|Year : 2019 | Volume
| Issue : 4 | Page : 233-242
Corticosteroids for diabetic macular edema
Jorge Chawan-Saad1, Max Wu2, Andres Wu3, Lihteh Wu4
1 Ophthalmology Department, Mexico Hospital, Costa Rican Social Security, San Jose, Costa Rica
2 College of Enginnering, Cornell University, Ithaca, NY, USA; Macula, Vitreous and Retina Associates of Costa Rica, San Jose, Costa Rica
3 Macula, Vitreous and Retina Associates of Costa Rica, San Jose, Costa Rica
4 Macula, Vitreous and Retina Associates of Costa Rica, San Jose, Costa Rica; Illinois Eye and Ear Infirmary, University of Illinois, Chicago, IL, USA
|Date of Submission||23-Aug-2019|
|Date of Acceptance||28-Sep-2019|
|Date of Web Publication||13-Dec-2019|
Dr. Lihteh Wu
Macula, Vitreous and Retina Associates of Costa Rica, San José; First Floor, Mercedes, Tower, Paseo Colon, San Jose
Source of Support: None, Conflict of Interest: None
Diabetic macular edema (DME) is a chronic condition with a multifactorial pathogenesis. Vascular endothelial growth factor (VEGF) and several inflammatory mediators are upregulated in eyes with DME. VEGF inhibitors and corticosteroids have all been used successfully in the management of DME. Currently available corticosteroids include triamcinolone acetonide (TA), the dexamethasone (DEX) intravitreal implant, and the fluocinolone acetonide (FA) intravitreal implant. The response to treatment can vary substantially with each treatment modality. Some cases of DME are VEGF driven, and in others, inflammation plays a key role. Chronicity appears to favor corticosteroid treatment. There are no clear guidelines to guide switching from an anti-VEGF to a corticosteroid. Combination therapy of an anti-VEGF drug and a corticosteroid does not appear to provide additional benefit over monotherapy with either drug. The main advantage of corticosteroids over VEGF inhibitors is their longer duration of action. Vitrectomy does not affect the pharmacokinetics of the corticosteroid implants. Common adverse events of corticosteroids include cataract formation, cataract progression, and ocular hypertension. TA may cause a sterile endophthalmitis and pseudoendophthalmitis. Migration of the intravitreal DEX and FA implants into the anterior chamber can be problematic. Because of their less favorable safety profile, corticosteroids are generally used as a second-line treatment for DME. Advantages of using an intravitreal corticosteroid implant include the reduction of treatment burden and predictable pharmacokinetics even in vitrectomized eyes. Pseudophakic eyes, previously vitrectomized eyes and eyes with long-standing DME, particularly of patients who have difficulty in maintaining a monthly appointment, may benefit from primary treatment with a corticosteroid intravitreal implant.
Keywords: Corticosteroids, dexamethasone implant, diabetic macular edema, diabetic retinopathy, fluocinolone implant, Iluvien, Ozurdex, Retisert, triamcinolone acetonide
|How to cite this article:|
Chawan-Saad J, Wu M, Wu A, Wu L. Corticosteroids for diabetic macular edema. Taiwan J Ophthalmol 2019;9:233-42
| Introduction|| |
Several clinical trials demonstrate that vascular endothelial growth factor (VEGF) inhibitors outperform macular laser photocoagulation (MLP) and have become first-line agents in the treatment of diabetic macular edema (DME).,,,,, Eyes treated with an anti-VEGF gain from 6 to 12 ETDRS letters depending on the baseline visual acuity. Up to 40% of eyes achieve an improvement of ≥3 lines of best-corrected visual acuity (BCVA) and up to 60% gain a BCVA of ≥20/40. Very few eyes lose vision. Nevertheless, despite an intensive anti-VEGF treatment, up to two-thirds of patients exhibit persistent DME at 6 months.,
Current alternatives for eyes that have a suboptimal response to VEGF inhibitors include corticosteroids. Triamcinolone acetonide (TA) was the first widely used intravitreal medication for DME. Currently available corticosteroids include TA, the dexamethasone (DEX) intravitreal implant, and the fluocinolone acetonide (FA) intravitreal implant.
| Pathophysiology of Diabetic Macular Edema|| |
A complete review of the pathophysiologic mechanisms in DME is beyond the scope of this paper. Other sources review this topic thoroughly. Briefly, eyes with DME exhibit intraocular upregulation of a myriad of different growth factors and cytokines, such as interleukin-6, interleukin-8, interleukin-1β, monocyte chemotactic protein-1, tumor necrosis factor α, and VEGF. This translates into retinal endothelial damage, thickening of the capillary basement membrane, deposition of extracellular matrix components, and retinal microvasculature damage. Breakdown of the blood–retinal barrier ensues and extracellular fluid accumulates in the macular area.,
VEGF inhibition is not 100% effective in all patients. Despite six consecutive monthly injections of a VEGF inhibitor, 40%–60% of eyes had persistent DME. This suggests that in some eyes, the main driver of DME is VEGF, whereas in other eyes, other cytokines predominate. Since several inflammatory mediators are upregulated in DME and corticosteroids have broad anti-inflammatory properties, it makes sense to use them in the management of DME.
| Intravitreal Pharmacokinetics of Corticosteroids|| |
TA has a 7.5-fold higher anti-inflammatory potency than cortisone. An intravitreal injection of a bolus of TA follows a two-compartment model characterized by an initial burst period followed by a duration period. In the burst period, the TA concentration exponentially decreases. In the duration period, there is a steady decline of drug. In nonvitrectomized eyes, the mean elimination half-life was 18.6 days compared to 3.2 days in the vitrectomized eye. A single intravitreal injection of 4 mg of TA lasts approximately 3 months in the nonvitrectomized human eye.,
DEX has a 25-fold higher anti-inflammatory potency than cortisol. Because of its higher water solubility, DEX's intravitreal half-life in human eyes is only of 5.5 h. An intravitreal biodegradable DEX sustained-release implant containing 700 μg of dexamethasone embedded in a poly (D, L-lactide-co-glycolide) has been developed (Ozurdex, Allergan Inc., Irvine, CA, USA). As the implant slowly releases DEX, the polymer slowly degrades into water and carbon dioxide. Eventually, the implant completely degrades.
FA has a similar anti-inflammatory potency as DEX. Retisert (Bausch and Lomb, Rochester, NY, USA) is a nonbiodegradable implant that contains 0.59 mg of FA. It is sutured to the pars plana and engineered to release 0.59 μg of FA per day for the 1st month and then 0.3–0.4 μg of FA per day for up to 30 months. The main indication for Retisert has been chronic noninfectious posterior uveitis. Another nonbiodegradable implant containing 0.19 mg of FA (Iluvien, Alimera Sciences, Alpharetta, GA, USA) has been commercialized and approved in several jurisdictions for eyes with DME. Unlike the Retisert implant, Iluvien is injected intravitreally via a 25-gauge needle. It is designed to release 0.20 μg FA per day with a low burst and near-zero order kinetics up to 3 years.
Jonas and Söfker  were the first to inject 20 mg of TA intravitreally in an eye with persistent DME following MLP. The DME regressed and the patient regained vision. The visual gains were maintained for at least 5 months. In contrast, most retina specialists started using 4 mg as the dose of intravitreal TA. This decision was based mostly on the ease of use of 4 mg since the readily available commercial preparation of TA was 40 mg/mL. A dose-escalating randomized clinical trial tested doses between 2 and 13 mg of TA in eyes with DME. The effect and duration were dose dependent. However, the rise of intraocular pressure was not.
A Cochrane systematic review from 2007 identified four clinical trials that studied the efficacy of intravitreal TA in a total of 183 eyes with persistent or chronic DME.,, On an average, eyes gained 5.7 letters (24 months) to 14.5 letters (9 months).
Posterior sub-Tenon delivery of TA in the hopes of diminishing the possible adverse events of an intravitreal injection has been explored and deemed not worthy of further study in the management of DME. Animal models have shown that suprachoroidal delivery of drugs provides more selectivity for the choroid and retina than intravitreal injections. Supposedly, less TA will be delivered to the anterior segment of the eye and caused less complications. A Phase I/II clinical trial assessed the safety and efficacy of a proprietary TA that was injected in the suprachoroidal space of eyes with DME with microneedles. This study showed that multiple suprachoroidal injections were well tolerated.
The MEAD study randomized 1048 patients to 0.7 mg DEX implant, 0.35 mg DEX implant, or sham injections. In this cohort of patients, 67% had prior MLP, 18% had intravitreal steroids, 9% had anti-VEGF, and 28% were treatment naive. Patients were re-injected every 6 months if persistent DME was documented in the optical coherence tomography (OCT). Only 67% of eyes in the DEX groups completed the 3-year study. Among the patients who completed the study, the mean number of implants received was 5. At 3 years, 22.2% of eyes treated with the 0.7 mg implant had a gain of ≥3 lines of BCVA compared to 18.4% in the 0.35 mg implant group and 12% in the sham group. The DEX-treated eyes gained eight letters compared to two letters in the sham group. At around 15 months, the visual improvement in the DEX-treated eyes was reduced and recovered toward the 3-year visit. This was attributed to the development of cataract around month 15 and later cataract extraction. A third of patients who were treated with the DEX implant required medication to control intraocular pressure (IOP) and 0.3% required incisional surgery to adequately control IOP. The DEX implant does not last 6 months as the manufacturer suggests. A more frequent dosing regimen may improve the visual outcomes.
The RELDEX study was a retrospective review of 128 eyes that were treated with DEX implant. At 3 years, the mean gain in visual acuity was 9.5 letters, 25% had a gain of ≥3 lines of BCVA, 36% had complete resolution of DME, and only 11.4% of eyes had a loss of ≥3 lines of BCVA. These outcomes were obtained with 3.6 DEX injections with a mean re-treatment time period of 7.3 months. Only 4% of eyes required rescue with an anti-VEGF drug.
Treatment-naive eyes fare better with the DEX implant than previously treated eyes.,,,, Previously treated eyes most likely have more chronic disease and as such may already have sustained irreversible damage.
Fluocinolone acetonide implants
One of the major drawbacks of anti-VEGF treatment of DME is the frequency and number of injections and office visits required to control the disease process. The FA implant can release drug for up to 3 years, which translates into a reduced retreatment frequency and may lower the risk of treatment-associated endophthalmitis., The calculated cumulative risk of endophthalmitis after 20–40 injections has been calculated to be around 1%. A retrospective study reviewed 160 eyes that were switched to the Iluvien-FA implant. Before the switch, eyes were being treated every 2.9 months. In contrast, after the switch, eyes were treated every 14.3 months.
The off-label use of the Retisert-FA implant was reported to be beneficial in eyes with DME that had persistent or recurrent DME despite MLP. In a multicenter prospective randomized study, 196 eyes with persistent or recurrent DME were randomized to receive the Retisert-FA implant or the standard of care, which could be additional laser or observation. There was a significant improvement in visual acuity in the eyes implanted with the Retisert-FA implant up to 2 years as compared to the eyes with the standard of care. By 3 years, the differences between the groups were no longer significant, suggesting that by this time the Retisert-FA implant was already being depleted of FA.
The FAME Studies randomly assigned 956 patients with DME refractory to MLP to three groups: 0.2 μg Iluvien-FA per day, 0.5 μg Iluvien-FA per day, or sham injection. Patients could receive rescue MLP 6 months after initial treatment. Eyes enrolled in this study had a mean duration of DME of 5.1 years. At 3 years, 28.7%, 27.8%, and 18.9% gained ≥15 letters, respectively. Despite 0.2 μg Iluvien-FA per day implantation, 40% of eyes required rescue MLP. A subgroup analysis of this study showed that eyes with chronic DME (defined as eyes having DME for >3 years) had a greater response to the Iluvien-FA than eyes with a shorter duration of DME.
In Europe, Iluvien-FA was approved for chronic DME, which was defined as persistent or recurrent DME despite prior treatment. Several European real-world studies have confirmed the functional and anatomic benefits of an Iluvien-FA 0.2 μg implant in DME eyes, with an insufficient response to an anti-VEGF or other corticosteroid. This is in contradistinction of the FAME Studies that enrolled eyes unresponsive to MLP.,,,,,, An electronic medical record (EMR)-based study from the United Kingdom validated the results of the FAME Studies. In this study, 345 eyes were followed for an average of 428 days. More than 75% of eyes had an insufficient response to an anti-VEGF agent. About 20% of the patients gained ≥15 letters and gained 5.1 letters from baseline. Importantly, the proportion of patients who achieved a BCVA of ≥20/40 improved from 18% at baseline to almost 40% at 24 months. The Iluvien Registry Safety Study was a Phase IV study that assessed the safety and efficacy of Iluvien in Europe. Almost 600 eyes were registered. Less than a third of eyes required additional treatment for DME. The percentage of eyes gaining a BCVA of ≥20/40 doubled from 19% at baseline to 40% at month 12.
The USER study demonstrated that the visual acuity, before the switch to the Iluvien-FA implant, was maintained while on the implant but with a much reduced treatment burden. However, even with the implant, one-third of eyes required additional treatment to control DME which was comparable to the FAME Studies.
A cost-effectiveness analysis from the United Kingdom concluded that the Iluvien-FA implant provided good value for patients with chronic DME, particularly pseudophakic patients.
| Corticosteroids Versus Macular Laser Photocoagulation|| |
At 2 years of follow-up, MLP was more effective and had less adverse events than repeated injections of 1 or 4 mg of TA. Early on, the TA caused a greater improvement in BCVA than the MLP-treated eyes. However, as time went on, the difference vanished. Subgroup analysis of only the pseudophakic eyes did not alter the results. At 2 years, the mean number of treatments for the laser arm was 2.9 compared to 3.5 and 3.2 for the 1 and 4 mg TA arms, respectively. These results were unchanged at 3 years of follow-up.,
The PLACID Study compared treatment with MLP to MLP plus the DEX implant. Patients were randomized to a DEX (n = 126) or sham implant (n = 127) at baseline plus MLP at month 1. Patients could receive up to three additional MLP treatments and one additional DEX or sham implant as needed. At 12 months, there was no difference between the two arms of the study in terms of 10-letter gain, the primary outcome of the study. However, significant differences were noted at 1 week, 1 month, and 9 months. Anywhere from 22.2% to 30.3% of eyes in the combination arm gained at least 10 letters from baseline. The area under the curve (AUC) analysis demonstrated that more visual gain was achieved in the combination arm than the MLP monotherapy arm. These results are further evidence that the DEX implant lasts less than 6 months in most patients. Similarly, the OZLASE Study randomized 80 eyes to combined DEX plus MLP or MLP monotherapy. The eyes in the combination arm received DEX at baseline and at 16 weeks. Thereafter, they were eligible for repeat DEX every 16 weeks or repeat MLP if re-treatment criteria were met. At 56 weeks, there was no statistical difference in the mean change in BCVA in the combination arm (−0.3 letters) and the MLP arm (+0.4 letters). The anatomic differences were statistically significant, however. The authors suggest that cataract formation in the combination arm confounded the BCVA results. In addition, the inclusion criteria of this trial only allowed patients with relatively good visual acuities to be enrolled, so there could have been a ceiling effect that affected the magnitude of improvement.
| Corticosteroids Versus Anti-vascular Endothelial Growth Factor|| |
Since steroids induce cataract progression in phakic eyes, the visual results may be confounded by the development of cataract. A few comparative trials between bevacizumab and TA have been conducted. Most of these have been small retrospective studies with a relatively short follow-up.,, Kriechbaum et al. conducted a prospective comparative trial of 2.5 mg of bevacizumab versus 8 mg of TA. At 6 months, the visual gains and decrease in macular thickness were comparable between two groups. At 12 months, the visual gains were superior with bevacizumab. This was attributed to cataract formation in the TA-treated eyes.
Protocol I of the Diabetic Retinopathy Clinical Research (DRCR) network compared intravitreal TA plus immediate MLP to MLP to ranibizumab plus deferred MLP to ranibizumab plus immediate MLP.,, Initially, the combination of TA and MLP was superior to MLP monotherapy. By 2 years, the combination of MLP and TA was similar to MLP monotherapy and inferior to both ranibizumab arms. A subgroup analysis of the pseudophakic eyes showed that by 2 years, the results were comparable to the ranibizumab arms. However, by 5 years, the ranibizumab arm was superior to the TA arm.
The BEVORDEX Study compared 42 eyes that were treated with intravitreal bevacizumab to 46 eyes that received a 0.7 mg DEX implant. Eyes in the bevacizumab group were re-injected every 4 weeks, whereas eyes in the DEX implant were re-injected every 16 weeks. At 12 months, there was no difference in either group achieving a ≥10-letter gain from baseline. However, the eyes treated with the DEX implant experienced a greater decrease in central macular thickness (CMT) with fewer injections. Furthermore, the DEX implant was more efficient than bevacizumab in eliminating hard exudates from the center of the fovea. At 2 years, the bevacizumab-treated eyes received an average of 14.6 injections with a mean re-treatment interval of 71 days, whereas the eyes in the DEX implant arm were injected an average of 5.6 times with a mean re-treatment interval of 145 days. Despite the increased treatment burden with bevacizumab, the improvement of vision-related quality of life outcomes in both groups was similar.
A noninferiority, multicenter, 12-month randomized study compared the DEX implant and ranibizumab. Eyes randomized to the DEX implant were injected at baseline and months 5 and 10. Eyes randomized to ranibizumab were injected monthly until maximal visual acuity was obtained (the patient's BCVA was stable for 3 consecutive monthly visits). Rescue MLP was available for both groups. A noninferiority margin of five letters was chosen. At 12 months, the mean gain in the DEX arm was 4.34 letters compared to 7.60 letters in the ranibizumab arm. Since the lower limit of the 95% confidence interval of the difference between both arms was − 4.74 letters, it was concluded that the DEX implant was noninferior to ranibizumab. There were more adverse events in the DEX arm, due to IOP elevation and cataract, compared to the ranibizumab arm. The DEX arm received on average 2.85 injections compared to 8.7 ranibizumab injections.
A comparison of the visual outcomes of the FAME Studies and the ranibizumab plus deferred MLP arm of Protocol I of the DRCR network using the AUC analysis showed that ranibizumab plus deferred MLP was more effective than the Iluvien-FA 0.2 μg per day implant. The AUC of the Iluvien-FA implant was depressed because of the development of cataract in phakic eyes during the 12–18-month time period. A subgroup analysis of pseudophakic eyes revealed that there was no significant difference between the ranibizumab-treated eyes and the Iluvien-FA treated eyes. In 3 years, eyes received 14 injections of ranibizumab compared to 1.3 injections of the Iluvien-FA implant. Major limitations of this study were that the data were derived from two different clinical trials with entirely different populations. It must be borne in mind that none of the eyes enrolled in FAME were treatment naive. In addition, Protocol I did not specifically look at chronicity of DME.
| Switching from Anti-vascular Endothelial Growth Factor to Corticosteroids|| |
A major difficulty in assessing the literature with respect to the effectiveness of the different treatment modalities is the lack of a consistent definition of what constitutes refractory DME. A post hoc analysis of Protocol I of the DRCR network found that the response to ranibizumab after the initial 3 monthly injections was associated with the long-term outcome. Approximately 40% of eyes that started treatment with monthly ranibizumab had persistent DME at 6 months. Eyes with <5-letter gain after three injections showed limited additional improvement for 3 years. At 3 years, despite continuing injections, only 29% of these eyes achieved >10 letters improvement in BCVA. Based on these data, some have recommended switching after the 3rd consecutive monthly anti-VEGF injection if DME persists. Switching studies must be interpreted with caution. Most of these are poorly designed and lack a control group which makes it impossible to know if the improvement was related to regression to the mean, time effects, or secondary to the new drug.
Despite the benefits shown by VEGF inhibition in eyes with DME, there are several barriers to treatment. In many parts of the world, particularly in developing countries, anti-VEGF therapy for DME is not sustainable. Pharmacological treatments are expensive and represent an important economic burden. Multiple visits also impose a burden on the caretakers and patients themselves. Since current anti-VEGF drugs are short acting, they need to be injected frequently. To obtain the best results, patients need to be injected and monitored intensively, particularly during the first 2 years., Patients in the real world were monitored less frequently and received fewer injections when compared to patients in clinical trials. Under-treatment is a real issue.,,, Advantages of using an intravitreal implant include the reduction of treatment burden.
| Combination of Anti-vascular Endothelial Growth Factor Plus Corticosteroid|| |
Monotherapy with corticosteroids or anti-VEGF drugs results in a suboptimal response in up to 60% of eyes. Given the multifactorial nature of DME, some have proposed combination therapy to search for possible synergies. A Cochrane review identified eight randomized clinical trials that compared a combination of a corticosteroid plus an anti-VEGF with anti-VEGF monotherapy. Most of these trials compared TA plus bevacizumab to bevacizumab monotherapy. One study compared the DEX implant plus bevacizumab to bevacizumab monotherapy  and another one DEX implant plus ranibizumab to ranibizumab monotherapy. In both of these two studies, the combination arm received the DEX implant every 4 months whereas anti-VEGF was injected monthly as needed. The superior anatomic results in the combination arm did not translate to superior visual outcomes, which were similar between the two arms., Based on the current evidence, the addition of a corticosteroid does not appear to add additional benefits to anti-VEGF monotherapy and may add potential complications.
| Previous Vitrectomy|| |
Vitrectomy causes a more rapid drug clearance from the vitreous cavity as illustrated by the significant reduction in the mean half-life of TA from 18.6 days in nonvitrectomized eyes compared to 3.2 days in vitrectomized eyes. Corticosteroid intravitreal implants release drugs at a constant rate and provide predictable pharmacokinetics even in vitrectomized eyes., The DEX implant improved vision and macular thickness with a peak effectiveness between 8 and 13 weeks in vitrectomized eyes with DME. Another study reported that there were no differences in the anatomic and functional outcomes between previously vitrectomized eyes to nonvitrectomized eyes with chronic refractory DME that were injected with a single Iluvien-FA implant.
| Diabetic Retinopathy Severity Score and Diabetic Retinal Neurodegeneration|| |
Worsening in the diabetic retinopathy severity score (DRSS) correlates with the development of proliferative diabetic retinopathy (PDR) and visual loss., A post hoc analysis of the FAME Studies concluded that sustained release of Iluvien-FA into the vitreous cavity of eyes with DME slows development of PRD and progression of diabetic retinopathy.
Interpretation of DRSS improvement merits caution. In a retrospective review of 18 eyes that underwent 3 consecutive monthly anti-VEGF injections, ultra-widefield color photographs and fluorescein angiograms were compared at baseline and 1 month after the last injection. The DRSS score improved by ≥1 step in 61% of eyes. Despite this improvement, the corresponding fluorescein angiograms in these same eyes showed that there was no reperfusion in the areas lacking perfusion. Eyes with DRSS improvement may still be at high risk of developing PDR.
Corticosteroids may slow down diabetic retinal neurodegeneration. The pre- and post-Iluvien-FA injection OCTs at 3-month intervals of 130 patients were compared. The inner neuroretinal thickness was used as a surrogate marker of retinal neurodegeneration. The rate of thinning of the area 1.5–3 mm from the center of the fovea slowed down after Iluvien-FA implantation.
| Adverse Events of Intravitreal Corticosteroids|| |
Up to 50% of eyes that are injected with a corticosteroid will develop a hypertensive response., After a follow-up of 5 years, 9% of eyes that had multiple injections of TA required a trabeculectomy.
The IOP response with the DEX implant has been reported.,, At 12 months, 13% of eyes that received two DEX implants had an increase of ≥10 mmHg in IOP from baseline after the first injection and 15% after the second injection. An additional 10% of eyes were started on IOP lowering medications after the second treatment. In general, the IOP elevations were transient and controlled with medication. The MEAD Study reported that over 40% of eyes required initiation of a topical ocular hypotensive agent and 0.3% of eyes required incisional glaucoma surgery. In these trials, the DEX implant was administered no more than every 6 months; however, in the current clinical practice, the DEX implant may be injected every 3–4 months.,, In a retrospective case series of 260 eyes that were treated with the DEX implant every 3 or 4 months, 26% and 7.7% developed an IOP greater than 25 and 35 mmHg, respectively.
During the 4 years of the Retisert-FA implant study, an elevation in IOP ≥30 mmHg was reported in more than 60% of eyes implanted with the Retisert-FA compared to 6% of eyes that did not have an implant. A third of all patients who were treated with the Retisert-FA implant developed uncontrolled ocular hypertension, which required glaucoma filtration surgery or explantation of the device.
Because of this high rate of uncontrolled ocular hypertension with the Retisert-FA implant, the Iluvien-FA implant was designed. In the FAME Studies, 18.4% of eyes that were injected with the 0.2 μg Iluvien-FA per day implant developed an IOP higher than 30 mm compared to 4.3% of eyes treated with the sham injection and 22.9% of the 0.5 μg Iluvien-FA per day implant. Incisional glaucoma surgery was performed in 0.5%, 4.8%, and 8.1% of eyes in the sham, 0.2 μg Iluvien-FA per day implant, and 0.5 μg Iluvien-FA per day implant, respectively. Because of this high risk of ocular hypertension, the Food and Drug Administration requires a prior course of corticosteroid without a significant rise in IOP in eyes that are deemed candidates of the Iluvien-FA implant. The glucocorticoid receptor binding affinity for TA, FA, and DEX is all very similar, so one could use TA or DEX to predict the IOP response for the Iluvien-FA implant. If the eye develops a substantial elevation in IOP with the corticosteroid challenge, the eye is deemed not suitable for the Iluvien-FA implant. A subanalysis of the FAME Studies compared eyes that had received a steroid challenge before their Iluvien-FA implant to those that did not. In eyes that did not develop a rise in IOP with a corticosteroid before Iluvien implant, none of the eyes developed a rise in IOP following Iluvien implant. Several studies confirmed these findings., An EMR-based study from the UK reported that 14% of eyes required ocular hypotensive therapy; 7.2% had an IOP ≥30 mmHg; and 0.3% underwent glaucoma surgery. In this same study, 10% and 4.3% of eyes without a steroid challenge and without an IOP elevation event required glaucoma topical treatment and developed an IOP ≥30 mmHg, respectively. The IRSS Study showed that 8.3% of eyes developed an IOP ≥30 mmHg and 2% of eyes required incisional glaucoma surgery.
The most common adverse event of intravitreal corticosteroids is steroid-induced cataract. Since DME is a chronic condition that requires multiple intravitreal injections, practically all phakic eyes will develop cataract. After 5 years of follow-up of a study that compared TA to placebo, 71% of phakic eyes underwent cataract extraction. In the MEAD Study, 60% of phakic eyes underwent cataract surgery. After 4 years, more than 90% of phakic eyes that had a Retisert-FA implant underwent cataract extraction compared to 20% of eyes that did not have the implant. In the FAME Studies, 75%, 85%, and 23% of the phakic eyes receiving the 0.2 μg Iluvien-FA per day, 0.5 μg Iluvien-FA per day, and sham injection underwent cataract removal, respectively.
Protocol P of the DRCR studied eyes that underwent cataract extraction in the presence of DME. Approximately two-third of eyes received some type of DME treatment preoperatively, intraoperatively, or postoperatively. Sixty percent of eyes had an improvement of ≥2 lines of BCVA, 30% remained within two lines of baseline BCVA, and 10% lost ≥2 lines. In addition, only 63% of eyes had a BCVA of ≥20/40. These results are comparatively worse than those routinely seen in modern cataract surgery. In contrast, the MEAD Study reported that eyes that developed cataract regained the visual loss after cataract extraction. Unlike Protocol P, the eyes that developed cataract in MEAD had their DME controlled as evidenced by the OCT measures of the CMT.
Infectious endophthalmitis, pseudoendophthalmitis, and sterile endophthalmitis
Intravitreal TA may cause endophthalmitis, pseudoendophthalmitis, and sterile endophthalmitis. Infectious endophthalmitis has been reported to occur up to 0.87%. Sterile endophthalmitis has been defined as an inflammatory reaction to any of the components of TA. Its incidence has been reported to be between 1.6% and 5.3%. Pseudoendophthalmitis refers to the phenomenon when TA crystals migrate from the vitreous to the anterior chamber and layer inferiorly resembling a hypopyon. The endophthalmitis rate following a DEX implant has been reported to be between 0% and 1.3%.,,, In the US, the rates of endophthalmitis between intravitreal anti-VEGF agents and corticosteroids were almost 7 times higher with corticosteroids than with anti-VEGF agents.
Rarely, corticosteroids can induce a state of relative immunosuppression inside the vitreous cavity that may lead to opportunistic infections such as cytomegalovirus retinitis.,,, The incidence of viral retinitis following an intravitreal injection of TA was 0.41%. The incidence climbed to 0.9% in patients with medical immunocompromising comorbidities such as diabetes mellitus, patients receiving multiple injections, and patients with a prior history of viral retinitis.
Both the DEX and FA implants have been reported to migrate into the anterior chamber, which can potentially lead to corneal endothelial decompensation, edema, and ocular hypertension.,, The incidence has been estimated between 4.8% and 5.9% in previously vitrectomized eyes., Risk factors associated with anterior-chamber migration include prior vitrectomy in combination with iris defects, zonular dehiscence, and an open or defective lens capsule. Corneal decompensation results from either direct mechanical trauma or toxicity from any of the implant components. If the eye presents with corneal edema, it is imperative to remove the implant as soon as possible to avoid permanent corneal decompensation. Removal of the DEX implant may be tricky. It is beyond the scope of this review to describe in detail the surgical maneuvers to remove these implants. These are nicely summarized elsewhere.,
The DEX implant has been injected accidentally into the crystalline lens rather than into the vitreous cavity. Cataract forms secondary to mechanical trauma and corticosteroid effect on the crystalline lens.
| Conclusion|| |
VEGF and inflammatory mediators are pharmacological targets of eyes with DME. The response to treatment can vary substantially. Some cases of DME are VEGF driven, and in others, inflammation plays a key role. Chronicity appears to favor corticosteroid treatment. Currently, there is still no evidence of synergism between an anti-VEGF drug and a corticosteroid. The main advantage of corticosteroids over VEGF inhibitors is their longer duration of action. Vitrectomy does not affect the pharmacokinetics of the corticosteroid implants. Common adverse events of corticosteroids include cataract formation, cataract progression, and ocular hypertension. Because of their less favorable safety profile, corticosteroids are generally used as a second-line treatment for DME. Pseudophakic eyes, previously vitrectomized eyes and eyes with long-standing DME, particularly of patients who have difficulty in maintaining a monthly appointment, may benefit from primary treatment with a corticosteroid intravitreal implant.
Financial support and sponsorship
Dr Lihteh Wu has participated in advisory boards for Novartis and Bayer.
Conflicts of interest
The authors declare that there are no conflicts of interests of this paper.
| References|| |
Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al.
Long-term outcomes of ranibizumab therapy for diabetic macular edema: The 36-month results from two Phase III trials: RISE and RIDE. Ophthalmology 2013;120:2013-22.
Korobelnik JF, Do DV, Schmidt-Erfurth U, Boyer DS, Holz FG, Heier JS, et al.
Intravitreal aflibercept for diabetic macular edema. Ophthalmology 2014;121:2247-54.
Rajendram R, Fraser-Bell S, Kaines A, Michaelides M, Hamilton RD, Esposti SD, et al.
A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: Report 3. Arch Ophthalmol 2012;130:972-9.
Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, Aiello LP, Beck RW, Bressler NM, et al.
Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: Three-year randomized trial results. Ophthalmology 2012;119:2312-8.
Schmidt-Erfurth U, Lang GE, Holz FG, Schlingemann RO, Lanzetta P, Massin P, et al.
Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: The RESTORE extension study. Ophthalmology 2014;121:1045-53.
Ho AC, Scott IU, Kim SJ, Brown GC, Brown MM, Ip MS, et al.
Anti-vascular endothelial growth factor pharmacotherapy for diabetic macular edema: A report by the American Academy of Ophthalmology. Ophthalmology 2012;119:2179-88.
Dugel PU, Hillenkamp J, Sivaprasad S, Vögeler J, Mousseau MC, Wenzel A, et al.
Baseline visual acuity strongly predicts visual acuity gain in patients with diabetic macular edema following anti-vascular endothelial growth factor treatment across trials. Clin Ophthalmol 2016;10:1103-10.
Bressler SB, Ayala AR, Bressler NM, Melia M, Qin H, Ferris FL 3rd
, et al.
Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment. JAMA Ophthalmol 2016;134:278-85.
Bressler NM, Beaulieu WT, Glassman AR, Blinder KJ, Bressler SB, Jampol LM, et al.
Persistent macular thickening following intravitreous aflibercept, bevacizumab, or ranibizumab for central-involved diabetic macular edema with vision impairment: A Secondary analysis of a randomized clinical trial. JAMA Ophthalmol 2018;136:257-69.
Jonas JB, Söfker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol 2001;132:425-7.
Das A, McGuire PG, Rangasamy S. Diabetic macular edema: Pathophysiology and novel therapeutic targets. Ophthalmology 2015;122:1375-94.
Zhang X, Zeng H, Bao S, Wang N, Gillies MC. Diabetic macular edema: New concepts in patho-physiology and treatment. Cell Biosci 2014;4:27.
Miller JW, Le Couter J, Strauss EC, Ferrara N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 2013;120:106-14.
Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al.
Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: Two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology 2016;123:1351-9.
Mansoor S, Kuppermann BD, Kenney MC. Intraocular sustained-release delivery systems for triamcinolone acetonide. Pharm Res 2009;26:770-84.
Beer PM, Bakri SJ, Singh RJ, Liu W, Peters GB 3rd
, Miller M, et al.
Intraocular concentration and pharmacokinetics of triamcinolone acetonide after a single intravitreal injection. Ophthalmology 2003;110:681-6.
Mason JO 3rd
, Somaiya MD, Singh RJ. Intravitreal concentration and clearance of triamcinolone acetonide in nonvitrectomized human eyes. Retina 2004;24:900-4.
Cantrill HL, Waltman SR, Palmberg PF, Zink HA, Becker B.In vitro
determination of relative corticosteroid potency. J Clin Endocrinol Metab 1975;40:1073-7.
Gan IM, Ugahary LC, van Dissel JT, van Meurs JC. Effect of intravitreal dexamethasone on vitreous vancomycin concentrations in patients with suspected postoperative bacterial endophthalmitis. Graefes Arch Clin Exp Ophthalmol 2005;243:1186-9.
Jaffe GJ, Martin D, Callanan D, Pearson PA, Levy B, Comstock T, et al.
Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: Thirty-four-week results of a multicenter randomized clinical study. Ophthalmology 2006;113:1020-7.
Campochiaro PA, Hafiz G, Shah SM, Bloom S, Brown DM, Busquets M, et al.
Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology 2010;117:1393-9.e3.
Spandau UH, Derse M, Schmitz-Valckenberg P, Papoulis C, Jonas JB. Dosage dependency of intravitreal triamcinolone acetonide as treatment for diabetic macular oedema. Br J Ophthalmol 2005;89:999-1003.
Grover D, Li TJ, Chong CC. Intravitreal steroids for macular edema in diabetes. Cochrane Database Syst Rev 2008;(1):CD005656. doi: 10.1002/14651858.CD005656.pub2.
Audren F, Erginay A, Haouchine B, Benosman R, Conrath J, Bergmann JF, et al.
Intravitreal triamcinolone acetonide for diffuse diabetic macular oedema: 6-month results of a prospective controlled trial. Acta Ophthalmol Scand 2006;84:624-30.
Massin P, Audren F, Haouchine B, Erginay A, Bergmann JF, Benosman R, et al.
Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: Preliminary results of a prospective controlled trial. Ophthalmology 2004;111:218-24.
Diabetic Retinopathy Clinical Research Network, Chew E, Strauber S, Beck R, Aiello LP, Antoszyk A, et al.
Randomized trial of peribulbar triamcinolone acetonide with and without focal photocoagulation for mild diabetic macular edema: A pilot study. Ophthalmology 2007;114:1190-6.
Patel SR, Berezovsky DE, McCarey BE, Zarnitsyn V, Edelhauser HF, Prausnitz MR, et al.
Targeted administration into the suprachoroidal space using a microneedle for drug delivery to the posterior segment of the eye. Invest Ophthalmol Vis Sci 2012;53:4433-41.
Wykoff CC, Khurana RN, Lampen SIR, Noronha G, Brown DM, Ou WC, et al.
Suprachoroidal triamcinolone acetonide for diabetic macular edema: The HULK trial. Ophthalmol Retina 2018;2:874-7.
Boyer DS, Yoon YH, Belfort R Jr., Bandello F, Maturi RK, Augustin AJ, et al.
Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014;121:1904-14.
Mathew R, Pearce E, Muniraju R, Abdel-Hay A, Sivaprasad S. Monthly OCT monitoring of Ozurdex for macular oedema related to retinal vascular diseases: Re-treatment strategy (OCTOME Report 1). Eye (Lond) 2014;28:318-26.
Malclès A, Dot C, Voirin N, Agard É, Vié AL, Bellocq D, et al.
Real-life study in diabetic macular edema treated with dexamethasone implant: The reldex study. Retina 2017;37:753-60.
Guigou S, Pommier S, Meyer F, Hajjar C, Merite PY, Parrat E, et al.
Efficacy and safety of intravitreal dexamethasone implant in patients with diabetic macular edema. Ophthalmologica 2015;233:169-75.
Iglicki M, Busch C, Zur D, Okada M, Mariussi M, Chhablani JK, et al.
Dexamethasone implant for diabetic macular edema in naive compared with refractory eyes: The International Retina Group Real-Life 24-Month Multicenter Study. The IRGREL-DEX study. Retina 2019;39:44-51.
Aknin I, Melki L. Longitudinal study of sustained-release dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmologica 2016;235:187-8.
Escobar-Barranco JJ, Pina-Marín B, Fernández-Bonet M. Dexamethasone implants in patients with naïve or refractory diffuse diabetic macular edema. Ophthalmologica 2015;233:176-85.
Castro-Navarro V, Cervera-Taulet E, Navarro-Palop C, Monferrer-Adsuara C, Hernández-Bel L, Montero-Hernández J, et al.
Intravitreal dexamethasone implant Ozurdex® in naïve and refractory patients with different subtypes of diabetic macular edema. BMC Ophthalmol 2019;19:15.
Eaton A, Koh SS, Jimenez J, Riemann CD. The USER study: A Chart review of patients receiving a 0.2 μg/day fluocinolone acetonide implant for diabetic macular edema. Ophthalmol Ther 2019;8:51-62.
McCannel CA. Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: Causative organisms and possible prevention strategies. Retina 2011;31:654-61.
Pearson PA, Comstock TL, Ip M, Callanan D, Morse LS, Ashton P, et al.
Fluocinolone acetonide intravitreal implant for diabetic macular edema: A 3-year multicenter, randomized, controlled clinical trial. Ophthalmology 2011;118:1580-7.
Campochiaro PA, Brown DM, Pearson A, Chen S, Boyer D, Ruiz-Moreno J, et al.
Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology 2012;119:2125-32.
Cunha-Vaz J, Ashton P, Iezzi R, Campochiaro P, Dugel PU, Holz FG, et al.
Sustained delivery fluocinolone acetonide vitreous implants: Long-term benefit in patients with chronic diabetic macular edema. Ophthalmology 2014;121:1892-903.
Figueira J, Henriques J, Amaro M, Rosas V, Alves D, Cunha-Vaz J, et al.
A nonrandomized, open-label, multicenter, Phase 4 pilot study on the effect and safety of ILUVIEN® in chronic diabetic macular edema patients considered insufficiently responsive to available therapies (RESPOND). Ophthalmic Res 2017;57:166-72.
Chakravarthy U, Taylor SR, Koch FH, Castro de Sousa JP, Bailey C; ILUVIEN Registry Safety Study (IRISS) Investigators Group. Changes in intraocular pressure after intravitreal fluocinolone acetonide (ILUVIEN): Real-world experience in three European countries. Br J Ophthalmol 2019;103:1072-7.
Bailey C, Chakravarthy U, Lotery A, Menon G, Talks J; Medisoft Audit Group. Real-world experience with 0.2 μg/day fluocinolone acetonide intravitreal implant (ILUVIEN) in the United Kingdom. Eye (Lond) 2017;31:1707-15.
Pessoa B, Coelho J, Correia N, Ferreira N, Beirão M, Meireles A, et al.
Fluocinolone acetonide intravitreal implant 190 μg (ILUVIEN®) in vitrectomized versus nonvitrectomized eyes for the treatment of chronic diabetic macular edema. Ophthalmic Res 2018;59:68-75.
Fusi-Rubiano W, Mukherjee C, Lane M, Tsaloumas MD, Glover N, Kidess A, et al.
Treating diabetic macular oedema (DMO): Real world UK clinical outcomes for the 0.19mg fluocinolone acetonide intravitreal implant (Iluvien™) at 2 years. BMC Ophthalmol 2018;18:62.
Augustin AJ, Bopp S, Fechner M, Holz F, Sandner D, Winkgen AM, et al.
Three-year results from the retro-IDEAL study: Real-world data from diabetic macular edema (DME) patients treated with ILUVIEN® (0.19 mg fluocinolone acetonide implant). Eur J Ophthalmol 2019:1120672119834474. doi: 10.1177/1120672119834474. [Epub ahead of print].
Young JF, Walkden A, Stone A, Mahmood S. Clinical effectiveness of intravitreal fluocinolone acetonide (FAc) (ILUVIEN™) in patients with diabetic macular oedema (DMO) refractory to prior therapy: The manchester experience. Ophthalmol Ther 2019;8:477-84.
Pochopien M, Beiderbeck A, McEwan P, Zur R, Toumi M, Aballéa S, et al.
Cost-effectiveness of fluocinolone acetonide implant (ILUVIEN®) in UK patients with chronic diabetic macular oedema considered insufficiently responsive to available therapies. BMC Health Serv Res 2019;19:22.
Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008;115:1447-9, 1449.e1-10.
Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, Bressler NM, Ferris F, et al.
Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol 2009;127:245-51.
Callanan DG, Gupta S, Boyer DS, Ciulla TA, Singer MA, Kuppermann BD, et al.
Dexamethasone intravitreal implant in combination with laser photocoagulation for the treatment of diffuse diabetic macular edema. Ophthalmology 2013;120:1843-51.
Heng LZ, Sivaprasad S, Crosby-Nwaobi R, Saihan Z, Karampelas M, Bunce C, et al.
A prospective randomised controlled clinical trial comparing a combination of repeated intravitreal Ozurdex and macular laser therapy versus macular laser only in centre-involving diabetic macular oedema (OZLASE study). Br J Ophthalmol 2016;100:802-7.
Penha FM, Maia M, Cardillo JA, Arevalo JF, Wu L, Rodriguez FJ, et al.
Comparison of a single intravitreal injection of bevacizumab versus triamcinolone acetonide as primary treatment for diffuse diabetic macular oedema. Acta Ophthalmol 2012;90:e160-1.
Taş M, Oner V, Alakuş MF, Türkcü FM, Işcan Y, Yüksel K, et al.
Single injection of triamcinolone versus three repeated injections of bevacizumab for treatment of diabetic macular edema. Int Ophthalmol 2013;33:375-80.
Sobaci G, Ozge G, Erdurman C, Durukan HA, Bayraktar ZM. Comparison of grid laser, intravitreal triamcinolone, and intravitreal bevacizumab in the treatment of diffuse diabetic macular edema. Ophthalmologica 2012;227:95-9.
Kriechbaum K, Prager S, Mylonas G, Scholda C, Rainer G, Funk M, et al.
Intravitreal bevacizumab (Avastin) versus triamcinolone (Volon A) for treatment of diabetic macular edema: One-year results. Eye (Lond) 2014;28:9-15.
Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, et al.
Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117:1064-77.e35.
Bressler SB, Glassman AR, Almukhtar T, Bressler NM, Ferris FL, Googe JM Jr., et al.
Five-year outcomes of ranibizumab with prompt or deferred laser versus laser or triamcinolone plus deferred ranibizumab for diabetic macular edema. Am J Ophthalmol 2016;164:57-68.
Gillies MC, Lim LL, Campain A, Quin GJ, Salem W, Li J, et al.
A randomized clinical trial of intravitreal bevacizumab versus intravitreal dexamethasone for diabetic macular edema: The BEVORDEX study. Ophthalmology 2014;121:2473-81.
Mehta H, Fraser-Bell S, Yeung A, Campain A, Lim LL, Quin GJ, et al.
Efficacy of dexamethasone versus bevacizumab on regression of hard exudates in diabetic maculopathy: Data from the BEVORDEX randomised clinical trial. Br J Ophthalmol 2016;100:1000-4.
Mehta H, Fraser-Bell S, Nguyen V, Lim LL, Gillies MC. The interval between treatments of bevacizumab and dexamethasone implants for diabetic macular edema increased over time in the BEVORDEX trial. Ophthalmol Retina 2018;2:231-4.
Aroney C, Fraser-Bell S, Lamoureux EL, Gillies MC, Lim LL, Fenwick EK, et al.
Vision-related quality of life outcomes in the BEVORDEX study: A Clinical trial comparing Ozurdex sustained release dexamethasone intravitreal implant and bevacizumab treatment for diabetic macular edema. Invest Ophthalmol Vis Sci 2016;57:5541-6.
Callanan DG, Loewenstein A, Patel SS, Massin P, Corcóstegui B, Li XY, et al.
A multicenter, 12-month randomized study comparing dexamethasone intravitreal implant with ranibizumab in patients with diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 2017;255:463-73.
Singer MA, Miller DM, Gross JG, Greven CM, Kapik B, Bailey C, et al.
Visual acuity outcomes in diabetic macular edema with fluocinolone acetonide 0.2 μg/day versus ranibizumab plus deferred laser (DRCR protocol I). Ophthalmic Surg Lasers Imaging Retina 2018;49:698-706.
Gonzalez VH, Campbell J, Holekamp NM, Kiss S, Loewenstein A, Augustin AJ, et al.
Early and long-term responses to anti-vascular endothelial growth factor therapy in diabetic macular edema: Analysis of Protocol I data. Am J Ophthalmol 2016;172:72-9.
Ferris FL 3rd
, Maguire MG, Glassman AR, Ying GS, Martin DF. Evaluating effects of switching anti-vascular endothelial growth factor drugs for age-related macular degeneration and diabetic macular edema. JAMA Ophthalmol 2017;135:145-9.
Smiddy WE. Economic considerations of macular edema therapies. Ophthalmology 2011;118:1827-33.
Arevalo JF, Lasave AF, Wu L, Acon D, Farah ME, Gallego-Pinazo R, et al.
Intravitreal bevacizumab for diabetic macular oedema: 5-year results of the Pan-American Collaborative Retina Study Group. Br J Ophthalmol 2016;100:1605-10.
Kiss S, Liu Y, Brown J, Holekamp NM, Almony A, Campbell J, et al.
Clinical utilization of anti-vascular endothelial growth-factor agents and patient monitoring in retinal vein occlusion and diabetic macular edema. Clin Ophthalmol 2014;8:1611-21.
Dugel PU, Layton A, Varma RB. Diabetic macular edema diagnosis and treatment in the real world: An analysis of Medicare claims data (2008 to 2010). Ophthalmic Surg Lasers Imaging Retina 2016;47:258-67.
Sheu SJ, Cheng CK, Kuo HK, Tsai CY, Lin TC, Tan J, et al.
Treatment patterns in diabetic macular edema in Taiwan: A retrospective chart review. Clin Ophthalmol 2018;12:2189-98.
Mehta H, Hennings C, Gillies MC, Nguyen V, Campain A, Fraser-Bell S, et al.
Anti-vascular endothelial growth factor combined with intravitreal steroids for diabetic macular oedema. Cochrane Database Syst Rev 2018;4:CD011599.
Maturi RK, Bleau L, Saunders J, Mubasher M, Stewart MW. A 12-month, single-masked, randomized controlled study of eyes with persistent diabetic macular edema after multiple anti-VEGF injections to assess the efficacy of the dexamethasone-delayed delivery system as an adjunct to bevacizumab compared with continued bevacizumab monotherapy. Retina 2015;35:1604-14.
Maturi RK, Glassman AR, Liu D, Beck RW, Bhavsar AR, Bressler NM, et al.
Effect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: A DRCR network Phase 2 randomized clinical trial. JAMA Ophthalmol 2018;136:29-38.
Boyer DS, Faber D, Gupta S, Patel SS, Tabandeh H, Li XY, et al.
Dexamethasone intravitreal implant for treatment of diabetic macular edema in vitrectomized patients. Retina 2011;31:915-23.
Klein R, Klein BE, Moss SE. How many steps of progression of diabetic retinopathy are meaningful? The Wisconsin epidemiologic study of diabetic retinopathy. Arch Ophthalmol 2001;119:547-53.
Grading diabetic retinopathy from stereoscopic color fundus photographs – An extension of the modified Airlie house classification. ETDRS report number 10. Early treatment diabetic retinopathy study research group. Ophthalmology 1991;98:786-806.
Wykoff CC, Chakravarthy U, Campochiaro PA, Bailey C, Green K, Cunha-Vaz J, et al.
Long-term effects of intravitreal 0.19 mg fluocinolone acetonide implant on progression and regression of diabetic retinopathy. Ophthalmology 2017;124:440-9.
Bonnin S, Dupas B, Lavia C, Erginay A, Dhundass M, Couturier A, et al.
Anti-vascular endothelial growth factor therapy can improve diabetic retinopathy score without change in retinal perfusion. Retina 2019;39:426-34.
Lynch SK, Lee K, Chen Z, Folk JC, Schmidt-Erfurth U, Gerendas BS, et al.
Intravitreal fluocinolone acetonide may decelerate diabetic retinal neurodegeneration. Invest Ophthalmol Vis Sci 2019;60:2134-9.
Jones R 3rd
, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: A brief review and update of the literature. Curr Opin Ophthalmol 2006;17:163-7.
Razeghinejad MR, Katz LJ. Steroid-induced iatrogenic glaucoma. Ophthalmic Res 2012;47:66-80.
Gillies MC, Simpson JM, Gaston C, Hunt G, Ali H, Zhu M, et al.
Five-year results of a randomized trial with open-label extension of triamcinolone acetonide for refractory diabetic macular edema. Ophthalmology 2009;116:2182-7.
Haller JA, Bandello F, Belfort R Jr., Blumenkranz MS, Gillies M, Heier J, et al.
Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011;118:2453-60.
Lowder C, Belfort R Jr., Lightman S, Foster CS, Robinson MR, Schiffman RM, et al.
Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol 2011;129:545-53.
Maturi RK, Pollack A, Uy HS, Varano M, Gomes AM, Li XY, et al.
Intraocular pressure in patients with diabetic macular edema treated with dexamethasone intravitreal implant in the 3-year mead study. Retina 2016;36:1143-52.
Hemarat K, Kemmer JD, Porco TC, Eaton AM, Khurana RN, Stewart JM, et al.
Secondary ocular hypertension and the risk of glaucoma surgery after dexamethasone intravitreal implant in routine clinical practice. Ophthalmic Surg Lasers Imaging Retina 2018;49:680-5.
Parrish RK 2nd
, Campochiaro PA, Pearson PA, Green K, Traverso CE; FAME Study Group. Characterization of intraocular pressure increases and management strategies following treatment with fluocinolone acetonide intravitreal implants in the FAME trials. Ophthalmic Surg Lasers Imaging Retina 2016;47:426-35.
Nehmé A, Lobenhofer EK, Stamer WD, Edelman JL. Glucocorticoids with different chemical structures but similar glucocorticoid receptor potency regulate subsets of common and unique genes in human trabecular meshwork cells. BMC Med Genomics 2009;2:58.
Diabetic Retinopathy Clinical Research Network Authors/Writing Committee, Bressler SB, Baker CW, Almukhtar T, Bressler NM, Edwards PA, et al.
Pilot study of individuals with diabetic macular edema undergoing cataract surgery. JAMA Ophthalmol 2014;132:224-6.
Jonas JB. Intravitreal triamcinolone acetonide for diabetic retinopathy. Dev Ophthalmol 2007;39:96-110.
Sakamoto T, Enaida H, Kubota T, Nakahara M, Yamakiri K, Yamashita T, et al.
Incidence of acute endophthalmitis after triamcinolone-assisted pars plana vitrectomy. Am J Ophthalmol 2004;138:137-8.
Stem MS, Todorich B, Yonekawa Y, Capone A Jr., Williams GA, Ruby AJ, et al.
Incidence and visual outcomes of culture-proven endophthalmitis following dexamethasone intravitreal implant. JAMA Ophthalmol 2017;135:379-82.
VanderBeek BL, Bonaffini SG, Ma L. The association between intravitreal steroids and post-injection endophthalmitis rates. Ophthalmology 2015;122:2311-5.e1.
Shah AM, Oster SF, Freeman WR. Viral retinitis after intravitreal triamcinolone injection in patients with predisposing medical comorbidities. Am J Ophthalmol 2010;149:433-40.e1.
Takakura A, Tessler HH, Goldstein DA, Guex-Crosier Y, Chan CC, Brown DM, et al.
Viral retinitis following intraocular or periocular corticosteroid administration: A case series and comprehensive review of the literature. Ocul Immunol Inflamm 2014;22:175-82.
Vertes D, Snyers B, De Potter P. Cytomegalovirus retinitis after low-dose intravitreous triamcinolone acetonide in an immunocompetent patient: A warning for the widespread use of intravitreous corticosteroids. Int Ophthalmol 2010;30:595-7.
Thrane AS, Hove M, Kjersem B, Krohn J. Acute retinal necrosis and ocular neovascularization caused by cytomegalovirus following intravitreal dexamethasone implant (Ozurdex ®
) in an immunocompetent patient. Acta Ophthalmol 2016;94:e813-4.
Papastavrou VT, Zambarakji H, Dooley I, Eleftheriadis H, Jackson TL. Observation: Fluocinolone acetonide (Iluvien) implant migration into the anterior chamber. Retin Cases Brief Rep 2017;11:44-6.
Gonçalves MB, Alves BQ, Moura R, Magalhães O Jr., Maia A, Belfort R Jr., et al.
Intravitreal dexamethasone implant migration into the anterior chamber: A multicenter study from the Pan-American Collaborative Retina Study Group. Retina 2019. doi: 10.1097/IAE.0000000000002475. [Epub ahead of print].
Adán A, Pelegrín L, Rey A, Llorenç V, Mesquida M, Molins B, et al.
Dexamethasone intravitreal implant for treatment of uveitic persistent cystoid macular edema in vitrectomized patients. Retina 2013;33:1435-40.
Chalioulias K, Muqit MM. Vitreoretinal surgery for inadvertent intralenticular Ozurdex implant. Eye (Lond) 2014;28:1523-4.
|This article has been cited by|
||The 0.19-mg Fluocinolone Acetonide Intravitreal Implant Reduces Treatment Burden in Diabetic Macular Edema
| ||Pauline T. Merrill, Nancy Holekamp, Daniel Roth, Jonathan Kasper, Ruben Grigorian |
| ||American Journal of Ophthalmology. 2023; 248: 16 |
|[Pubmed] | [DOI]|
||Vitreous humor proteome: unraveling the molecular mechanisms underlying proliferative and neovascular vitreoretinal diseases
| ||Fátima Milhano dos Santos, Sergio Ciordia, Joana Mesquita, João Paulo Castro de Sousa, Alberto Paradela, Cândida Teixeira Tomaz, Luís António Paulino Passarinha |
| ||Cellular and Molecular Life Sciences. 2023; 80(1) |
|[Pubmed] | [DOI]|
||Diabetic Macular Oedema Guidelines: An Australian Perspective
| ||Yew Sen Yuen, Jagjit Singh Gilhotra, Michelle Dalton, Jaskirat S. Aujla, Hemal Mehta, Sanj Wickremasinghe, Gurmit Uppal, Jennifer Arnold, Fred Chen, Andrew Chang, Samantha Fraser-Bell, Lyndell Lim, Janika Shah, Ellie Bowditch, Geoffrey K. Broadhead, Paolo Milani |
| ||Journal of Ophthalmology. 2023; 2023: 1 |
|[Pubmed] | [DOI]|
||REal-world treatment outcomes after delayed intRavitreal therapy in center-involving diabetic macular edema – RETORT study
| ||Sai Prashanti Chitturi, Ramesh Venkatesh, Rubble Mangla, Yash Parmar, Rohini Sangoram, Naresh Kumar Yadav, Jay Chhablani |
| ||International Journal of Retina and Vitreous. 2023; 9(1) |
|[Pubmed] | [DOI]|
||The 0.19-mg Fluocinolone Acetonide Implant for the Treatment of Diabetic Macular Edema: An Expert Consensus
| ||Anton M. Kolomeyer, David A. Eichenbaum, Daniel F. Kiernan, Ivan J. Suñer, Seenu M. Hariprasad |
| ||Ophthalmic Surgery, Lasers and Imaging Retina. 2023; 54(3): 166 |
|[Pubmed] | [DOI]|
||Retinal Diseases: The Next Frontier in Pharmacodelivery
| ||Assaf Ben-Arzi, Rita Ehrlich, Ron Neumann |
| ||Pharmaceutics. 2022; 14(5): 904 |
|[Pubmed] | [DOI]|
||Current and Novel Therapeutic Approaches for Treatment of Diabetic Macular Edema
| ||Muhammad Z. Chauhan, Peyton A. Rather, Sajida M. Samarah, Abdelrahman M. Elhusseiny, Ahmed B. Sallam |
| ||Cells. 2022; 11(12): 1950 |
|[Pubmed] | [DOI]|
||The Role of Intravitreal Corticosteroids in the Treatment of DME: Predictive OCT Biomarkers
| ||Marion R. Munk, Gabor Mark Somfai, Marc D. de Smet, Guy Donati, Marcel N. Menke, Justus G. Garweg, Lala Ceklic |
| ||International Journal of Molecular Sciences. 2022; 23(14): 7585 |
|[Pubmed] | [DOI]|
||Dexamethasone suppresses the proliferation and migration of VSMCs by FAK in high glucose conditions
| ||Ali Akbar Soleimani, Asghar Mohammadi, Ghasem Ghasempour, Borhan Rahimi Abkenar, Nafiseh Shokri, Mohammad Najafi |
| ||BMC Pharmacology and Toxicology. 2022; 23(1) |
|[Pubmed] | [DOI]|
||Drugs associated with cataract formation represent an unmet need in cataract research
| ||Jack Carlson, Kate McBride, Michael O’Connor |
| ||Frontiers in Medicine. 2022; 9 |
|[Pubmed] | [DOI]|
||Real-Life Efficacy, Safety, and Use of Dexamethasone Intravitreal Implant in Posterior Segment Inflammation Due to Non-infectious Uveitis (LOUVRE 2 Study)
| ||Bahram Bodaghi, Antoine P. Brézin, Michel Weber, Cécile Delcourt, Laurent Kodjikian, Alexandra Provost, Marie-Ève Velard, Doris Barnier-Ripet, Sybil Pinchinat, Laure Dupont-Benjamin |
| ||Ophthalmology and Therapy. 2022; |
|[Pubmed] | [DOI]|
||Management of Diabetic Macular Edema: Guidelines from the Emirates Society of Ophthalmology
| ||Noura Al Qassimi, Igor Kozak, Maysoon Al Karam, Piergiorgio Neri, Patricio M. Aduriz-Lorenzo, Alaa Attawan, Mohamed Awadalla, Ahmed El Khashab, Mohamed Abdul-Nabi, Ammar Safar, Hanan Al Shamsi, Prasan Rao, Madhav Rao, Amr Farid, Avinash Gurbaxani |
| ||Ophthalmology and Therapy. 2022; |
|[Pubmed] | [DOI]|
||Newer therapeutic agents for retinal diseases
| ||Ashish Markan, Swechya Neupane, Rupesh Agrawal, Vishali Gupta |
| ||Expert Review of Ophthalmology. 2022; : 1 |
|[Pubmed] | [DOI]|
||Intravitreal steroids compared to anti-vascular endothelial growth factor treatment for diabetic macular edema: a meta-analysis
| ||Nikhil S. Patil, Andrew Mihalache, Amin Hatamnejad, Marko M. Popovic, Peter J. Kertes, Rajeev H. Muni |
| ||Ophthalmology Retina. 2022; |
|[Pubmed] | [DOI]|
||Studies of the retinal microcirculation using human donor eyes and high-resolution clinical imaging: Insights gained to guide future research in diabetic retinopathy
| ||Chandrakumar Balaratnasingam, Dong An, Martin Hein, Paula Yu, Dao-Yi Yu |
| ||Progress in Retinal and Eye Research. 2022; : 101134 |
|[Pubmed] | [DOI]|
||Primary cilia in retinal pigment epithelium development and diseases
| ||Chunjiao Sun,Jun Zhou,Xiaoqian Meng |
| ||Journal of Cellular and Molecular Medicine. 2021; |
|[Pubmed] | [DOI]|
||Long-term outcomes of administration of intravitreal triamcinolone acetonide after posterior vitreous detachment during pars plana vitrectomy for proliferative diabetic retinopathy
| ||Mengyu Liao, Yunli Huang, Jiaxing Wang, Xiangda Meng, Yuanyuan Liu, Jinguo Yu, Hua Yan |
| ||British Journal of Ophthalmology. 2021; : bjophthalm |
|[Pubmed] | [DOI]|
||Anti-inflammatory Effect of Curcumin, Homotaurine, and Vitamin D3 on Human Vitreous in Patients With Diabetic Retinopathy
| ||Mariaelena Filippelli,Giuseppe Campagna,Pasquale Vito,Tiziana Zotti,Luca Ventre,Michele Rinaldi,Silvia Bartollino,Roberto dellæOmo,Ciro Costagliola |
| ||Frontiers in Neurology. 2021; 11 |
|[Pubmed] | [DOI]|
||Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema
| ||Milagros Mateos-Olivares,Luis García-Onrubia,Fco. Javier Valentín-Bravo,Rogelio González-Sarmiento,Maribel Lopez-Galvez,J. Carlos Pastor,Ricardo Usategui-Martín,Salvador Pastor-Idoate |
| ||Cells. 2021; 10(7): 1683 |
|[Pubmed] | [DOI]|
||Guidelines for the Management of Center-Involving Diabetic Macular Edema: Treatment Options and Patient Monitorization
| ||João Figueira,José Henriques,Ângela Carneiro,Carlos Marques-Neves,Rita Flores,João Paulo Castro-Sousa,Angelina Meireles,Nuno Gomes,João Nascimento,Miguel Amaro,Rufino Silva |
| ||Clinical Ophthalmology. 2021; Volume 15: 3221 |
|[Pubmed] | [DOI]|
||Efficacy of intravitreal dexamethasone implant as a starting monotherapy and when switching from an anti-VEGF drug in diabetic macular edema
| ||M.M. Bikbov, R.M. Zainullin, K.I. Kudoyarova, M.R. Kalanov |
| ||Vestnik oftal'mologii. 2021; 138(6): 5 |
|[Pubmed] | [DOI]|
||Early treatment with dexamethasone intravitreal implants in diabetic macular edema: Naïve versus refractory patients
| ||Anna V Bux, Francesca Fortunato, Antonio Barone, Vincenzo Russo, Nicola Delle Noci, Cristiana Iaculli |
| ||European Journal of Ophthalmology. 2021; : 1120672121 |
|[Pubmed] | [DOI]|
||Ultrasound and Microbubbles for the Treatment of Ocular Diseases: From Preclinical Research towards Clinical Application
| ||Charis Rousou, Carl C. L. Schuurmans, Arto Urtti, Enrico Mastrobattista, Gert Storm, Chrit Moonen, Kai Kaarniranta, Roel Deckers |
| ||Pharmaceutics. 2021; 13(11): 1782 |
|[Pubmed] | [DOI]|
Rapid Structural and Functional Improvements with the 0.19 mg Fluocinolone Acetonide Intravitreal Implant for Patients with DME and Low Visual Acuity: 6-Month Data from the UAE
| ||Ahmed Mohammed Elbarky |
| ||Clinical Ophthalmology. 2020; Volume 14: 823 |
|[Pubmed] | [DOI]|
||Anterior Migration of Triamcinolone Acetonide after Posterior Subtenon Injection for Macular Edema Predisposes to Intraocular Pressure Elevation
| ||Yun-Hsiang Yang,Wei-Cherng Hsu,Yi-Ting Hsieh |
| ||Current Eye Research. 2020; : 1 |
|[Pubmed] | [DOI]|