|Year : 2021 | Volume
| Issue : 2 | Page : 98-103
Bromfenac 0.09% for the treatment of macular edema secondary to noninfectious uveitis
Joanna S Saade1, Rachid Istambouli1, Marwan AbdulAal2, Rafic Antonios1, Rola N Hamam1
1 Department of Ophthalmology, American University of Beirut Medical Center, Beirut, Lebanon
2 Department of Ophthalmology, Case Western Reserve University, Cleveland, Ohio, USA
|Date of Submission||26-Apr-2021|
|Date of Acceptance||06-Jul-2021|
|Date of Web Publication||25-Sep-2021|
Dr. Rola N Hamam
American University of Beirut Medical Center, Riad El Solh 11072020, P. O. Box: 11-0236/D41, Beirut
Source of Support: None, Conflict of Interest: None
| Abstract|| |
PURPOSE: The topical nonsteroidal anti-inflammatory drug bromfenac 0.09% has a potential benefit in uveitic macular edema (UME) with a safe side effect profile. The aim of the study is to assess the efficacy of bromfenac sodium solution in the treatment of UME.
METHODS: The charts of 10 patients with macular edema due to noninfectious uveitis treated with bromfenac 0.09% were reviewed retrospectively. The main outcomes studied were the best-corrected visual acuity (BCVA) and the central retinal thickness (CRT) compared 4 months before bromfenac initiation, at the time of its initiation, and 4 months later.
RESULTS: Twelve eyes of 10 patients were included. BCVA and CRT were unchanged 4 months befoew bromfenac compared to the time of bromfenac initiation (P = 1.0 and P = 0.2, respectively). There were a significant improvement in BCVA after 4 months of bromfenac treatment (P = 0.043) and a significant decrease in CRT (P = 0.002). Subretinal fluid resolved completely in 8/9 eyes, and 4/9 eyes had a complete resolution of cystoid macular edema at 4 months.
CONCLUSION: Bromfenac may be a useful addition to the treatment of UME.
Keywords: Bromfenac, macular edema, nonsteroidal anti-inflammatory drugs, ocular inflammation, uveitis
|How to cite this article:|
Saade JS, Istambouli R, AbdulAal M, Antonios R, Hamam RN. Bromfenac 0.09% for the treatment of macular edema secondary to noninfectious uveitis. Middle East Afr J Ophthalmol 2021;28:98-103
|How to cite this URL:|
Saade JS, Istambouli R, AbdulAal M, Antonios R, Hamam RN. Bromfenac 0.09% for the treatment of macular edema secondary to noninfectious uveitis. Middle East Afr J Ophthalmol [serial online] 2021 [cited 2022 Jan 16];28:98-103. Available from: http://www.meajo.org/text.asp?2021/28/2/98/326663
| Introduction|| |
It is estimated that about 35% of patients affected by uveitis have visual impairment, making it responsible for about 10% of visual impairment in the western world. The most common risk factor is macular edema, resulting in 29% of blindness and 41% of visual impairment. Although macular edema is most commonly associated with panuveitis, it can complicate all other forms of uveitis.
The pathophysiology of uveitic macular edema (UME) involves the breakdown of the blood–retinal barrier, as well as fluid leakage through the retinal pigment epithelium. Several factors have been identified as culprits, including prostaglandins and vascular endothelial growth factor (VEGF).
Steroids are the mainstay of treatment of UME, whether administered systemically, topically, as periocular injections, or as intraocular injections. Due to frequent need for chronic or repeated treatment with steroids, and considering their various ocular and systemic side effects, several other modalities have been investigated and were proven to be effective, either alone or as adjuncts, in controlling UME. These include nonsteroidal immunomodulators, topical and systemic nonsteroidal anti-inflammatory drugs (NSAIDs), systemic acetazolamide, and anti-VEGF injections. Topical NSAIDs, by decreasing prostaglandin formation through inhibition of COX1 and COX2, are particularly interesting in this setting due to their high tolerability and low side effect profile.
Topical NSAIDs are widely used to prevent postoperative cystoid macular edema (CME) in cataract surgery. Meta-analyses on this role of NSAIDs have found some evidence of their efficacy and suggested that their use alone or in combination with topical steroids may be superior to the use of steroids alone. They may also be useful in the treatment of pseudophakic CME. Their efficacy in the management UME is currently less clear.
Bromfenac 0.09%, given twice daily, is approved by the United States Food and Drug Administration (FDA) for the treatment of postoperative inflammation and the prevention of ocular pain in patients undergoing cataract surgery. Several studies and reports have suggested that it may be effective in the treatment of both acute and chronic pseudophakic CME., In the treatment of UME, it has been shown to have a synergistic effect with intraocular triamcinolone acetonide. In the same study, however, it did not have any significant effect on UME when administered alone.
Our preliminary results suggest that bromfenac 0.09% may be beneficial in UME. Here, using a modified cohort of patients, we aim to describe the efficacy of topical bromfenac sodium solution on eyes with UME by analyzing its effect on best-corrected visual acuity (BCVA) and central retinal thickness (CRT).
| Methods|| |
Data were collected retrospectively from medical records of patients presenting to the American University of Beirut Medical Center between 2010 and 2017 who were diagnosed with macular edema secondary to noninfectious uveitis and were started on bromfenac eye drops by the uveitis specialist. Only patients maintained on the medication for at least 4 months were included. In contrast to our previous analysis, in this study, we only included patients having at least 4 months of follow-up before bromfenac initiation. In addition, other new patients were included in this study by extension of the previous recruitment period. This study was approved by the Institutional Review Board at the American University of Beirut Medical Center and is in accordance with the ethical standards of the Declaration of Helsinki. Written informed consent was not required for this retrospective chart review.
The data extracted included patient characteristics (age and gender), diagnosis and location of uveitis, inflammation activity at each visit (as defined by the Standardization of Uveitis Nomenclature criteria), visual acuity using the Snellen chart, and status of the lens (phakic or pseudophakic). The concomitant treatment modalities that were used were noted: oral, topical, and intraocular steroids, immunomodulators, systemic or topical NSAIDs, and any associated side effects.
Spectral-domain optical coherence tomography (OCT) (Cirrus HD-OCT: Carl Zeiss, Dublin, California, USA) data on CRT, the presence of subretinal fluid (SRF), and CME were collected. Macular edema was defined as the presence of either CME or SRF on OCT. The absolute value of the CRT was not used in our determination of the presence or absence of macular edema.
The main outcomes of this study were analyzed using the repeated measures design. The BCVA converted to the logarithm of the minimal angle of resolution (LogMAR) and the CRT (in μm) were compared 4 months before the initiation of treatment with bromfenac (t = −4 months), at the time of initiation (t = 0), and 4 months afterward (t = 4 months). Changes in SRF, CME, inflammation activity, and treatment modalities were reported descriptively.
The median and interquartile range (IQR) were used as estimates for BCVA and CRT due to the small sample size. Friedman analysis (nonparametric repeated-measures analysis of variance) was used to detect significant change in CRT and BCVA during the study. Post hoc pairwise analysis using the Dunn–Bonferroni test was used to detect the time at which significant change occurred. Sensitivity analysis was done using only one eye for all patients (excluding the eye with better BCVA and lower CRT of patients with bilateral disease). Statistical analysis was done using IBM SPSS v23 (IBM Corp. Released 2015. IBM SPSS Statistics for Windows, Version 23.0. Armonk, NY: IBM Corp.). A P < 0.05 was considered statistically significant.
| Results|| |
A total of 12 eyes of 10 patients diagnosed with noninfectious uveitis were included in this study. Mean age at presentation was 54.8 years (range: 30–86). All eyes had macular edema at the time of bromfenac initiation (SRF, CME, or both), and 8/12 eyes included were pseudophakic. None of the patients had undergone intraocular surgery within the 6 months before bromfenac initiation, and macular edema was not related to cataract surgery in any of the study eyes. Baseline characteristics of the study patients and eyes are shown in [Table 1]. No side effects from bromfenac administration were reported in any of the patients.
Median LogMAR BCVA [Figure 1]a was 0.43 (IQR = 0.57) 4 months before bromfenac therapy (t = −4 months), 0.31 (IQR = 0.2) at the initiation of bromfenac (t = 0), and decreased to 0.17 (IQR = 0.32) 4 months later (t = 4 months). There were a statistically significant difference in BCVA between these time points (P = 0.029), with post hoc pairwise comparison showing no difference between t = −4 months and t = 0 (P = 1.0), and a significant decrease between t = 0 and t = 4 months (P = 0.043). Excluding the eyes with better BCVA of the two patients with bilateral disease, the change in LogMAR BCVA was still significant (P = 0.05).
|Figure 1: Boxplots for (a) best-corrected visual acuity and (b) central retinal thickness 4 months before bromfenac initiation (−4), at the time of initiation (0), and 4 months later (4). *P < 0.05; **P < 0.01|
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After 4 months of bromfenac treatment, 4/12 eyes gained more than two lines of visual acuity on the Snellen chart, while the rest had stable visual acuity.
Similarly, the CRT [Figure 1]b and [Table 2] changed significantly during the study period (P = 0.003), with medians of 380 μm (IQR = 176) at t = −4 months, 426.5 (IQR = 258) at t = 0, and 336.5 (IQR = 121) at t = 4 months. The difference between t = −4 and t = 0 was not significant (P = 0.2); however, there was significant decrease in CRT between t = 0 and t = 4 (P = 0.002). Excluding the 2 eyes with lower baseline CRT for patient with bilateral disease, the change in CRT remained significant (P = 0.004).
|Table 2: Central retinal thickness with concomitant treatment modalities of the 12 eyes four months prior, at the beginning and four months after initiation of bromfenac|
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Eight out of nine eyes with SRF had complete resolution [Figure 2] of the SRF after bromfenac initiation (four phakic, four pseudophakic; all eight without active inflammation). CME resolved [Figure 2] in four out of the nine eyes (one phakic, three pseudophakic; all four without active inflammation).
|Figure 2: Optical coherence tomography macula of eyes 1, 2, 8, and 10 at (a) t = 0 and at (b) t = 4 months|
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Concomitant treatment modalities
The treatments administered to these patients during the study period are detailed in [Table 2]. Seven eyes were on topical steroids at the time of bromfenac initiation, four of which were able to stop it on follow-up 4 months later. Three patients were taking prednisone (oral steroids) during the study period: one patient tapered from 80 mg 4 months before bromfenac to 15 mg at the last follow-up, one patient remained on a stable dose of 7.5 mg, and one patient was started oral steroids following bromfenac initiation by her rheumatologist for joint inflammation.
Periocular triamcinolone acetonide was administered to four eyes during the study period for inflammation control, only one of which needed the injection after bromfenac initiation. Intravitreal triamcinolone acetonide (IVTA) was injected in two eyes: 4 months before bromfenac in one eye, where the edema did not resolve even with intravitreal bevacizumab. In the other eye, IVTA was injected at the time of bromfenac initiation and 6 months prior.
Topical NSAIDs other than bromfenac were given for five eyes before bromfenac initiation (diclofenac 0.5%, ketorolac 0.5%, and indomethacin 0.1%) with no improvement in macular edema. An escalation in steroid-sparing immunomodulators was observed in three eyes, one of which was done for extraocular manifestations of sarcoidosis and two for uveitis control.
Case presentation [Eye 4]
A 20-year-old woman presented with recalcitrant macular edema secondary to spondyloarthritis-associated bilateral uveitis. CME persisted throughout 4 years despite treatment with topical and periocular corticosteroid injections, systemic and topical NSAIDs, and immunomodulators (indomethacin, ketorolac eye drops, systemic acetazolamide, and infliximab infusions). [Figure 3]a displays the OCT macula before bromfenac initiation, and [Figure 3]b displays the macular OCT after bromfenac use and no other change in therapy. The macular edema significantly improved 3 months after initiation of bromfenac and was progressively improving until full resolution 3 months later.
|Figure 3: Optical coherence tomography macula of eye 4 (a) before and (b) 6 months after bromfenac initiation|
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| Discussion|| |
There is some evidence supporting the use of NSAIDs for the prevention and management of pseudophakic CME., They inhibit the COX1 and COX2 enzymes, thereby decreasing the intraocular levels of prostaglandins, which are responsible for the disruption of the blood–retinal barrier. There is, however, limited evidence regarding their effect on UME.
The only randomized trial investigating the role of a topical NSAIDs compares the use of indomethacin 0.5% to placebo in a cohort of 46 eyes with UME. Central foveal thickness decreased significantly, and visual acuity improved significantly in the treatment group. Further published data on topical NSAIDs for UME are retrospective. A case series by Hariprasad et al. reported improvement in macular thickness and visual acuity with nepafenac 0.1% in 6 eyes with UME, five of which were resistant to previous therapy. In a letter to the editor, Petrushkin et al. retrospectively analyzed visual acuity and central macular thickness in 281 patients with UME who took nepafenac 0.1%. Four months after this treatment, significant improvement in visual acuity and central macular thickness was observed.
Among the ophthalmic NSAIDs approved by the FDA for the treatment of postoperative ocular inflammation and pain, bromfenac ophthalmic solution 0.09% has hypothetical advantages over other ophthalmic NSAIDs considering its high lipophilic potential, allowing better penetration, sustained drug levels in all ocular tissues with faster reduction of ocular inflammation as compared to other agents. While some studies show similar efficacy to other topical NSAIDs, others show a superiority of bromfenac in the prevention and management of pseudophakic macular edema.
Radwan et al., comparing bromfenac alone to bromfenac with intravitreal bevacizumab or with intravitreal triamcinolone in the treatment of UME, reported that bromfenac alone was ineffective but had a synergistic effect when added to intravitreal triamcinolone in the reduction of the macular thickness. In our study, the 12 eyes were unresponsive to previous treatment modalities, with no significant change in BCVA and CRT between 4 months before bromfenac and the time of initiation, despite the various treatment modalities [Table 2]. However, 4 months after bromfenac initiation, there was significant improvement in both visual acuity (median LogMAR decreased from 0.31 to 0.17) and CRT (median CRT decreased from 426.5 to 336.5). SRF resolved in eight out of nine eyes, while CME resolved in four out of nine. Bromfenac was well tolerated by the patients, with no side effects reported in any of the 12 study eyes.
Topical NSAIDs other than bromfenac were ineffective in the treatment of UME in 5 of the study eyes, while bromfenac was able to reduce macular thickness and improve BCVA in the presented patients. Others have reported a similar finding in both acute and chronic pseudophakic CME refractory to a different topical NSAID., One of the study eyes received an intravitreal steroid injection at the time of bromfenac initiation, which might have affected the result in this eye. The improvement in CRT and BCVA in this eye, however, could be explained by the previously reported synergy between bromfenac and intravitreal steroids.
This study has several limitations. It is a retrospective uncontrolled study on a limited number of eyes. Furthermore, the follow-up time was limited, primarily due to the limited availability of bromfenac in our country. Moreover, the patients were on different concomitant treatment modalities that may have affected the results. However, the majority of the studied eyes had recurrent or persistent UME despite the concomitant treatment [Table 2] and were free of inflammation at the time of UME treatment with bromfenac. Despite these limitations, we believe that the data analyzed herein would be a valuable addition to the literature and may be of help in studying the role of bromfenac in the treatment of UME through future meta-analyses.
| Conclusion|| |
UME is a vision-threatening complication of uveitis, with several treatment modalities available with variable outcomes. Topical bromfenac may have a beneficial effect in improving vision and decreasing macular thickness in some patients with UME either alone or synergistically. With the potential of a topical treatment with limited side effects and improved compliance (twice daily) having a favorable outcome for UME treatment, a properly powered prospective randomized trial is needed to elucidate and confirm this effect.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Ethics approval and consent to participate
This study was approved by the Institutional Review Board at the American University of Beirut Medical Center and is in accordance with the ethical standards of the Declaration of Helsinki. Written informed consent was not required for this retrospective chart review.
Consent for publication
No permission was needed from ARVO to reuse data from our published abstract as authors of IOVS articles “retain the right to reuse materials from their own articles in their future work, with proper attribution."
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]