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Original Investigation
April 2018

Aqueous Humor Cytokine Levels and Anatomic Response to Intravitreal Ranibizumab in Diabetic Macular Edema

Author Affiliations
  • 1Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, Ontario, Canada
  • 2Department of Ophthalmology, St. Michael’s Hospital, Toronto, Ontario, Canada
  • 3Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
  • 4Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom
  • 5Save Sight Institute, University of Sydney, Sydney, Australia
  • 6Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  • 7The John and Liz Tory Eye Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
  • 8Department of Ophthalmology and Visual Sciences, University of British Columbia, Vancouver, British Columbia, Canada
  • 9Centre for Research on Inner City Health, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
  • 10Kensington Vision and Research Centre, Toronto, Ontario, Canada
JAMA Ophthalmol. 2018;136(4):382-388. doi:10.1001/jamaophthalmol.2018.0179
Key Points

Question  Are particular aqueous cytokines associated with anatomic response to ranibizumab in patients with diabetic macular edema?

Findings  A prospective cohort study of 48 study participants found that elevated intercellular adhesion molecule 1 and reduced vascular endothelial growth factor levels at baseline were associated with favorable anatomic response following 3 monthly injections of ranibizumab for diabetic macular edema.

Meaning  These findings suggest aqueous biomarkers of anatomic response have the potential to guide treatment algorithms for anti–vascular endothelial growth factor therapy for diabetic macular edema.


Importance  Variability in response to anti–vascular endothelial growth factor (VEGF) treatment in diabetic macular edema (DME) remains a significant clinical challenge. Biomarkers could help anticipate responses to anti-VEGF therapy.

Objectives  To investigate aqueous humor cytokine level changes in response to intravitreal ranibizumab therapy for the management of DME, and to determine the association between baseline aqueous levels and anatomic response.

Design, Setting, and Participants  In this prospective multicenter cohort study, 49 participants with diabetes mellitus complicated by center-involving DME, with a central subfield thickness of 310 μm or greater on spectral-domain optical coherence tomography (SD-OCT), were recruited from December 22, 2011, to June 13, 2013 and statistical analysis were performed from March 1, 2017, to June 1, 2017. A total of 48 participants proceeded to follow-up.

Interventions  Participants received monthly injections of ranibizumab, 0.5 mg, for 3 months. Aqueous fluid for cytokine analysis was obtained at baseline and repeated at the 2-month visit. Multiplex immunoassay was carried out in duplicate for VEGF, placental growth factor, transforming growth factor beta 2, intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), IL-8, IL-10, vascular intercellular adhesion molecule, and monocyte chemoattractant protein 1.

Main Outcomes and Measures  Baseline and 2-month change in aqueous cytokine levels, 3-month change in SD-OCT central subfield thickness and macular volume (MV), and the statistical association between baseline aqueous cytokine levels and these measures of anatomic response to ranibizumab in center-involving DME.

Results  Among the 48 participants, the mean (SD) age was 61.9 (7.1) years and 36 participants (75.0%) were men. The following cytokines were lower at month 2 vs baseline: ICAM-1 (median change, −190.88; interquartile range [IQR], −634.20 to −26.54; P < .001), VEGF (median change, −639.45; IQR, −1040.61 to −502.61; P < .001), placental growth factor (median change, −1.31; IQR, −5.99 to −0.01; P < .001), IL-6 (median change, −38.61; IQR, −166.72 to −2.80; P < .001), and monocyte chemoattractant protein 1 (median change, −90.13; IQR, −382.74 to 109.47; P = .01). When controlling for age, foveal avascular zone size, and severity of retinopathy, multiple linear regression determined that increasing baseline aqueous ICAM-1 was associated with a favorable anatomic response, in terms of reduced SD-OCT MV at 3 months (every additional 100 pg/mL of baseline ICAM-1 was associated with a reduction of 0.0379 mm3; P = .01). Conversely, increasing baseline aqueous VEGF was associated with a less favorable SD-OCT MV response at 3 months (every additional 100 pg/mL of baseline VEGF was associated with an increase of 0.0731 mm3; P = .02) and was associated with lower odds of being a central subfield thickness responder (odds ratio, 0.868; 95% CI, 0.755-0.998).

Conclusions and Relevance  Elevated aqueous ICAM-1 and reduced VEGF levels at baseline are associated with a favorable anatomic response to ranibizumab in DME, although there is not always direct correlation between anatomic and visual acuity response.