title: Systemic counterregulatory response of placental growth factor levels to intravitreal aflibercept therapy.
abstract: OBJECTIVE
  Placental growth factor (PlGF) has been implicated as a contributor to resistance against anti-VEGF therapy. The purpose of the present study was to analyze the systemic levels of PlGF, VEGF-A, and VEGF-B in patients with neovascular age-related macular degeneration (AMD) after treatment with aflibercept, ranibizumab, or bevacizumab.
  
  
  METHODS
  Totals of 19 patients were treated with intravitreal aflibercept, 19 with ranibizumab, and 18 with bevacizumab. The cytokine levels were measured by ELISA just before the injection, and 7 days and 1 month thereafter. Age- and sex-matched participants (n = 22) served as controls.
  
  
  RESULTS
  The median PlGF plasma concentration at baseline was <12.0 pg/mL in the control group as well as in all three anti-VEGF treatment cohorts. After intravitreal aflibercept injection, a significant upregulation of systemic PlGF could be observed in all treated patients (38.0 [31.0-44.0] pg/mL after 1 week [P < 0.001] and 16.0 [0.0-19.0] pg/mL [P = 0.005] after 4 weeks). No significant effects on plasma PlGF concentrations could be detected in those treated with ranibizumab and bevacizumab. The systemic VEGF-A levels were significantly reduced 1 and 4 weeks after intravitreal aflibercept (P < 0.001, P < 0.001) and bevacizumab (P < 0.001, P < 0.01) injections. No significant effects on plasma cytokine concentrations could be observed in the ranibizumab cohort. No significant effects on systemic VEGF-B could be observed in any of the treatment groups.
  
  
  CONCLUSIONS
  In this study, we report a significant systemic upregulation of the proangiogenic cytokine PlGF after intravitreal administration of aflibercept. This might represent a counter-regulatory response to antiangiogenic therapy.
authors.affiliation: Department of Ophthalmology Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Claus
authors.initials: C
authors.lastname: Zehetner
authors.affiliation: Department of Ophthalmology Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Nikolaos E
authors.initials: NE
authors.lastname: Bechrakis
authors.affiliation: Department of Ophthalmology Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Stattin
authors.affiliation: Department of Internal Medicine, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Kirchmair
authors.affiliation: Department of Medical Statistics, Informatics and Health Economics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Hanno
authors.initials: H
authors.lastname: Ulmer
authors.affiliation: Department of Ophthalmology Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Martina T
authors.initials: MT
authors.lastname: Kralinger
authors.affiliation: Department of Ophthalmology Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Gerhard F
authors.initials: GF
authors.lastname: Kieselbach
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D008297:Male; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000068258:Bevacizumab; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000097:blood / Q000188:drug therapy; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000097:blood; D011446:Prospective Studies; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000097:blood; D014792:Visual Acuity
chemical_list: C533178:aflibercept; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D016207:Cytokines; C000608036:PGF protein, human; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D042461:Vascular Endothelial Growth Factor A