Why Do Anti-VEGF Agents Not Work in All Patients with Neovascular AMD?
Age-related macular degeneration (AMD) is the most common cause of legal blindness in industrialized countries. Most cases of severe vision loss from AMD are due to the neovascular, or "wet", form of the disease. The vision outcomes of patients with wet AMD have improved significantly with the use of anti-vascular endothelial growth factor (anti-VEGF) therapy.1-4 However, there are non-responders and suboptimal responders to anti-VEGF treatment, and the question arises as to why some patients respond favorably to anti-VEGF therapy and some do not.
The etiology of wet AMD is multifactorial.5 Known steps in the development of "wet AMD" include drusen formation with concomitant thickening of Bruch's membrane, reduced transport of nutrients and waste products, ischemia, inflammation6-10 and, finally, the development of choroidal neovascularization (CNV). It has been reported that macular degenerative changes may be induced by an inappropriate response to inflammation caused by polymorphisms of the complement factor H (CFH) gene; under normal conditions, CFH inhibits the complement system.6-9 Further downstream, several cytokines are expressed, with VEGF being one of the key molecules involved in the development of CNV.11
When questioning why anti-VEGF agents do not work in all patients with neovascular AMD, there are several factors to consider:
There is growing evidence that inflammation is one of the key events occurring upstream in the cascade of events leading to neovascular AMD. This has been supported by trials showing that topical anti-inflammatory therapy, with or without the administration of anti-VEGF therapy, is able to suppress the development of neovascular AMD.12-14 In another study of patients with neovascular AMD unresponsive to anti-VEGF monotherapy, combination therapy of anti-VEGF with triamcinolone acetonide was reported to be effective.15
In one recently published study, single nucleotide polymorphisms (SNPs) in the VEGF-A gene were studied. Patients with particular SNPs showed a significantly better visual outcome and a higher probability of responding to anti-VEGF therapy.16 In another retrospective study of 150 patients, there was no statistically significant association between the response to anti-VEGF therapy and known high risk disease loci.17 In yet another study, individuals with a particular polymorphism of the CFH gene had a decreased chance of visual acuity improvement after intravitreal anti-VEGF therapy.18
3. Level of CNV maturation
Another potential contributing factor associated with responsiveness to anti-VEGF therapy is the level of CNV maturation. "Mature" vessels in CNV have been reported to be covered with pericytes, thereby making the vessels less accessible to antibodies. Such "mature" CNV lesions have been reported to respond better to combination treatments or aflibercept, with the latter phenomenon being yet unexplained.19-22
4. Type of neovascular lesion
It has been reported that retinal angiomatous proliferation (RAP)23-25 and CNV associated with polypoidal choroidal vasculopathy (PCV)26,27 respond less favorably to anti-VEGF therapy compared to AMD-associated CNV.
5. Timing of treatment related to disease course
The later in the disease course that anti-VEGF therapy is initiated, the less favorable the visual outcomes may be. For example, if treatment is not initiated until substantial fibrosis and scarring have occurred, there is already significant damage to the tissues which anti-VEGF therapy cannot reverse.
6. Vitreomacular traction
It has been reported that vitreomacular attachment is associated with the development of neovascular AMD.28 Tractional forces and the adhesion, which may act as a semi-permeable membrane, may inhibit the effect of anti-VEGF medications.29
Although intravitreal anti-VEGF therapy has been associated with a dramatic improvement in the vision outcomes associated with neovascular AMD, some patients are unresponsive, or suboptimally responsive, to anti-VEGF treatment. Understanding the factors that may contribute to suboptimal anti-VEGF treatment responsiveness is important to guide research for future therapies. In addition, earlier identification of patients with neovascular AMD may improve final vision outcomes. Finally, identification of patients at high risk of developing neovascular AMD may lead to strategies for prevention.
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About our author(s):
Vera K. Schmit-Eilenberger, MD
Department of Ophthalmology
Städtisches Klinikum Karlsruhe
Albert J. Augustin, MD
Department of Ophthalmology
Städtisches Klinikum Karlsruhe