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Wet age-related macular degeneration refractory to aflibercept but responsive to systemic everolimus

      A 69-year-old Caucasian woman with a history of metastatic breast cancer had been receiving injections of aflibercept every 4–8 weeks for wet age-related macular degeneration in her right eye for the past 4 years. Despite the regular frequency of the aflibercept injections, her optical coherence tomography had always demonstrated significant levels of intraretinal fluid (Fig. 1). It was decided in the past to maintain her schedule of aflibercept in order to maintain her baseline level of vision of 20/60. Her left eye had some drusen and a visual acuity of 20/30.
      Fig 1
      Fig. 1Optical coherence tomography of the right eye over 11 months. The intraretinal fluid is present despite regular aflibercept and only resolves under everolimus. However, after the everolimus is stopped, the intraretinal fluid reappears. The patient received an injection of aflibercept during all visits except for September 28, 2018, when the injection was deferred due to the minimal intraretinal fluid.
      The patient developed pleural effusions secondary to her metastatic breast cancer, which prompted her oncologist to start her on systemic everolimus. Three weeks later, at her scheduled visit with her retina specialist, it was noted that the amount of intraretinal fluid had decreased. Aflibercept was administered at this visit. At the following visit, 2 months after starting everolimus, her optical coherence tomography was almost absent of any intraretinal fluid for the first time since she first started receiving the injections (Fig. 1). Her vision improved from her baseline of 20/60 to 20/40. Therefore, after discussing with the patient, it was decided to defer her aflibercept.
      Unfortunately, the patient's pleural effusions were not responding to the everolimus, and after 3 months on the medication, she was switched to etoposide. She was seen by her retina specialist a month later, and the level of intraretinal fluid had returned to baseline (Fig. 1). After a discussion with the patient, it was decided to restart the aflibercept. Despite this, her vision returned to its baseline of 20/60 at the next visit.

      Discussion

      Age-related macular degeneration (AMD) is the leading cause of vision loss in patients over the age of 65 years in developed countries.
      • Pascolini D.
      • Mariotti S.P.
      • Pokharel G.P.
      • et al.
      2002 global update of available data on visual impairment: a compilation of population-based prevalence studies.
      The advent of intravitreal antiangiogenesis therapy has greatly benefited the treatment of the wet form of AMD.
      • Rosenfeld P.J.
      • Brown D.M.
      • Heier J.S.
      • et al.
      Ranibizumab for neovascular age-related macular degeneration.
      • Brown D.M.
      • Michels M.
      • Kaiser P.K.
      • et al.
      Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: two-year results of the ANCHOR study.
      • Schmidt-Erfurth U.
      • Kaiser P.K.
      • Korobelnik J.-F.
      • et al.
      Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies.
      However, 10%–17% of patients do not respond.
      • Suzuki M.
      • Nagai N.
      • Izumi-Nagai K.
      • et al.
      Predictive factors for non-response to intravitreal ranibizumab treatment in age-related macular degeneration.
      • Otsuji T.
      • Nagai Y.
      • Sho K.
      • et al.
      Initial non-responders to ranibizumab in the treatment of age-related macular degeneration (AMD).
      Everolimus is an inhibitor of the mechanistic/mammalian target of rapamycin (mTOR). mTOR serves as the core of protein complexes that are involved in the regulation of direct protein synthesis, cell growth, and cell proliferation. Because mTOR is also integral in allowing lymphocytes to enter the S phase, everolimus is also effectively a T-cell inhibitor.
      Part of the pathophysiology of wet AMD is thought to involve the immune system. Indeed, there are associations between AMD and complement factor H,
      • Haines J.L.
      • Hauser M.A.
      • Schmidt S.
      • et al.
      Complement factor H variant increases the risk of age-related macular degeneration.
      and with high temperature serine protease (HTRA-1)
      • Yang Z.
      • Camp N.J.
      • Sun H.
      • et al.
      A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration.
      —which is thought to regulate tumor necrosis factor-beta and cleaves fibronectin. Fas ligand has also been shown to play a role in the inhibition of angiogenesis in the retinal pigment epithelium.
      • Kaplan H.J.
      • Leibole M.A.
      • Tezel T.
      • Ferguson T.A.
      Fas ligand (CD95 ligand) controls angiogenesis beneath the retina.
      Indeed, systemic immunosuppression, specifically sirolimus, has been shown to inhibit choroidal neovascularization in animal models.
      • Dejneka N.S.
      • Kuroki A.M.
      • Fosnot J.
      • Tang W.
      • Tolentino M.J.
      • Bennett J.
      Systemic rapamycin inhibits retinal and choroidal neovascularization in mice.
      However, intravitreal corticosteroids have been shown to not be effective in treating wet AMD.
      • Lee J.
      • Freeman W.R.
      • Azen S.P.
      • Chung E.J.
      • Koh H.J.
      Prospective, randomized clinical trial of intravitreal triamcinolone treatment of neovascular age-related macular degeneration: one-year results.
      A small pilot study did seem to suggest that systemic immunosuppression could decrease the number of anti-vascular endothelial growth factor injections needed.
      • Nussenblatt R.B.
      • Byrnes G.
      • Sen H.N.
      • et al.
      A randomized pilot study of systemic immunosuppression in the treatment of age-related macular degeneration with choroidal neovascularization.
      Everolimus is a derivative of sirolimus—both are mTOR inhibitors. In the Study Assessing double-masKed Uveitis tREAtrement 1 study, patients with uveitis were randomized to 44, 440, and 880 mcg of intravitreal sirolimus.
      • Nguyen Q.D.
      • Merrill P.T.
      • Clark W.L.
      • et al.
      Intravitreal sirolimus for noninfectious uveitis: a Phase III Sirolimus Study Assessing Double-masKed Uveitis TReAtment (SAKURA).
      The primary outcome was the control of inflammation—the 440 and 880 mcg groups were the intervention arms and compared with the 44 mcg group, which was the minimal dose calculated to have any therapeutic effect according to regression models. Although the 440 and 880 mcg groups showed the best control of inflammation, all 3 groups showed similar reductions in macular edema—in around half of the patients. Subconjunctival and intravitreal sirolimus has also been shown to decrease diabetic macular edema.
      • Dugel P.U.
      • Blumenkranz M.S.
      • Haller J.A.
      • et al.
      A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema.
      To the best of our knowledge, this is the first documented case of wet age-related macular degeneration that has responded to everolimus. Causality is supported by the temporal relationship between the initiation of everolimus with the near resolution of intraretinal fluid and the subsequent cessation of everolimus with the return of intraretinal fluid. More research, such as with a pilot study, would help further characterize the effect of everolimus on wet AMD and possibly open up a new avenue of therapy.

      Footnotes and Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

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