This article discusses the off-label use of triamcinolone acetonide.
Steroids have both anti-inflammatory and anti-angiogenic properties; because of these properties, they are increasingly becoming a popular therapeutic option in retinal practice. Intravitreal steroids can be used in the treatment of various retinal conditions including diabetic and vasculo-occlusive macular edema, exudative macular degeneration, pseudophakic cystoid macular edema, and posterior uveitis.1 Although there are well known serious potential complications with intravitreal steroids, including glaucoma and cataracts, recent studies have shown that intravitreal steroids may be used as a safe alternative to the standard practice of laser therapy for the treatment of macular edema secondary to diabetes or vein occlusions.2,3 Although there are several steroid formulations that may be used, this article focuses on the use of intravitreal dexamethasone and triamcinolone acetonide in the clinic setting.
CRITERIA FOR USING STEROIDS
The decision of whether to use intravitreal dexamethasone
or triamcinolone acetonide depends on the
patient's clinical diagnosis and the goals of treatment. It
should be noted that the US Food and Drug
Administration (FDA) has approved the use of intraocular
steroids only for a select number of conditions.1
Intravitreal preservative-free triamcinolone acetonide
(Triescence, Alcon Laboratories, Inc.) is approved for
treatment of sympathetic ophthalmia, temporal arteritis,
non-infectious ocular inflammatory conditions, and for
visualization of the vitreous during a vitrectomy. The
intravitreal dexamethasone implant (Ozurdex, Allergan,
Inc.) is FDA-approved for the treatment of macular
edema associated with central and branch retinal vein
occlusions (CRVO, BRVO). Although intravitreal steroids
are used in clinical practice to treat a wider range of ocular
diseases, such as dexamethasone (dexamethasone
sodium phosphate, American Regent, Inc.) and preserved
triamcinolone acetonide (Kenalog-40, Bristol-Myers
Squibb, Inc.), these uses are considered “off label.”
MECHANISM OF ACTION
Intraocular steroids (triamcinolone acetonide and dexamethasone)
have been used to treat the sequela of retinal disease involving inflammation, macular edema, and
angiogenesis.4,5 These two steroids have been the mainstay
of most clinic-based therapies and although they differ
in structure and potency (Table 1), they are selected
primarily based on their duration of action. Although
these glucocorticoids mediate their effects through modulation
of inflammatory cytokines and their anti-VEGF
effect to achieve a clinical outcome, they also affect both
common and unique gene expression pathways involving
oxidative stress and neuroprotection, which are also
important pathways affecting retinal disease (Table 2).
This is mediated through complex interactions with the
glucocorticoid receptor in the cytoplasm, which is then
transported to the nucleus where gene expression pathways
are activated or repressed. Nongenomic effects of
steroids involving steroid activated signaling also occurs
that can have profound clinical effects.6
GENOMIC EFFECTS
We have reported that both intravitreal dexamethasone
and intravitreal triamcinolone alter approximately
5% of the retinal genes expressed7 at 1 week post injection
in mice using clinically relevant doses of dexamethasone
(0.1 mg/mL) and triamcinolone (1 mg/mL).
Although both steroids alter expression of common retinal
genes at 1 week and 1 month, unique genes specific
for each steroid are also up- or down-regulated affecting
the inflammatory, angiogenesis, apoptosis/neuroprotection
and oxidative stress pathways shown in Table 3.
Surprisingly, the gene expression pathways are affected long after the steroid has been metabolized in the eye suggesting a cascade-like effect with secondary signaling or perhaps resetting the homeostasis balance point in the tissue. Dexamethasone and triamcinolone acetonide affect unique sets of genes within the same pathways and appear to affect different pathways at different times and in different ways. In some cases, opposite effects are observed.7,8 This suggests that steroids in the future may be selected for the specific effect they may elicit.
TISSUE-SPECIFIC EFFECTS
Figure 1A shows differential gene expression between
the retinal tissue and RPE/choroid tissue. Figures 1B and
C are comparisons of genes that have changed by at least
twofold in response to either dexamethasone and triamcinolone
acetonide in the retina (B) and RPE/choroid (C).
Analysis of the different tissue effects reveals that different
sets of genes are altered between the retina and retinal
pigment epithelium (RPE)/choroid. Furthermore,
fewer genes are altered in the RPE/choroid compared to
the retina; this effect is accentuated further with time,8
which may be due to the differences in cellular complexity
of the retina vs the RPE. Alternatively, the RPE/choroid
may metabolize the steroids more rapidly, in addition to
the tissue differences in gene responsiveness. Accordingly,
one must consider carefully the goal of the therapeutic
intervention.
CLINICAL EXAMPLES
Dexamethasone. Dexamethasone is a potent antiinflammatory
agent that inhibits multiple inflammatory
cytokines. Dexamethasone has a relatively short half-life
(3.5 hours), but is five times more potent than intravitreal
triamcinolone. Intravitreal dexamethasone comes
in a 4 mg/mL solution, and most retinal physicians inject 0.4 mg in the intravitreal space.
The intravitreal dexamethasone
implant is an innovative biodegradable
implant that contains 0.7 mg of dexamethasone
and allows for sustained
and extended release of corticosteroids
in the intravitreal cavity.
Intravitreal dexamethasone is predominantly used in clinical practice as a part of adjuvant therapy to treat either exudative age-related macular degeneration (AMD) or macular edema secondary to retinal vein occlusion (RVO). Exudative AMD is a multifactorial condition that involves neovascularization, vascular leakage, and inflammation. A triple therapy approach to wet AMD that addresses these pathologies can be employed when more traditional methods (ie, repeated antivascular endothelial growth factor [anti-VEGF] agents) have failed. Triple therapy consists of reduced-fluence photodynamic therapy (PDT), bevacizumab (Avastin, Genentech, Inc.), and dexamethasone. The range of dexamethasone dose used ranges from 200 µg to 800 µg per injection. Several recent studies9-11 have shown that triple therapy may reduce the total number of injections needed in some patients and stabilize vision in those patients who do not respond to single therapy with anti-VEGF agents.
The intravitreal dexamethasone implant is the most developed biodegradable device used in retinal practice and is approved as first-line therapy for the treatment of macular edema secondary to RVO.12 The intravitreal dexamethasone implant allows a longer duration of pharmacological effect with lower administration frequency compared to other intravitreal steroids.
In our practice we have found dramatic improvements in macular edema in patients with RVO. For example, we saw a 64-year-old male with a history of an RVO with significant macular edema with count finger vision that did not improve with five prior intravitreal anti-VEGF injections (Figure 2A). He received the dexamethasone implant, and 2 months later he experienced a significant decrease in macular edema and improvement in vision to 20/200 (Figure 2B).
Triamcinolone acetonide. Triamcinolone acetonide has a longer intravitreal half-life than dexamethasone— approximately 18 days in a surgically naïve eye. Kenalog- 40 is a common preparation available in 40 mg/mL preparations, and often used at a dosage of 4 mg per 0.1 mL. Triescence is similar to Kenalog-40, but preservative- free and FDA-approved for intraocular use in certain conditions.
Several major trials have recently supported the use of intravitreal triamcinolone acetonide for treatment of macular edema, although focal/grid macular laser is still considered the gold standard in many cases. The Diabetic Retinopathy Clinical Research Network showed that there were no significant differences in visual acuity in patients treated with either 1 mg of intravitreal triamcinolone, 4 mg of triamcinolone, or focal/grid laser for diabetic macular edema 1 year after treatment.2 Two years after treatment, however, visual acuity and macular thickness measurements were better in the focal/grid laser group. Further, 33% of patients who received 4 mg of intravitreal triamcinolone had an intraocular pressure that increased from baseline by 10 mm Hg, compared to 16% of patients in the 1 mg group, and 4% of patients in the focal/grid laser group. Over a 2-year period, focal/grid laser did have fewer side effects and better visual acuity outcomes than either dose of intravitreal steroid.
In our practice, we often combine intravitreal triamcinolone acetonide with focal/grid laser for the treatment of diabetic macular edema, with care to avoid injecting patients with a history of glaucoma or who are phakic. Intravitreal steroids often decrease macular edema allowing subsequent lower power density laser treatment with focal/grid laser several weeks after the injection. Intravitreal steroids have a longer lasting effect than the anti-VEGF agents and also treat the inflammatory component in patients who often have ischemic comorbidities. We recently treated a 62-yearold pseudophakic patient without a history of glaucoma with triamcinolone acetate for clinically significant macular edema (Figure 2C). Two months after the steroid injection, the clinically significant macular edema resolved, and there was a decrease in macular edema and exudates on OCT (Figure 2D). Vision improved from 20/40 to 20/30 in 2 months.
IMPLICATIONS FOR TREATMENT
OF RETINAL DISEASE
Table 4 (page 7) shows the spectrum of retinal disease
that affects retinal tissues and those that affect the
RPE/choroidal tissue. Already, clinical evidence is mounting
suggesting that the cytokine signaling produced by
CD4+ T helper (Th) cells may be an important determinant
of clinical pathology in a variety of diseases for
which steroids are being tested (Table 5). Type 1 helper
T cells (Th1) secrete IFNg, IL2, and TNFα, while Type 2
helper T (Th2) cells produce IL4, IL-6, and IL-10.
The disturbance of the balance of Th1/Th2 cytokine production is an underlying cause of neural damage in several neurologic diseases; restoration promotes neuroprotection. 13-16
The finding of differential gene expression and tissuespecific effects between dexamethasone and triamcinolone acetonide may have clinical implications for treatment of retinal disease. Although the side effects of currently used steroids are profound, the potent clinical effects cannot be ignored and may be more precisely directed once the pathogenic mechanisms of retinal disease is better understood. This information may allow the development of other generations of steroids that do no have the adverse effects and have more specific targeting. Additionally, biomarkers for determining who may be at risk for the adverse effects are being studied and may reduce these complications for future use.
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