Update on the Use Of Intraocular Steroids For Posterior-segment Diseases
More choices exist than ever before, but complications persist as well.
Daniel B. Roth, MD, is an associate clinical professor at Rutgers Robert Wood Johnson Medical School in New Brunswick, NJ, and director of clinical research at NJ Retina. Kunjal K. Modi is a fourth-year medical student at Rutgers Robert Wood Johnson Medical School. Ingrid U. Scott, MD, MPH, is professor of ophthalmology and health evaluation sciences at Pennsylvania State University College of Medicine. Harry W. Flynn, Jr, MD, is professor and J. Donald M. Gass Distinguished Chair of Ophthalmology at the Bascom Palmer Eye Institute at the Leonard M. Miller School of Medicine at the University of Miami. Dr. Roth reports financial interest in Allergan, Forsight Labs, Regeneron, and Thrombogenics. Dr. Scott reports financial interest in Genentech and Thrombogenics. Dr. Flynn reports financial interest in Santen and Vindico. Mr. Modi reports no financial interests. Dr. Roth can be reached via e-mail at email@example.com.
DANIEL B. ROTH, MD · KUNJAL K. MODI · INGRID U. SCOTT, MD, MPH · HARRY W. FLYNN, JR, MD
Intraocular steroids have been in use since the 1970s, when adjunctive use of dexamethasone was reported to decrease inflammation in eyes with postoperative or post-traumatic bacterial endophthalmitis.1
Corticosteroids inhibit inflammatory mediators, that induce increased permeability of retinal capillaries. This hyperpermeability allows for extravasation of proteins and fluids into the extracapillary space, resulting in cystoid macular edema (Figure 1).2
Although CME may occur with many conditions, the most common are diabetic macular edema, central and branch retinal vein occlusions, pseudophakic CME, and age-related macular degeneration.2 Data suggest that corticosteroids are more effective against macular edema when delivered intravitreally, compared to topically.2
The Diabetic Retinopathy Clinical Research (DRCR) Network reported that peribulbar triamcinolone acetonide was not associated with significant benefits in patients with less severe DME.3
THE BIG THREE
Studies have investigated three synthetic corticosteroids with similar chemical structures as intravitreal treatments for CME: triamcinolone, dexamethasone, and fluocinolone acetonide.4
In general, the eye clears intravitreal medications relatively rapidly. To increase the duration of action, the medication may dissolve slowly from a crystal structure (eg, triamcinolone), or via a specific slow-release device (eg, dexamethasone, fluocinolone).4
Figure 1. Optical coherence tomography image (A) of uveitis-associated CME with multiple intraretinal-fluid cysts and another OCT image (B) showing resolution of CME, one month after treatment with the dexamethasone biodegradable implant.
Figure 2. Fluorescein angiogram (late frame recirculation phase) of diabetic retinopathy-associated CME (top) and resolution of CME one month after intravitreal triamcinolone injection (bottom).
Intravitreal triamcinolone suspension has a half life of 18.6 days5 and is typically effective for approximately three months in nonvitrectomized eyes.6 As a result, repeated injections may be necessary to maintain a treatment effect. Furthermore, in vitrectomized eyes, the steroid will clear more rapidly, requiring more frequent injections to maintain a therapeutic effect. To mitigate the cumulative risks associated with repeated intravitreal injections, studies have investigated extended-release steroid implants for the treatment of CME.
In addition, some authors have suggested that continuous delivery of lower doses of steroids may be more effective than intermittent bolus delivery of higher doses.7 In general, nonbioerodable implants (eg, Retisert [Bausch + Lomb, Rochester, NY], Iluvien [Alimera Sciences, Alpharetta, GA]) have been associated with more precise drug release than bioerodable implants (eg, Ozurdex [Allergan, Irvine, CA]).8
Several different preparations of triamcinolone are available for intravitreal injection: Kenalog-40 (Bristol-Myers Squibb, Princeton, NJ); Triesence (Alcon, Fort Worth, TX); and preservative-free triamcinolone obtained from compounding pharmacies. Several clinical trials have investigated the efficacy of TA for DME and macular edema secondary to RVO (Figure 2; Table, pages 52-53).
Figure 3. The injection device of the biodegradable dexamethasone intravitreal implant, which is deployed by depressing the gray button after the needle is inserted through the pars plana, releasing the implant into the vitreous cavity. The implant releases the drug over months, and the device dissolves in the vitreous.
Neovascular AMD refractory to anti-VEGF treatment is a candidate for triple therapy, consisting of intravitreal anti-VEGF injection, photodynamic therapy, and an intravitreal steroid.
In one study that included triamcinolone as the steroid component of triple therapy for wet AMD, mean visual acuity improved from 20/133 at baseline to 20/101 at six months and 20/84 at one year.9
In a study that included dexamethasone as the steroid component in triple therapy, mean VA improved from 20/80 at baseline to 20/60 after 13.7 months of triple therapy.10
In addition to its use for CME, triamcinolone may also be used to aid visualization of transparent tissue, especially the vitreous and epiretinal membranes, during ophthalmic surgery.
In one survey, 59 of 60 vitreoretinal surgeons reported that triamcinolone improved subjective visualization of posterior-segment structures intraoperatively.11 This benefit occurs because the drug crystals become trapped in the formed vitreous, providing a strong visual contrast between the transparent liquid vitreous and formed vitreous coated with triamcinolone crystals.
Because dexamethasone has a short half-life in the vitreous, the Ozurdex bioerodable, extended-release dexamethasone implant was developed and received FDA approval for the treatment of CME associated with RVO12 and for noninfectious posterior-segment uveitis (Figure 3).13
The device, which can be injected in the clinic, contains 700 μg dexamethasone in a solid, bioerodable polymer. In a monkey model, peak concentrations of dexamethasone appeared in the vitreous and retina for the first two months, followed by a gradual decrease to below the limits of quantitation by six months.14
In patients with DME, BCVA improved by at least 10 letters in 33% of those treated with the dexamethasone implant, compared to 12.3% of patients in an observation group at 90 days of follow-up. The significant improvement in BCVA remained at 180 days of follow-up.15
In a small, open-label clinical trial, a single dexamethasone implant was associated with improved vision and retinal thickness in vitrectomized eyes with DME at 26 weeks of follow-up.16
In the GENEVA trial, which included patients with macular edema secondary to RVO, VA improved by ≥15 letters in 29.3% of eyes treated with the dexa-methasone implant, compared to 11.3% of sham-injected eyes by 60 days.12
In another study of eyes with ME due to RVO, central macular thickness decreased from a mean of 632 μm at baseline to 229 μm at 10 months following injection of the dexamethasone implant.17
Another series of patients with macular edema secondary to RVO resistant to treatment with bevacizumab (Avastin, Genentech, South San Francisco, CA) showed an additional mean reduction in central macular thickness of 146.8 μm after adding the dexamethasone implant to the treatment regimen.18
Uveitis and Vitreous Haze
In patients with noninfectious intermediate or posterior uveitis, the proportion of eyes with a vitreous haze score of 0 at eight weeks following injection was 47% in the dexamethasone implant group vs 12% in the sham group.13
The difference in haze score was greatest at eight weeks, but the significant effect persisted to week 26. The treatment group in this study also had significantly decreased macular thickness compared to the sham injection group.13
The Retisert nonbioerodable, extended-release fluocinolone implantable device, which must be sutured to the sclera in an operating room, received FDA approval for the treatment of noninfectious posterior-segment uveitis (Figure 4).19 The device contains 0.59 mg fluocinolone coated with polyvinyl alcohol and releases approximately 0.5 μg per day for approximately three years.
Figure 4. Enlarged view of the Retisert extended-release fluocinolone implantable device, which is sutured to the sclera and releases medication over several years.
Figure 5. The nonbioerodable, extended-release, injectable fluocinolone device, which is injected into the vitreous cavity and releases medication over several years.
Uveitis recurrence occurs significantly less frequently in patients treated with the FA implant; 62% having sufferred recurrence in the one year before implantation, compared to 4% during one year postimplantation.19
In another study of patients treated with the fluocinolone implantable device for chronic noninfectious uveitis, 51.4% experienced recurrence of uveitis during the 34 weeks before implantation, compared to 6.1% during the 34 weeks postimplantation.20
Investigators also looked at the FA implantable device for the treatment of DME, for which it has been shown to improve visual and anatomic outcomes. The FAMOUS study, conducted in the United States, demonstrated the device provides therapeutic levels of intraocular fluocinolone, and BCVA in treated patients improved by a mean of 7.5, 6.9, and 5.7 letters at three, six, and 12 months, respectively.7
Two Options Available
Studies have also investigated the much smaller, nonbioerodable, extended-release injectable Iluvien fluocinolone device, which is injected in the clinic setting, for the treatment of DME (Figure 5).21 The FAMOUS study was a phase 2, randomized, controlled trial enrolling 37 patients to receive either a 0.2- or 0.5-μg/day device. The group reported sustained intraocular release of medication in both groups at one year.7
The FAME studies were two phase 3, randomized, controlled trials that collectively involved 956 patients with persistent DME following photocoagulation to receive a 0.2-μg/day implant, a 0.5-μg/day implant, or a sham injection.
The primary endpoint was improvement in BCVA of at least 15 letters at 24 months. In both treatment groups, approximately 28% of patients achieved this endpoint, compared to approximately 16% of sham-treated patients.22
The physician must weigh the benefits of intraocular steroids against their potential complications. The most commonly reported complications associated with intraocular steroids include cataract onset and progression,23 elevated intraocular pressure,24 infectious endophthalmitis, and pseudoendophthalmitis.
The cataractogenic properties of injectable steroids are likely related to oxidative damage and receptor stimulation in the lens epithelial cells.25 A study of patients with DME showed progression of cataracts in 81% (22/27) of eyes by two years after a single intraocular injection of 4 mg triamcinolone.7
Table. Data Summarizing Recent Trials of TA for DME and ME Secondary to RVO
|SCORE-BRVO37||411||Macular edema secondary to BRVO||1 mg and 4 mg doses of IVTA||Grid photocoagulation||Gain in VA letter score of ≥15 from baseline to one year follow-up||29% in observation, 27% in 1-mg TA, 26% in 4-mg TA achieved primary efficacy outcome||Cataract and IOP elevation, highest in 4 mg TA group|
|SCORE-CRVO38||271||Macular edema secondary to CRVO||1 mg and 4 mg doses of IVTA||Observation||Gain in VA letter score of ≥15 from baseline to one year follow-up||7% in observation, 27% in 1-mg TA, 26% in 4-mg TA achieved primary eficacy outcome||Cataract and IOP elevation|
|DRCR Protocol B #339||840||DME (with VA of 20/40 to 20/320)||1-mg and 4-mg doses of IVTA||Focal/grid photocoagulation||Change in VA at two-year follow-up||VA improved in 4-mg TA group at four-month follow-up, but at 2 years VA change was +2 letters in laser group, -2 in 1-mg TA group, -4 in 4-mg TA group||Cataract and IOP elevation. IOP elevation more frequent in 4 mg group. Four retinal detachments in 4 mg group; two in both of the other groups|
|DRCR Protocol B #440||306||DME (with VA of 20/40 to 20/320)||1 mg and 4 mg doses of IVTA||Focal/grid photocoagulation||Change in VA at three-year follow-up||VA change was 0 in each TA group and +5 letters in photocoagulation group||Cataract and IOP elevation, mostly in 4 mg TA group|
|*DRCR Protocol E3||129||DME (with VA of 20/40 or better)||Anterior and posterior sub-Tenon injection of TA (see below)||Focal photocoagulation||Change in VA and retinal thickness on OCT at 34 weeks||Change in retinal thickness or VA was not significantly different among the five groups||IOP elevation, progression of cataract, and ptosis associated with injection groups|
|DRCR Protocol I41||854||DME (with VA 20/32 to 20/320)||4 mg IVTA + prompt laser||Sham injection + prompt laser; 0.5 mg ranibizumab + prompt laser; 0.5 mg ranibizumab + deferred laser (>24 weeks)||BCVA at one-year follow-up||Ranibizumab + prompt laser and deferred laser were both +9 letters, TA + prompt laser was +4, and sham + laser was +3||Injection-related endophthalmitis in ranibizumab group, but IOP elevation more common in TA group|
|DRCR Protocol J42||345||DME (with VA 20/320 or better) in eyes receiving panretinal photocoagulation||0.5 mg ranibizumab at baseline and four weeks, or 4 mg IVTA at baseline and sham at four weeks||Sham injections||Mean change in VA at 14-week follow-up||VA change +2 in TA group, +1 letters in ranibuzumab group, -4 in sham injection group||Cataract, IOP elevation, 3% of eyes in sham group had retinal detachment|
|Gillies et al43||84||DME||IVTA + laser||Laser treatment alone||ain in VA >10 logMAR letters from baseline to two-year follow-up||36% in treatment vs 17% in control achieved primary efficacy outcome; CMT did not differ||Cataract and IOP elevation, and one case of culture-negative endophthalmitis|
* DRCR Protocol E treatment groups: (1) 20 mg anterior sub-Tenon TA injection; (2) 20 mg anterior sub-Tenon injection, followed by focal photocoagulation in four weeks; (3) 40 mg posterior sub-Tenon TA injection; or (4) 40 mg posterior sub-Tenon injection followed by focal photocoagulation after four weeks.
KEY: TA = triamcinolone acetonide; IVTA = intravitreal triamcinolone acetonide.
In the SCORE central and branch RVO trials, cataract surgery was most frequent between the one- and two-year follow-ups after initiation of treatment with 4 mg triamcinolone.
In the SCORE CRVO trial, 21 eyes in the 4-mg group received cataract surgery between months 12 and 24, compared to three eyes in the 1-mg group and no eyes in the observation group.24
In the SCORE BRVO trial, 35 eyes in the 4-mg group received cataract surgery between months 12 and 24, compared to eight eyes in the 1-mg group and six eyes in the standard care group.25
After treatment with the dexamethasone implant in the GENEVA trial, cataract progression occurred over 12 months in 90 of 302 phakic eyes (29.8%) that received two implants vs five of 88 sham-treated phakic eyes (5.7%). Four of 302 (1.3%) and one of 88 (1.1%) eyes underwent cataract surgery, respectively.12
The fluocinolone implantable device has shown high rates of cataract progression. In one study of 278 postimplant eyes, lens opacity increased >2 grades in 19.8% of phakic implanted eyes, and 9.9% had undergone cataract surgery by the 34th week of follow-up.20
Thirty-six months after Iluvien implantation, 41% of eyes that received a 0.2-μg/day implant, 51% of eyes that received a 0.5-μg/day implant, and 7% of eyes that received the sham injection underwent cataract surgery.22
Increased IOP is another known side effect of intravitreal steroid injection, due to increased resistance of aqueous outflow through specific receptor-ligand interactions.26
A study of 929 eyes reported IOP elevations in 28.2%, 34.6%, 41.2%, and 44.6% of eyes at six, 12, 18, and 24 months, respectively, after triamcinolone injections.27 The same study showed that pre-existing glaucoma, younger age, and a history of an IOP elevation after triamcinolone injections were risk factors for these pressure elevations.
In a series of eyes treated with intravitreal dexamethasone implants for noninfectious uveitis, a ≥10 mm Hg increase in IOP from baseline occurred in 12.6% of eyes after the first treatment and 15.4% after the second injection.28
In another study of eyes with posterior uveitis treated with the fluocinolone implant, IOP increased at least 5 mm Hg in 69% of eyes and by 10 mm Hg in 50% of eyes at some time during three-year follow up.19
Implantable fluocinolone devices have been shown to be associated with high rates of IOP elevation, likely due to fluocinolone having greater portioning into the lens and trabecular meshwork than dexamethasone, making exit of aqueous humor more difficult.
After receiving the fluocinolone implant, 78% of eyes were treated with IOP-lowering drops at some point within three years postimplantation.20
In another study, approximately 40% of patients with the fluocinolone implant underwent surgical correction of IOP within three years of implantation.29
Increased IOP after Iluvien requiring incisional glaucoma surgery was reported in 3.7% of eyes that received a 0.2-μg/day implant, 8.1% that received a 0.5-μg/day implant, and 0.5% that received a sham injection.22
Intravitreal injections in general are associated with approximately a 0.05% risk of infectious endophthalmitis per injection.30
Intravitreal triamcinolone is also associated with noninfectious endophthalmitis, which is believed to be a sterile immune reaction to the drug or its preparation, and pseudoendophthalmitis, which represents a collection of triamcinolone crystals in the anterior chamber and vitreous. These noninfectious reactions have been reported to occur following 0.5% to 2.0% of intravitreal triamcinolone injections.31
A final consideration when injecting intravitreal steroids, especially those obtained from a compounding pharmacy, is the possibility of product contamination. In September 2012, a severe outbreak of meningitis, associated with 61 deaths, occurred after nonophthalmic injections of methylprednisolone, obtained from a specific compounding pharmacy; the methylprednisolone was contaminated with Exserohilum rostratum.32
Multiple outbreaks of bacterial and fungal endophthalmitis have occurred due to contamination occurring in compounding pharmacies, often with visually devastating consequences.33-36
Preservative-free triamcinolone is FDA-approved for uveitis, ocular inflammation, and visualization during vitrectomy. The bioerodable dexamethasone implant is approved as an extended-release device for RVO and noninfectious posterior segment uveitis, and the fluocinolone implantable device is approved for noninfectious posterior-segment uveitis.
The fluocinolone injectable device is not FDA-approved, but the device has achieved approval in several European nations, and the pharmaceutical company has reapplied for FDA approval.
The use of intravitreal steroids in the United States for DME, either as a primary or adjunctive therapy, is off-label. As data from randomized, controlled trials continue to accumulate, we will obtain a better understanding of the role of intraocular steroids for posterior-segment diseases. RP
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36. Goldberg RA, Flynn HW Jr, Isom RF, et al. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012;153:204-208.
37. Scott IU, Ip MS, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: The Standard Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127:1115-1128.
38. Ip MS, Scott IU, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127:1101-1114.
39. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008;115:1447-1449.
40. Diabetic Retinopathy Clinical Research Network (DRCR.net); Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127:245-251.
41. Elman MJ, Bressler NM, Beck RW, et al; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118:609-614.
42. Diabetic Retinopathy Clinical Research Network, Googe J, Brucker AJ, et al. Randomized trial evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema after focal/grid laser for diabetic macular edema in eyes also receiving panretinal photocoagulation. Retina. 2011;31:1009-1027.
43. Gillies MC, McAllister IL, Zhu M, et al. Intravitreal triamcinolone prior to laser treatment of diabetic macular edema: 24-month results of a randomized clinical trial. Ophthalmology. 2011; 118:866-872.