Status of Dry AMD Management

Risk management in patients with early dry AMD includes nutritional supplementation. Researchers seek to understand the pathogenesis of AMD in order to develop treatment options.

By Derek N. Cunningham, OD, and Alan Franklin, MD, PhD

The nonexudative, or dry, form of age-related macular degeneration (AMD) is characterized by progressive macular changes that can lead to significant visual impairment. In 2004, it was estimated that 7.3 million people in the United States were considered to have high-risk features of dry AMD in one or both eyes.1 The primary risk factors for developing AMD include advanced age, female sex, lighter skin pigmentation, cigarette smoking, low dietary intake of antioxidants, and multiple genetic factors.

AMD accounts for approximately 46% of cases of severe visual loss (visual acuity of 20/200 or worse) in the United States.2 Although dry AMD accounts for approximately 80% of all cases of AMD, it is responsible for only approximately 10% of the cases with severe visual loss; the other cases are attributable to exudative, or wet, AMD.3

Dry AMD has multiple clinical features, including drusen, alterations in the retinal pigment epithelium (RPE) resulting in hyper- or hypopigmentation of the macula, and RPE atrophy. The most frequently used classification system for dry AMD, described in the Age-Related Eye Disease Study (AREDS),4 includes four categories.

  • • Category 1: No AMD (Figure 1), characterized by no or few small drusen (< 63 µm);
  • • Category 2: Early AMD (Figure 2), characterized by multiple small drusen, few intermediate drusen
    (63-124 µm), or mild RPE abnormalities;
  • • Category 3: Intermediate AMD, characterized by multiple intermediate drusen, at least one large druse
    (>124 µm), or geographic atrophy (GA) not involving the center of the fovea; and
  • • Category 4: Advanced AMD (Figure 3), characterized by GA involving the foveal center.

Figure 1. Category 1 dry AMD (left); Category 2 dry AMD.

Figure 3. Category 4 AMD (A); FA (B) and OCT (C).

RESEARCH: DRY AMD PIPELINE

Recent advances in the understanding of geographic atrophy (GA) have led to numerous ongoing clinical trials targeting different molecules shown to be associated with the underlying disease pathophysiology. Most disease processes that include age-related macular degeneration (AMD) have common pathophysiologic themes that include altered immune status, immune dysregulation, oxidative damage, and increased apoptosis. Current molecules under investigation aim to inhibit GA progression by a variety of mechanisms including reducing toxic byproduct generation and accumulation, slowing the visual cycle, and inhibiting the complement pathway, which has been shown to be involved in the pathogenesis of AMD.

The products of oxidative stress trigger a chronic low-grade inflammation (pathophysiological parainflammation) process in AMD patients. In early AMD, soft drusen contain many mediators of chronic low-grade inflammation such as C-reactive protein, adducts of the carboxyethylpyrrole protein, immunoglobulins, and acute-phase molecules, as well as the complement-related proteins C3a, C5a, C5, C5b-9, complement factor H (CFH), CD35, and CD46.1 Inappropriate activation of the complement system, mainly the alternative pathway, mediates chronic autologous pathophysiological parainflammation in dry and exudative AMD. CFH, which functions to inactivate the alternate complement pathway, has been found to harbor potential loss of function in genetic alterations associated with both complement activation and dry AMD progression. In addition, cigarette smoking decreases CFH function thereby exacerbating dry AMD progression and chronic inflammation mediated by C-reactive protein.

There are multiple clinical trials now enrolling for various inhibitors of the alternate complement pathway, such as lampalizumab, and APL-2.2 Visual cycle end products have been shown to accumulate in the subretinal and subretinal pigment epithelium (RPE) space, which ultimately act as a barrier between RPE and photoreceptor molecular chaperoning and transfer. Therefore, some visual cycle inhibitors (eg, emixustat) are undergoing testing to slow the progression of dry AMD.3 Dicer enzyme deficiency leads to inappropriate accumulation of Alu RNA, which over time becomes toxic to the RPE.4

More recently, the HIV reverse transcriptase drugs, NRTIs, have been shown to reduce Alu RNA, thereby demonstrating that some NRTIs may be a good candidate treatment for AMD progression.5

There is also supporting research that the involvement of Rho-associated kinase (ROCK) has also been indicated as a key factor in the progression of AMD.6 ROCK involvement suggests age-induced innate immune imbalance as an underlying AMD pathogenesis, which may open up new possibilities for more effective AMD treatment by targeting macrophage plasticity. Oxidative stress has also been shown as an important mediator of dry AMD progression. Current nutriceutical formulations have shown some benefit, and there are more potent antioxidant compounds currently under development for the treatment of dry AMD. Microglial activation can injure photoreceptor cells and lead to the development of dry AMD.

For a disease that is so prevalent in eye care, there is still a considerable amount of speculation as to the specific nature and pathogenesis of AMD. Although many novel compounds are in clinical trials, and other established molecules may be found to have a new indication as effective treatments for both dry and wet AMD progression, there are no approved pharmacologic treatments for dry AMD. There is research pointing to seemingly endless potential avenues for treatment, but let’s take a look at what we know for now. The number of promising and diverse treatments for AMD progression are certainly encouraging, and over the next 5 years will likely lead to a quantum improvement in our ability to treat this common and visually threatening disease.

1. Nita M, Grzybowski A, Ascaso FJ, Huerva V, et al. Age-related macular degeneration in the aspect of chronic low-grade inflammation (pathophysiological parainflammation). Mediators Inflamm. 2014;2014:930671. doi: 10.1155/2014/930671.

2. Rhoades W, Dickson D, Do DV et al. Potential role of lampalizumab for treatment of geographic atrophy. Clin Ophthalmol. 2015;11;9:1049-1956. doi: 10.2147/OPTH.S59725. eCollection 2015. Review. Erratum in: Clin Ophthalmol. 2015;9:1135.

3. Dugel PU, Novack RL, Csaky KG, et al. Phase 2, randomized, placebo-controlled, 90-day study of emixustat hydrochloride in geographic atrophy associated with dry age-related macular degeneration. Retina. 2015;35(6):1173-1183.

4. Kaneko H, Dridi S, Tarallo V, Gelfand BD, et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature. 2011;471(7338):325-330.

5. Fowler BJ, Gelfand BD, Kim Y, et al. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science. 2014:21;346(6212):1000-1003.

6. Zandi S, Nakao S, Chun KH, et al. ROCK-isoform-specific polarization of macrophages associated with age-related macular degeneration. Cell Rep. 2015;10(7):1173-1186.

In AREDS, at 10 years, progression from either category 1 or 2 to high-risk disease (ie, category 3) occurred in only 15% of patients.5 However, patients with intermediate AMD were at much higher risk of disease progression and vision loss. Further, patients with advanced AMD in one eye are at high risk of developing advanced disease in the fellow eye at 5 years (35%-50%).6

Contemporary treatment recommendations for dry AMD are based on the results of the AREDS and AREDS2 studies.5-7 AREDS demonstrated a significant benefit from the combination antioxidant vitamins (vitamin A, C, and E) and zinc, resulting in a 34% reduction of the risk of developing advanced AMD (ie, category 4) over a median of 6.3 years of follow-up in persons at high risk of developing advanced AMD (category 3).4 The authors concluded that patients with extensive intermediate size drusen, at least one large druse, noncentral GA in one or both eyes, or advanced AMD or vision loss due to AMD in one eye, and without contraindications, should consider taking a supplement of antioxidants plus zinc.

The AREDS2 study was designed to determine whether adding lutein plus zeaxanthin, docosahexaenoic acid plus eicosapentaenoic acid, or both to the original AREDS formulation decreases the risk of developing advanced AMD and to evaluate the effect of eliminating beta-carotene, lowering zinc doses, or both in the AREDS formulation.7 The study’s results demonstrated that addition of lutein plus zeaxanthin, docosahexaenoic acid plus eicosapentaenoic acid, or both to the AREDS formulation did not further reduce risk of progression to advanced AMD. Because of potential increased incidence of lung cancer in former smokers, lutein plus zeaxanthin could be an appropriate carotenoid substitute in the formulation.7

A post-hoc analysis of the AREDS has suggested that AMD patients with certain genotypes, as determined by genetic testing for AMD risk alleles, may derive greater benefit from specific supplements (antioxidants alone, zinc alone), but these data have been disputed, and the conclusions from these post-hoc analyses have not as of yet been supported by additional statistical analysis or replicated with a prospective study.8-10

At present, the most evidence-based, cost-efficient, and practical approach to management of dry AMD seems to be to recommend AREDS2 vitamins to all high-risk dry AMD patients and to defer genetic testing until prospective studies support an alternative approach. This approach is consistent with the recommendations of the American Academy of Ophthalmology.

GOAL OF MANAGEMENT

Optical coherence tomography (OCT) is a useful tool in the diagnosis and management of patients with dry AMD. OCT imaging allows the identification and characterization of drusen and GA and provides quantitative information about the disease state and its progression. OCT can also detect subtle changes resulting from wet AMD, such as a fibrovascular pigment epithelial detachment or shallow subretinal fluid that may be difficult to appreciate on clinical examination alone (Figure 3C).w

Significant vision loss related to dry AMD is typically the result of GA. In contrast to wet AMD, there is no effective treatment to halt or reverse vision loss in patients affected by GA. Additionally, GA can result in progressive vision loss in patients with concomitant wet AMD who are being treated with antivascular endothelial growth factor injections.

Recent advances in the understanding of GA have led to numerous ongoing clinical trials targeting different molecules shown to be associated with the underlying disease pathophysiology (see Research: Dry AMD Pipeline). Molecules under investigation aim to inhibit GA progression by a variety of mechanisms including reducing the generation and accumulation of toxic byproducts, slowing the visual cycle, and inhibiting the complement pathway, which has been shown to be involved in the pathogenesis of AMD.

The goal of managing patients with dry AMD is to slow progression of the disease with AREDS supplementation and to promptly identify patients progressing to wet AMD, allowing early and more effective treatment of the exudative disease. All dry AMD patients should be instructed on the appropriate use of an Amsler grid and should monitor their vision daily.

Recently, an alternative home visual field monitoring device to detect metamorphopsia, the ForeseeHome AMD Monitoring Program (Notal Vision Inc.), was described.11 The system has been demonstrated to provide earlier detection of choroidal neovascularization development, increasing the likelihood of better visual acuity results with intravitreal antivascular endothelial growth factor therapy.11 This device will likely gain more widespread use and will be a consideration for monitoring dry AMD patients.

When progression to wet AMD is detected, patients should be evaluated and treated by a retina specialist, preferably within 1 to 2 weeks. Retina evaluation should be strongly considered in the absence of definitive exudative disease in patients with new or progressive metamorphopsia, an unexplained decrease in visual acuity, or new or progressive GA that may meet inclusion criteria for one of the numerous ongoing clinical trials. n

1. Friedman DS, O’Colmain BJ, Muñoz B, et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564-572.

2. Congdon N, O’Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122(4):477-485.

3. Ferris FL 3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. 1984;102(11):1640-1642.

4. Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS Report No. 8. Arch Ophthalmol. 2001;119(10):1417-1436.

5. Chew EY, Clemons TE, Agron E, et al. The Age-Related Eye Disease Study (AREDS) Research Group. Ten-year follow-up of age-related macular degeneration in the age-related eye disease study: AREDS report no. 36. JAMA Ophthalmol. 2014;132(3):272-277.

6. Ferris FL, Davis MD, Clemons TE, et al. The Age-Related Eye Disease Study (AREDS) Research Group. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005;123(11):1570-1574.

7. Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005-2015.

8. Awh CC, Hawken S, Zanke BW. Treatment response to antioxidants and zinc based on CFHand ARMS2 genetic risk allele number in the Age-Related Eye Disease Study. Ophthalmology. 2015;122(1):162-169.

9. Chew EY, Klein ML, Clemons TE, Agrón E, Abecasis GR. Genetic testing in persons with age-related macular degeneration and the use of the AREDS supplements: to test or not to test? Ophthalmology. 2015;122(1):212-215.

10. Wittes J, Musch DC. Should we test for genotype in deciding on age-related eye disease study supplementation? Ophthalmology. 2015;122(1):3-5.

11. AREDS2-HOME Study Research Group, Chew EY, Clemons TE, Bressler SB, et al. Randomized trial of a home monitoring system for early detection of choroidal neovascularization home monitoring of the Eye (HOME) study. Ophthalmology. 2014;121(2):535-544.

Section Editor Derek N. Cunningham, OD
• Director of optometry and research at Dell Laser Consultants in Austin, Texas
• Founding member and chair of the American Society of Cataract and Refractive Surgery’s Integrated Ophthalmic Managed Eyecare Delivery Task Force
• Chief medical editor of Advanced Ocular Care
dcunningham@dellvision.com
• Financial interest: none acknowledged

Medical Editor Alan Franklin, MD, PhD
• Practices at the Retina Specialty Institute in Mobile, Alabama
afranklin@retinaspecialty.com
• Financial interest: none acknowledged