Effect of posterior sub-tenon injection of triamcinolone acetonide as ‎an adjunct therapy to intravitreal anti-vascular endothelial growth ‎factor in the management of diabetic macular oedema

INTRODUCTION
Diabetic macular oedema (DME) is one of the main causes of visual deterioration in patients with DM.1 The Early Treatment Diabetic Retinopathy Study has suggested that grid laser photocoagulation for clinically significant macular oedema effectively decreased the incidence of moderate visual loss.
Later studies demonstrated that grid/ laser photocoagulation might cause decreased vision because of a progressive macular scar and subretinal fibrosis.2 Focal/grid laser photocoagulation has considered the main treatment for diabetic macular oedema (DME) within the last 25 years. However, their results are limited in patients with DME caused by the extensive breakdown of the inner blood-retinal barrier.3,4 this has driven many investigators to look for alternative treatments for the management of DME. Treatment modalities for DME today are increasing in number. The efficacy of intravitreal injection of anti vascular endothelial growth factor (anti-VEGF),5 intravitreal and sub-Tenon injection of triamcinolone acetonide (STTA),4 intravitreal sustained release dexamethasone implant,6 and also combined therapies,7 for DME are reported. combination of these therapies that consider different pathways of this multifactorial disease offers better results. By increasing the efficacy with additive effects and decreasing the therapy time and thus the costs, combination therapies may provide advantage both for the patients and physicians. In our study, we tried to asses the efficacy and safety of combined posterior STTA and intravitreal ranibizumab (IVR) therapy in patients with diabetic macular oedema (DME).
PATIENT AND MATERIALS
A prospective interventional comparative clinical trial conducted at ‎Al-Azhar University Hospitals (Cairo, Egypt) from January 2018 to ‎August 2019 and were followed-up for 6 months‎.‎ The study included two groups; each included 25 eyes, all of ‎which had type ΙΙ diabetes mellitus with CSME according to the Early Treatment Diabetic Retinopathy ‎Study (ETDRS) criteria.‎ Patients were included if they clinically and angiographically (FFA) ‎diagnosed as DME and have a central foveal thickness (CFT) greater ‎than 250 um on optical coherence tomography (OCT).‎
Exclusion criteria: were significant media opacity preventing retinal view, presence of traction on the macula evidenced by OCT, previous ocular surgery, history of previous laser photocoagulation, IV or PSTI of TA, history of uveitis attacks, any chorioretinal disease (other than diabetic retinopathy), glaucoma or ocular hypertension, diabetic papillopathy or ischemic maculopathy, and contraindications for ranibizumab or TA.
The systemic status of all patients was controlled. Each patient ophthalmologically examined briefly at baseline and at every follow-up visit, this included best-corrected visual acuity (BCVA), intraocular pressure (IOP) measurement by the Goldman applanation tonometer, and slit-lamp biomicroscopy with +90D noncontact lens.
Fundus fluorescein angiography (using IMAGE net 2000, Topcon TRC50IX; Topcon Corporation, Tokyo, Japan) was obtained at baseline for all patients and was repeated at follow-up visits if it was necessary for some patients. OCT was performed for all patients during preinjection and post injections follow-up visits to determine the CMT using spectral-domain OCT (Spectralis; Heidelberg Engineering, Germany). The Auto Rescan function of Spectralis OCT allows the repetition of follow-up scans for every patient.
Surgical procedures: The first group underwent 3 intravitreal injections (one-month interval) of 0.3mg ‎Ranibizumab delivered in 0.05ml (Lucentis®, Genentech, Inc., South ‎San Francisco, CA)‎, While the second group underwent the same injections but combined during the 1st injection with posterior sub-tenon (PST) ‎injection of 40 mg/ml Triamcinolone acetonide (Kenacort -A® Bristol-‎Myers Squibb Company New York – Cairo). ‎Under standard aseptic techniques in the ophthalmic surgical theatre, A volume of 0.05 ml containing 0.3mg ‎Ranibizumab was injected inside the vitreous cavity through pars plana 3.5–4mm posterior to the limbus using a sterile 30Gneedle in the inferotemporal quadrant. For posterior sub-tenon injection, Following disinfection and draping, supero-temporal or infero-nasal ‎subconjunctival anaesthesia (2% lidocaine); a small conjunctival and ‎Tenon's incision (7 mm posterior and either supero-temporal or infero-‎nasal to the limbus) was made to bare sclera. Using a curved blunt ‎cannula (NAGATA® sub-tenon canula), the medication was infused in the ‎posterior juxta-scleral space. Afterwards, the surgical incision was cauterized, and topical ‎antibiotic was instilled.‎
Follow-up: All patients underwent ophthalmic examination on days 1 and 7 post injections, to asses injection-related complications such as anterior chamber reaction or IOP rise, etc. Follow-up was performed regularly by determining the BCVA, IOP measurement, and fundus biomicroscopy. Anatomical (CMT) and functional (BCVA) outcomes were evaluated monthly using spectral-domain OCT and visual acuity chart, respectively.
Statistical analysis: Statistical analyses were performed by the use of SPSS software of Windows (version 15; SPSS Inc., Chicago, Illinois, The USA). Preinjection and post-injection measurements at 1st, 3rd and 6th months for all variables were tested by the paired sample t-test and AnOVa test. All values are expressed as MD±SD. P-values less than 0.05 were accepted as significant.
Ethical approval: The study was accepted by the Ethics Board of Al-Azhar University. Informed written consent was obtained from every patient before being included in the study.
RESULTS
Twenty five eyes of 20 patients (11 females and 9 males) were enrolled in group 1 ‎‎(intravitreal ranibizumab injection), 25 eyes of 24 patients (14 females and 10 ‎males) were enrolled in group 2 (posterior sub-tenon TA injection with intravitreal ‎ranibizumab injection).‎The ages in group 1 ranged from 56 to 67 years 62.94± 4.92 (mean + SD), ‎while the ages in group 2 ranged from 58 to 66 years 61.62 ± 4.60 (mean + SD). There was not a statistically significant difference in both study groups concerning age, gender, duration and status of diabetes.
The mean preoperative CMT of the combined group (IVRI+PSTA) ‎‎(group 2) was 584.4μ ±120.28μ, higher than mean preoperative CMT of ‎the control group (group 1) 422.32μ ±114.45μ. At one-month post-injection, group 2 had reached a CMT of ‎‎365.16±68μ, showing an improvement of 37.5% from baseline. The ‎group 1 had reached 3592±96.6μ showing an improvement of 14.9% ‎from baseline. But the absolute CMT is close and insignificant (p=0.8) ‎when compared, with even a lower CMT in the group1.‎At the next visits, the statistical significance remained, with ‎‎(p≤0.000) at 3rd and 6th months. So, the clinical ‎difference was significant, with a CMT of 253.28±37.6μ and ‎‎288.64±71.99μ at 3rd month (p=0.034) and finally 235.94±27.49μ and 305.24±82.5μ at 6th months (p≤0.000) in ‎the group 2 and group 1 respectively (Figure 1&2 and table 1).‎‎ There was recurrent and residual oedema in 8 patients (32%) in group 1, While ‎in group 2; only 2 cases (8%) with residual oedema mostly due to drug reflux.‎

Fig. 1: This graph is showing comparison between both groups in CMT over follow up period. Data are presented as mean deviation
(µm micrometer, CMT central macular thickness, IVRI intra vitreal ranibizumab injection, PSTA posterior subtenon triamcinolone acetonid).

Fig. 2: This graph is showing a comparison in percentage change of CMT over the follow-up period between both groups.
Data are presented as mean deviation
(CMT central macular thickness, IVRI intra vitreal ranibizumab injection, PSTA posterior subtenon triamcinolone acetonid).

CMT (µm) IVRI (MD±SD) IVRI+PSTA (MD±SD) t-test p-value
Baseline ‎422.32±‎114.45 ‎584.4±‎120.28 5.0 < 0.001
1 month ‎359.2±‎96.6 ‎365.16±‎68 0.25 0.8
3 months ‎288.64±‎71.99 ‎253.28±‎37.6 2.17 0.034
6 months ‎305.24±‎82.5 ‎235.94±‎27.49 3.98 < 0.001
F-test 9.9 120.9
p-value ‎Table 1: This table is showing mean and Standard deviations of CMT of studied groups over the follow up period.
Data are presented as mean ±SD
(µm micrometer, CMT central macular thickness, IVRI intra vitreal ranibizumab injection, PSTA posterior subtenon triamcinolone acetonid, MD mean deviation, SD standard deviatin).
The mean BCVA prior to injection was worse in the combined ‎group (group 2) (‎0.15±0.15‎) than the IVRI only group (group 1) (‎0.21±0.15‎). At the ‎‎1st month post-injection it had improved to 0.28 and 0.29 respectively, ‎the difference being statically insignificant between the two groups ‎‎(P=0.93). At 3rd months it was 0.41 in the combined group (group 2) ‎, and 0.36 in the IVRI only group (group 1) with the difference in ‎between the two groups is insignificant (P=0.08).At the last follow-up visit it was 0.46 in the combined group (group 2), and 0.37 in the ‎PSTTA only group (group 1) and again the difference in between is ‎insignificant (P=0.1) this insignificance is due to the starting difference in ‎MD of BCVA in between both groups. The BCVA is significantly ‎improved in both groups during the follow-up period being more in the ‎combined group (86.7%-33.3%, 173.3%-71.4% and 206.7%-76.1% ‎group 2 and group 1 at the 1st, 3rd and 6th month respectively) these data is shown in figure 3&4 and table 2.‎

Fig. 3: This Graph is showing comparison between both groups in BCVA over the follow up period.
Data are presented as mean deviation. (BCVA best corrected visual acuity, IVRI intra vitreal ranibizumab injection, PSTA posterior subtenon triamcinolone acetonid)

Fig. 4: This graph is showing a comparison in percentage change of BCVA over the follow-up period between both groups.
Data are presented as number (%) ( BCVA best corrected visual acuity, IVRI intra vitreal ranibizumab injection, PSTA posterior subtenon triamcinolone acetonid)

BCVA IVRI (MD±SD) IVRI+PSTA (MD±SD) t-test p-value
Baseline 0.21±0.15 0.15±0.15 1.42 0.16
1 month ‎0.286±‎0.16 ‎0.28±‎0.14 0.08 0.93
3 months ‎0.36±‎0.16 ‎0.41±‎0.18 1.76 0.08
6 months ‎0.37±‎0.16 ‎0.46±‎0.19 1.64 0.10
F-test 5.67 18.9
p-value 0.0013 ‎<0.001
Table 2:Table showing mean and Standard deviations of BCVA of studied groups over the follow up period.
Data are presented as mean ±SD
(µm micrometer, BCVA best corrected visual acuity, IVRI intra vitreal ranibizumab injection, PSTA posterior subtenon triamcinolone acetonid, MD mean deviation, SD standard deviatin).
Comparing the IOP of both groups in our study; mean IOP of both groups over the follow up period are shown in (Figure 5), Four patients (16%) showed a mild increase in IOP after injection ‎during the first month which was transient and well-controlled by only ‎one anti-glaucoma drug, and this is mostly due to steroid responders.

Fig. 5: This graph is showing a comparison between both groups in IOP over the follow-up period.
Data presented as mean deviation.
(IOP intra ocular pressure, IVRI intra vitreal ranibizumab injection, PSTA posterior subtenon triamcinolone acetonid).
DISCUSSION
Diabetic macular oedema (DME) is the fundamental driver of dynamic lessening of vision in diabetic retinopathy patients that may occur at any stage of the retinopathy.9 Many factors are involved in the pathogenic process of DME; so, many alternatives are needed to be suggested for the management of these patients either surgical or pharmacologic.10 Monotherapies are often not effective enough to well treat DME.11 The roles of inflammatory mediators and VEGF in DME have been proved.12 Anti-VEGF drugs can decrease the concentration of free VEGF but do not change the concentrations of other pro-inflammatory molecules.13 Combining corticosteroids with anti-VEGF drugs may produce the greatest possible suppression of vascular permeability.14 However, the use of intravitreal triamcinolone injection had been linked to the development of many complications.15 The PSTI of TA had a comparable effect with the IV TA and showed a lower risk of these complications.16
The underlying rationale for using sub-Tenon’s capsule injection of TA for DME is that, apart from its safety, it also can penetrate the sclera and diffuse into the vitreous cavity.17 Bakri and Kaiser 18 evaluated the role of PSTI of TA in improving visual acuity in patients with refractory DME. They found significant improvement in visual acuity at 1st month, which was maintained till 12months. Therefore, PSTI of TA may be offered as a good alternative for the treatment of diffuse DME.16
The outcome of the present study revealed that combined IV ‎ranibizumab with PSTI of TA was effective for the management of DME in ‎terms of decreasing CMT and improving BCVA. This combined ‎treatment protocol decreased CMT effectively below 300 μm in 24 eyes ‎‎(96%) and provided improvement of visual acuity in all eyes (100%). ‎The combined injection also greatly decreased the need for frequent ‎injections as there was recurrent and residual oedema in 8 patients (32%) ‎in group 1, While in group 2; only 2 cases (8%) with residual oedema ‎mostly due to drug reflux.‎The improvement in the anatomical (CMT) and functional ‎‎(BCVA) outcomes in the present study may be attributed to patients’ ‎selection criteria including the exclusion of ischemic DME cases and absent ‎history of previous laser or ocular surgeries before enrollment.‎
In the present study, No eyes developed rise in IOP that ‎necessitated anti-glaucoma drugs for longe time during the follow-up ‎period. Only one eye developed nuclear cataract at the end of the study ‎‎(4%) and undergone phacoemulsification. ‎Kim et al.19 reported that combined therapy with IV bevacizumab injection and PSTI-TA (4.0 mg) produced better clinical outcomes, especially at 1st month after injection compared with single injections of each one of them. Ahmadieh et al.20 compared IV bevacizumab with or without IV TA in DME and found that the addition of TA induced earlier visual improvement. Aly and Tag Eldin reported that combined IV ‎bevacizumab with PSTI-TA was effective for the management of persistent ‎DME in terms of decreasing CMT and improving BCVA.21
As regards the effect on IOP, Our results are nearly similar to that of Abdelkader SA Et al. study that ‎revealed that there was no critical difference between the two groups in ‎terms of IOP increase before injection and at 3 months follow up. ‎However, there was a significant difference between the two groups after ‎‎1 month follow up.22 ‎Our results are also nearly similar to that of Ercalik NY et al. ‎study, 5.2% of the eyes developed moderate IOP elevation In the ‎combined group.23
Limitations of our study include the relatively small number of enrolled patients and the short follow-up time. Therefore, further, long-term studies on a larger number of patients are required to confirm the long-term efficacy and safety of this combined treatment as a treatment option for DME.
CONCLUSION
The results of the present study show that adding PSTI-TA to IV ranibizumab has a great role in the treatment of DME not only in improving BCVA and decreasing CMT but also in minimizing the number of frequent injections when compared to anti-VEGF treatment alone, so the cost will be cheaper.