symptoms of redness, pain, and photophobia and to reduce complications such as posterior synechiae, macular edema, and cataract. Topical corticosteroids have good penetration into the anterior chamber (AC) and can be given very frequently when uveitis is active and can be tapered as the inflammation is controlled. Prednisolone acetate 1% is considered the chief topical corticosteroid therapy. However, prednisolone acetate 1% usually demands frequent dosing particularly for severe cases, in which increased administration frequency is required,.
Difluprednate is a potent prednisolone acetate derivative that is augmented by two fluorinations at carbons 6 and 9, a butyrate group at carbon 17, and an acetic acid group at carbon 21. Relative to its parent molecule, the fluorinations enhance the corticosteroid potency of difluprednate, the butyric acid augments anti-inflammatory activity, and the acetic acid increases penetration. Difluprednate 0.05% has been shown to be effective in reducing inflammation and pain in patients undergoing ocular surgery.
The aim of this study to compare topical difluprednate 0.05% and prednisolone acetate 1% in the management of active AU regarding their efficacy and safety.
| Patients and Methods|| |
This was a prospective clinical trial of two parallel groups including patients with mild to moderate endogenous AU. Informed consent was obtained from all patients before administration of difluprednate 0.05% and prednisolone acetate 1% eye drops including their acceptance to use the drops, know the advantages, disadvantages, risks, possible complications and periodical treatment for 2 weeks and follow up for 2 weeks. The study duration was about 6 months conducted between December 2018 and June 2019. All patients were observed until day 35. Informed consent was obtained from all patients before administration of the treatment, including their acceptance to use it; know the advantages, disadvantages, risks, and possible complications; and undergo periodical treatment for 2 weeks and follow-up for 3 weeks.
Regarding patient selection, 48 patients (26 males and 22 females aged between 28 and 52 years) were included in this study. Inclusion criteria included patients with mild to moderate AAU in at least one eye, having at least six cells in the AC according to slit-lamp microscopy, and having a flare grade of 1 or higher in the eligible eye. Patients diagnosed with intermediate uveitis, posterior uveitis, panuveitis, ulceration, corneal abrasion, and presence of any confirmed or suspected active bacterial, viral, or fungal keratoconjunctival disease in either eye were excluded. Other exclusion criteria included pregnancy or lactation, allergy to other corticosteroids, history of corticosteroid-induced increased intraocular pressure (IOP), any corticosteroid depot within 6 weeks before start of study drug, periocular injection of any corticosteroid solution within 1 week before instillation of study drug, history of glaucoma or clinically significant ocular hypertension documenting an IOP of 21 mmHg or higher in either eye. The use of contact lenses during the study was prohibited.
All patients were subjected to history taking, including personal history (name, age, gender, occupation, and residence), complaint, present history, and past history, especially ophthalmic history, including history of ocular inflammation, infection, traumatic disorders, systemic complains, and joint problems. The ophthalmological examination included assessment of the visual acuity using 'Landolt's chart,' slit-lamp biomicroscopy examination to examine AC reactivity and its cause, determine cells number and flare grade, determine any complication of uveitis such as posterior synechiae or membrane formation, fundus examination for excluding posterior uveitis and determine any complication, and Goldmann applanation tonometer for measuring IOP.
The study assessments were conducted at baseline, on days 3 and 7, and every 7 days through day 35. A slit-lamp examination was performed through the high-power lens to assess AC inflammatory signs. A 1 × 1-mm slit beam with high magnification was directed through the AC and counted the number of cells visible in the lit area following relative dark adaptation. AC cells were graded as cell grade and count.
Method of administration, the first group of patients was instructed to instill 1 drop 4 times daily of difluprednate 0.05% for 2 weeks. The other group of patients was instructed to instill 1 drop 8 times daily of prednisolone acetate 1%. All were also instructed to maintain punctual occlusion and close their eyes for at least 1 min after drug instillation to reduce systemic drug absorption. The use of mydriatic or cycloplegic drops was permitted 3 times daily to reduce photophobia and ciliary spasm pain. All patients were instructed to instill the eye drops first and wait at least 5 min before instilling other drops.
Patients were tapered off the study medication during days 14–27 at the discretion of the investigator. On day 14, individuals who responded satisfactorily began tapering of study drug, by successively halving the number of doses per day at each step. All patients were observed until day 35.
Regarding the study end points, the primary efficacy end point was the change from baseline in AC cell grade on day fourteen. The secondary exploratory efficacy end points included the following: change from baseline at all other time points during the study for AC cell grade and count, and at all time points for flare grade. The safety end point included the changes in IOP.
Regarding follow-up protocol, evaluations were performed on days 3, 7, 14, 21, 28, and 35, and they included slit-lamp examinations for grading of cells and flare of uveitis. IOP is measured in every visit. Best-corrected visual acuity (BCVA) is obtained at baseline and after discontinuation of the cycloplegic eye drops.
A total of 48 patients were admitted to this study. All data were collected, tabulated, and statistically analyzed using SPSS (Statistical Package for the Social Sciences) version 19 (SPSS Inc., Chicago, Illinois, United States). Continuous quantitative variables were expressed as the mean ± SD and median (range), and categorical qualitative variables were expressed as absolute frequencies (number) and relative frequencies (percentage). Continuous data were checked for normality by using the Shapiro–Wilk test. Independent samples Student t-test was used to compare two groups of normally distributed data. Mann–Whitney test was used to compare two groups of not normally distributed data. Paired t-test was used to compare repeated normally distributed data. Categorical data were compared using χ2-test and Fisher's exact test if the expected cell was less than 5.
| Results|| |
Patients' demographics and pathological features are present in [Table 1]. A total of 48 patients participated in this study. All were diagnosed with AAU. Overall, 50% of the patients (24 eyes) received difluprednate 0.05% eye drops four times daily for 2 weeks, and the other group of patients (50%, 24 eyes) received prednisolone acetate 1% eight times per day for 2 weeks. Dose tapering was done for 2 weeks. Then follow-up for all patients was done at day 35.
Patient baseline demographic and pathological characteristics are balanced between the two treatment groups. Patients in the difluprednate group comprised 50% males and 50% females, whereas 58.3% of patients in the prednisolone group were males and 41.7% were females. The mean age of patients in the difluprednate treated group was 37.6 years, which ranged between 34 and 52, whereas in the prednisolone-treated group, the age ranged between 28 and 50 years, with a mean of 40.7 years. There were no significant differences between the two groups regarding age [Table 1].
Baseline grading of AC activity was balanced between the two treatment groups. This study shows that 22 eyes (22/24; 91.7%) have grade 1 of cells, whereas two eyes (2/24; 8.3%) have grade 2 of cells in the difluprednate group at baseline assessment. Prednisolone group has 16 eyes (16/24; 66.7%) with grade 1 of cells, four eyes (4/24; 16.7%) with grade 2 of cells, and four eyes (4/24; 16.7%) with grade 3 of cells [Table 2].
Regarding baseline flare grading, this study shows that eight eyes (8/24; 33.3%) have grade 1 of flare and 16 eyes (16/24; 66.7%) have grade 2 of flare in difluprednate group, whereas 41.7% (10 eyes) have grade 1 flare, 33.3% (eight eyes) have grade 2 of flare, 16.7% (four eyes) have grade 3 of flare, and 8.3% (two eyes) have grade 5 of flare in prednisolone group. There was no significant difference between the two studied groups [Table 2].
Regarding the primary efficacy end point of cell grading on day 14, this study shows that all cases were detected to have grade 0 in both groups after 2 weeks of intervention, and there was no significant difference between the two studied groups. Regarding AC flare grading, it was noticed that 22 eyes (22/42; 91.7%) in difluprednate group were of grade 0 compared with 66.7% (16/24; 66.7%) in prednisolone group on day 14th of intervention, and 24 eyes (24/24; 100%) of the studied participants receiving difluprednate were of grade 0 of flare compared with 22 eyes (22/24; 91.7%) of those receiving prednisolone after 3 weeks of the intervention. Cases in both groups had grade 0 of flare on day 28 [Table 3].
There was no significant difference between the studied groups regarding changes in cell count at different day measurements. It was noticed that the change in the cells was higher among the difluprednate group when compared with the prednisolone group. There was no significant difference between the studied groups regarding changes in flare at different day measurements. It was noticed that the change in flare was higher among the difluprednate group when compared with the prednisolone group, except on day 14, where flare change was the same in both groups [Table 4].
Regarding IOP, there was no significant difference between the studied groups regarding IOP at different day measurements. It was noticed that the change in IOP was higher among the prednisolone group at 7th and 14th days when compared with the difluprednate group, except on day 3, where IOP change was the same in both groups [Table 5].
| Discussion|| |
Corticosteroids are the mainstay of the management of patients with uveitis. Topical corticosteroids are effective in the control of AU but vary in ocular penetration, potency, and adverse effect profile. Difluprednate ophthalmic emulsion 0.05% was approved in June 2008 by the US Food and Drug Administration for the treatment of pain and inflammation associated with ocular surgery and intraocular inflammation. This was the first ophthalmic steroid approved by the Food and Drug Administration since 1973, as it is high in potency and has a good safety profile as well as the ability to reduce ocular inflammation and pain. Corticosteroids reduce intraocular inflammation, which is mostly measured by anterior segment cell and flare reaction. They also reduce associated symptoms, such as pain, photophobia, swelling, and tenderness.
Regarding the primary efficacy end point of cell grading on day 14, this study shows that all cases were detected to have grade 0 in both groups after 2 weeks of intervention. There was no significant difference between the two studied groups, and that was consistent with the results of Sheppard et al., who reported similar results between groups in change in AC cell grade at the 14th day. Kim et al. reported that the mean AC cell grade improved by 2.1 in the difluprednate group vs 1.9 in the prednisolone group. In contrary with our study, Foster et al. reported that the percentage of patients with clearing at day 14 was numerically higher on difluprednate than on prednisolone acetate (68.8 vs 61.5%), but the difference was not statistically significant and the effect in favor of difluprednate persisted to day 35. Mithal et al. reported that there is a statistically significant improvement in mean AC cell score from baseline to day 14 in the difluprednate group compared with potent corticosteroid betamethasone 0.1%. Regarding the secondary end point of AC cells grading and count changes, this study shows that there was a complete clearance of cells from AC noticed in eight eyes (8/24; 33.3%) in both group at day 3, but Sheppard et al. reported that complete clearing of AC cells at day 3 was 13.0% in difluprednate group vs 2.1% in prednisolone group. At day 7, this study shows a complete clearance of cells from AC noticed in 20 eyes (20/24; 83.3%) in difluprednate group, whereas 12 eyes (12/24; 66.7%) showed complete clearance of AC from cells in prednisolone group. This was similar to the results of Jamal and Callanan, who reported complete clearance of cells from AC in a greater proportion of patients receiving difluprednate (69%) than those using prednisolone (62%). This study shows that there was no significant difference between the studied groups as regarding changes in cell count at different day measurements, which is in agreement with the results of Sheppard et al.. These observations suggest that difluprednate may have greater potency. Regarding AC flare grading, it was noticed that 22 eyes (22/42; 91.7%) in the difluprednate group were of grade 0 compared with 66.7% (16/24; 66.7%) in prednisolone group at day 14th of intervention. This study shows that there was a non-significant difference between the two groups regarding changes in flare grading at different day measurements, which is in agreement with Sheppard et al. who reported that improvement in flare grades from baseline was seen in both groups and was comparable at all visits. Kim et al. reported that the resolution of AC flare occurred more rapidly in the difluprednate group compared with the prednisolone group on day 14, where the flare change was the same between the two groups, which was consistent with the results of our study. This study shows that there were highly significant differences between different timing measurements in the AC cells, as AC flare was found to be significantly decreased by time passage in both groups, which is in agreement with the result of Sheppard et al. Regarding IOP, this study shows the change of IOP was higher among prednisolone group at 7th and 14th days when compared with difluprednate group, except at day 3, where IOP change was the same between the two groups, but the difference was statistically nonsignificant. This was consistent with the result of Korenfeld et al., who noticed that previous studies have found that difluprednate has a comparable IOP increase incidence to prednisolone 1%. and there are no other case reports of dramatic or rapid-onset IOP elevation secondary to difluprednate use. On the contrary, Sheppard et al. reported a significant difference between groups in the mean IOP increase seen on day 3, but not at other time points, and IOP increase was reported for 16.1% in the difluprednate group and for 11.1% in the prednisolone acetate group at all time points. Meehan et al. reported that difluprednate has the potential to cause significant IOP elevation and possible secondary glaucoma. This study shows that there was a significant difference between the seventh day of the intervention compared with the baseline measurement in difluprednate group and between the 3rd and 21st days of the intervention compared with the baseline measurement in prednisolone group. However, the difference between the remaining days was statistically nonsignificant. The mean IOP values in both groups remained less than 21 mmHg throughout the study, and this was consistent with the results of Foster et al., who reported that there were no clinically significant differences between the treatment groups in mean change from baseline in IOP at any time point. On the contrary, Nakano Goto et al. reported an increase in IOP occurred in 11% of cases following treatment with difluprednate but controlled with topical ocular hypotensive drugs. Regarding visual acuity, this study shows that there were nonsignificant differences between the two studied groups regarding change in BCVA from baseline to day 21 visits, and this was consistent with the result of Sheppard et al., but Kim et al. reported that BCVA improved significantly and much more rapidly in the difluprednate group compared with the prednisolone group. Siddique et al. reported that BCVA was significantly better in the difluprednate group at days 21, 28, and 35, which was achieved more rapidly and was maintained throughout the study period. No patients in both groups' arm withdrew from the study. However, Foster et al. reported that no patients in the difluprednate group withdrew, but 12.5% of patients using prednisolone withdrew owing to lack of efficacy or adverse effects. Study limitations include the moderate sample size available for establishing an IOP safety profile. Studies with a longer follow-up period may be useful in clarifying between-treatment differences in the duration of remission and other long-term outcomes. Another limitation of our study is that the causes of uveitis among patients, outside of the exclusion criteria, were not addressed.
| Conclusion|| |
Difluprednate ophthalmic emulsion 0.05% is safe and well-tolerated, with no reported ocular or systemic toxicities. Difluprednate is a potent new topical corticosteroid that exhibits enhanced penetration, better bioavailability, rapid local metabolism, and strong efficacy, with a low incidence of adverse effects. It does not require shaking and is effective in treating both postoperative inflammation and AU.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]