Abstract
Introduction
The aim of this real-life study was to analyze the prevalence and risk factors of ocular hypertension (OHT) after fluocinolone acetonide implant (FAc-I) intravitreal injections in the treatment of macular edema of various etiologies.
Methods
This retrospective, monocentric study included all consecutive patients with ≥ 1 FAc-I injection. The primary endpoint was the occurrence of OHT, defined as intraocular pressure (IOP) of at least 25 mmHg and/or an increase ≥ 10 mmHg from baseline.
Results
A total of 171 eyes of 127 patients were injected with FAc-I for diabetic macular edema (61.4%), post-surgical macular edema (19.9%), uveitis (11.1%), and retinal vein occlusion or radiation maculopathy (7.6%). The prevalence of OHT after FAc-I injections was 24.6% (n = 42) and did not differ among groups according to disease (p = 0.943). In most cases, OHT was successfully treated with topical medication alone (14% of the whole cohort, n = 24, 57% of the hypertonic cases). Selective laser trabeculoplasty (SLT) was used in 12 eyes (7.0%). The rate of incisional IOP-lowering surgery was 3.5% (n = 6). In multivariable analysis, risk factors for OHT included younger age (p = 0.036) and pre-existing OHT or glaucoma (p = 0.034). The positive predictive value for the absence of OHT after DEX-I injections was 80.4%.
Conclusions
OHT occurred in approximately one in four eyes after FAc-I injection and was commonly and successfully treated with topical treatment alone or SLT in 95% of the hypertonic cases (40/42). Risk factors for OHT after FAc-I included younger age and pre-existing OHT or glaucoma. Uveitis and retinal vein occlusion were not risk factors for OHT. Previous DEX-I injection seems to be a useful predictive test. Therefore, regular IOP monitoring is essential for all patients receiving FAc-I injections, especially those with risk factors for OHT.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40123-026-01339-8.
Keywords: Corticosteroid intravitreal injection, Fluocinolone acetonide implant, Ocular hypertension
Key Summary Points
| Why carry out this study? |
| Fluocinolone acetonide (FAc-I) intravitreal injections are an efficient treatment method for macular edema but may induce ocular hypertension (OHT). |
| The aim of this real-life study was to analyze the prevalence and risk factors of OHT after FAc-I intravitreal injections in the treatment of macular edema of various etiologies. |
| What was learned from the study? |
| OHT occurred in approximately one in four eyes after FAc-I injection and was commonly and successfully treated with topical treatment alone or selective laser trabeculoplasty in 95% of the hypertonic cases. |
| Risk factors for OHT after FAc-I include younger age and pre-existing OHT or glaucoma. Uveitis and retinal vein occlusion were not risk factors for OHT. |
| The absence of a clinically significant intraocular pressure (IOP) elevation after DEX-I had an 80.4% probability of predicting the absence of IOP elevation after FAc-I injection: DEX-I injections can help anticipate the probability of OHT after FAc-I injection. |
| Regular IOP monitoring is essential for all patients receiving FAc-I injections, especially those with risk factors for OHT. |
Introduction
Intravitreal corticosteroids are used to treat a variety of ocular pathologies including diabetic macular edema (DME) [1], retinal vein occlusion (RVO) [2], uveitis [3], and post-surgical macular edema (PSME) [4]. Two molecules are used by ophthalmologists for intravitreal administration—dexamethasone implant (DEX-I, Ozurdex®, AbbVie, Chicago, IL, USA) and fluocinolone acetonide implant (FAc-I, ILUVIEN®, Alimera, Nice, France)—which both deliver corticosteroids into the vitreous cavity. In contrast to DEX-I, FAc-I is a non-biodegradable tube (3.5 × 0.37 mm) that delivers corticosteroids (0.2 µg of FAc per day) over a longer period of up to 3 years [5]. The peak vitreous concentration of FAc-I is lower than that of DEX-I, but a plateau concentration is supposed to be reached at 6 months, then remaining stable for up to 36 months [6]. FAc-I has been approved for the treatment of DME in patients who have previously received conventional treatment without a good response, and for noninfectious posterior uveitis [7].
Ocular hypertension (OHT) is a long-known adverse effect of corticosteroids [8]. Steroid-induced OHT is the result of increased resistance to the drainage of aqueous humor caused by histological changes in the trabecular microstructure. The accumulation of proteins in the extracellular matrix causes damage to the trabecula and reduces its filtration, resulting in OHT [9, 10]. According to observational studies, OHT affects approximately 33% of DEX-I-treated patients and is generally managed by topical treatment alone [10, 11]. Risk factors for developing DEX-I-induced OHT are also well known, with past medical history of glaucoma/OHT or uveitis as the leading cause [10, 11]. Similarly, OHT was detected in 37% of patients treated with FAc included in the FAME clinical trial [5]. However, the prevalence decreased to 11–25% in first reports from real-world practice [12–14]. In contrast to DEX-I, and as a recent standard of care in DME, risk factors for developing FAc-I-induced OHT are not well understood, with only a few low-powered studies having been reported [14]. For example, no study to date has evaluated the intraocular pressure (IOP) tolerance profile of FAc-I according to the different diseases.
Therefore, the present study aims to analyze the prevalence, time to onset, and risk factors of FAc-I-induced OHT according to the initial pathology.
Methods
Study Design and Patient Selection
A retrospective, observational and monocentric study was conducted at the ophthalmology department of the Croix-Rousse University Hospital (Hospices Civils de Lyon, Université de Lyon, Lyon, France). All consecutive patients treated with at least one FAc-I between December 2018 and October 2023 for any possible indication were included. FAc-I could be administered either alone or in combination with DEX-I at the clinician’s discretion. In the case of combination treatment, the interval between the two injections did not exceed 1 month. According to international guidelines, patients were monitored at month 1 (M1) and month 3 (M3) after the first injection, and then every 3 months. After each visit, the patients could receive additional treatment (DEX-I or anti-vascular endothelial growth factor [anti-VEGF] if ME relapsed). After 24 months, clinicians could also prescribe another FAc-I [15].
The study population reflects routine clinical practice in this retrospective study. Most included eyes were pseudophakic, while eyes with uncontrolled or advanced glaucoma were uncommon. All eyes had previously been treated with DEX-I prior to FAc-I administration. The IOP response to previous DEX-I was not used as an inclusion criterion but was analyzed retrospectively. However, eyes that had experienced uncontrolled OHT due to DEX-I were generally not injected with FAc-I and therefore not included in this study.
This research was conducted in accordance with the Declaration of Helsinki. Patients' informed consent was obtained, and the local ethics committee (Hospices Civils de Lyon) approved the study, registered under number 20-156.
Data Collection
Patient demographics, medical history, and clinical features were collected at baseline and during the follow-up. IOP was measured at every visit using non-contact tonometry. In cases of suspected OHT (IOP ≥ 21 mmHg), measurements were systematically confirmed using Goldmann applanation tonometry to detect false-positive results. If OHT was confirmed, we retained the IOP value obtained by Goldmann applanation tonometry. OHT was defined as IOP ≥ 25 mmHg and/or an increase of ≥ 10 mmHg over the monitoring period compared with baseline IOP [10]. Based on the highest IOP measured during follow-up, the patients were classified as “non- or low responders” (IOP increase of 1–5 mmHg), “intermediate responders” (IOP increase of 6–15 mmHg), or “high responders” (increase > 15 mmHg).
Outcome Measures
The primary outcome measure was the prevalence of OHT in patients treated with FAc-I according to etiology subgroup. Secondary outcome measures included the time to OHT diagnosis, mean time to IOP peak, and proportion of low/intermediate/high IOP responders according to etiology subgroups. Data on OHT management after FAc-I were also collected.
Risk factors for OHT occurrence were then calculated in univariate and multivariate analysis. Finally, analyses regarding repeated injections of DEX-I and/or FAc-I and increased risk of OHT were performed to evaluate the risk of a cumulative effect.
Statistical Analysis
Categorical variables were presented as count and proportions and compared using chi–square tests. Continuous variables were presented as mean and standard deviation and compared using Student t-tests or Wilcoxon rank-sum tests according to their distribution. Median follow-up was calculated using the reverse Kaplan–Meier method. Survival outcome was estimated by the Kaplan–Meier method from the FAc-I to OHT occurrence or last follow-up. Prognostic factors were explored using the log-rank test and multivariate time-dependent Cox proportional hazards models, since assessment of Schoenfeld residuals indicated violations of the proportional hazards assumption. Age was included as a continuous variable in the multivariate model. The log-linearity relationship between the log hazard and the covariates was verified by assessing the Martingale residuals. To prevent multicollinearity, only the most statistically significant factor was considered if the variance inflation factor (VIF) was > 2. All tests were two-tailed, and a p-value < 0.05 was considered significant. Statistical analyses were performed using R software version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria).
Results
A total of 171 eyes of 127 patients were included in this study. The indications for FAc-I treatment were as follows: DME (n = 105), PSME (n = 34), uveitis (n = 19), RVO or radiation maculopathy (RM) (n = 13). The mean (SD) age of the cohort was 68.4 (11.1) years. Sixty-one (48.0%) patients were male. Three eyes (1.8%) were phakic at inclusion, and 68 eyes (45.6%) were treated for OHT or glaucoma at inclusion, with a mean (SD) of 1.5 (1.0) hypotensive medications. Seven (4.1%) eyes had undergone incisional IOP-lowering surgery before inclusion (i.e., trabeculectomy, deep sclerectomy, or microinvasive glaucoma surgery). All eyes had been previously injected with at least one DEX-I before inclusion (two with a single DEX-I, and the remaining 169 with ≥ 2 injections). A history of corticosteroid-induced OHT after DEX-I was reported in 59 (34.5%) eyes (Table 1).
Table 1.
Patients’ characteristics at baseline
| DME | PSME | Uveitis | RVO/RM | Total | |
|---|---|---|---|---|---|
| Eyes, n (%) | 105 (61.4%) | 34 (19.9%) | 19 (11.1%) | 13 (7.6%) | 171 (100%) |
| Mean age, years (SD) | 68.8 (10.0) | 69.2 (8.9) | 63.4 (17.5) | 70.6 (12.5) | 68.4 (11.1) |
| Sex, male, n (%) | 29 (41.4%) | 20 (66.7%) | 6 (40.0%) | 6 (50.0%) | 61 (48.0%) |
| Lens status, pseudophakic, n (%) | 102 (97.1%) | 34 (100%) | 19 (100%) | 13 (100%) | 168 (98.2%) |
| Baseline mean IOP, mmHg (SD) | 13.0 (3.1) | 11.7 (4.1) | 9.1 (2.9) | 12.1 (2.9) | 12.3 (3.5) |
| Pre-existing POAG/OHT, n (%) | 49 (46.7%) | 17 (50.0%) | 7 (36.8%) | 5 (38.5%) | 78 (45.6%) |
| Mean number of hypotensive medications in cases of pre-existing POAG/OHT, n (SD) | 1.6 (1.0) | 1.2 (0.8) | 1.7 (1.1) | 1.2 (0.7) | 1.5 (1.0) |
| History of SLT, n (%) | 8 (7.6%) | 2 (5.9%) | 1 (5.3%) | 0 | 11 (6.4%) |
| History of incisional IOP-lowering surgery, n (%) | 4 (3.8%) | 1 (2.9%) | 2 (10.5%) | 0 | 7 (4.1%) |
| History of treatment with DEX-I, n (%) | 105 (100.0%) | 34 (100.0%) | 19 (100.0%) | 13 (100.0%) | 171 (100%) |
| Mean number of DEX-I injections, n (SD) | 6.5 (4.3) | 5.7 (2.9) | 8.0 (5.6) | 7.9 (3.1) | 6.6 (4.2) |
| History of DEX-I-induced OHT, n (%) | 32 (30.5%) | 14 (41.2%) | 8 (42.1%) | 5 (38.5%) | 59 (34.5%) |
| History of treatment with anti-VEGF, n (%) | 74 (70.5%) | 6 (17.6%) | 3 (15.8%) | 4 (30.8%) | 87 (50.9%) |
| Mean number of anti-VEGF injections, n (SD) | 5.5 (6.6) | 1.0 (2.5) | 1.8 (6.0) | 1.0 (2.0) | 3.9 (6.1) |
| Eyes treated with more than 1 FAc-I injection, n (%) | 24 (22.9%) | 1 (2.9%) | 2 (10.5%) | 1 (7.7%) | 28 (16.4%) |
| Follow-up duration since FAc-I, months (SD) | 29.1 (14.7) | 16.9 (11.3) | 21.2 (9.4) | 17.3 (7.7) | 24.9 (14.1) |
DEX-I dexamethasone implant, DME diabetic macular edema, FAc-I fluocinolone acetonide implant, IOP intraocular pressure, OHT ocular hypertension, POAG primary open-angle glaucoma, PSME post-surgical macular edema, RM radiation maculopathy, RVO retinal vein occlusion, VEGF vascular endothelial growth factor
Twenty-eight (16.4%) eyes received ≥ 2 FAc-I injections. A total of 205 FAc-I were delivered including 120 (58.5%) co-administered with an injection of DEX-I. The mean (SD) follow-up was 24.9 (14.1) months after the first FAc-I injection.
Prevalence of OHT after FAc-I Injections
The prevalence of OHT (IOP ≥ 25 mmHg and/or an increase of ≥ 10 mmHg after FAc-I) during follow-up was 24.6% (n = 42) in the whole cohort and did not differ among the etiology groups (p = 0.943) (Table 2, Fig. 1). The mean (SD) time to OHT diagnosis was 8.3 (8.1) months, with a minimum of 1 month and a maximum of 31 months. In 15 cases (8.8%), it was diagnosed within the first 3 months after the FAc-I injection. The mean (SD) increase in IOP was +7.0 (6.9) mmHg and did not differ among groups (p = 0.667). The IOP peak was detected at a mean (SD) of 8.6 (7.3) months and occurred earlier in the RVO/RM group and later in the DME group (p = 0.007). The proportion of high responders (IOP increase > 15 mmHg) was 11.1% (n = 19) in the whole cohort (Fig. 2). There was no statistical difference in the proportions of low, intermediate, and high responders among the etiology groups (p = 0.971). Severe OHT ≥ 35 mmHg occurred in eight eyes (4.7%) and was not significantly different among groups (p = 0.703).
Table 2.
Incidence and management of OHT after FAc-I injections
| DME | PSME | Uveitis | RVO/RM | Total | p Value | |
|---|---|---|---|---|---|---|
| Occurrence of OHT, n (%) | 25 (23.8%) | 8 (23.5%) | 5 (26.3%) | 4 (30.8%) | 42 (24.6%) | 0.943 |
| Mean increase in IOP during follow-up, mmHg (SD) | 6.6 (6.6) | 6.8 (7.3) | 8.2 (7.8) | 8.5 (6.8) | 7.0 (6.9) | 0.667 |
| Mean time to IOP peak after FAc-I, months (SD) | 10.2 (8.1) | 6.4 (5.1) | 6.5 (5.0) | 4.2 (3.9) | 8.6 (7.3) | 0.007 |
| IOP response, n (%) | ||||||
| No IOP increase | 17 (16.2%) | 5 (14.7%) | 2 (10.5%) | 1 (7.7%) | 25 (14.6%) | 0.971 |
| Low responders (IOP increase of 1–5 mmHg) | 36 (34.3%) | 13 (38.2%) | 8 (42.1%) | 5 (38.5%) | 62 (36.3%) | |
| Intermediate responders (IOP increase of 6–15 mmHg) | 42 (40.0%) | 11 (32.4%) | 6 (31.6%) | 6 (46.2%) | 65 (38.0%) | |
| High responders (IOP increase > 15 mmHg) | 10 (9.5%) | 5 (14.7%) | 3 (15.8%) | 1 (7.7%) | 19 (11.1%) | |
| Eyes with IOP ≥ 35 mmHG, n (%) | 6 (5.7%) | 1 (2.9%) | 0 | 1 (7.7%) | 8 (4.7%) | 0.703 |
| OHT treated with IOP-lowering medication only, n (%) | 12 (11.4%) | 6 (17.6%) | 4 (21.1%) | 2 (15.4%) | 24 (14.0%) | 0.401 |
| OHT treated with SLT, n (%) | 9 (8.6%) | 0 | 1 (5.3%) | 2 (15.4%) | 12 (7.0%) | 0.259 |
| OHT treated with incisional IOP-lowering surgery, n (%) | 4 (3.8%) | 2 (5.9%) | 0 | 0 | 6 (3.5%) | 0.675 |
DEX-I dexamethasone implant, DME diabetic macular edema, FAc-I fluocinolone acetonide implant, IOP intraocular pressure, OHT ocular hypertension, POAG primary open-angle glaucoma, PSME post-surgical macular edema, RM radiation maculopathy, RVO retinal vein occlusion, VEGF vascular endothelial growth factor
Fig. 1.
Prevalence of ocular hypertension according to etiology subgroup. DME diabetic macular edema, OHT ocular hypertension, PSME post-surgical macular edema, RM radiation maculopathy, RVO retinal vein occlusion
Fig. 2.
Prevalence of high responders, medium responders, low responders, and nonresponders according to etiology subgroup. DME diabetic macular edema, IOP intraocular pressure, OHT ocular hypertension, PSME post-surgical macular edema, RM radiation maculopathy, RVO retinal vein occlusion
Management of OHT after FAc-I injections
In most cases, OHT was treated with topical medication alone (14.0% of the whole cohort, 57% of the hypertonic cases, n = 24). Selective laser trabeculoplasty (SLT) was used successfully to treat OHT in 12 eyes (7.0%). A total of six (3.5%) eyes required incisional IOP-lowering surgery in the whole cohort (two cases of trabeculectomy, two cases of non-penetrating deep sclerectomy, and two cases of PRESERFLO™ MicroShunt). The management of OHT after FAc-I did not differ significantly among the pathology groups (Table 2).
Risk Factors for OHT after FAc-I Injections
The univariate analysis identified five risk factors for OHT after FAc-I: younger age (p = 0.007), pre-existing OHT or glaucoma (p = 0.005), topical IOP-lowering monotherapy (p = 0.006), topical IOP-lowering dual therapy (p = 0.005), and history of corticosteroid-induced OHT after DEX-I injection (p = 0.047) (Table 3).
Table 3.
Risk factors of OHT secondary to FAc-I
| Characteristics | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| Hazard ratio (95% CI) | p Value | Hazard ratio (95% CI) | p Value | |
| Age (per year) | 0.97 (0.95; 0.99) | 0.007 | 0.97 (0.94; 1.00) | 0.036 |
| Sex | ||||
| Male | Ref | |||
| Female | 0.84 (0.46;1.53) | 0.56 | ||
| Etiology | ||||
| DME | Ref | |||
| PSME | 1.28 (0.58; 2.86) | 0.54 | ||
| Uveitis | 1.28 (0.49; 3.34) | 0.62 | ||
| RVO/RM | 1.82 (0.63; 5.29) | 0.27 | ||
| Pre-existing OHT or glaucoma | ||||
| No | Ref | |||
| Yes | 2.50 (1.32; 4.76) | 0.005 | 2.06 (1.06; 4.03) | 0.034 |
| Pre-existing OHT treatment | ||||
| None | Ref | |||
| Topical IOP-lowering monotherapya | 2.77 (1.33; 5.74) | 0.006 | ||
| Topical IOP-lowering dual therapya | 3.13 (1.41; 6.98) | 0.005 | ||
| Topical IOP-lowering triple or quadruple therapy | 1.37 (0.18; 10.4) | 0.76 | ||
| History of SLT | 0 (0; Inf) | > 0.99 | ||
| History of incisional IOP-lowering surgery | 2.05 (0.47; 8.97) | 0.34 | ||
| History of DEX-I-induced OHT | ||||
| No | Ref | |||
| Yesa | 1.85 (1.01; 3.41) | 0 .047 | ||
CI confidence interval, DEX-I dexamethasone implant, DME diabetic macular edema, FAc-I fluocinolone acetonide implant, IOP intraocular pressure, OHT ocular hypertension, POAG primary open-angle glaucoma, PSME post-surgical macular edema, RVO retinal vein occlusion, SLT selective laser trabeculoplasty, VEGF vascular endothelial growth factor
aVariables excluded due to multicollinearity, with VIF > 2
The multivariate analysis statistically confirmed two significant risk factors for OHT after FAc-I: younger age (p = 0.036) and pre-existing OHT or glaucoma (p = 0.034). Due to important multicollinearity with pre-existing OHT or glaucoma, three factors were not included in the multivariate analyses (topical IOP-lowering monotherapy, topical IOP-lowering dual therapy, and history of corticosteroid-induced OHT).
Subgroup of Patients with OHT or Glaucoma
Among eyes with pre-existing OHT or glaucoma, the risk of OHT did not differ between eyes treated with IOP-lowering monotherapy versus dual therapy (p = 0.7). There was no statistically significant difference in the risk of OHT between eyes treated with local monotherapy or dual therapy and those treated with triple therapy or quadruple therapy (Figure S1). Moreover, the mean (SD) time to the diagnosis of OHT was 9.8 months (8.6) in eyes with pre-existing OHT or glaucoma, versus 5.1 months (6.3) in eyes without pre-existing OHT or glaucoma.
Repeated Injections and the Risk of OHT
There was no statistically significant difference in the total mean number of DEX-I injections between eyes with and without OHT (9.7 versus 9.2 injections, respectively, p = 0.64). Similarly, no significant differences were found between eyes with and without OHT, regardless of whether DEX-I was administered before FAc-I (6.9 versus 6.8 injections, respectively, p = 0.92), in combination (0.8 versus 0.6, respectively, p = 0.09), or as a top-up treatment after FAc-I (2.0 versus 1.7 injections, respectively, p = 0.67). Among the 42 eyes with OHT after FAc-I, more than half, 23 eyes (24.6% of the whole cohort), had received a DEX-I injection within the 3 months prior to the diagnosis of OHT.
Regarding anti-VEGF injections, there was no statistically significant difference in the total mean number of anti-VEGF injections between eyes with and without OHT (5.7 versus 4.4 injections, respectively, p = 0.33). This remained nonsignificant whether anti-VEGF agents were administered before FAc-I (5 versus 3.5 injections, respectively, p = 0.17) or as a top-up treatment after FAc-I (0.4 versus 0.8 injections, respectively, p = 0.27).
Among the 28 eyes injected with more than one FAc-I, OHT was diagnosed after the second FAc-I injection in seven eyes and after the third in one eye.
Predictability of IOP Elevation Associated with FAc-I Based on OHT Following DEX-I
Absence of clinically significant IOP elevation after DEX-I demonstrated an 80.4% probability of predicting absence of IOP elevation after FAc-I injection. This means that if there was no OHT after DEX-I injections, there was an 80.4% probability that there would be no OHT after a FAc-I injection. In contrast, 33.9% of patients who developed OHT under DEX-I experienced OHT under FAc-I (Table S1).
During the follow-up, two of the three phakic eyes (1.2% of the overall cohort) underwent cataract surgery. Three cases (1.8%) of infectious endophthalmitis were detected after FAc-I. However, these cases of endophthalmitis occurred late, at 3, 6, and 17 months after FAc injection, but a few days after a top-up treatment (two after DEX-I and one after anti-VEGF).
Discussion
The prevalence of OHT after FAc-I injection was 24.6% in this study, which is lower than that reported in the FAME randomized controlled trial (RCT) [5] but consistent with other observational studies [12–14]. The discrepancy between clinical trial and real-world studies can be explained by the lack of steroid-induced OHT screening under DEX-I in the RCT without any specific hypotensive treatment. In our study, all eyes had received at least one DEX-I injection prior to FAc-I. However, eyes with uncontrolled OHT due to DEX-I were not candidates for FAc-I. Here, eyes with OHT after DEX-I accounted for 34.5% of our cohort, which is however lower than the prevalence of OHT after FAc-I. This indicates that the therapeutic measures implemented before FAc-I injection in eyes predisposed to OHT were effective. However, DEX-I-induced OHT still remained a significant risk factor for OHT after FAc-I injection in univariate analysis. We also showed that the absence of a clinically significant IOP elevation after DEX-I had an 80.4% probability of predicting the absence of IOP elevation after FAc-I injection. It should be noted that this result applies to pseudophakic eyes with controlled IOP and chronic or recurrent macular edema, representing the patients for whom FAc-I injections are clinically indicated, as in our study population. However, this result confirms the conclusions of the USER study, which demonstrated a high positive predictive value (94%) for a lack of IOP response observed with DEX-I in determining the likelihood of a lack of IOP response with FAc-I. These results reinforce the importance of treatment with DEX-I before FAc-I in order to identify eyes with steroid-induced OHT [16]. The SAFODEX 2 study showed that almost 60% of steroid-induced OHT cases occurred after the first DEX-I injection, whereas nearly 90% of cases were diagnosed when considering the first three DEX-I injections [11]. The predictability of steroid-induced OHT after intravitreal implant injection has prompted experts to recommend at least 2–3 DEX-I injections before FAc-I to screen for steroid-induced OHT [17].
OHT was managed here with topical medication alone or SLT in most cases (n = 36, 21.1% of the whole cohort), the remaining patients being treated with filtering surgery (n = 6, 3.5% of the whole cohort). The need for surgery in this study aligns with other real-world data in DME [12] and is lower than in the RCT [5]. However, it should be noted that nearly half of the cohort included eyes with pre-existing OHT or glaucoma. We previously showed that eyes with a history of OHT or glaucoma could be treated with DEX-I if IOP was well controlled, whether by topical treatment [10], laser [18], or even filtering surgery [19]. The good pressure tolerance found here suggests that FAc-I would not be contraindicated in cases of well-controlled OHT or glaucoma. Nevertheless, OHT and glaucoma emerged as risk factors for OHT after FAc-I in the multivariate analysis, emphasizing the need for close monitoring of those eyes. The relatively small sample of patients with OHT under FAc-I prevents any conclusions on secondary outcomes, such as the observation of longer delay between injection and first diagnosis of OHT in eyes without pre-existing OHT or glaucoma, as well as differences between eyes according to the number of hypotensive therapies.
The multivariable analysis also found that younger age increased the risk of FAc-I-induced OHT. This intriguing result has been previously shown in other studies with DEX-I [10, 11, 20] and is supposed to be due to less cellular trabecular meshwork present with aging, making outflow pathways potentially less affected by cell morphological changes than in younger patients [21]. No increased risk of OHT was observed according to sex, although another study identified male sex as a risk factor for OHT after DEX-I [10]. This association remains debated by other studies, however, and should be further confirmed [20]. Regarding the underlying ocular disease, no increased risk of OHT after FAc-I injection was observed based on the pathology group. This is in contrast to the SAFODEX study, which demonstrated that RVO and uveitis were risk factors for OHT after DEX-I [10, 11]. The disparity in sample sizes among the etiology groups in the present study could explain the absence of significant differences, as FAc-I was approved for the treatment of DME before being approved for uveitis. It is not yet approved for the treatment of PSME, RVO, or RM, which explains the smaller number of patients and the shorter follow-up duration in these groups. Data from the present cohort could suggest similar results to the SAFODEX study, since the IOP peak occurred significantly earlier in the RVO/RM, uveitis, and PSME groups than in the DME group [10]. A longer follow-up could therefore determine whether the etiologies treated with FAc-I are a risk factor for OHT, as shown with DEX-I. Nevertheless, a molecule-specific effect cannot be excluded, as DEX-I and FAc-I may differentially induce OHT depending on the underlying etiology.
It is not clear whether there is a cumulative effect of steroids on the risk of OHT. The REALFAc study showed that eyes developing OHT after FAc-I had previously received more DEX-I injections than eyes without OHT, whereas this was not observed with anti-VEGF [13]. It is also known that eyes receiving long-term DEX-I injections may develop late-onset OHT, with around 20% of OHT cases diagnosed after the fourth injection in some studies [11, 18]. All these findings suggest that steroids may have a cumulative effect, inducing trabecular modifications and leading to an increased risk of OHT. However, in the present study, no difference was found in the number of DEX-I injections performed before FAc-I, in combination with FAc-I, or as top-up treatment between eyes with OHT after FAc-I and those without OHT. On the other hand, eight eyes presented with late-onset OHT after a second or third FAc-I injection. Nevertheless, half of the 42 eyes developing OHT after FAc-I had also received a DEX-I injection within the 3 months preceding diagnosis of OHT. In these cases, the IOP elevation may be related to recent DEX-I exposure. A synergistic effect of steroids on IOP can also be hypothesized, leading to trabecular saturation and an increased risk of OHT when the peak intravitreal concentrations of DEX-I and FAc-I overlap. Indeed, we recently showed that, in a cohort of 61 eyes that were treated with two consecutive FAc-I injections, the incidence of OHT was numerically higher after the second injection (19.7% versus 11.5%). However, a greater proportion of patients had received DEX-I in combination with the second FAc-I compared to the first FAc-I injection (54.1% versus 26.2%), which may explain why OHT was more frequent after the second FAc-I [22]. These findings emphasize the importance of monitoring IOP closely when combining FAc-I and DEX-I, particularly in eyes with risk factors for steroid-induced OHT.
We must acknowledge several limitations. First, the retrospective nature of the study may limit the systematic reporting of data and the regularity of follow-up. Given that the mean follow-up was 24.9 months, some patients did not reach 36 months of follow-up after each FAc-I injection. Some IOP spikes might have been missed between two visits, underestimating the actual incidence of OHT. Secondly, OHT was routinely screened using non-contact air tonometry and was confirmed using Goldmann applanation tonometry. Although this approach reflects routine clinical practice, the use of two different tonometry methods may have introduced measurement variability in this retrospective study. OHT management and use of IOP-lowering medication were not strictly planned by a protocol but left at the physicians’ discretion. However, several national and international guidelines were followed in our tertiary center, thereby harmonizing patient care. Moreover, the number of patients treated for DME is higher than in the other etiological groups, and with longer follow-up. As discussed earlier, this is because of the indication of FAc, which was initially approved for DME and then noninfectious uveitis. Currently, the implant is not allowed for RVO or RM, therefore limiting its use. The difference in sample size may explain the absence of uveitis and RVO etiologies as risk factors for OHT, as was demonstrated with DEX-I [11] and triamcinolone [20]. Similarly, the absence of differences in the risk of OHT between eyes treated with IOP-lowering monotherapy, dual therapy, or more intensive regimens may also be related to the limited statistical power due to the small number of eyes in each subgroup. Another important limitation of this study is the frequent combined injections of DEX-I and FAc-I. As a result, some IOP elevations attributed to FAc-I may in fact be related to recent DEX-I exposure. Due to the retrospective design, we were unable to differentiate the respective effects of FAc-I and DEX-I using time-varying analyses. This should be addressed in future prospective studies, as FAc-I and DEX-I are frequently injected in combination in real-world practice. Lastly, both eyes were included in the analysis for 44 out of 127 patients in the cohort. The intra-patient correlation may have led to an overestimation of p-values and confidence intervals that was not corrected in our statistical analysis. Given the retrospective nature of the study, the findings will require confirmation in future prospective studies using statistical models that should take intra-patient correlation into account.
Conclusion
In conclusion, OHT after FAc-I injections affected approximately a quarter of eyes in the present study, specifically young patients or those with pre-existing OHT or glaucoma. Although most of the eyes were managed with topical treatment or SLT alone, a few eyes required filtering surgery, highlighting the need for long-term IOP screening.
Supplementary Information
Below is the link to the electronic supplementary material.
Author Contributions
Conceptualization: Laurent Kodjikian, Yasmine Serrar; methodology: Laurent Kodjikian, Yasmine Serrar, Thibaud Mathis, and Lucas Sejournet; validation: Laurent Kodjikian, Thibaud Mathis, Lucas Sejournet, Philippe Denis, and Ariane Malclès; investigation: Yasmine Serrar, Lucas Sejournet, Sami Bounetta, Marwa Deiri, and Chloé Gullon; data curation: Yasmine Serrar, Lucas Sejournet, Benoît Allignet, Sami Bounetta, Marwa Deiri, and Chloé Gullon; writing—original draft preparation: Yasmine Serrar; writing—review and editing: Yasmine Serrar, Lucas Sejournet, Laurent Kodjikian, and Thibaud Mathis; visualization: Yasmine Serrar, Lucas Sejournet, Laurent Kodjikian, Thibaud Mathis, and Ariane Malclès; supervision: Laurent Kodjikian, Thibaud Mathis, and Philippe Denis. Benoît Allignet conducted the statistical analyses. All authors have read and agreed to the published version of the manuscript.
Funding
This research received no funding. The journal’s Rapid Service Fee was funded by the authors.
Data Availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflicts of Interest
Yasmine Serrar, Lucas Sejournet, Benoît Allignet, Sami Bounetta, Marwa Deiri, and Chloé Gullon have no conflict of interest to report. Laurent Kodjikian is consultant for AbbVie, Alimera, Bayer, Celltrion, MS-Pharma, Krys, Horus, Novartis, and Roche. Thibaud Mathis is consultant for AbbVie, Bayer, GSK, Horus, Kol, Novartis, and Roche. Philippe Denis is a consultant for AbbVie and Horus. Ariane Malclès is a consultant for Bayer and Roche.
Ethics Approval
This research was conducted in accordance with the Declaration of Helsinki. Patients' informed consent was obtained, and the local ethics committee (Hospices Civils de Lyon) approved the study, registered under number 20-156.
References
- 1.Kodjikian L, Bellocq D, Bandello F, Loewenstein A, Chakravarthy U, Koh A, et al. First-line treatment algorithm and guidelines in center-involving diabetic macular edema. Eur J Ophthalmol. 2019;29(6):573–84. [DOI] [PubMed] [Google Scholar]
- 2.Haller JA, Bandello F, Belfort R, Blumenkranz MS, Gillies M, Heier J, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117(6):1134-1146.e3. [DOI] [PubMed] [Google Scholar]
- 3.José-Vieira R, Ferreira A, Menéres P, Sousa-Pinto B, Figueira L. Efficacy and safety of intravitreal and periocular injection of corticosteroids in noninfectious uveitis: a systematic review. Surv Ophthalmol. 2022;67(4):991–1013. [DOI] [PubMed] [Google Scholar]
- 4.Bellocq D, Korobelnik J-F, Burillon C, Voirin N, Dot C, Souied E, et al. Effectiveness and safety of dexamethasone implants for post-surgical macular oedema including Irvine–Gass syndrome: the EPISODIC study. Br J Ophthalmol. 2015;99(7):979–83. [DOI] [PubMed] [Google Scholar]
- 5.Campochiaro PA, Brown DM, Pearson A, Ciulla T, Boyer D, Holz FG, et al. Long-term benefit of sustained-delivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Ophthalmology. 2011;118(4):.e2-635.e2. [DOI] [PubMed] [Google Scholar]
- 6.Campochiaro PA, Nguyen QD, Hafiz G, Bloom S, Brown DM, Busquets M, et al. Aqueous levels of fluocinolone acetonide after administration of fluocinolone acetonide inserts or fluocinolone acetonide implants. Ophthalmology. 2013;120(3):583–7. [DOI] [PubMed] [Google Scholar]
- 7.Mushtaq Y, Mushtaq MM, Gatzioufas Z, Ripa M, Motta L, Panos GD. Intravitreal fluocinolone acetonide implant (ILUVIEN®) for the treatment of retinal conditions. A review of clinical studies. Drug Des Dev Ther. 2023;17:961–75. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics: I. The effect of dexamethasone* in the normal eye. Arch Ophthalmol. 1963;70(4):482–91. [DOI] [PubMed] [Google Scholar]
- 9.Polansky JR, Fauss DJ, Chen P, Chen H, Lütjen-Drecoll E, Johnson D, et al. Cellular pharmacology and molecular biology of the trabecular meshwork inducible glucocorticoid response gene product. Ophthalmologica. 1997;211(3):126–39. [DOI] [PubMed] [Google Scholar]
- 10.Malclès A, Dot C, Voirin N, Vié A-L, Agard É, Bellocq D, et al. Safety of intravitreal dexamethasone implant (OZURDEX): the SAFODEX study. Incidence and risk factors of ocular hypertension. Retina. 2017;37(7):1352–9. [DOI] [PubMed] [Google Scholar]
- 11.Rezkallah A, Mathis T, Abukhashabah A, Voirin N, Malclès A, Agard É, et al. Long-term incidence and risk factors of ocular hypertension following dexamethasone-implant injections: the SAFODEX-2 study. Retina. 2021;41(7):1438–45. [DOI] [PubMed] [Google Scholar]
- 12.Singer MA, Sheth V, Mansour SE, Coughlin B, Gonzalez VH. Three-year safety and efficacy of the 0.19-mg fluocinolone acetonide intravitreal implant for diabetic macular edema. Ophthalmology. 2022;129(6):605–13. [DOI] [PubMed] [Google Scholar]
- 13.Mathis T, Papegaey M, Ricard C, Rezkallah A, Matonti F, Sudhalkar A, et al. Efficacy and safety of intravitreal fluocinolone acetonide implant for chronic diabetic macular edema previously treated in real-life practice: the REALFAc study. Pharmaceutics. 2022;14(4):723. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Lebrize S, Arnould L, Bourredjem A, Busch C, Rehak M, Massin P, et al. Intraocular pressure changes after intravitreal fluocinolone acetonide implant: results from four european countries. Ophthalmol Ther. 2022;11(3):1217–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Kodjikian L, Bandello F, de Smet M, Dot C, Zarranz-Ventura J, Loewenstein A, et al. Fluocinolone acetonide implant in diabetic macular edema: International experts’ panel consensus guidelines and treatment algorithm. Eur J Ophthalmol. 2022;32(4):1890–9. [DOI] [PubMed] [Google Scholar]
- 16.Eaton A, Koh SS, Jimenez J, Riemann CD. The USER study: a chart review of patients receiving a 0.2 µg/day fluocinolone acetonide implant for diabetic macular edema. Ophthalmol Ther. 2019;8(1):51–62. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Dot C, Poli M, Aptel F, Labbe A, Kodjikian L, Baillif S, et al. Ocular hypertension and intravitreal steroids injections, update in 2023. French guidelines of the French glaucoma society and the French ophthalmology society. J Fr Ophtalmol. 2023;46(8):e249–e256. [DOI] [PubMed] [Google Scholar]
- 18.Billant J, Douma I, Agard E, Levron A, Bouvarel H, Leroux P, et al. Late steroid-induced ocular hypertension after intravitreal dexamethasone implants: a series of 20 cases. J Fr Ophtalmol. 2023;46(9):1039–46. [DOI] [PubMed] [Google Scholar]
- 19.Rezkallah A, Kodjikian L, Barbarroux A, Laventure C, Motreff A, Chacun S, et al. Intra-ocular pressure response to dexamethasone implant injections in patients with a history of filtering surgery: the TRABEX study. Pharmaceutics. 2022;14(9):1756. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Kiddee W, Trope GE, Sheng L, Beltran-Agullo L, Smith M, Strungaru MH, et al. Intraocular pressure monitoring post intravitreal steroids: a systematic review. Surv Ophthalmol. 2013;58(4):291–310. [DOI] [PubMed] [Google Scholar]
- 21.Choi W, Bae HW, Choi EY, Kim M, Kim EW, Kim CY, et al. Age as a risk factor for steroid-induced ocular hypertension in the non-paediatric population. Br J Ophthalmol. 2020;104(10):1423–9. [DOI] [PubMed] [Google Scholar]
- 22.Serrar Y, Sejournet L, Thomeret V, Dot C, Bonnin S, Soler V, et al. Efficacy and safety of multiple fluocinolone acetonide implants in diabetic macular oedema: comparison between first and second intravitreal injections. Eye. 2025;39:2678–2685. [DOI] [PMC free article] [PubMed]
- 23.Ng JSK, Fan DSP, Young AL, Yip NKF, Tam K, Kwok AKH, et al. Ocular hypertensive response to topical dexamethasone in children. Ophthalmology. 2000;107(11):2097–100. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.