Aqueous Interleukin-6 (IL-6) Level Is a Marker for Treatment Resistance to Bevacizumab in Age-Related Macular Degeneration —Aqueous Cytokines after Bevacizumab


Background: To prospectively evaluate the effect of intravitreal bevacizumab on aqueous levels of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) in patients with exudative age-related macular degeneration (AMD) and to correlate clinical outcomes of patients and aqueous cytokine levels before and after injection. Methods: The study group consisted of 30 eyes from 30 patients with exudative AMD who underwent intravitreal injection of bevacizumab three times at monthly intervals. The aqueous samples prior to the 1st injection (baseline) and 3rd injection were analyzed for VEGF and IL-6 levels, evaluating the effect of 2 doses of intravitreal bevacizumab. Study patients were sub-grouped based upon change in central subfield (CSF) macular thickness on SD-OCT, at 8 weeks. Group 1 included patients (n = 14) with a decrease in CSF thickness greater than 10% from the baseline and were categorized to have improved. Group 2 included patients (n = 16) who had a decrease in CSF thickness 10% or less and were considered treatment-resistant. Results: There was no statistically significant change in aqueous VEGF and IL-6 levels after intravitreal bevacizumab. In sub-group analysis, in both Groups 1 and 2 patients, aqueous IL-6 levels showed a better correlation with CSF thickness on SD-OCT (r = 0.72 and 0.71, respectively). Conclusions: Data from our study suggest that aqueous IL-6 may be an important marker of treatment response or resistance. Future therapeutic strategies may include targeted treatment against both VEGF and IL-6, in patients who do not respond to anti-VEGF treatment alone.

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Chalam, K. , Grover, S. , Balaiya, S. and Murthy, R. (2014) Aqueous Interleukin-6 (IL-6) Level Is a Marker for Treatment Resistance to Bevacizumab in Age-Related Macular Degeneration —Aqueous Cytokines after Bevacizumab. Open Journal of Ophthalmology, 4, 24-30. doi: 10.4236/ojoph.2014.41005.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] N. Congdon, B. O’Colmain, C. C. Klaver, R. Klein, B. Munoz, D. S. Friedman, J. Kempen, H. R. Taylor and P. Mitchell, Eye Diseases Prevalence Research Group, “Causes and Prevalence of Visual Impairment among Adults in the United States,” Archives of Ophthalmology, Vol. 122, No. 4, 2004, pp. 477-485.
[2] J. Seddon and C. Chen, “The Epidemiology of Age Related Macular Degeneration,” In: J. Heier, Ed., Controversies and Advancement in the Treatment of Retinal Disease, Lippincott Williams & Wilkins, Philadelphia, 2004, pp. 17-39.
[3] W. Richard Green, “Histopathology of Age-Related Macular Degeneration,” Molecular Vision, Vol. 5, 1999, pp. 27-36.
[4] E. J. Duh, H. S. Yang, J. A. Haller, E. De Juan, M. S. Humayun, P. Gehlbach, M. Melia, D. Pieramici, J. B. Harlan, P. A. Campochiaro and D. J. Zack, “Vitreous Levels of Pigment Epithelium-Derived Factor and Vascular Endothelial Growth Factor: Implications for Ocular Angiogenesis,” American Journal of Ophthalmology, Vol. 137, No. 4, 2004, pp. 668-674.
[5] L. P. Aiello, R. L. Avery, P. G. Arrigg, B. A. Keyt, H. D. Jampel, S. T. Shah, L. R. Pasquale, H. Thieme, M. A. Iwamoto, J. E. Park, H. V. Nguyen, L. M. Aiello, N. Ferrara and G. L. King, “Vascular Endothelial Growth Factor in Ocular Fluid of Patients with Diabetic Retinopathy and Other Retinal Disorders,” The New England Journal of Medicine, Vol. 331, No. 22, 1994, pp. 1480-1487.
[6] E. S. Gragoudas, A. P. Adamis, E. T. Cunningham Jr., M. Feinsod and D. R. Guyer, “Pegaptanib for Neovascular Age-Related Macular Degeneration,” The New England Journal of Medicine, Vol. 351, No 27, 2004, pp. 2805-2816.
[7] D. M. Brown, P. K. Kaiser, M. Michels, G. Soubrane, J. S. Heier, R. Y. Kim, J. P. Sy and S. Schneider, ANCHOR Study Group, “Ranibizumab versus Verteporfin for Neovascular Age-Related Macular Degeneration,” The New England Journal of Medicine, Vol. 355, No. 14, 2006, pp. 1432-1444.
[8] R. L. Avery, D. J. Pieramici, M. D. Rabena, A. A. Castellarin, M. A. Nasir and M. J. Giust, “Intravitreal Bevacizumab (Avastin) for Neovascular Age-Related Macular Degeneration,” Ophthalmology, Vol. 113, No. 3, 2006, pp. 363.e5-372.e5.
[9] A. Kijlstra, E. C. La Heij and F. Hendrikse, “Immunological Factors in the Pathogenesis and Treatment of AgeRelated Macular Degeneration,” Ocular Immunology and Inflammation, Vol. 13, No. 1, 2005, pp. 3-11.
[10] A. Kvanta, P. V. Algvere, L. Berglin and S. Seregard, “Subfoveal Fibrovascular Membranes in Age-Related Macular Degeneration Express Vascular Endothelial Growth Factor,” Investigative Ophthalmology & Visual Science, Vol. 37, No. 9, 1996, pp. 1929-1934.
[11] T. Cohen, D. Nahari, L. W. Cerem, G. Neufeld and B. Z. Levi, “Interleukin 6 Induces the Expression of Vascular Endothelial Growth Factor,” The Journal of Biological Chemistry, Vol. 271, No. 2, 1996, pp. 736-741.
[12] A. Saidi, M. Hagedorn, N. Allain, C. Verpelli, C. Sala, L. Bello, A. Bikfalvi and S. Javerzat, “Combined Targeting of Interleukin-6 and Vascular Endothelial Growth Factor Potently Inhibits Glioma Growth and Invasiveness,” International Journal of Cancer, Vol. 125, No. 5, 2009, pp. 1054-1064.
[13] J. M. Seddon, S. George, B. Rosner and N. Rifai, “Progression of Age-Related Macular Degeneration: Prospective Assessment of C-Reactive Protein, Interleukin 6, and Other Cardiovascular Biomarkers,” Archives of Ophthalmology, Vol. 123, No. 6, 2005, pp. 774-782.
[14] R. K. Sharma, A. T. Rogojina and K. V. Chalam, “Bevacizumab Therapy Normalizes the Pathological Intraocular Environment beyond Neutralizing VEGF,” Molecular Vision, Vol. 16, 2010, pp. 2175-2184.
[15] K. V. Chalam, S. Balaiya and R. K. Murthy, “Accurate Estimation of Vascular Endothelial Growth Factor Levels in Microsamples with a Low-Cost Bead-Based Assay,” Retina, Vol. 30, No. 5, 2010, pp. 815-819.
[16] H. Noma, H. Funatsu, M. Yamasaki, H. Tsukamoto, T. Mimura, T. Sone, T. Hirayama, H. Tamura, H. Yamashita, A. Minamoto and H. K. Mishima, “Aqueous Humour Levels of Cytokines Are Correlated to Vitreous Levels and Severity of Macular Oedema in Branch Retinal Vein Occlusion,” Eye, Vol. 22, No. 1, 2008, pp. 42-48.
[17] M. I. Roh, S. J. Lim, J. M. Ahn, J. B. Lim and O. W. Kwon, “Concentration of Cytokines in Age-Related Macular Degeneration after Consecutive Intravitreal Bevacizumab Injection,” Graefe’s Archive for Clinical and Experimental Ophthalmology, Vol. 248, No. 5, 2010, pp. 635-640.
[18] M. Funk, G. Schmidinger, N. Maar, M. Bolz, T. Benesch and G. J. Zlabinger, U. M. Schmidt-Erfurth, “Angiogenic and Inflammatory Markers in the Intraocular Fluid of Eyes with Diabetic Macular Edema and Influence of Therapy with Bevacizumab,” Retina, Vol. 30, No. 9, 2010, pp. 1412-1419.
[19] M. I. Roh, H. S. Kim, J. H. Song, J. B. Lim, H. J. Koh and O. W. Kwon, “Concentration of Cytokines in the Aqueous Humor of Patients with Naive, Recurrent and Regressed CNV Associated with Amd after Bevacizumab Treatment,” Retina, Vol. 29, No. 4, 2009, pp. 523-529.
[20] P. A. Keane, S. Liakopoulos, K. T. Chang, M. Wang, L. Dustin, A. C. Walsh and S. R. Sadda, “Relationship between Optical Coherence Tomography Retinal Parameters and Visual Acuity in Neovascular Age-Related Macular Degeneration,” Ophthalmology, Vol. 115, No. 12, 2008, pp. 2206-2214.
[21] I. Golbaz, C. Ahlers, G. Stock, C. Schütze, S. Schriefl, F. Schlanitz, C. Simader, C. Prünte and U. M. Schmidt-Erfurth, “Quantification of the Therapeutic Response of Intraretinal, Subretinal, and Subpigment Epithelial Compartments in Exudative AMD during Anti-VEGF Therapy,” Investigative Ophthalmology & Visual Science, Vol. 52, No. 3, 2011, pp. 1599-1605.
[22] D. J. Browning, C. M. Fraser and B. W. Propst, “The Variation in Optical Coherence Tomography-Measured Macular Thickness in Diabetic Eyes without Clinical Macular Edema,” American Journal of Ophthalmology, Vol. 145, No. 5, 2008, pp. 889-893.

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