Inflammation is a key pathogenic factor involved in the development of common retinal diseases, such as age-related macular degeneration, retinal venous occlusive disease and, the focus of this article, diabetic retinopathy (DR). Recognizing the important role inflammation plays in DR leads to greater recognition of clinical inflammatory features, increased awareness of modifiable systemic pro-inflammatory risk factors, and a better understanding of current and emerging anti-inflammatory therapies for DR.
Inflammation’s role
Inflammatory pathways contribute to both neovascularization and macular edema in DR.1-3 Specifically, various pro-inflammatory vitreous mediators, such as adhesion molecules, chemokines, cytokines, and growth factors, are upregulated in eyes that have DR.1 (See “Risk of pseudophakia cystoid macular edema post cataract surgery.”)
Risk of pseudophakic cystoid macular edema post cataract surgery
The risk of pseudophakic cystoid macular edema post-cataract surgery is increased in patients who have diabetes and especially in eyes that have DR.34 This is likely attributable to additive effects of proinflammatory cytokine release. 35
Differentiation between pseudophakic cystoid macular edema and DME can be clinically valuable, as more invasive management, such as intravitreal anti-VEGF therapy, may be needed in DME cases.
Features suggestive of DME include preserved foveal pit, presence of microaneurysms and/or exudates, lack of subretinal fluid, as well as fluid cysts involving the ganglion cell layer and/or nerve fiber layer, in addition to the inner nuclear layer.35 The pattern of edema is also typically more focal in DME compared to centrally located in pseudophakic cystoid macular edema. In addition, OCT intraretinal hyperreflective foci were present in nearly all eyes that had DME and no eyes that had pseudophakic cystoid macular edema.35
Additionally, inflammatory cytokines, such as ICAM-1 and TNF-α, mediate migration and adhesion of leukocytes to vascular endothelium, as well as increase vascular permeability, breakdown of the inner blood retinal barrier, and incite thrombus formation.1,2 Leukostasis and microvascular occlusion then occur, as leukocytes and platelets adhere to retinal capillary endothelium.1 Further, increased growth factors production, including vascular endothelial growth factor (VEGF) and insulin-like growth factor-1 (IGF-1), facilitate vascular permeability and angiogenesis.1 (See “Breaking down the blood aqueous barrier.”)
The formation of advanced glycation end products (AGEs) is also accelerated in eyes with DR and occurs as excess glucose bonds non-enzymatically to proteins and lipids.1 AGEs are pro-inflammatory mediators that bind to endothelial cells and further exacerbate breakdown of the inner blood retinal barrier.
Clinical inflammatory features
Potential imaging biomarkers of local retinal inflammation that have been identified include intraretinal hyperreflective microfoci, subretinal fluid (or subfoveal neuroretinal detachment [SND]) accompanying diabetic macular edema (DME), and foveal hyperautofluorescence on fundus autofluorescence (FAF) imaging.4-7 Their clinical presentations:
• Intraretinal hyperreflective microfoci. On OCT, these appear as bright dots of less than or equal to 30 µm to 50 µm in diameter that have been found in eyes with DR (Figure 1).4,8 It is hypothesized that these hyperreflective microfoci represent either lipoprotein exudates or activated inflammatory cells (aggregates of microglial cells). Hyperreflective microfoci that represent the latter are more likely to exhibit a reflectivity level similar to the nerve fiber layer, lack posterior shadowing, and are located in both the inner and outer retinal layers. 4,6-8 Additionally, hyperreflective microfoci may reflect the severity of disease and a negative visual prognosis in patients with DME. 8-10 In the phase 3 clinical trials YOSEMITE and RHINE, hyperreflective microfoci volume at baseline was correlated with retinopathy severity, as well as OCT central subfoveal thickness and local distributions of cystoid intraretinal fluid.8 Reduction in the number of hyperreflective microfoci has been demonstrated with both anti-VEGF and steroid therapies.9,11
• Subretinal fluid. This is seen via OCT in eyes that have DME. Also, the subretinal fluid in these eyes has been found to have greater concentrations of vitreous inflammatory cytokines, such as IL-6 and a greater number of OCT hyperreflective microfoci (Figure 1).4,12
Subretinal fluid in DME decreases with anti-VEGF therapy and intravitreal steroids. The latter’s drying effect supports the hypothesis that subretinal fluid is driven primarily by inflammation.4,9 Based on my clinical experience, vascular staining, especially when widespread and diffuse, upon intravenous fluorescein angiography is suggestive of either inner retinal ischemia, inflammation or, in most instances of advanced DR, a combination of the two. The clinical correlate that may sometimes be visualized is vascular sheathing (Figure 2).
• Foveal hyperautofluorescence This is imaged via fundus autofluorescence (FAF).
Modifiable systemic pro-inflammatory risk factors
Although the key systemic risk factors that fuel DR are poor glycemic control and hypertension, other pro-inflammatory systemic risk factors also likely exacerbate DR. These include smoking, vasculitis, elevated inflammatory marker labs, diet and, as a result, gut health, as well as exercise (limiting sedentary lifestyle).13,14
Smoking has been found to increase the risk of DR and proliferation in patients who have type 1 diabetes.15
Systemic inflammatory markers, such as high levels of C-reactive protein (CRP), are associated with a higher risk of DR, and the Diabetic Retinopathy Diabetes Control and Complications Trial reveals a statistically significant association with CRP and clinically significant macular edema.16-19
Current and emerging treatments
Armed with an understanding of the current and emerging treatments aimed at the inflammatory component of DR, ODs can educate DR patients on their options for intervention. These current and emerging interventions:
• Anti-VEGF agents. VEGF is known to play a major role in the vasculogenic and angiogenic processes of DR progression. Anti-VEGF drugs, including aflibercept, bevacizumab, and ranibizumab, can be used to halt the disease progression associated with this influenced vasculogenesis and angiogenesis. Faricimab, FDA approved for diabetic macular edema (DME) in January 2022, 21 inhibits VEGF-A and angiopoietin-2. Activation of the angiopoietin–Tie2 pathway in DR has been linked to increased vascular permeability and inflammation, and independent inhibition of angiopoietin-2 has been shown to reduce vascular leakage.20-22
• Intravitreal steroids. Intravitreal steroids are often reserved for pseudophakic eyes that have refractory DME that is poorly responsive to anti-VEGF therapy. This is due to the risk of complications, such as cataracts and secondary open-angle glaucoma. Their duration of effect is an advantage.23 Intravitreal steroid implantation proves to be very effective at improving macular edema, as demonstrated in the FAME A and FAME B trials. Steroid implantation is beneficial in regard to the number of injections required but may have more IOP-related complications than intravitreal injections. Early clinical trials suggest that 4 mg triamcinolone injections are effective in reducing central macular thickness in cases of DME, including cases that fail to respond to previous laser photocoagulation.24, 23 Intravitreal steroid injection also demonstrates high efficacy in treating diabetic macular edema, including diffuse cases. The use of intravitreal injections may require a higher injection burden on the patient, but they serve as an excellent treatment method. Both intravitreal steroid implants and injections are effective at improving best-corrected visual acuity and reducing CRT.
• Antilipemic agents. Oral fenofibrate is an off-label treatment shown to contribute to reduced vascular permeability and have antiangiogenic effects on DR.25 (It is approved for DR treatment in Australia and Singapore.26) The typical dose when treating DR is 160 mg per day, however caution should be exercised in patients who have kidney disease, as these agents increase the risk of toxicity or treatment failure. Therefore, a lower dose of approximately 54 mg should be used in these patients.27
Two huge randomized controlled trials show that fenofibrate used as an adjunctive treatment to standard-of-care DR treatments can slow progression of preexisting DR and reduce the need for treatment of DME and proliferative DR in patients who have type 2 diabetes. These two studies are the 2005 Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, and the 2007 Action to Control Cardiovascular Risk in Diabetes (ACCORD) study.28-30
The FIELD study comprised over 1,000 type 2 DM patients who were randomized to use fenofibrate 200 mg/day or placebo.28,29 The results: In eyes that had preexisting DR, 14% on placebo had 2-step worsening of the Early Treatment Diabetic Retinopathy Study severity score vs. 3% using fenofibrate after more than 2 years of follow up. Additionally, the study shows that fenofibrate decreased the need for laser treatment for proliferative DR or DME. Also, fenofibrate reduced the rate of nonfatal heart attack and minor amputations.28,29 A caveat: Fenofibrate did not reduce the occurrence of new DR in eyes that had no retinopathy at baseline.
The Diabetic Retinopathy Clinical Research Network is currently recruiting for Protocol AF (Fenofibrate for Prevention of DR Worsening), which is enrolling patients who have mild-to-moderately severe nonproliferative DR and no center-involved DME at baseline. Results are expected in 2029.27
In clinical practice, fenofibrate should be considered in patients who have type 2 DM and mild-to-moderate nonproliferative DR and normal kidney function. 25,26,31 It may be particularly beneficial among those who have moderate-to-very high cardiovascular risk factors (e.g., hypertension, dyslipidemia, previous history of cardiovascular events) and those at high risk for DR progression).25
• Ocular nutritional supplementation. Many patients who have DR have concurrent vitamin and mineral deficiencies that fuel retinal microvascular damage and inflammation.32 Therefore, supplementation with vitamins, minerals, and nutraceuticals can complement current standard-of-care treatments.
The goals of supplementation in DR are to decrease inflammatory mediators, reduce oxidative stress, support retinal metabolism, and promote microvascular health.32
• Anti-inflammatory agents. Salicylates or minocycline taken by patients who have DR provide evidence that regulating the inflammatory response can be beneficial in precluding irreversible vascular and neuronal perturbations over time.33
Playing a part
With a knowledge of the role of inflammation in DR, its clinical inflammatory features, modifiable systemic pro-inflammatory risk factors, and current and forthcoming interventions, optometrists are in an excellent position to play a substantial role in educating patients on the effective management of DR. OM
Breaking down the blood aqueous barrier
Not only do increased VEGF and inflammatory cytokine levels break down the blood retinal barrier, but they also break down the blood aqueous barrier upon diffusion into the anterior chamber. This may result in an anterior chamber reaction primarily comprised of flare (more so than cells) that is sometimes referred to as an “ischemic uveitis.” Patients with this type of anterior chamber reaction are typically asymptomatic unless neovascular glaucoma develops.
A sequence of 1) anterior chamber reaction, 2) iris neovascularization, 3) neovascularization of the angle, 4) and neovascular glaucoma often occurs, although a small percentage of eyes may develop angle neovascularization prior to iris neovascularization. In such cases, it is important to not only evaluate the iris carefully for neovascularization in patients who have diabetes, but also intently look for an anterior chamber reaction. If an anterior chamber reaction is present, the optometrist should consider performing gonioscopy.
Similarly, if an equivocal/questionable iris neovascularization is identified, the coexisting presence of an anterior chamber reaction is suggestive of true iris neovascularization (Figure 3). In the management of neovascular glaucoma, it is often valuable to add topical steroids and cycloplegics to combat inflammation, in addition to IOP-lowering medications.
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