Inflammatory processes are increasingly recognized to play a significant role in many diseases of the retina. As a result, there has been burgeoning research interest in the extent to which inflammation is a factor in highly prevalent retinal disorders such as age-related macular degeneration (AMD), diabetic retinopathy, and venous occlusive disease, and into expanding molecular targeting to encompass inflammationrelated mediators other than just vascular endothelial growth factor to improve clinical outcomes in these diseases. Corticosteroids are a class of drugs that has been used via a variety of routes for many years for ocular indications, and more recently in the posterior segment, as a primary therapy and to improve the response to surgical intervention or to enhance therapeutic agents as an adjunctive measure.1-11
This article offers a brief overview of selected points in the history of intravitreal corticosteroid monotherapy for retinal disease.
PRECLINICAL WORK
The first reported intravitreal injection of a corticosteroid
was performed by Graham and Peyman in 1974, when they
injected dexamethasone for an experimentally induced case
of endophthalmitis.12 Subsequently, Peyman et al13-15 published
further cases where this agent was used in combination
with gentamycin to treat bacterial endophthalmitis. In
1977, Floman and Zor16 elucidated that the mechanism of
corticosteroid action against inflammation as involving the
inhibition of prostaglandins. Later that decade, Machemer
and Tano17,18 showed that a single injection of dexamethasone
in rabbit models inhibited fibroblast growth and significantly
reduced the incidence of retinal detachment. They
repeated the study using intravitreal triamcinolone (IVTA)
with similar results.19 They also saw a reduction in retinal vascularization
caused by fibrous strands coming into contact
with the vascularized retina with IVTA to a greater extent than
when they had used dexamethasone in the earlier studies.
Ishibashi et al20 investigated the effects of corticosteroids on a primate model of laser-induced lesions and found that eyes infused with either dexamethasone or dexamethasone combined with triamcinolone less frequently developed subretinal neovascularization when compared with controls, suggesting an antiangiogenic effect. In a later study using a rabbit model for preretinal neovascularization, a significantly fewer number of eyes developed new blood vessels after being treated with triamcinolone and then injected with dermal fibroblasts compared with controls.21
INTRAVITREAL STEROIDS FOR AMD
In 1995, Penfold et al23 performed a pilot study using IVTA
in patients to treat age-related macular degeneration (AMD).
In this 30-eye study (n=28), IVTA was shown to decrease exudation
and improved vision in patients with wet AMD and
subfoveal and juxtafoveal choroidal neovascularization. With
18-month follow-up, there were no serious side effects and
visual acuity was reported as significantly better than the data
showed for untreated lesions.
In a study that was published in Retina in 2000, a single injection of 4-mg IVTA was administered to patients with wet AMD (n=27) and compared for 6-months follow-up against untreated patients. The patients in the treated group had significantly better visual acuity at 3 and 6 months (P<.005) and although an intraocular pressure (IOP) rise was seen in 25% of treated patients, this was managed with topical pressure-lowering medications.24
Gillies et al27 reported a biologic effect with one injection 4-mg IVTA for AMD at 3 months in their study in 2003, and in 1-year follow-up, found that one injection of IVTA did not increase the risk of visual loss in their 151 eye, randomized study.
Jonas et al25 performed a study evaluating high-dose 25-mg IVTA for wet AMD. Their study included 71 eyes of 67 patients and sought to find the duration of effect and side effects of the treatment over the course of an average of approximately 7-months follow-up. They found a significant increase in mean visual acuity (P<.001); however, they also saw a significant mean increase in IOP (P<.001). In another high-dose IVTA study with 1-year follow-up (39 eyes), however, no beneficial effect was found in the treated group vs the control group, who were treated with intravitreal dexamethasone. 26 Further, all eyes in the treated group developed marked cataract progression.
INTRAVITREAL STEROIDS FOR UVEITIS
Steroids have been used for uveitis for many years, and their intravitreal use was one of the obvious indications once this route of drug delivery became commonly employed. A key development for chronic intravitreal administration of steroids was the advent of extended delivery.
Pilot and clinical trials for the 0.59-mg fluocinolone acetonide sustained-delivery device (Retisert, Bausch & Lomb) for the treatment of chronic posterior uveitis proved that it was beneficial in controlling inflammation over a prolonged period of time.28,29 Patients in the clinical trial (n=168) were followed for 3 years and, although the side effects of IOP and cataract progression were significant, they did not outweigh the damaging effects of the disease.30,31 The US Food and Drug Administration (FDA) approved the device in 2005.
INTRAVITREAL STEROIDS FOR DIABETIC
MACULAR EDEMA
Virtually all types of recalcitrant macular edema, diabetic
macular edema (DME) being the most prevalent, have been
reported to respond at least transiently to the use of intravitreal
steroid therapy. An evidence-based paradigm for
intravitreal steroid use, however, particularly in complex,
multifactorial and chronic disease states such as DME,
remains elusive. Multiple case series and small trials have
investigated the use of intravitreal steroids for DME. For
example, Gillies et al32 recently reported a small series of eyes
(n=41) who were treated with IVTA for DME refractory to
laser. Patients were randomized to IVTA or placebo. A
greater percentage of patients achieved visual acuity
improvement in the IVTA group (42%) than placebo (32%),
and in 5-year follow-up, patients who responded to IVTA
maintained their visual acuity gains.
The largest clinical trial to date on the efficacy and safety of IVTA for DME was from the Diabetic Retinopathy Clinical Research Network. The study compared focal/grid laser photocoagulation (n=330) to 1-mg IVTA (n=256), and 4-mg IVTA (n=254). Although IVTA 4 mg showed a benefit over laser at 4 months, by year 1, no differences in visual acuity were seen between the three groups. At 16 months and 2 years, patients in the laser group had significantly better visual acuity that the 1-mg IVTA group (P=.02) and the 4-mg IVTA group (P=.002).33 The 3-year results were similar and supported laser as the best treatment option of those specific protocols tested for patients with DME similar to those recruited in the study.34Whether other protocols could show a benefit to intravitreal steroids in DME or other types of eyes respond better remains to be investigated in a large-scale fashion.35-38
The use of intravitreal steroids for macular edema due to
retinal venous occlusive disease was first described in a series
of case reports by Ip and Greenberg.39 Recently, steroids have
been in the spotlight for central retinal vein occlusion (CRVO)
and branch retinal vein occlusion (BRVO) because of the
report of results of two groups of clinical trials.
The 6-month results of identical multicenter, doublemasked, randomized, parallel phase 3 trials comparing the sustained-delivery intravitreal 0.7-mg dexamethasone implant (n=427) to sham (n=426) demonstrated a significant benefit with the dexamethasone implant (P<.001) for patients with CRVO and BRVO.40 The FDA gave approval to the dexamethasone implant (Ozurdex, Allergan, Inc.) for CRVO and BRVO earlier this year.
The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study group also recently released their results on steroids vs laser for CRVO and steroids vs laser for BRVO. SCORE-BRVO enrolled 411 patients and randomized them to treatment with laser, 1-mg IVTA, and 4-mg IVTA.41 No significant difference was seen in the 12-month visual acuity outcomes between the three groups. The rate of adverse events (IOP increase and cataract) was similar between the 1-mg IVTA and laser groups and highest in the 4-mg IVTA groups. The conclusion was that laser should remain the standard of care for patients with BRVO. SCORE-CRVO enrolled 271 patients and randomized them to either observation, treatment with 1-mg IVTA, or treatment with 4-mg IVTA.42 The patients treated with both 1-mg and 4-mg IVTA achieved an equally significantly better visual outcome than patients in the observation group (P=.001). The rate of complications was higher in the 4-mg group than in the 1-mg group. The authors concluded that 1-mg IVTA should be considered for patients with CRVO.
SUMMARY
Intravitreal injection of pharmacological agents was a radical
concept when first introduced by Blumenkranz et al.43
Unique drug delivery issues in the posterior segment and the
increasingly available and effective therapies for posterior segment
disease processes have resulted in intravitreal administration
becoming a routine line of therapy. Steroids are a class
of drug that has been available for many years, and used via
different routes for a variety of ocular conditions. As evidence
of the inflammatory pathobiology underlying many prevalent
retinal disorders continues to emerge, further support for the
potential of steroids to impact on these disease processes has
evolved. Careful prospective evaluation of these pharmacological
options as monotherapy or in combination with other
drugs and procedures holds significant promise for an expanding
population of patients with blinding eye disorders.
Julia A. Haller, MD, is Professor and Chair of Ophthalmology at Thomas Jefferson University and Thomas Jefferson University Hospital. She is also Ophthalmologist in Chief at Wills Eye Institute. Dr. Haller can be reached at +1 215 928 3000.
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