by Funatsu et al. suggests that vitreous levels of ICAM-1 and VEGF correlate independently with increased vascular permeability and the severity of DME [46]. Previous reports have also implicated interleukin-6 (IL-6). IL-6 is a proinflammatory cytokine with multiple functions. It can be involved in the pathogenesis of uveitis [47], is associated with breakdown of the blood-retina barrier, and can lead to VEGF expression [48]. After analyzing aqueous humor samples obtained from 54 diabetic patients during cataract surgery, Funatsu et al. also reported that aqueous levels of VEGF and IL-6 correlate with the severity of DME [12]. In addition to VEGF, it is possible that the profile of other proteins within a patient’s vitreous at a given point in time may affect the severity of DME and the response to treatment. Analysis of biomarkers may have a role in the management of DME, especially as treatments with different mechanisms of action become established. Nevertheless, care should be taken when interpreting such studies as an elevated cytokine level does not necessarily prove that there is a role for it in the pathophysiology of DME. If the receptor for the cytokine is downregulated or if a soluble, inhibitory receptor is present, then the measured cytokine level may not have the expected effect [49].

Another potentially important consideration is the balance between VEGF angiogenic and antiangiogenic isoforms. Through differential splicing, an antiangiogenic VEGF- A isoform called VEGF165b can be produced. VEGF165b has a different C-terminal amino acid sequence from angiogenic forms of VEGF [50]. It inhibits angiogenesis by binding to, but not activating, VEGF receptor 2. While studying colonic carcinoma cells, Varey et al. found that bevacizumab inhibited the growth of cells predominantly expressing VEGF 165, while those cells predominantly expressing VEGF 165b were resistant to treatment with bevacizumab [51]. Perrin et al. have found that under normal conditions, the eye expresses VEGF165b and other potentially antiangiogenic isoforms of VEGF [52]. They have suggested that a shift in the balance of antiangiogenic and angiogenic isoforms of VEGF occurs in diabetic retinopathy. One would expect that patients with DME would predominantly have the angiogenic isoforms of VEGF but still might have some expression of VEGF165b. As discussed by Perrin et al., it is not known whether current anti-VEGF treatments also target VEGF165b, potentially limiting their own efficacy. Therefore, the levels of angiogenic vs. antiangiogenic VEGF isoforms could serve as biomarkers that would predict the response to anti-VEGF treatment.

COMBINATION TREATMENT FOR DME

While ranibizumab and triamcinolone have been compared to laser treatment, it is possible that combination laser treatment may be superior to any of these individual treatments. As discussed with the READ-2 trial [33], laser may be more effective and provide longer lasting benefit after an agent has been given to temporarily reduce the macular edema. When the combination of ranibizumab and laser was studied by the READ-2 trial at 6 months, the improvement in BCVA was not statistically different from the ranibizumab alone group or the laser alone group. However, as the follow-up period was short at the primary end point in the READ-2 study, it is worthwhile to further investigate combination treatments that attack DME with complimentary mechanisms. The DRCR has completed enrollment for a trial comparing combination treatments.

The mentioned DRCR protocol compares four groups: (A) sham injections plus laser,

(B) 0.5 mg of ranibizumab followed by laser, (C) 0.5 mg of ranibizumab followed by deferred laser, and (D) 4 mg of intravitreal triamcinolone followed by laser [53]. For groups A, B, and D, the laser treatment occurs 3–10 days after the injection. For group C, there is no laser during the first 24 weeks. After 24 weeks, patients within this group receive laser treatment if there has been no improvement from the last two injections and there is macular edema for which laser would be indicated. The primary outcome is the visual acuity after 1 year of follow-up. With this study design, the trial may provide a more definitive answer regarding the potential benefit of combination therapy for DME.

DME AND QUALITY OF LIFE

On a separate note from the details of VEGF mechanisms and the pathogenesis of DME, clinicians must continuously listen to the visual needs of each individual patient. Recommendations based on clinical trial data are based primarily on visual acuity outcomes. Visual acuity measurements are not necessarily always the most comprehensive means of quantifying how DME may affect a patient’s daily visual needs and emotional well-being. One must ask if intensive treatments are actually making an improvement on the patient’s visual needs and not just the patient’s visual acuity measurements. Such visual needs may include the patient’s ability to read, to pick an item off the shelf at a grocery store, to interact socially with others, and to perform well at work. It is not surprising that past reports have shown an association between diabetic retinopathy and psychosocial well-being [54–56]. The National Eye Institute 25-Item Visual Function Questionnaire (NEI-VFQ-25) is a questionnaire that can assess the impact that an eye disease can have on quality of life [57]. The NEI-VFQ-25 has been validated and used for different eye diseases [58–63]. Recently, Bressler et al. have shown that treatment of neovascular AMD patients with ranibizumab positively affects the NEI-VFQ-25 scores at 24 months [64]. Such data supports the use of ranibizumab for neovascular AMD patients and demonstrates how qualify-of-life measurements can be used within clinical trials. The NEI-VFQ-25 has utility as a measurement of central visual function in patients with diabetes [60, 63]. However, there is limited literature on how visual function is specifically affected by DME. With a group of 33 patients, Hariprasad has shown that patients with DME can have NEI-VFQ-25 scores similar to patients with AMD [65]. Lamoureux has used the vision-specific functioning scale (VF-11) to show that patients with proliferative diabetic retinopathy (PDR) and vision-threatening diabetic retinopathy (VTDR) have difficulty with vision-specific daily activities [66]. In this study, VTDR was defined as severe nonproliferative retinopathy, PDR, or macular edema within 500 mm of the foveal center, or focal laser scars at the macula. Of the 357 study participants, only 5% had macular edema, and this was determined by photographs and not by clinical exam. There is a need for further studies demonstrating the relationship between DME and vision-related quality of life. As future clinical trials are developed for DME, it will be important to determine if new treatments positively affect a patient’s quality of life. Lastly, considerations of quality of life should include lowvision referrals as part of the management regimen. The sometimes overlooked benefits that a patient may have from an evaluation by a low-vision specialist should be recog-

nized. While improved anti-VEGF treatments are on the forefront, a low-vision referral for the patient with significantly decreased vision from refractory DME can be helpful and improve their quality of life.

CONCLUSIONS

There is ample evidence that VEGF plays a critical role in the pathogenesis of DME. Recent clinical trials, such as the READ-2 study and early studies with VEGF Trap-Eye, have demonstrated that anti-VEGF therapy can be effective for DME [33]. Importantly, evidence suggests that such treatment may be more effective than the current gold standard of focal/grid laser photocoagulation. As anti-VEGF therapy for DME becomes more established, one can expect that ranibizumab and bevacizumab may be used by practitioners for DME; currently, there is no clinical trial demonstrating that one medication is inferior to the other. The optimal dosing schedule for these treatments is unclear, but additional information will be forthcoming to help resolve this issue. Depending on the results of further clinical trials, the use of these anti-VEGF treatments in combination with laser or other therapies is a possible trend that will emerge. There are many reasons to be optimistic about these new treatment regimens for DME. Nevertheless, one limitation of current anti-VEGF therapies is the requirement of frequent dosing. If a safe and long-lasting anti-VEGF therapy is developed, then it would be especially effective in reducing the societal burden of DME.

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