Skip to main content

Advertisement

SpringerLink
Log in

Cytokine profiles in the aqueous humor following brolucizumab administration for exudative age-related macular degeneration

  • Retinal Disorders
  • Published:
Graefe's Archive for Clinical and Experimental Ophthalmology Aims and scope Submit manuscript

Abstract

Purpose

To identify the inflammatory cytokine profile in the aqueous humor (AH) of patients with intraocular inflammation (IOI) after intravitreal administration of brolucizumab (IVBr) for neovascular age-related macular degeneration.

Methods

Eight eyes from seven patients with IOI after initial IVBr (IVBrIOI +) were enrolled. Sixteen eyes from 16 patients without IOI after IVBr (IVBrIOI −) and aflibercept (IVA) were used as controls. AH samples were analyzed using a multiplex immunoassay.

Results

C–C motif chemokine ligand (CCL)2, C-X-C motif chemokine ligand (CXCL)1, CXCL10, CXCL13, interleukin (IL)-6, IL-8, IL-10, matrix metalloproteinase (MMP)-1, MMP-9, granulocyte colony-stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), intercellular adhesion molecule (ICAM)-1, E-selectin, and P-selectin levels were significantly higher in IVBrIOI + than in IVBrIOI − and IVA. Vascular endothelial growth factor (VEGF) was significantly lower in IVBrIOI − compared to that in IVBrIOI + and IVA. In the IVBrIOI + group, there were significant correlations between CCL2, CXCL1, IL-6, IL-8, IL-10, G-CSF, GM-CSF, ICAM-1, and E-selectin, which also exhibited significant correlations in the IVBrIOI − group.

Conclusion

The number of inflammatory cytokines increases during IOI, which is associated with type IV hypersensitivity and vascular inflammation. Some cytokines exhibit correlations even in non-inflamed eyes, indicating a subclinical response to IVBr.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Apte RS (2021) Age-related macular degeneration. N Engl J Med 385:539–547. https://doi.org/10.1056/NEJMcp2102061

    Article  PubMed  PubMed Central  Google Scholar 

  2. Schmidt-Erfurth U, Waldstein SM (2016) A paradigm shift in imaging biomarkers in neovascular age-related macular degeneration. Prog Retin Eye Res 50:1–24. https://doi.org/10.1016/j.preteyeres.2015.07.007

    Article  CAS  PubMed  Google Scholar 

  3. Schmidt-Erfurth U, Chong V, Loewenstein A, Larsen M, Souied E, Schlingemann R, Eldem B, Mones J, Richard G, Bandello F, European Society of Retina S (2014) Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). Br J Ophthalmol 98:1144–1167. https://doi.org/10.1136/bjophthalmol-2014-305702

    Article  Google Scholar 

  4. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY, Group MS (2006) Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 355:1419–1431. https://doi.org/10.1056/NEJMoa054481

    Article  Google Scholar 

  5. Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Groetzbach G, Sommerauer B, Sandbrink R, Simader C, Schmidt-Erfurth U, View, Groups VS (2012) Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 119:2537–2548. https://doi.org/10.1016/j.ophtha.2012.09.006

    Article  Google Scholar 

  6. Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J, Weichselberger A, Holz FG, Hawk IHS (2020) HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 127:72–84. https://doi.org/10.1016/j.ophtha.2019.04.017

    Article  PubMed  Google Scholar 

  7. Dugel PU, Singh RP, Koh A, Ogura Y, Weissgerber G, Gedif K, Jaffe GJ, Tadayoni R, Schmidt-Erfurth U, Holz FG (2021) HAWK and HARRIER: ninety-six-week outcomes from the phase 3 trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 128:89–99. https://doi.org/10.1016/j.ophtha.2020.06.028

    Article  PubMed  Google Scholar 

  8. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, Brown DM, Chong V, Nguyen QD, Ho AC, Ogura Y, Simader C, Jaffe GJ, Slakter JS, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Sowade O, Zeitz O, Norenberg C, Sandbrink R, Heier JS (2014) Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 121:193–201. https://doi.org/10.1016/j.ophtha.2013.08.011

    Article  PubMed  Google Scholar 

  9. Iyer PG, Peden MC, Suner IJ, Patel N, Dubovy SR, Albini TA (2020) Brolucizumab-related retinal vasculitis with exacerbation following ranibizumab retreatment: a clinicopathologic case study. Am J Ophthalmol Case Rep 20:100989. https://doi.org/10.1016/j.ajoc.2020.100989

    Article  PubMed  PubMed Central  Google Scholar 

  10. Haug SJ, Hien DL, Uludag G, Ngoc TTT, Lajevardi S, Halim MS, Sepah YJ, Do DV, Khanani AM (2020) Retinal arterial occlusive vasculitis following intravitreal brolucizumab administration. Am J Ophthalmol Case Rep 18:100680. https://doi.org/10.1016/j.ajoc.2020.100680

    Article  PubMed  PubMed Central  Google Scholar 

  11. Jain A, Chea S, Matsumiya W, Halim MS, Yasar C, Kuang G, Sepah YJ, Khanani AM, Do DV, Nguyen QD (2020) Severe vision loss secondary to retinal arteriolar occlusions after multiple intravitreal brolucizumab administrations. Am J Ophthalmol Case Rep 18:100687. https://doi.org/10.1016/j.ajoc.2020.100687

    Article  PubMed  PubMed Central  Google Scholar 

  12. Baumal CR, Spaide RF, Vajzovic L, Freund KB, Walter SD, John V, Rich R, Chaudhry N, Lakhanpal RR, Oellers PR, Leveque TK, Rutledge BK, Chittum M, Bacci T, Enriquez AB, Sund NJ, Subong ENP, Albini TA (2020) Retinal vasculitis and intraocular inflammation after intravitreal injection of brolucizumab. Ophthalmology 127:1345–1359. https://doi.org/10.1016/j.ophtha.2020.04.017

    Article  PubMed  Google Scholar 

  13. Maruko I, Okada AA, Iida T, Hasegawa T, Izumi T, Kawai M, Maruko R, Nakayama M, Yamamoto A, Koizumi H, Tamashiro T, Terao N, Wakugawa S, Mori R, Onoe H, Tanaka K, Wakatsuki Y, Itagaki K, Kasai A, Ogasawara M, Sekiryu T, Shintake H, Sugano Y, Japan AMDRC (2021) Brolucizumab-related intraocular inflammation in Japanese patients with age-related macular degeneration: a short-term multicenter study. Graefes Arch Clin Exp Ophthalmol 259:2857–2859. https://doi.org/10.1007/s00417-021-05136-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Inoda S, Takahashi H, Inoue Y, Tan X, Tampo H, Arai Y, Yanagi Y, Kawashima H (2022) Cytokine profiles of macular neovascularization in the elderly based on a classification from a pachychoroid/drusen perspective. Graefes Arch Clin Exp Ophthalmol 260:747–758. https://doi.org/10.1007/s00417-021-05445-0

    Article  CAS  PubMed  Google Scholar 

  15. Joo JH, Kim H, Shin JH, Moon SW (2021) Aqueous humor cytokine levels through microarray analysis and a sub-analysis based on optical coherence tomography in wet age-related macular degeneration patients. BMC Ophthalmol 21:399. https://doi.org/10.1186/s12886-021-02152-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sijssens KM, Rijkers GT, Rothova A, Stilma JS, Schellekens PA, de Boer JH (2007) Cytokines, chemokines and soluble adhesion molecules in aqueous humor of children with uveitis. Exp Eye Res 85:443–449. https://doi.org/10.1016/j.exer.2007.06.011

    Article  CAS  PubMed  Google Scholar 

  17. Martin CM, Lacomba MS, Molina CI, Chamond RR, Galera JM, Estevez EC (2000) Levels of soluble ICAM-1 and soluble IL-2R in the serum and aqueous humor of uveitis patients. Curr Eye Res 20:287–292

    Article  CAS  PubMed  Google Scholar 

  18. Spindler J, Zandi S, Pfister IB, Gerhardt C, Garweg JG (2018) Cytokine profiles in the aqueous humor and serum of patients with dry and treated wet age-related macular degeneration. PLoS One 13:0203337. https://doi.org/10.1371/journal.pone.0203337

    Article  CAS  Google Scholar 

  19. Abu El-Asrar AM, Berghmans N, Al-Obeidan SA, Gikandi PW, Opdenakker G, Van Damme J, Struyf S (2020) Local cytokine expression profiling in patients with specific autoimmune uveitic entities. Ocul Immunol Inflamm 28: 453–462 https://doi.org/10.1080/09273948.2019.1604974

  20. Park J, Kim JT, Lee SJ, Kim JC (2020) The anti-inflammatory effects of angiogenin in an endotoxin induced uveitis in rats. Int J Mol Sci 21 https://doi.org/10.3390/ijms21020413

  21. Garcia-Otero X, Mondelo-Garcia C, Gonzalez F, Perez-Fernandez R, Avila L, Antunez-Lopez JR, Gonzalez-Barcia M, Adan A, Aguiar P, Otero-Espinar FJ, Bermudez MA, Fernandez-Ferreiro A (2021) Anti-inflammatory effect of tacrolimus/hydroxypropyl-beta-cyclodextrin eye drops in an endotoxin-induced uveitis model. Pharmaceutics 13 https://doi.org/10.3390/pharmaceutics13101737

  22. Wilkerson RG (2022) Drug hypersensitivity reactions. Emerg Med Clin North Am 40:39–55. https://doi.org/10.1016/j.emc.2021.09.001

    Article  PubMed  Google Scholar 

  23. Phillips EJ, Bigliardi P, Bircher AJ, Broyles A, Chang YS, Chung WH, Lehloenya R, Mockenhaupt M, Peter J, Pirmohamed M, Roujeau JC, Shear NH, Tanno LK, Trubiano J, Valluzzi R, Barbaud A (2019) Controversies in drug allergy: testing for delayed reactions. J Allergy Clin Immunol 143:66–73. https://doi.org/10.1016/j.jaci.2018.10.030

    Article  CAS  PubMed  Google Scholar 

  24. Dispenza MC (2019) Classification of hypersensitivity reactions. Allergy Asthma Proc 40:470–473. https://doi.org/10.2500/aap.2019.40.4274

    Article  CAS  PubMed  Google Scholar 

  25. Isabwe GAC, Garcia Neuerde Las Vecillas Sanchez L, Lynch DM, Marquis K, Castells M, M (2018) Hypersensitivity reactions to therapeutic monoclonal antibodies: phenotypes and endotypes. J Allergy Clin Immunol 142(159–170):152. https://doi.org/10.1016/j.jaci.2018.02.018

    Article  CAS  Google Scholar 

  26. Morgenstern-Kaplan D, Vasquez-Echeverri E, Carrillo-Martin I, Chiarella SE, Gonzalez-Estrada A (2021) Cytokine-release hypersensitivity reaction after the first dose of benralizumab for severe eosinophilic asthma. Ann Allergy Asthma Immunol 127:701–702. https://doi.org/10.1016/j.anai.2021.08.006

    Article  CAS  PubMed  Google Scholar 

  27. Witkin AJ, Hahn P, Murray TG, Arevalo JF, Blinder KJ, Choudhry N, Emerson GG, Goldberg RA, Kim SJ, Pearlman J, Schneider EW, Tabandeh H, Wong RW (2020) Occlusive retinal vasculitis following intravitreal brolucizumab. J Vitreoretin Dis 4:269–279. https://doi.org/10.1177/2474126420930863

    Article  PubMed  PubMed Central  Google Scholar 

  28. Demerath E, Towne B, Blangero J, Siervogel RM (2001) The relationship of soluble ICAM-1, VCAM-1, P-selectin and E-selectin to cardiovascular disease risk factors in healthy men and women. Ann Hum Biol 28:664–678. https://doi.org/10.1080/03014460110048530

    Article  CAS  PubMed  Google Scholar 

  29. Hayashi S, Watanabe N, Nakazawa K, Suzuki J, Tsushima K, Tamatani T, Sakamoto S, Isobe M (2000) Roles of P-selectin in inflammation, neointimal formation, and vascular remodeling in balloon-injured rat carotid arteries. Circulation 102:1710–1717. https://doi.org/10.1161/01.cir.102.14.1710

    Article  CAS  PubMed  Google Scholar 

  30. Jaakkola K, Jalkanen S, Kaunismaki K, Vanttinen E, Saukko P, Alanen K, Kallajoki M, Voipio-Pulkki LM, Salmi M (2000) Vascular adhesion protein-1, intercellular adhesion molecule-1 and P-selectin mediate leukocyte binding to ischemic heart in humans. J Am Coll Cardiol 36:122–129. https://doi.org/10.1016/s0735-1097(00)00706-3

    Article  CAS  PubMed  Google Scholar 

  31. Chen YH, Lightman S, Eskandarpour M, Calder VL (2022) Adhesion molecule targeted therapy for non-infectious uveitis. Int J Mol Sci 23 https://doi.org/10.3390/ijms23010503

  32. Avaylon J, Lee S, Gallemore RP (2020) Case series on initial responses to intravitreal brolucizumab in patients with recalcitrant chronic wet age-related macular degeneration. Int Med Case Rep J 13:145–152. https://doi.org/10.2147/IMCRJ.S252260

    Article  PubMed  PubMed Central  Google Scholar 

  33. Tietz J, Spohn G, Schmid G, Konrad J, Jampen S, Maurer P, Schmidt A, Escher D (2015) Affinity and potency of RTH258 (ESBA1008), a novel inhibitor of vascular endothelial growth factor A for the treatment of retinal disorders. Invest Ophthalmol Vis Sci 56:1501–1501

    Google Scholar 

  34. Chakraborty D, Sheth JU, Mondal S, Boral S (2022) Role of intravitreal brolucizumab with intravitreal rtPA and pneumatic displacement for submacular hemorrhage: a case series. Am J Ophthalmol Case Rep 25:101390. https://doi.org/10.1016/j.ajoc.2022.101390

    Article  PubMed  PubMed Central  Google Scholar 

  35. Tadayoni R, Sararols L, Weissgerber G, Verma R, Clemens A, Holz FG (2021) Brolucizumab: a newly developed anti-VEGF molecule for the treatment of neovascular age-related macular degeneration. Ophthalmologica 244:93–101. https://doi.org/10.1159/000513048

    Article  CAS  PubMed  Google Scholar 

  36. Takahashi H, Nomura Y, Nishida J, Fujino Y, Yanagi Y, Kawashima H (2016) Vascular endothelial growth factor (VEGF) concentration is underestimated by enzyme-linked immunosorbent assay in the presence of anti-VEGF drugs. Invest Ophthalmol Vis Sci 57:462–466. https://doi.org/10.1167/iovs.15-18245

    Article  CAS  PubMed  Google Scholar 

  37. Becher B, Spath S, Goverman J (2017) Cytokine networks in neuroinflammation. Nat Rev Immunol 17:49–59. https://doi.org/10.1038/nri.2016.123

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Mayumi Chiba for technical assistance and Editage (www.editage.com) for English language editing.

Author information

Authors and Affiliations

  1. Department of Ophthalmology, Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan

    Ryo Terao, Ryo Obata, Atsushi Okubo, Shuichiro Aoki, Keiko Azuma & Tazbir Ahmed

  2. Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA

    Ryo Terao

  3. Department of Ophthalmology, Jichi Medical University, Tochigi, Japan

    Satoru Inoda, Yuto Hashimoto, Ryota Takahashi, Hana Yoshida, Manami Misawa, Hironori Takahashi & Hidenori Takahashi

Authors
  1. Ryo Terao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ryo Obata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Atsushi Okubo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuichiro Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Keiko Azuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tazbir Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Satoru Inoda
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yuto Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ryota Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hana Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Manami Misawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hironori Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Hidenori Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ryo Obata.

Ethics declarations

Ethics approval

This study involves human participants and was approved by the Institutional Board of Jichi Medical University Hospital (Ethics approval number: CU22-R003).

Competing interests

Ryo Obata received honoraria for speaking/consulting from Santen, Bayer, Novartis, Chugai, Senju, and Boehringer Ingelheim.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Terao, R., Obata, R., Okubo, A. et al. Cytokine profiles in the aqueous humor following brolucizumab administration for exudative age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 261, 2465–2476 (2023). https://doi.org/10.1007/s00417-023-06038-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00417-023-06038-9

Keywords

Search

Navigation