Article Date: 1/1/2007

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Laser and Pharmacologic Therapies in the Treatment of Diabetic Macular Edema

VICTOR H. GONZALEZ, MD

INTRODUCTION
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.

PATHOPHYSIOLOGY OF DR/DME

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

DIAGNOSIS

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 DME^25-27; 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

TREATMENT

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

One 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 Approaches

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 corticosteroid.

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.

Several 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
vascular permeability, some 50 000 times greater than
histamine⁸⁰; mechanisms 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 2).⁹²
 

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.

SELECTIVE AND NONSELECTIVE ANTAGONISTS OF VEGF

Pegaptanib sodium

Pegaptanib sodium, administered intravitreally, has shown clinical efficacy against all angiographic subtypes of drs 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
�75 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
652 injections were administered.

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
8 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

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 administered
3 injections of either 0.3 mg or 0.5 mg ranibizumab over
2 months. 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.

Bevacizumab

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
neovascularization.^107,108

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

Several 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 treatment.¹¹⁶

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-
istaurin 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
K 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
306 patients 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 currently underway.¹²⁹

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 vascular damage.

The 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 of
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 5 of
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.

CONCLUSIONS

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 maculadoc@aol.com. Dr. Gonzalez is a consultant for Pfizer, Inc, and has received a research grant from the company.

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