Significance of monitoring vascular endothelial growth factor, monocyte chemoattractant protein-1 and Interleukin-8 in diabetic macular edema towards early identification of nonresponders to ranibizumab therapy

Abstract

Purpose: Identification of nonresponders prior to anti-vascular endothelial growth factor (anti-VEGF) therapy would help in the judicious clinical management of diabetic macular edema (DME) patients. Thus, a systematic study was initiated to identify nonresponding DME patient population undergoing ranibizumab treatment to figure out additional inflammatory components that may contribute to their nonresponsiveness to anti-VEGF therapy. Methods: A total of 40 patients recruited to this investigator-initiated trial received intravitreal ranibizumab monthly for 3 months. The fourth- and fifth-month injections were according to PRN protocol and the sixth-month injection was mandatory. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and VEGF in aqueous humor were measured for all the patients. Patients were grouped into responders/nonresponders on the formulated criteria and the levels of key pro-inflammatory cytokines were also measured between the two groups at baseline, 2 month and 5 months using cytometric bead array (CBA). Results: Eleven patients were categorized (29.72%) as responders and 10 patients (27.02%) as nonresponders. Nonresponders showed poorer BCVA ( P = 0.024, 0.045, and 0.048 for 4, 5, and 6 months) and higher CMT ( P = 0.021, 0.0008 and <0.0001 for baseline, 1, 2, 3, 4, 5, and 6 months) compared to responders. The cytokines IL-8, MCP-1 were significantly up regulated ( P = 0.0048 and 0.029 for MCP-1 and IL-8) in nonresponders. Conclusion: Elevated MCP-1 and IL-8 levels found in the nonresponders could be used as a prognostic marker to identify these groups of patients and can help in developing alternative treatment options along with anti-VEGF therapy.

Switching to an Intravitreal Dexamethasone Implant after Intravitreal Anti-VEGF Therapy for Diabetic Macular Edema: A Review

“…When categorizing a patient as such, it is important to keep in mind that the precise meaning of limited therapeutic response and poor response is variable. In fact, in post hoc assessments of DRCR.net and VISTA/VIVID data, persistent DME was identified as a central subfield thickness (CST) of more than 250 microns for over six months despite monthly anti-VEGF injections [ 20 ]. Conversely, other clinical studies classified DME as refractory when the CST decreased by less than 50 microns or by less than 10% following three monthly anti-VEGF intravitreal injections or when the best-corrected visual acuity (BCVA) worsened [ 21 , 22 , 23 ].…”

The Role of Intravitreal Corticosteroids in the Treatment of DME: Predictive OCT Biomarkers

“…However, the exact definition of limited treatment response and poor response is heterogeneous and warrants attention when classifying a patient as such. Persistent DME in a post-hoc analyses of the DRCR.net and the VISTA/VIVID data was defined as a central subfield thickness (CST) of >250 µm for ≥6 months despite monthly treatment [ 14 , 15 , 25 ]. Other studies considered DME as refractory, when there was a less than 10% reduction in the CST after 3 monthly injections, a CST decrease <50 µm or a worsening of BCVA [ 26 , 27 , 28 ].…”

“…Several AGEs, including N-epsilon-carboxymethyl lysine (N-Ɛ-CML) and pentosidine, are potential biomarkers for detecting early DR and for progression prediction [ 30 ]. Vascular endothelial growth factor (VEGF) is a vitreous biomarker for DR and plays a crucial role in the pathogenesis of DR through stimulation of angiogenesis, neovascularisation and vascular leakage [ 25 , 31 , 32 , 33 , 34 , 35 , 36 ]. Increased levels of platelet-derived growth-factor BB chain (PDGF-BB), which again induces expression of VEGF, are found in diabetic eyes [ 36 ].…”

Effect of dexamethasone implant on intraocular cytokines in diabetic macular edema

“…Multiple studies prove that DME has an inflammatory component. [ 12 - 14 ] Compared to diabetic patients without DME, diabetic patients with DME have significantly higher concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), interferon-gamma inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor (VEGF) in the aqueous humor and lower concentrations of interleukin-10 (IL-10) and interleukin-2 (IL-2). [ 15 ] VEGF is a potent permeability agent which is associated with increased vasopermeability and an important factor in angiogenesis and neovascularization in DR.[ 16 ]…”