Letter to the Editor: Steroid/AntiVascular Endothelial Growth Factor Combination Therapy for Neovascular Age-Related Macular Degeneration

Dear Editor:

I read with interest the article by Pietzuch et al., “Intravitreal dexamethasone as a rescue for anti-vascular endothelial growth factor therapy in neovascular age-related macular degeneration with persistent disease activity and high treatment demand.” ¹ In this retrospective noncomparative multicenter longitudinal case series of 16 eyes in 16 patients who were in need of frequent intravitreal antivascular endothelial growth factor (VEGF) dosing to control their disease, the addition of intravitreal dexamethasone resulted in a sustained increase in treatment intervals in the 24-month observation period.

We have long been searching for improved duration and efficacy in treatment of exudative age-related macular degeneration (AMD). In a study that was published in this journal in 2008 (and not referenced in the above article), ² I described the short-term optical coherence tomography results of 30 eyes that were treated with combination intravitreal triamcinolone and bevacizumab therapy for exudative AMD. That study showed that the combination therapy resulted in a reduction in foveal edema and subfoveal fluid in patients with macular neovascularization associated with AMD, observed in a shorter term.

As I pointed out at that time, the complementary roles of angiogenic and inflammatory systems in the pathogenesis of macular neovascularization in AMD suggest that treatments directed at both of these pathways should improve efficacy compared with monotherapy approaches. Anti-VEGF agent monotherapy to treat macular neovascularization in exudative AMD has been a standard therapeutic approach in AMD. Importantly, though, clinicopathological studies have demonstrated macrophage migration in association with large drusen ³ (a hallmark of AMD), demonstrating the importance of inflammation in AMD.

Anti-inflammatory steroids such as dexamethasone and triamcinolone also inhibit the positive feedback regulation between matrix metalloproteinase-9 and VEGF, ⁴ theoretically leading to the synergy in treatment with anti-VEGF agents.

Perhaps just as important is the theoretical inhibition of associated progressive geographic atrophy (GA) when steroids are added to and anti-VEGF regimen for neovascular AMD, without the concern for retinal vasculitis that is (although rarely) seen with anticomplement agents. Bioactive C3a and C5a fragments, present in drusen of patients with AMD, are thought to be associated with the development of GA, which is often seen in conjunction with neovascular AMD. Steroids inhibit complement activation, potentially mitigating GA progression.

We should be encouraged by ongoing investigations of combination therapy for neovascular AMD; in particular, a combination steroid/anti-VEGF preparation could allow for improved treatment efficiency, something sorely needed in this population.