A Randomized Pilot Study of Systemic Immunosuppression in the Treatment of Age-Related Macular Degeneration With Choroidal Neovascularization

Abstract

Background Age-related macular degeneration remains the leading cause of irreversible blindness in the United States and the developed world. Intravitreal injections of anti–vascular endothelial growth factor (VEGF) medications have become standard of care for the treatment of the wet form of the disease. Recent reports have demonstrated an association with various immune factors. We aimed to investigate the effect of immunosuppressive therapy in the clinical course of the wet form of the disease. We compared anti-VEGF therapy plus one of three systemic immunosuppressive therapies versus anti-VEGF therapy alone for recurrent choroidal neovascularization associated with age-related macular degeneration. Methods This was a pilot, Phase I/II, prospective, randomized, unmasked, single-center trial. Patients with subretinal exudation secondary to recurrent choroidal neovascularization associated with age-related macular degeneration were included in the study. Patients were randomized to 1 of 3 systemic arms immunosuppressive agents (daclizumab, rapamycin, or infliximab) for 6 months plus intraocular anti-VEGF therapy if indicated, compared with a group who received only anti-VEGF therapy if indicated. Results The number of anti-VEGF injections per group, visual acuity, retinal thickness, and safety measures were assessed in all groups. Thirteen patients were randomized; comparing anti-VEGF injections before and during the study, a decrease in the number of injections from 0.73 injections per month to 0.42 for daclizumab and from 0.67 to 0.34 for sirolimus was seen, while no apparent decrease was seen for either infliximab or observation. Visual acuities were maintained in all groups. Conclusion These preliminary data suggest that some immunosuppressive agents given systemically can alter the clinical course of the wet form of the disease and support the notion that more definitive clinical trials of immune mediation of age-related macular degeneration are indicated.

Inflammatory Cytokines Induce Expression of Chemokines by Human Retinal Cells: Role in Chemokine Receptor Mediated Age-related Macular Degeneration

“…Inflammatory reactions are widely thought to be one of the initiating and /or promoting factors in CNV in AMD [56][57][58][59]. Recent studies on the role of chemokines and their receptors in CNV in AMD [60][61][62] indicate potential new avenues for exploration of chemokine targeting in search of AMD therapies.…”

The purpose of the HIF-1/PHD feedback loop: To limit mTOR-induced HIF-1α

“…73,74 A recent pilot clinical trial appears to support this notion. 75 Cellular senescence is characterized by a hyper-secretory phenotype. [76][77][78] Also noteworthy, mTOR stimulates translation of HIF-1α.…”

Intravitreal Tumor Necrosis Factor-Alpha Inhibitors for Neovascular Age-Related Macular Degeneration Suboptimally Responsive to Antivascular Endothelial Growth Factor Agents: A Pilot Study from the Pan American Collaborative Retina Study Group

“…A randomized pilot study of systemic immunosuppresion with infliximab (3 mg/kg monthly for 6 months) as an adjuvant to anti-VEGF treatment did not appear to reduce the treatment burden of intravitreal anti-VEGF injections. 30 Rabbit models have shown that intravitreal adalimumab in doses up to 5 mg are safe. 14,15 Five patients with refractory cystoid macular edema secondary to noninfectious uveitis were treated with intravitreal adalimumab for 3 months with no apparent benefit.…”