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Retinal Physician

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Non-CNV Predictors of Success of Anti-VEGF for AMD

Clarifying the role of biomarkers is important in determining prognostic implications.

By: Harkaran S. Rana, DO, Daniel F. Kiernan, MD, FACS
Retinal Physician April 1, 2020 Vol 17, Issue April 2020 Page(s): 24-26, 28, 29

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Visual acuity (VA) outcomes and structural changes associated with anti-VEGF treatment for neovascular age-related macular degeneration (nAMD) vary tremendously among patients, some losing as many as 5 lines, and others gaining as much as 6 lines of VA after initial treatment. Factors such as the level of VA at presentation and the age of the patient influence response to treatment, but together with other baseline predictors, these account for the minority of variable changes found in vision scores.1,2 Evidence also exists that characteristics of choroidal neovascularization (CNV) lesions can predict response to anti-VEGF treatment for nAMD (Table 1),3 but there is far less research focused on non-CNV predictors of success. Based on the Preferences and Trends Survey of the American Society of Retinal Surgeons (PAT survey), physician prescribers of anti-VEGF therapy in 2018 described different indicators of persistent disease activity. These indicators include VA gain, loss, or stability, as well as anatomic presence or absence of retinal fluid on OCT to determine the intersession efficacy of the previous treatment, but respondents indicated that the presence of subretinal fluid (%) followed by intraretinal fluid are the primary biomarkers of recurrent disease activity.4

Table 1: Patient Demographics, Baseline Characteristics, and Assessments Included in Statistical Modeling of Baseline Predictors of 12-Month Treatment Response to Ranibizumab in Patients With Wet Age-Related Macular Degeneration*
VARIABLES THAT WERE BASELINE PREDICTORS OF VISUAL OUTCOMES AT MONTH 12
Age; BCVA; area of occult CNV with no classic component; total CNV leakage area; subretinal fluid presencea
VARIABLES THAT WERE BASELINE PREDICTORS OF TREATMENT FREQUENCY IN THE FIRST 12 MONTHS
Subretinal fluid thicknessa
VARIABLES THAT WERE NOT BASELINE PREDICTORS OF VISUAL OUTCOMES OR TREATMENT FREQUENCY
  • Sex
  • Race
  • Ethnicity
  • Current smoking status
  • Lens status
  • Treatment regimen (monthly vs PRN)
  • Central foveal thickness
  • Central subfield thickness
  • Area of classic CNV
  • Percentage of classic CNV area
  • CNV classification
  • Evidence of fluid from CNV
  • Percentage of total CNV area
  • Area of subretinal fibrous tissue
  • Percentage of subretinal fibrous tissue
  • Greatest linear dimension of lesion
  • Percentage of occult CNV with no classic component
  • Area of other lesion component with no CNV
  • PED
  • PED thickness
  • Presence of blood
  • Presence of classic CNV
  • Presence of fibrous tissue
  • Presence of neovascular AMD
  • Presence of occult CNV
  • Presence of photocoagulation scar
  • Presence of serous PED
  • Total macular volume
  • Total area of CNV
  • Total area of lesion
  • Macula dryb
  • Macula dry-2b
  • Macula totally dryb
  • Macula totally dry-2b
  • Retina dryb
  • Retina dry-2b
  • Retinal fluid atrophy (none, extrafoveal, remote, subfoveal)
  • RPE rip (none, outside,b remote,b subfoveal)
AMD; age-related macular degeneration; BCVA; best-corrected visual acuity, CNV; choroidal neovascularization, PED; pigment epithelial defect, RPE; retinal pigment epithelium.
aBaseline predictors are variables that were statistically significant (P<.05) in the final model.
bSee supplemental material available at AJO.com for definition, as provided by the Digital Angiography Reading Center (DARC).
*Reprinted with permission by Elsevier from Regillo CD, Busbee BG, Ho AC, Ding B, Haskova Z. Baseline predictors of 12-month treatment response to ranibizumab in patients with wet age-related macular degeneration. Am J Ophthalmol. 2015;160(5):1014-1023.

Although anti-VEGF treatment has resulted in dramatic visual improvements for many patients with nAMD, there is a great degree of variability in treatment response. Nearly 10% of patients with nAMD show a visual reduction of at least 15 Early Treatment Diabetic Retinopathy Study (ETDRS) score letters (ie, 3 lines) on the letter chart, despite treatment.5-7 Early identification of patients with poor treatment response is a critical step in optimizing AMD treatment. Patients classified as nonresponders based on an absence of VA improvement after anti-VEGF injections might have better outcomes with higher frequency of dosing along with regular monitoring, although there is no definitive proof of this at this time.8 Also, alternative therapies with the potential for longer action are currently being developed for nAMD,9 and it is possible that other therapeutic options will become available. Therefore, establishing which factors are involved in treatment response variability could aid in the stratification of patients for the best treatment regime or therapeutic option.10 Genetics, family history, age, gender, iris color, and axial length are factors that have been hypothesized to be associated with positive or negative response to anti-VEGF treatment. This article aims to present other accessible factors that may influence the efficacy of treatment that are otherwise overlooked when guiding therapy.

GENETICS AND FAMILY HISTORY

Genetic factors have been indicated to affect treatment outcome in patients with nAMD, although contradictory results have been reported. Some ophthalmologists have also speculated that a genetic predisposition may also contribute to resistance to anti-VEGF therapy. A large study of genome analysis analyzing genetic variants suggested that certain specific mutations may imply either treatment benefit or a lack thereof.1 It is prudent to note that at initial presentation, the patient’s age and VA have been the most consistently documented elements influencing response to treatment with anti-VEGF.11,12

Van Asten et al showed that rs12138564 variants in the CCT3 gene were associated with a small visual benefit of 1.7 letters. However, additional unified sequence kernel association testing of less common variants showed that C10orf88 and UNC93B1 were associated with poorer visual outcomes and patients with a rare variant in C10orf88 lost a mean of 30.6 letters (6.09 lines) and those with a variant in UNC93B1 lost 26.5 letters (5.29 lines), despite therapy with anti-VEGF.13

Another group hypothesized that AMD response may be influenced by both genetic factors and environmental factors. The genetic variants, including CFH, HTRA1/ARMS2, C3, CFB/C2, and APOE genes, are associated with significant risk for developing AMD.14 Variant rs1061170 (T1277C, Y402H) has been found to be strongly associated with AMD progression including the development of nAMD.15,16 The presence of all adverse factors (both risk genotypes, smoking, and body mass index ≥25) increased risk 19-fold.17

When investigating the association between this variant and the treatment response of nAMD, patients harboring the homozygous CC genotype for the variant risk C allele demonstrated a 60% reduced treatment response compared to patients carrying the ancestral TT genotype.18 Lee et al found that the response to treatment of AMD with ranibizumab differed according to the patient’s specific CFH genotype. Specifically, patients harboring homozygous mutations of the CFH Y402H allele had an increased requirement for recurrent/repeated ranibizumab injections (~40%); otherwise stated, a poorer response to therapy.19

Elsewhere, a single nucleotide variant rs10490924 (A69S) in the ARMS2 gene was also associated with poor outcome of intravitreal anti-VEGF injections to treat nAMD.20 This was validated by a separate meta-analysis that was performed on studies relating to the A69S variant in the ARMS2 gene and the response to anti-angiogenesis treatment. An additional finding was that A69S could be considered predictive of the anti-angiogenic effects, especially in Asian populations.21 The authors hypothesized that these patients with such genetic variants might have higher background levels of inflammation, which may affect the disease progression in the form of more rapid recurrence of neovascularization, causing the apparent diminished therapeutic effect.19-21 It is conceivable, then, that future AMD treatments may depend on the patient’s individual genetic risk profile to develop individualized therapy.22 An example of such treatment may include intravitreal exogenous CFH or CFH-related complement inhibitors as a beneficial therapy for patients with variant rs1061170.14

Because the findings of these studies suggest that specific, protein-altering genetic variants may signal a particular response to anti-VEGF therapy in patients with nAMD, it is conceivable that future AMD treatments may be tailored to patients individually.22 However, further investigations are necessary before information obtained from similar research can be realistically applied to personalize nAMD management, wherein research into specific anti-VEGF agents are used in combination with individually identified genetic anomalies. It is worth mentioning that, according to the American Academy of Ophthalmology, routine genetic testing for genetically complex disorders like AMD is not recommended, and widespread commercial genetic testing is not currently considered to be included in the standard of care for AMD diagnosis or treatment, nor is commercial genetic testing offered by the majority of retina specialists to their patients.23

AGE

Evidence has suggested that worse treatment outcomes are associated with a younger age at nAMD treatment onset, with an increasing number of risk alleles in known risk genes, including CFH, ARMS2, and HTRA, and variants in the VEGF-A gene. When assessing for adequate outcomes, it is important to note that the main consideration is best-corrected visual acuity (BCVA). Clinical factors, such as higher age, a better VA, a larger CNV lesion at baseline, and a delay between symptom onset and initiation of treatment of more than 3 weeks, also impact outcomes. Conversely, a worse acuity at baseline predicted more gain in vision. Overall, patients presenting with better acuity at baseline were more likely to have good acuity at follow-up, but the improvement that was achieved may have been limited by a ceiling effect.24 It should be noted that, although age is an important gauge in determining BCVA, and therein treatment outcome, it does not necessarily influence anatomical changes.25

Furthermore, age as a lone entity may not be an ideal metric that can guide treatment expectations. Lanzetta et al found that younger age, lower VA, and smaller CNV size at baseline were all associated with greater vision gains over 52 weeks; however, when younger age is combined with higher VA and smaller CNV size at treatment start, those patients were more likely to achieve BCVA 20/40 or better after a year of treatment, suggesting the benefit of early anti-VEGF treatment.26 Ashraf et al show that older patients with larger CNV and pigment epithelial detachment (PED), intraretinal cysts, and vitreomacular adhesion (VMA) had lower visual gains.27 Patients having VMA or vitreomacular traction required more intensive treatment with increased treatment frequency. Patients with both posterior vitreous detachment and subretinal fluid require infrequent injections. Patients with PED are prone to recurrences of fluid activity with a reduction in VA.27 Pedrosa et al went a step further to distinguish age and its correlation with another common predictor for various disease processes, gender. They found that at 1 year of follow-up, only baseline BCVA was significant; however, at 5 years, younger age at diagnosis, female gender, higher number of injections, and no development of subretinal fibrosis were also independently associated with better visual outcomes.28

GENDER

Stemming from Pedrosa et al, as discussed above, gender may demonstrate prognostic prediction of treatment success in nAMD, as it may with many other disease processes. Older age and male sex may predict recurrence after 3 monthly ranibizumab injections, and polypoidal choroidal vasculopathy may be associated with shorter interval to recurrence.29 This research highlights the importance of planning further follow-up. Conversely, the Blue Mountains Eye Study results, which have been analyzed in multiple different facets and will be discussed in terms of iris color later, showed that women may have a higher predilection to AMD than men.30 This is hypothesized to be secondary to the antioxidative effects of estrogen as is crucial in cataract development.31

These 2 studies, which both have reliable analyses and statistical significance, have altering outcomes. Thus, it suffices to say that gender alone may not necessarily be a risk factor that is clearly defined. At this juncture these confounding results may seem to represent more of a sociological and economic disparity in risk factor as opposed to a truly objective cause.

IRIS COLOR

A review of the literature reveals a relative incongruence when analyzing data regarding iris color and its relation to AMD. The research done by Mitchell et al demonstrated a statistically significant correlation with lighter iris color and prevalence of AMD and age at onset.32 A number of studies have reported an increased risk of late AMD in individuals with blue or light iris color compared with those with darker iris pigmentation, with one study showing worse AMD in subjects with light iris color. Contrary to this, however, most studies have found no significant association between iris color and AMD. The reasons for this disparity are not evident, although a variety of clinical definitions of AMD have been used and many studies have not employed masked photographic grading techniques.32

Further review shows that this trend only seems to be relevant when applied to a decline in overall pigment with age. Holz et al reported that this waning of pigment, whether by age or pigment epithelial defects, seems to have a correlation with eventual development of AMD.33 This paper is often cited in conjunction with a study by Feeney-Burns et al, which shows a 25% decline in melanin content of macular RPE, with moderate variability.34 A study by Weiter et al was soon to follow; among 650 patients with AMD studied, 494 (76%) had light-color irises, and the age of onset was also younger.35

A biologically plausible explanation for the lower risk of AMD among subjects with nonblue irises is that these subjects may have an increase in tissue melanin, including the choroid and retina. This melanin may provide some protection to the retina from exposure to direct sunlight, reducing direct oxidative damage and thus decreasing the risk of AMD.4,26,27 An alternative explanation for this finding may be that an underlying genetic factor, correlated with light iris color but independent of sunlight exposure, is associated with an increased risk of AMD. This is supported by previously mentioned work of Feeney-Burns et al34 and a recent report by Bito et al, who reported changes in eye color in around 10% to 15% of white subjects during adulthood.36

Despite the aforementioned research, there also are studies that were unable to demonstrate a correlation between AMD and iris color or change in color. Khan et al compounded a study of 446 cases of geographic atrophy or CNV and this was one of the larger studies to highlight the lack of significant correlation between AMD and iris color. The study goes further to show one significant drawback to all related studies being done: the cases evaluated tended to be based on broad definitions of macular degeneration that also may include cases of age-related maculopathy as well.37

Given the confounding data, it still remains to be seen whether iris color can be used to gauge any prediction of success. What first must be established, concretely, is whether iris color is truly a risk factor for the development of AMD. It would also be of great utility to determine the type of AMD that may develop in a patient (ie, exudative vs nonexudative). Only when this is determined can researchers further analyze whether patients with certain iris colors tend to lean one way or another in response to treatment.

AXIAL LENGTH

Axial length (AL) has been shown definitively, in multiple studies, to be protective against diabetic retinopathy (DR) and diabetic macular edema (DME). Although the mechanism remains unproven, it is hypothesized to be a result of axial elongation of the eye leading to decreased blood flow and subsequently reduced metabolic demand.37-40

When used in reference to prevalence and severity of AMD, very little is reported about this characteristic. A study of 853 eyes age >65, including 397 eyes at various AMD stages and 456 controls, found that eyes with late AMD have distinctly reduced subfoveal choroidal thickness and elongated AL. It is worth noting that the same hemodynamics that are theorized to be protective against DR and DME may be what affect the choroid and, consequently, the subfoveal choroidal thickness. This study from Taiwan did well to point out that these results may also be more prevalent in Asian countries where the rate of myopia is exceedingly high.41

A notable systematic review and meta-analysis providing a large data pool of more than 5,800 patients showed that hyperopia and increasing diopters are linked to greater risk of early AMD. Additionally, the opposite relationship existed between early AMD and AL. It is worth noting that the obvious concerns for this sort of meta-analysis do arise in that homogeneity when establishing exclusion criteria does exist.42 This theme seems to be consistent with the strong literature found elsewhere.43-45

As with iris color, a definitive determination or general trend, at the least, should be defined regarding AL as a risk factor for the development of AMD before a treatment success with anti-VEGF can be adequately studied.

CONCLUSION

When evaluating the efficacy of anti-VEGF agents in the treatment of AMD, further study is needed of the non-CNV predictors discussed above. To a limited extent, patients’ genetics show promise for guiding the response to treatment with anti-VEGF. Age may be a useful metric when assessing the potential benefit from anti-VEGF treatment; however, age may be a more useful prognostic indicator when considered in tandem with other factors. Gender does not seem to have concrete evidence supporting its role in the prediction of developing AMD, therefore age may be of lower value when gauging anti-VEGF treatment response. Similarly, the relationship of iris color and axial length with treatment response is fairly obscure. As newer anti-VEGF agents enter the field, elucidating the role of these and other biomarkers is an important part of determining prognostic implications in treating patients with wet AMD. RP

Harkaran S. Rana, DO, is with Walter Reed National Military Medical Center in Bethesda, Maryland. Daniel F. Kiernan, MD, FACS, is a retina specialist with Ophthalmic Consultants of Long Island in Rockville Centre, New York. The authors report no related disclosures. Reach Dr. Kiernan at dkiernan@ocli.net. Editor’s note: This article is discussed in an episode of The Retina Podcast. Listen at www.retinapodcast.com .

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