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Exploring the angiographic-biologic phenotype in the IMAGINE study: quantitative UWFA and cytokine expression
  1. Joseph R Abraham1,
  2. Charles C Wykoff2,3,
  3. Sruthi Arepalli4,
  4. Leina Lunasco1,
  5. Hannah J Yu2,
  6. Alison Martin1,
  7. Christopher Mugnaini1,
  8. Ming Hu1,5,
  9. Jamie Reese1,
  10. Sunil K Srivastava1,4,
  11. David M Brown2,3,
  12. Justis P Ehlers1,4
  1. 1 The Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research, Cleveland Clinic Cole Eye Institute, Cleveland, Ohio, USA
  2. 2 Retina Consultants of Texas, Retina Consultants of America, Houston, Texas, USA
  3. 3 Blanton Eye Institute, Houston Methodist Hospital & Weill Cornell Medical College, Houston, Texas, USA
  4. 4 Vitreoretinal Service, Cleveland Clinic Cole Eye Institute, Cleveland, Ohio, USA
  5. 5 Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
  1. Correspondence to Dr Justis P Ehlers, Cleveland Clinic Cole Eye Institute, Cleveland, Ohio, USA; ehlersj1{at}


Background This study investigates the association of intraocular cytokine expression and ultrawide-field fluorescein angiography (UWFA) quantitative imaging biomarkers and their association with angiographical feature response after antivascular endothelial growth factor (VEGF) therapy in diabetic macular oedema (DME).

Methods The IMAGINE DME study is a post hoc imaging biomarker and intraocular cytokine assessment from the DAVE study, a prospective DME clinical trial that included aqueous humour sampling and UWFA imaging. Fifty-four cytokines associated with inflammation and angiogenesis were evaluated through multiplex arrays. UWFA parameters were assessed using an automated feature analysis platform to determine ischaemic and leakage indices and microaneurysm (MA) count. Eyes were classified into UWFA responder or non-responder groups based on longitudinal quantitative UWFA parameter improvement. Cytokine expression was correlated with UWFA metrics and evaluated in the context of therapeutic response.

Results Twenty-one eyes were included with a mean age of 55±10 years. Increased panretinal leakage index correlated with VEGF (r=0.70, p=0.0005), angiopoietin-like 4 (r=0.77, p=4.6E-5) and interleukin (IL)-6 (r=0.64, p=0.002). Panretinal ischaemic index was associated with tissue inhibitor of metalloproteinases 1 (TIMP-1, r=0.49, p=0.03) and peripheral ischaemia correlated with VEGF (r=0.45, p=0.05). MA count correlated with increased monocyte chemotactic protein-4 (MCP-4, r=0.60, p=0.004) and platelet and endothelial cell adhesion molecule 1 (PECAM-1, r=0.58, p=0.005). Longitudinal MA reduction was associated with decreased baseline VEGF and urokinase receptor (uPAR) (p<0.05). High baseline VEGF and IL-6 were associated with dramatic reduction in macular leakage (p<0.05).

Conclusions Baseline and longitudinal quantitative UWFA imaging parameters correlated with multiple aqueous humour cytokine concentrations, including VEGF and IL-6. Further research is needed to assess the possible implications of using these findings for evaluating treatment response.

  • aqueous humour
  • imaging
  • retina
  • macula

Data availability statement

Data are available upon reasonable request.

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Data availability statement

Data are available upon reasonable request.

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  • Contributors JRA: formal analysis, investigation, writing (original draft) and project administration. CCW: resources, investigation, supervision, writing (review and editing). SA: formal analysis and writing (review and editing). LL: formal analysis, investigation, project administration and writing (review and editing).HJY: investigation and writing (review and editing). AM: formal analysis. CM and MH: formal analysis. JR: supervision and project administration. SKS: resources and writing (review and editing). DMB: resources, investigation and writing (review and editing. JPE: conceptualisation, resources, methodology, software, writing (review and editing), supervision, project administration and funding acquisition.

  • Funding JPE: RPB Unrestricted Grant to the Cole Eye Institute. RPB1508DM; NIH K23-EY022947. Regeneron REGE1901JE; JRA: Betty Powers Retina Research Fellowship. No associated grant number. The funding organisations and sources had no role in the design or conduct of this research.

  • Competing interests JRA, SA, LL, HJY, MH, JR: none; CCW, Adverum (research funding (F)), Alimera Sciences (consultant (C)) Allergan (C, F), Allegro (C), Apellis (C, F), Alynylam (C), Bayer (C), Clearside (C, F), DORC (C), EyePoint (C, F), Genentech/Roche (C, F), Kodiak (C), Neurotech (F), Notal Vision (C), ONL Therapeutics (C), Novartis (C, F), Polyphontonix (C), Regeneron (C, F, S), Regenxbio (C, F), Samsung (F), Santen (C, F); SKS: Regeneron (F), Allergan (F), Gilead (F), Bausch and Lomb (C), Santen (C), Leica (patent (P)); DMB, Adverum (F) Allergan (C, F), Apellis (F), Bayer (C), Biotime (C), Clearside (F), Chengdu Kanghong Biotechnology (C), Gemini (C), Genentech/Roche (C, F), Heidelberg (C), Novartis (C, F), OHR (C), Opthea (F), Optos (C), Zeiss (C), Regeneron (C, F), Regenxbio (C, F), Samsung (F), Santen (C), Senju (C); JPE: Aerpio (C, F), Alcon (C, F), Thrombogenics/Oxurion (C, F), Regeneron (C, F), Genetech (C, F), Novartis (C,F), Allergan (C, F), Roche (C), Leica (C, P), Zeiss (C), Santen (C).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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