Laser and Pharmacologic
in the Treatment of Diabetic
H. GONZALEZ, MD
Diabetic retinopathy is
a major cause of blindness in Europe and North America,1 affecting persons
in all phases of their working lives.2 Diabetic retinopathy (DR) has
several levels of severity, ranging from a mild nonproliferative form characterized
by the existence of microaneurysms, through more serious manifestations characterized
by vascular abnormalities of increasing prominence.3 At any stage of
DR, patients may also develop diabetic macular edema (DME), resulting from breakdown
of the blood retinal barrier (BRB).3 The formal definition of DME established
by the Early Treatment Diabetic Retinopathy Study (ETDRS)4 is thickening
of the retina and/or the presence of hard exudates within 1 disc diameter of the
center of the macula. This definition is further classified as clinically significant
if at least
1 of the following conditions are met: retinal thickening within
500 μm of the center of the macula; hard exudates within 500 μm of the
center of the macula if there is thickening of the adjacent retina; or a zone of
retinal thickening 1 disc area in size providing some part is within 1 disc diameter
of the center of the macula (Figure 1). Recently, a severity scale for DME has been
proposed to facilitate patient screening. It includes two principal DME levels,
absent and present, based on whether there is thickening or hard exudates in the
posterior pole. Where present, DME is defined as mild, moderate, or severe, corresponding
to whether these sequelae are distant, near, or involving the center of the macula.5
The risk of developing DME is substantial
in individuals with diabetes mellitus. In a 10-year study, risk was found to be
20.1% in patients with type 1 diabetes, 25.4% in insulin-dependent type 2 disease,
and 13.9% in type 2 patients not requiring insulin.6 In DME, leakage
from hyperpermeable capillaries and microaneurysms are major contributors to vision
loss.7 This review will discuss current practices in DME management,
with a particular focus on novel approaches that have been developed as a result
of deeper understanding of the underlying pathophysiology of this disease.
The pathophysiology of DR/DME is
complex, involving changes in both the retinal vasculature and in retinal neurons.
While abnormal neuronal function, as observed in the electroretinogram, is common8
and can be detected even before the onset of microvascular lesions,9-11
the focus of current treatment strategies is on the edema and neovascularization
that accompany DR. DME-related disturbances of vision reflect the formation of leaky
vessels, while closure of existing vasculature, followed by proliferative neovascularization
and associated complications, further exacerbates the visual deficits. The initial
changes in the retinal vasculature include the degeneration and loss of the pericytes
enveloping the retinal capillaries, together with thickening of the capillary basement
membrane, adherence by leukocytes to the endothelium, and capillary blockage. These
blockages, in turn, promote the loss of endothelial cells and the formation of acellular
vessels.12,13 The resultant nonperfusion and local hypoxia lead to increased
local expression of promoters of angiogenesis14 such as vascular endothelial
growth factor (VEGF), one of the principal molecular targets of new therapies for
DME discussed in the following sections.
Several molecular mechanisms have
been posited as candidates for mediating the link between hyperglycemia and vascular
damage, including the accumulation of polyols, the formation of advanced glycation
end products, the overall increase in oxidative stress with concomitant generation
of free radicals, and the pathological activation of protein kinase C (PKC) (for
reviews see Caldwell et al12; Sheetz and King15; and Fong
et al16). It should also be noted that both reactive oxygen intermediates17
and advanced glycation end products18 act to induce the elevated expression
of VEGF, another therapeutic target.
Finally, it should be noted that
the vascular damage that accompanies diabetes bears many of the hallmarks of an
inflammatory process.10 McLeod et al19 reported that intercellular
adhesion molecule-1 (ICAM-1), which promotes leukocyte adhesion, was significantly
elevated throughout the choroidal vasculature and in retinal blood vessels in diabetic
patients. Moreover, diabetic patients showed increases in the numbers of neutrophils
in the retina and choroid, suggesting that this increased neutrophil adhesion via
ICAM-1 may contribute to the capillary blockage. In addition, vitreous levels of
ICAM-1 are elevated in DME, while patients with DR also have elevated plasma levels
of tumor necrosis factor-a (TNF-a), a key inflammatory cytokine.20
Medical history and fundus examination
are the bases for diagnosis of DR. The standard method for assessing the severity
of DR/DME was defined by the ETDRS and involves stereoscopic fundus photography
of 7 standard fields through dilated pupils.21 Owing to its complexity,
however, it is not employed routinely in the clinic. While ophthalmoscopy is the
common clinical tool, its use by nonophthalmologists has relatively poor sensitivity
compared with the ETDRS standard.22 One approach to simplifying the screening
process is through the use of nonmydriatic retinal imaging platforms such as the
Joslin Vision Network system (Boston), with electronic transmission to a central
reading center for evaluation; this technique has shown a close match to determinations
made by dilated retinal examinations in assessing the level of DR and DME.23
Fluorescein angiography, while able to detect early indications of DME through fluorescein
leakage from capillaries, is primarily used to confirm clinical diagnosis, to stage
retinopathy, and to plan treatment, rather than simply for screening, owing to its
inherent invasiveness and expense.3 In addition, capillary leakage does
not necessarily signal DME. Optical coherence tomography (OCT) is increasingly being
employed to assess retinal thickness as a surrogate marker for efficacy in treating
DME.24 Several groups have reported that OCT measurements of retinal
thickness show significant correlations with visual acuity (VA) in patients with
DME25-27; however, other studies have reported contradictory findings.28,29
Thus, the applicability of OCT in the management of patients with DME is still questionable.
Finally, another noninvasive approach, the Heidelberg Retinal Tomograph, based on
confocal laser imaging, has also shown promise as an assay system for macular edema.30
Laser Ablation of Affected Areas
Current treatment approaches for
DME are derived from the ETDRS; in patients with DME and mild to moderate nonproliferative
DR, focal laser photocoagulation decreased the probability of a 15-letter loss in
VA from 8% to 5% at 1 year and from 24% to 12% at 3 years.4 Benefit was
restricted to patients whose DME was defined as clinically significant. While visual
prognosis was worse for eyes with decreased VA at baseline, eyes with 20/40 VA were
more likely to show an improvement of �6 letters in VA. Because the treatment is
inherently destructive, it may entail side effects such as paracentral scotomas,
alterations in color perception, choroidal neovascularization, metaplasia of the
retinal pigment epithelium (RPE), and inadvertent burns to the center of the macula.7,12
Laser scars may also expand significantly after treatment,31 an issue
of particular concern for burns close to the macula. Macular grid photocoagulation
technique could theoretically reduce the risk of such complications by sparing the
fovea region. However, a recent study presented at the American Academy of Ophthalmology
(AAO) Subspecialty Day 2006 compared the modified ETDRS focal laser photocoagulation
(m-ETDRS) with a mild macular grid (MMG) technique and suggested that m-ETDRS should
continue to be the standard treatment for DME. A total of 323 study eyes with DME
were randomized 1:1 to these 2 treatment options, and after a 1-year follow-up,
there was a trend favoring
m-ETDRS group in both VA and anatomical (OCT) results.32
approach to minimizing the retinal destruction is through the use of a micropulsed
laser in which short bursts of laser are applied rather than a continuous burn.
Friberg and Karatza,33 treating patients with macular edema secondary
to branch vein occlusion or DR, reported that 26 of 34 (76%) newly treated patients
and 10 of 15 (67%) previously treated patients experienced clinical improvement
at 6 months. Similarly, Moorman and Hamilton34 reported that panretinal
and grid pattern photocoagulation performed using the micropulse mode with the laser
on for 100 to 300 μs and off for a cycle of 1700 to 1900 μs resulted in
the resolution of macular edema at 6 months in 22 of 39 eyes (56%). Although laser
therapy is the only proven treatment, it does not address the underlying pathogenic
mechanism of the disease. In addition, some patients with DME may qualify for laser
therapy as defined by ETDRS guidelines because of the diffuse nature of their edema
but have poor outcomes.4,35 Pharmacological therapies provide us with
an opportunity to treat this important group of patients.
Pharmacological treatments for
DME are premised on interference with the molecular processes that lead to the development
of diabetic vascular damage, not only to reverse it after it has developed, but
also, in the ideal case, to prevent its occurrence. These initiatives have led to
several new therapies that have shown promise in clinical trials or case series,
including drugs targeting VEGF, PKC, and TNF-a, as well as the use of an anti-inflammatory
Inhibition of VEGF
VEGF is the most potent of the
known factors promoting both physiological and pathological angiogenesis (for a
review, see Ferrara36). Splicing of the human VEGF gene leads to 6 principal
isoforms containing 121, 145, 165, 183, 189, and 206 amino acids;36,37
the corresponding rodent isoforms are 1 amino acid shorter. VEGF165,
the most extensively studied isoform, exists both in a soluble form as well as bound
to the extracellular matrix; in contrast, VEGF121 lacks the heparin-binding
domain and is not matrix-bound, while isoforms larger than VEGF165 are
highly basic and exist primarily in association with the matrix.36 VEGF
is a ligand for 2 receptor tyrosine kinases, VEGFR-1 and VEGFR-2, that act through
downstream signaling cascades.38 VEGF acts through many mechanisms in
promoting angiogenesis (Table 1).39-49 A concerted research effort over
the last decade has established that VEGF is both necessary and sufficient for the
neovascularization that is characteristic of ocular diseases such as age-related
macular degeneration (AMD) and DR (for a review, see Ng and Adamis50).
For example, intravitreal injection of VEGF into eyes of nondiabetic monkeys leads
to the development of many of the changes typically seen in diabetes, including
the development of microaneurysms and tortuous, leaky vessels.51,52
It should be noted, however, that
VEGF acts in a wide variety of physiological processes, some related to its importance
for angiogenesis and others not; these latter include bone growth,53,54
female reproductive cycling,53,55 kidney development and tissue maintenance,56,57
wound healing,58,59 skeletal muscle regeneration,60 maintenance
of the health of hepatic cells,61 vasorelaxation,62 and survival
of a wide variety of neuronal cell types,63,64 including retinal neurons.65
VEGF plays an ongoing role in trophic maintenance of capillaries in a variety of
organs66; in the eye it is essential for the development of the choriocapillaris,67
a tissue that receives continuing trophic support through VEGF secretion by the
RPE.68 Thus, therapeutic strategies based on the inactivation of VEGF
must take heed of potential adverse events. For example, intravenous administration
of bevacizumab (Avastin, Genentech), an antibody that inactivates all VEGF isoforms
indicated for the treatment of colorectal cancer, has been accompanied by increased
incidences of hypertension, bleeding, gastrointestinal perforations, and thromboembolic
events.69-72 For ocular diseases, these concerns are reduced in some
measure when intravitreally administered,73 but even here caution may
be warranted since there is continuity between the vitreous and plasma compartments,
especially in the context of diabetes, where the BRB is compromised (for a discussion,
see van Wijngaarden et al74). While these are theoretical concerns, no
clear evidence has been generated in the clinical trials using selective vs nonselective
VEGF-blocking strategies. Continued surveillance will help address these questions.
properties of VEGF are of importance for the particular pathophysiology of DME.
First, the expression of VEGF is upregulated by hypoxia,75,76 which,
in turn, is a local consequence of capillary dropout. In the retina, VEGF is expressed
by many cell types, including pericytes, endothelial cells, glial cells, neurons,
and the RPE,68, 77,78 and upregulation of VEGF by hypoxia is common to
all.68,77,79 Second, VEGF is the most potent known promoter of
permeability, some 50 000 times greater than
underlying this enhanced permeability include the induction of fenestrations in
the endothelial cell membrane,81 disruption of tight junctions through
phosphorylation of their constituent proteins,82 and the development
of caveolae, which may result in the formation of transendothelial pores83
(for reviews, see Olsson et al38 and Weis and Cheresh84).
There is also good evidence that
VEGF plays a key role in mediating the inflammatory changes that are characteristic
of DR/DME. In an early study, VEGF was found to be elevated in the vitreous of patients
with DR.85 These elevations were also accompanied by increases in ICAM-1
levels.86 Furthermore, investigations into the the development of BRB
breakdown in a rodent model of diabetes provided strong evidence that retinal vascular
damage is mediated by increases in VEGF. This induces upregulation of ICAM-1, leading
to retinal leukostasis and endothelial cell damage through Fas-FasL-mediated apoptosis.87-91
Detailed studies of the involvement
of VEGF indicate that one isoform, VEGF165 (or the rodent counterpart
164), may play an especially important role in both diabetes-induced retinal damage,
as well as in the hypoxia-related neovascularization that can be a manifestation
of DR. Compared to VEGF120, intravitreal injection of VEGF164
in nondiabetic rats led to approximately twice the level of ICAM-1 upregulation,
retinal leukostasis, and BRB breakdown. In addition, intravitreal injection of pegaptanib
sodium (Macugen, [OSI] Eyetech/Pfizer), a polyethylene-glycolated RNA aptamer that
binds to VEGF164 but not to VEGF120, was able to reverse these
effects in diabetic animals, leading to significant restoration of the BRB (Figure
In a mouse model of retinopathy of prematurity, pathological ischemic
neovascularization was accompanied by a dramatic increase in the upregulation of
VEGF164 compared to VEGF120, and intravitreal injection of
pegaptanib inhibited this pathological neovascularization while sparing normal physiological
retinal neovascularization.93 In contrast, injection of a VEGFR-Fc fusion
protein that inactivates all VEGF isoforms inhibited both physiological and pathological
neovascularization (Figure 3).93 Additional studies determined that VEGF164
was dispensable in protecting retinal neurons against cell death under conditions
of ischemia.65 Together with its actions in reversing BRB breakdown,
this selectivity for pathological neovascularization suggested that intravitreal
pegaptanib might provide a safe treatment for reducing the excess permeability of
DME, as well as the neovascularization that can be a feature of DR.
AND NONSELECTIVE ANTAGONISTS OF VEGF
Pegaptanib sodium, administered
intravitreally, has shown clinical efficacy against all angiographic subtypes of
and �15 letters of VA (34% vs 10%, P=.003, and 18% vs 7%, P=.12, respectively).
Moreover, proportions of patients with absolute decreases in retinal thickness of
μm and �100 μm also favored 0.3 mg pegaptanib over sham (49% vs 19%, P=.008,
and 42% vs 16%, P=.02, respectively).98 Pegaptanib was well tolerated
at all doses. One case of endophthalmitis was reported; a total of
In a post hoc analysis of a subset
of 16 patients with documented retinal neovascularization at study entry, 8 of the
13 (62%) receiving pegaptanib showed evidence of regression on fundus photographs
at 36 weeks. In contrast, none oflkawbhklfbalskdbfajksbdvklubam,snbvbasm,dnbvklajbwembfm,ZBx,bvm,bzS The experimental design included an intravitreal
injection of 0.3 mg pegaptanib every 6 weeks for 30 weeks (for a total of 6 injections),
with results compared to patients (or fellow eyes) receiving panretinal photocoagulation.
Of 10 eyes receiving pegaptanib, 9 showed total regression after 3 weeks with the
remaining eye showing partial regression; regression at 6 weeks was 89%. Of
eyes receiving photocoagulation, 7 remained active at
6 weeks. Mean changes in
VA at 6 weeks were a gain of
4.9 and of 6.5 letters in the pegaptanib and photocoagulation
groups, respectively, while only the pegaptanib-treated group experienced a reduction
in foveal thickness.
Ranibizumab (Lucentis, Genentech)
is a fragment antigen binding (Fab) fragment, which, like bevacizumab, reactsrthrthrthrthrthrth with
all VEGF isoforms (for a review, see Ferrara et M101). Ranibizumab has
shown efficacy in phase 3 trials as an intravitreal treatment for AMD.102,103
More recently, it has been examined as a treatment for DME in open-label pilot-scale
studies, r4porting the outcomes of 10 patients. Nguyen et al104 administered
5 injections of 0.5 mg ranibizumab over 6 months and reported significant improvements
in mean VA (20/80 to 20/40) and reductions in macular volume and retinal thickness;
no ocular or systemic events were observed. In the second study, Chun et al105
3 injections of either 0.3 mg or 0.5 mg ranibizumab over
At 3 months, 4 patients had gained �15 letters, gained �10 letters,
while the mean retinal thickness decrease was 45.3 ±196.3 μm for the 0.3-mg
group, and 197.8 ±85.9 μm for the 0.5-mg group. While there were no systemic
adverse events, 5 cases of mild to moderate ocular inflammation were reported.
There is considerable interest
in the use of bevacizumab as an intravitreally administered agent, especially as
it may bring considerable cost advantages if efficacy and safety can be demonstrated.
Although no studies evaluating bevacizumab in the management of DME have been published
to date, data were recently presented at the 2006 AAO meeting. A multicountry retrospective
review of the outcomes of 82 eyes following a 1.25 mg dose of bevacizumab found
a significant improvement in mean BCVA and central macular thickness on OCT (P=.0001
for each outcome) at an average of 12.7 ±4.9 weeks.106 No ocular
or systemic adverse events were observed. With respect to DR, there have been several
small studies showing success in achieving regression of DR-induced ocular
Avery et al109 have
reported on the use of intravitreal bevacizumab in treating 45 eyes of 32 patients
with retinal and/or iris revascularization. Intravitreal doses ranging from 6.2
μg to 1.25 mg were given. All patients (44/44 eyes) had complete or partial
reduction in leakage, as assessed by fluorescein angiography, within 1 week of injection.
Leakage of iris neovascularization completely resolved in 9 of
11 eyes (82%),
while complete resolution of leakage of neovascularization of the disc was achieved
in 19 of 26 eyes (73%). In 2 cases, both involving doses of 1.25 mg, there was also
a subtle decrease in neovascularization of the uninjected fellow eye, suggesting
that significant systemic levels were achieved at this dose. This observation led
to the use of the smaller doses, with therapeutic effects seen with as low a dose
as 6.2 μg in the study eye. Recurrence of leakage was seen as early as 2 weeks
postinjection, whereas in some cases none was observed throughout the 11 weeks of
follow-up. The authors suggest that while the relatively rapid recurrence may ultimately
prove limiting, this issue requires more detailed study and that in any event intravitreal
bevacizumab may provide a useful adjunctive therapy together with panretinal photocoagulation
and surgical approaches.
Inhibition of PKC-b
Protein kinase Cs are a family
of enzymes, some of which have been found to be activated in diabetes owing to elevated
levels of diacyl glycerol, advanced glycation end products, and reactive oxygen
intermediates (for a review, see Sheetz and King15), as well as VEGF.110
PKC-b2 activation has in turn been linked to mechanisms mediating leukostasis and
vascular damage. Ruboxistaurin is an orally administered inhibitor specific for
PKC-b2 in rats; both orally and intravitreally administered ruboxistaurin significantly
inhibited increased retinal permeability induced by intravitreally administered
VEGF.111 In rats with streptozotocin-induced diabetes mellitus, ruboxistaurin
administered intravitreally restored the retinal circulatory parameters to values
approximating those of nondiabetic animals,112 while intravitreal injection
of another PKC inhibitor, GF109203X, was shown to reverse BRB breakdown, resulting
in retinal permeability essentially identical to that of control animals.113
recent clinical trials examining the use of ruboxistaurin have now reported varying
results in treating diabetes-related retinal complications. In a multicenter, double-masked,
randomized, placebo-controlled study involving 252 patients with moderately severe
to very severe nonproliferative DR, orally administered daily doses ranging from
8 mg to 32 mg or placebo were given for up to 46 months. While the drug was well
tolerated, it did not prevent the progression of DR, although the 32-mg dose did
provide a significant benefit in reducing the risk of moderate vision loss and also
reduced the risk of sustained moderate vision loss from 25% to 10% in eyes with
significant macular edema at baseline.114 Qualitatively similar results
were seen in an 18-month trial involving 41 patients with macular edema.115
In a 4-week study examining retinal blood flow parameters, diabetes-associated impacts
on retinal blood flow and retinal circulation time were ameliorated by ruboxistaurin
In a 3-year, randomized, double-masked,
placebo-controlled trial involving 686 patients to assess the impact of ruboxistaurin
treatment (32 mg/day) on visual loss associated with moderately severe to very severe
nonproliferative DR, the drug reduced the incidence of sustained moderate visual
loss from 9.1% in the placebo group to 5.5% in the ruboxistaurin group (P=.034).117
For patients with baseline clinically significant macular edema >100 μm
from the center of the macula, ruboxistaurin significantly reduced the probability
of progression to within the 100-μm zone
(68% vs 50%; P=.003); in
addition, initial laser treatment for DME was reduced from 37.9% in the control
group to 28.0% in those receiving the drug (P=.008).117 Rubox-
was well tolerated with no evidence of increased incidence of adverse events linked
to the drug. It should be noted, however, that despite these encouraging results,
the Food and Drug Administration has recently requested that a new phase 3 trial
be performed before ruboxistaurin can be approved as a treatment for DR.118,119
Modulators of inflammation
Triamcinolone acetonide. The inflammatory nature of the retinal vascular
pathology and neovascularization in DR/DME suggests that standard anti-inflammatory
agents such as corticosteroids could be of use as therapies. The most commonly employed
is the synthetic corticosteroid triamcinolone acetonide. In preclinical studies
triamcinolone inhibited cytokine-induced upregulation of ICAM-1 by endothelial cells120
and reduced hypoxia-induced upregulation of VEGF by cultured RPE cells.121
In other studies, triamcinolone inhibited preretinal and optic nerve head neovascularization
following experimentally induced retinal vein occlusion in pigs.122
Off-label triamcinolone has been
used investigationally for a variety of ocular diseases, including DME and AMD (for
a review, see Jonas123). Principal adverse events include ocular hypertension
in approximately 40% of eyes, medically uncontrollable ocular hypertension in 1%
to 2% of eyes, and development of cataracts (predominantly subcapsular) in approximately
15% to 20% of patients.123 The high risk of adverse events may preclude
the use of triamcinolone as monotherapy for conditions requiring long-term therapy.124
Recently, the results of prospective,
placebo-controlled, randomized studies were reported using triamcinolone for treating
DME. Jonas et al125 randomized 28 eyes to receive a single intravitreal
injection of 20 mg triamcinolone while
12 eyes received placebo injections. At
6 months, VA was increased significantly in the triamcinolone group vs the control
group, with 11 of 23 (48%) of the triamcinolone-treated group having at least a
2-line improvement compared to none of the controls. In a 2-year, double-masked
study involving eyes with DME that persisted or recurred following laser treatment,
69 eyes of 43 patients were randomized to receive 4 mg intravitreal triamcinolone
or placebo (subconjunctival saline).126 Eyes with a loss of at least
5 letters in VA from the previous visit and persistent central macular thickness
exceeding 250 μm were retreated with triamcinolone, with a minimum of 6 months
required between repeat treatments. At 2 years, VA improvement of �5 letters was
seen in 19 of 34 (56%) eyes receiving triamcinolone compared with 9 of 35 (26%)
control eyes (P=.006); the authors suggested that improvement among controls
may have reflected intensified efforts by patients in the trial to control their
hyperglycemic risk factors. Glaucoma medication was required in 15 of 34 (44%) treated
eyes compared to 1 of 30 (3%) of controls (P=.0002) with 2 of the treated
eyes requiring trabeculectomy; cataract surgery was performed in 15 of 28 (54%)
vs none of 21 control eyes.
Finally, it should be noted that
implantable devices are being developed to permit long-term release of steroids
in the vitreous while obviating the need for repeated injections. These include
an intravitreal implant for the delivery of fluocinolone for treatment of noninfectious
uveitis in the posterior segment and indications such as DME,127 as well
as a biodegradable implant for the intravitreal delivery of dexamethasone to treat
various ocular ischemic diseases.128 Although the long-acting fluocinolone
implant showed promising results in improving visual acuity and decreasing retinal
thickness in patients with DME at both 1 and 2 years after initiating therapy, nearly
all phakic eyes develop cataracts within 2 years of use and over 30% of patients
require a surgical procedure to control intraocular pressure (IOP). Fluocinolone
acetonide implant is currently approved for patients with uveitis only. A biodegradable,
implantable extended-release product that delivers dexamethasone directly to the
posterior segment has been evaluated in a phase 2 clinical trial in
with DME. Patients administered 700 μg had a significant improvement in VA
of �2 or more lines on the ETDRS chart when compared with patients who did not receive
the implant (P=0.02). IOP increased to
�25 mm Hg at some point in 32 eyes
but was controlled with topical antihypotensive medications. Phase 3 trials are
K Infliximab. Infliximab
is a chimeric monoclonal antibody against TNF-a, a major inflammatory cytokine (for
a review, see Siddiqui and Scott130) that is elevated in the plasma of
diabetic patients relative to controls.20 Studies in a rat model of diabetes
showed that inactivation of TNF-a by a soluble TNF-a-receptor/Fc protein could reduce
leukocyte adhesion and BRB breakdown.90 The effects of TNF-a in potentiating
leukocyte adhesion to retinal endothelial cells appear to be mediated in part by
PKC-b2-dependent phosphorylation of the glycosylating enzyme core 2 b 1,6-N-acetylglucosaminyltransferase.131
In addition, TNF-a can upregulate endothelial cell expression of VEGF132
and ICAM-1,110 providing yet another pathway for inducing leukocyte-mediated
clinical evidence for efficacy of infliximab treatment is slim, based on only 1
case report using intravenous infusion of infliximab at monthly intervals at a dose
5 mg/kg in 7 eyes of 4 patients with DME, 6 of which were refractory to laser
photocoagulation. Within 1 month of treatment, macular thickness had decreased in
7 eyes with DME, with further reductions in macular thickness and improvements
in VA reported at 2 months.133 Very similar positive results have been
reported by this same group of investigators in treating AMD with intravenous infliximab.134
These preliminary findings suggest that TNF-a inhibition may be beneficial in treating
ocular neovascular diseases. While the only clinical experience to date has involved
systemic administration of infliximab, the advantages of lower overall doses and
ready tissue access suggest that intravitreal injection of this agent, either alone
or in combination with therapies such as pegaptanib, might be a useful strategy
in treating DR/DME.
The recommendations of the ETDRS
constituted a major advance in the treatment of DR and DME. These treatment options
have now been extended by the research effort of the last decade into the pathophysiology
of the disease. It should be noted that the ETDRS macular laser studies required
3 years to observe a clear benefit from the laser therapy, whereas the pharmacological
approach appears to yield results within weeks after administration. The pathogenesis
of DR involves many pathways, but the data appear to suggest that, in some cases,
the macular edema is dependent on high VEGF levels.98 This may explain
why some patients demonstrate a marked improvement of their edema with anti-VEGF
therapy. Pharmacologic therapies may allow us to reduce our need for macular laser
in select patients and perhaps employ more selective peripheral retinal ablation,
instead of the nonselective approach we currently utilize with combination therapy.
Current ongoing trials and those in development are needed to further define the
best treatment protocols for this complicated group of patients. As with AMD, it
appears that pharmacologic therapies for the management of DR/DME will cause a paradigm
shift in how we care for these patients. RP
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Victor Gonzalez, MD, is the principal
of the Valley Retina Institute in McAllen, Texas. He can be reached at email@example.com.
Dr. Gonzalez is a consultant for Pfizer, Inc, and has received a research grant
from the company.
Retinal Physician, Issue: January 2007