Optical coherence tomography biomarkers after intravitreal triamcinolone acetonide in patients with diabetic macular edema

Maria João Matias; Vítor Miranda; Catarina Pestana Aguiar; Lilianne Duarte

doi:10.4103/pajo.pajo_3_23

ORIGINAL ARTICLE

Year : 2023 | Volume : 5 | Issue : 1 | Page : 10

Optical coherence tomography biomarkers after intravitreal triamcinolone acetonide in patients with diabetic macular edema

Maria João Matias, Vítor Miranda, Catarina Pestana Aguiar, Lilianne Duarte
Department of Ophtalmology of the Centro Hospitalar de Entre o Douro e Vouga, Santa Maria da Feira, Portugal

Date of Submission	05-Jan-2023
Date of Decision	15-Jan-2023
Date of Acceptance	16-Jan-2023
Date of Web Publication	27-Apr-2023

Correspondence Address:
Maria João Matias
Department of Ophtalmology, Centro Hospitalar de Entre o Douro e Vouga, Rua Dr. Cândido Pinho, Santa Maria da Feira
Portugal

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/pajo.pajo_3_23

Abstract

Background and Objective: Optical coherence tomography (OCT) plays a crucial role in guiding the treatment and establishing the prognosis of diabetic macular edema (DME). We aimed to determine which OCT biomarkers respond better to intravitreal triamcinolone acetonide (IVTA) switch after antivascular endothelial growth factor (anti-VEGF) treatment poor response.
Materials and Methods: Fifty-eight eyes with DME, submitted to IVTA switch, were included in this retrospective study. OCT biomarkers and best-corrected visual acuity (VA) were assessed, before and after treatment with a mean follow-up of 2.9 months.
Results: IVTA switch resulted in improved VA, central foveal thickness (CFT), and macular volume. Intraretinal cysts decreased or disappeared completely (P = 0.007) in 84.2% of the eyes, as well as the hyperreflective foci (P = 0.004) and the subretinal fluid (P = 0.02).
Conclusion: We show that IVTA switch is an effective rescue therapy in anti-VEGF therapy refractory DME. OCT plays an important role in selecting the most appropriate treatment, namely between anti-VEGF and steroids.

Keywords: Diabetic macular edema, intravitreal triamcinolone acetonide, optical coherence tomography biomarkers

How to cite this article:
Matias MJ, Miranda V, Aguiar CP, Duarte L. Optical coherence tomography biomarkers after intravitreal triamcinolone acetonide in patients with diabetic macular edema. Pan Am J Ophthalmol 2023;5:10

How to cite this URL:
Matias MJ, Miranda V, Aguiar CP, Duarte L. Optical coherence tomography biomarkers after intravitreal triamcinolone acetonide in patients with diabetic macular edema. Pan Am J Ophthalmol [serial online] 2023 [cited 2023 Jun 3];5:10. Available from: https://www.thepajo.org/text.asp?2023/5/1/10/374740

Introduction

Over 20% of patients with diabetes mellitus (DM) develop diabetic macular edema (DME).^[1] This is concerning since DME is a major cause of blindness in patients with diabetes. There are multiple mechanisms suggested for the occurrence of DME in DM patients.^[1],[2],[3] Pivotal in this process appears to be the hyperglycemia and associated disrupted pathways that contribute to increased oxidative stress and retinal neurodegeneration and microvasculopathy.^[4] Furthermore, this is associated with low-grade chronic inflammation, which promotes the breakdown of the blood–retina barrier and intraretinal and subretinal fluid (SRF) accumulation with progressive retinal layers and cellular damage.^[5] We should also not understate the role of vascular endothelial growth factor (VEGF)-dependent mechanisms in DME pathophysiology.^[6] The increased levels of VEGF orchestrate pathological neoangiogenesis and vasculogenesis, as well as increasing capillary permeability and subsequently retinal edema.^[6]

Tight control of modifiable risk factors, namely glycemia and blood pressure, continues to be the pillar of the treatment of DME.^[7] In addition to this, laser photocoagulation, when timely performed, significantly slows down the occurrence of retinal neovascularization, possibly due to reduced production of VEGF.^[8] Furthermore, tackling the VEGF pathways, anti-VEGF therapy with agents such as pegaptanib (Macugen, OSI/Eyetech, New York, NY, USA), ranibizumab (Lucentis, Genentech, Inc., South San Francisco, CA, USA), aflibercept (EYLEA; Regeneron, Tarrytown, NY, USA), and intravitreal bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA, USA) has revolutionized the treatment of DME.^{[9],[10],[11],[12],[13],[14]} These adjuvant medical therapies result in improved best-corrected visual acuity (BCVA) and lower Central foveal thickness (CFT) than laser photocoagulation therapy alone.^{[9],[10],[11],[12],[13],[14]} Effective therapy of DME is also attained with corticosteroid therapy, possibly due to its inhibitory effects on VEGF and leukostasis, which reduces vascular permeability and macular edema.^[14],[15] Several corticosteroids have been postulated for the treatment of DME, including intravitreal triamcinolone (Triesence, Alcon), intravitreal dexamethasone (Ozurdex, Allergan plc), and fluocinolone acetonide (Iluvien, Alimera Sciences, Inc.).^{[14],[15],[16],[17],[18],[19]} Furthermore, corticosteroid therapy has been recently explored for the treatment of DME refractory to other anti-VEGF therapies with compelling results.^[20]

For effective therapy to be selected, early diagnosis of DME is paramount. Currently, noninvasive optical coherence tomography (OCT) plays a crucial role in guiding treatment and establishing prognosis, since it provides high-resolution images that reproduce the histology of the retina.^[21],[22] The aim of this study was to determine if steroid switch with intravitreal triamcinolone acetonide (IVTA) is an effective rescue therapy for anti-VEGF refractory DME. Furthermore, we aimed to assess which DME OCT biomarkers have a better response to IVTA and which can guide treatment choice. With this, we aim to open new avenues in preventing the development of the complications of DME.

Materials and Methods

Study patients, inclusion criteria, and data collection

This study adhered to the principles of the Declaration of Helsinki, and ethics approval was obtained from the Comissão de Ética para a Saúde at Centro Hospitalar de Entre o Douro e Vouga (CHEDV). We selected 58 patients submitted to IVTA between January 2019 and August 2021 at X. All patients in this study had the diagnosis of DME by OCT, without other known eye pathology, and were submitted to various intravitreous anti-VEGF treatments before the IVTA switch. Furthermore, we had pre- and post-IVTA follow-up records of patients' age, gender, DM-II diagnosis and treatment, visual acuity (VA), central foveal thickness (CFT), intraretinal cysts (IRC), SRF, hyperreflective foci (HRF), macular volume (MV), disorganization of the retinal inner layers (DRIL), external limiting membrane, ellipsoid zone (EZ), and vitreomacular interface.

Data analysis

Statistical analysis was performed using jamovi version 2.3.2 (the jamovi project, Sydney, Australia).^{[23],[24],[25],[26]} Variables were tested for their normal distribution using the Shapiro–Wilk test. To compare continuous variables at the time points before and after triamcinolone acetonide switch, if normality was present, we used parametric paired samples Student's t-test, and if normality was not present, we used nonparametric paired samples Wilcoxon rank test. For categorical variables, we used paired samples McNemar's test. Differences were considered significant for P < 0.05 and represented as * for P < 0.05; **P < 0.01; ***P < 0.001.

Results

Our study included 58 patients [Table 1]. Their median age was 76 ± 9.02 years, with 37.6% of them being female and 62.1% being male. Most of our patient cohort was diagnosed with Type II DM (98.3%), with only 1.7% diagnosed with Type I DM. Henceforth, most patients were exclusively under oral antidiabetic treatment regimens (74.1%), with 22.4% of patients receiving insulin together with oral antidiabetic agents or exclusively under insulin regimens (3.5%). All patients were previously treated for DME, with 84.5% having received ranibizumab intravitreal injection, 15.6% aflibercept intravitreal injection, and 20.7% laser treatment. Overall, the patients in our cohort received a mean of 3 ± 1 anti-VEGF injections before the IVTA switch.

Table 1: Demographic characteristics of the study cohort

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IVTA resulted in a marked improvement of VA in our patient cohort, from a median of 0.300 ± 0.214 LogMAR to 0.200 ± 0.205 LogMAR [Figure 1]. Considering this result, we evaluated several biomarkers related to the development of clinical complications in patients diagnosed with DME [Table 2]. Before IVTA, our patient cohort presented a median CFT of 391 ± 122.1 μm and a median MV of 9.5 ± 1.504 μm³. Furthermore, we observed that most patients had IRC (98.3%) and HRF (74.1%). The presence of DRIL (23.3%), epiretinal membrane (ERM) (17.2%), SRF (13.8%), and vitreomacular traction (VMT) (3.4%) was less prevalent [Table 2].

Figure 1: Following IVTA, patients showed improved VA. VA scores before and after IVTA. Comparisons between time points were performed using the nonparametric paired samples Wilcoxon rank test, with the mean ± 95% CI and the median. IVTA: Intravitreal triamcinolone acetonide, VA: Visual acuity, CI: Confidence interval, **P < 0.01; ***P < 0.001

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Table 2: Comparison of optical coherence tomography biomarkers before and after intravitreal triamcinolone acetonide switch

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Following IVTA, we observed that our patients showed decreased CFT, from median 391 ± 122.1 μm to 306 ± 94.5 μm [Table 2] and [Figure 2]a, of which representative images of the before (left) and after (right) results are shown in [Table 2] and [Figure 2]b. Simultaneously, there was a reduction in MV, from a median of 9.5 ± 1.504 μm³ to 8.87 ± 1.504 μm³ [Table 2] and [Figure 2]c.

Figure 2: Following IVTA, patients showed improvement of several OCT biomarkers, including CFT, MV, intraretinal cysts, and HRF. In (a), we show the CFT before and after IVTA, with the before (left) and after (right) representative OCT photographs in (b). In (c), we show the MV before (left) and after IVTA (right). In (d), we show the percentages of patients that showed improvement (reduction) in intraretinal cyst following IVTA, with representative before and after OCT photographs in (e). In (f), we show the percentage of patients that showed improvement (reduction) in the presence of HRF following IVTA, with representative OCT photographs before (left) and after (right) IVTA in (g). In (h), we show the percentage of patients with decreased DRIL following IVTA. In (i), we show the percentage of patients with reduced SRF following IVTA with representative OCT photographs in (j). In (a) and (c), comparisons between time points were performed using the nonparametric paired samples Wilcoxon rank test, with the mean ± 95% confidence interval and the median. MV: Macular volume, IVTA: Intravitreal triamcinolone acetonide, OCT: Optical coherence tomography, CFT: Central foveal thickness, HRF: hyperreflective foci, SRF: Subretinal fluid, DRIL: Disorganization of the retinal inner layers, IRC: Intraretinal cysts, **P < 0.01; ***P < 0.001

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Triamcinolone treatment resulted in a marked reduction in the prevalence of IRC, from 98.3% to 63.4% of the patient cohort [Table 2]. It should be noted that of this 63.4%, many showed a decreased number of IRC. Because of this, from the total patient cohort, 81% of the patients showed a reduced presence of IRC (P = 0.002), and those without IRC before treatment did not develop them afterward [Figure 2]d and [Figure 2]e. Our patient cohort also showed a reduced prevalence of HRF, from 74.1% to 56.9% [Table 2]. At the same time, 55.2% of the patients showed reduced HRF (P < 0.001), representing 74.4% of those diagnosed with HRF before treatment, and we also did not see any patient not diagnosed before treatment aggravating [Figure 2]f and [Figure 2]g. Regarding the presence of the less prevalent biomarkers, the prevalence of DRIL was comparable before and after [Table 2], yet 17.6% of those with DRIL showed an improvement following triamcinolone switch [P < 0.001, [Figure 2]h]. Meanwhile, the prevalence of SRF reduced, with no patients showing SRF following the triamcinolone switch [Table 2] and [Figure 2]i and [Figure 2]j. Concerning vitreomacular interface, there were no changes in the prevalence of ERM or VMT after switch [Table 2].

Considering the improvement in VA and the decrease in the prevalence of some of the OCT biomarkers, following the triamcinolone switch, we aimed to understand if the degree in improvement in VA was directly correlated with the magnitude of improvement of the patients' OCT biomarkers following the treatment switch. For this, we correlated VA, CFT, and MV before and after the triamcinolone switch [Table 3]. We observed that the worse the VA prior to the switch, the worse the VA afterward. This also occurred for CFT and MV. Of interest, we also observed that the higher the CFT, the worse the VA, both before and after the triamcinolone switch. While MV was not directly correlated with VA, it was directly correlated with CFT, both before and after the triamcinolone switch.

Table 3: Correlation between visual acuity and CV risk score before and after IVTA

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Discussion

Herein, we studied how patients diagnosed with DME refractory to anti-VEGF treatment responded to IVTA switch. While recent studies show clear benefits in VA, following corticosteroid intravitreous switch therapy, the treatment of anti-VEGF refractory DME is still posed with several challenges, notably the ideal timing for the switch to occur, the need for implants, and how to appropriately assess the DME improvement outcomes.^{[27],[28],[29],[30]} Among corticosteroid therapies, IVTA is considered by some as more advantageous compared to others using dexamethasone or fluocinolone acetonide, since there is no need for implants.^[20],[28] Alternatively, steroid implants allow a longer duration of the treatment effect, henceforth decreasing the burden of frequent reinjections. In our department, IVTA is used as a proof test for steroid response before the use of long-duration steroid implants. Regarding the timing for the switch to occur, in average, our patient cohort received 3 ± 1 anti-VEGF intravitreous injections before the IVTA switch, yet our study did not address the benefit of the IVTA switch to occur at different thresholds of numbers of anti-VEGF intravitreous injections. Decision to switch to steroid treatment was based on poor response to anti-VEGF criteria, namely as a decrease in reverse transcription <20% and an improvement in BCVA of <5 letters, and based on the persistency of OCT biomarkers and hard exudates. The combination of response criteria and OCT biomarkers led to the early decision to switch to steroid treatment.

Comparably to a previous report,^[20] our results suggest that IVTA switch is effective in improving DME, since there was improved VA following rescue therapy. To assess what may have caused this improved VA, we used OCT imaging, since this allows precise measurements and follow-up of patients undergoing treatment. In this work, we showed that OCT was able to monitor the response to treatment with IVTA, by quantitative measurement of CFT and MV and by qualitative analysis of retinal architecture. We observed that improved VA was accompanied by decreased CFT. Of novel, we also showed that the IVTA switch resulted in overall reduced MV, and qualitative reduction in the number of IRC, and HRF. Notably, following IVTA, no patients showed SRF. It is also remarkable that those patients with DME without IRC, HRF, or SRF before the IVTA switch did not develop them afterward. This suggests that earlier IVTA switch, before the development of these biomarkers, should be studied. In contrast, IVTA did not result in the decreased prevalence of ERM or VMT, yet it may have occurred that IVTA prevented further development of these complications.

The ESASO group proposed an OCT biomarker-based DME classification considering the need for improved selection of treatment regimens, pointing to markers on OCT that can prognose the functional and/or anatomical effects.^[31] Efficacy treatment results and treatment options decisions (switch and/or stop) based uniquely on CFT and BVCA are for sure limited. Atrophy of the EZ, drill, and markers of structural anatomy should be considered on trials and clinical practice when evaluating the functional prognosis. Furthermore, the presence of vitreoretinal interface abnormalities may suggest the need for other surgical treatments than intravitreal injections. Other OCT biomarkers such as cysts and cyst reflectivity, HRF, SRF, and hard exudates can be important indicators for the better treatment decision in DME.

It is important to denote that OCT biomarkers are more than simple measures of DME progression. They appear to be correlated with VA, since we observed that VA before and after IVTA switch was directly correlated with CFT, which was itself correlated with MV. Therefore, our study also suggests that OCT plays an important role in early diagnosis and in the selection of the most appropriate in the treatment decision between anti-VEGF, steroids, and other options, according to the biomarkers presented. Randomized studies, with OCT biomarkers defined as progression and treatment response parameters, comparing anti-VEGF and steroid treatment in DME are required for the buildup of clinically relevant evidence with real impact as decision facilitators.

Acknowledgments

We thank all ophthalmology surgeons at X for performing the anti-VEGF and IVTA treatments of the patients included in this study as well as providing their respective clinical follow-up.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet 2010;376:124-36.
2.	Wang W, Lo AC. Diabetic retinopathy: Pathophysiology and treatments. Int J Mol Sci 2018;19:816.
3.	Lin KY, Hsih WH, Lin YB, Wen CY, Chang TJ. Update in the epidemiology, risk factors, screening, and treatment of diabetic retinopathy. J Diabetes Investig 2021;12:1322-5.
4.	Brownlee M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes 2005;54:1615-25.
5.	Antonetti DA, Barber AJ, Bronson SK, Freeman WM, Gardner TW, Jefferson LS, et al. Diabetic retinopathy: Seeing beyond glucose-induced microvascular disease. Diabetes 2006;55:2401-11.
6.	Wirostko B, Wong TY, Simó R. Vascular endothelial growth factor and diabetic complications. Prog Retin Eye Res 2008;27:608-21.
7.	Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: A systematic review. JAMA 2007;298:902-16.
8.	Aiello LP. Angiogenic pathways in diabetic retinopathy. N Engl J Med 2005;353:839-41.
9.	Cao WJ, Zhang XC, Wan LY, Li QY, Mu XY, Guo AL, et al. Immune dysfunctions of CD56(neg) NK cells are associated with HIV-1 disease progression. Front Immunol 2021;12:811091.
10.	Sivaprasad S, Prevost AT, Vasconcelos JC, Riddell A, Murphy C, Kelly J, et al. Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): A multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial. Lancet 2017;389:2193-203.
11.	Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, Glassman AR, Jampol LM, Inusah S, Aiello LP, et al. Panretinal photocoagulation versus intravitreous ranibizumab for proliferative diabetic retinopathy: A randomized clinical trial. JAMA 2015;314:2137-46.
12.	Massin P, Bandello F, Garweg JG, Hansen LL, Harding SP, Larsen M, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE study): A 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care 2010;33:2399-405.
13.	Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118:615-25.
14.	Ehlers JP, Yeh S, Maguire MG, Smith JR, Mruthyunjaya P, Jain N, et al. Intravitreal pharmacotherapies for diabetic macular edema: A report by the American academy of ophthalmology. Ophthalmology 2022;129:88-99.
15.	Danis RP, Sadda S, Li XY, Cui H, Hashad Y, Whitcup SM. Anatomical effects of dexamethasone intravitreal implant in diabetic macular oedema: A pooled analysis of 3-year phase III trials. Br J Ophthalmol 2016;100:796-801.
16.	Augustin AJ, Kuppermann BD, Lanzetta P, Loewenstein A, Li XY, Cui H, et al. Dexamethasone intravitreal implant in previously treated patients with diabetic macular edema: Subgroup analysis of the MEAD study. BMC Ophthalmol 2015;15:150.
17.	Campochiaro PA, Brown DM, Pearson A, Chen S, Boyer D, Ruiz-Moreno J, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology 2012;119:2125-32.
18.	Boyer DS, Yoon YH, Belfort R Jr., Bandello F, Maturi RK, Augustin AJ, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014;121:1904-14.
19.	Watanabe A, Tsuzuki A, Arai K, Gekka T, Kohzaki K, Tsuneoka H. Efficacy of intravitreal triamcinolone acetonide for diabetic macular edema after vitrectomy. J Ocul Pharmacol Ther 2016;32:38-43.
20.	Hong IH, Choi W, Han JR. The effects of intravitreal triamcinolone acetonide in diabetic macular edema refractory to anti-VEGF treatment. Jpn J Ophthalmol 2020;64:196-202.
21.	Drexler W, Fujimoto JG. State-of-the-art retinal optical coherence tomography. Prog Retin Eye Res 2008;27:45-88.
22.	Markan A, Agarwal A, Arora A, Bazgain K, Rana V, Gupta V. Novel imaging biomarkers in diabetic retinopathy and diabetic macular edema. Ther Adv Ophthalmol 2020;12:1-16.
23.	Lenth R. Emmeans: Estimated Marginal Means, Aka Least-SquaresMeans. [R Package]; 2020, Available from: https://github.com/rvlenth/emmeans. [Last accessed on 2022 Dec 20].
24.	Singmann H. Afex: Analysis of Factorial Experiments. [R Package]; 2018, Available from: https://github.com/singmann/afex. [Last accessed on 2022 Dec 20].
25.	R Core Team. R: A Language and Environment for Statistical Computing. Ver. 4.1. Vienna, Austria: R Core Team; 2022.
26.	The jamovi project. jamovi (Version 2.3) [Computer Software]. 2022.Retrieved from https://www.jamovi.org. [Last accessed on 2022 Dec 20].
27.	Pacella F, Romano MR, Turchetti P, Tarquini G, Carnovale A, Mollicone A, et al. An eighteen-month follow-up study on the effects of intravitreal dexamethasone implant in diabetic macular edema refractory to anti-VEGF therapy. Int J Ophthalmol 2016;9:1427-32.
28.	Kim MW, Moon H, Yang SJ, Joe SG. Effect of posterior subtenon triamcinolone acetonide injection on diabetic macular edema refractory to intravitreal bevacizumab injection. Korean J Ophthalmol 2016;30:25-31.
29.	Dutra Medeiros M, Postorino M, Navarro R, Garcia-Arumí J, Mateo C, Corcóstegui B. Dexamethasone intravitreal implant for treatment of patients with persistent diabetic macular edema. Ophthalmologica 2014;231:141-6.
30.	Busch C, Zur D, Fraser-Bell S, Laíns I, Santos AR, Lupidi M, et al. Shall we stay, or shall we switch? Continued anti-VEGF therapy versus early switch to dexamethasone implant in refractory diabetic macular edema. Acta Diabetol 2018;55:789-96.
31.	Panozzo G, Cicinelli MV, Augustin AJ, Battaglia Parodi M, Cunha-Vaz J, Guarnaccia G, et al. An optical coherence tomography-based grading of diabetic maculopathy proposed by an international expert panel: The European school for advanced studies in ophthalmology classification. Eur J Ophthalmol 2020;30:8-18.