Single Dexamethasone Intravitreal Implant in the Treatment of Noninfectious Uveitis

Abstract

Purpose:

To investigate the effect of a single intravitreal dexamethasone implant (IVT-DI; Ozurdex; Allergan, Inc.) on visual acuity, macular thickness, and intraocular pressure (IOP) in active noninfectious uveitis.

Methods:

Medical records of patients with noninfectious active uveitis treated by IVT-DIs were retrospectively reviewed. Uveitis etiologies, treatment indications, best corrected visual acuity (BCVA), central retinal thickness measured by ocular coherence tomography, IOP, and systemic, local, and topical treatments were collected. Parameters were analyzed before the injection of the implant, after 1.5 ± 0.8 months and 4.4 ± 0.9 months for the BCVA, after 2 ± 1.3 months and 4.6 ± 1.3 months for the ocular coherence tomography, and after 1.3 ± 0.7 months and 4.4 ± 1 months for the IOP.

Results:

We included 14 patients (20 eyes, 20 implant injections) with cystoid macular edema (78%), vasculitis (7%), choroiditis (7%), and vasculitis associated with choroiditis (7%). Before the injection, mean visual acuity was 0.4 ± 0.5 logMAR (logarithm of the minimum angle of resolution) that improved to 0.3 ± 0.5 logMAR (P = 0.0002) after 1.5 ± 0.8 months and to 0.3 ± 0.5 logMAR (P = 0.005) after 4.4 ± 0.9 months. A statistically significant decrease of macular thickness was observed both at 2 ± 1.3 months and at 4.6 ± 1.3 months after IVT-DI. Mean IOP was 16 ± 5 mmHg before injections, 18 ± 6 mmHg (P = 0.13) at 1.3 ± 0.7 months, and 15 ± 4 mmHg (P = 0.65) at 4.4 ± 1 months. By Kaplan–Meier analysis, we found that after 3.3 months, 17% of the eyes still present a BCVA amelioration ≥0.3 logMAR.

Conclusions:

In our patients with active noninfectious uveitis, injection of a first single dexamethasone implant was found to improve visual acuity and decrease macular thickness without significant increase of IOP, although the effect seems limited in time.

Introduction

Uveitis is a potentially blinding inflammatory disease with an estimated prevalence of 38 to 714 cases per 100,000.¹ Macular edema occurs in up to one-third of uveitis patients as a consequence of chronic intraocular inflammation, leading to reduced visual acuity.²

A systemic treatment based on steroids and/or immunosuppressors can be classically proposed.³ However, this approach exposes the patients to several side effects. A local approach, either subconjunctival or intravitreal, offers an interesting alternative. Intravitreal steroid administration has been widely studied in this context.^4–8 Intravitreal corticosteroids have been demonstrated to induce cataract and sight-threatening glaucoma.^4,6 In this regard, the safety profile of the intravitreal dexamethasone implant (IVT-DI) might be safer than the fluocinolone acetonide intravitreal implant. The eyes treated with fluocinolone acetonide implant may need more glaucoma medications, surgery or laser, and developed more cataract than the eyes treated with IVT-DI. However, eyes treated with DI may more likely need a second implant.⁹

In this study, we are evaluating the effect of a single injection of IVT-DI for the treatment of active noninfectious uveitis.

Methods

We conducted a retrospective study including 14 patients with an active noninfectious uveitis not responsive to standard treatment with oral corticosteroids and/or immunosuppressive therapy (according to standard of care^10–12). The dose of the systemic treatment was adapted according to the clinical response to the injection. Twenty IVT-DIs were injected into 20 eyes between March 2013 and November 2014. The study design adhered to the Declaration of Helsinki. The use of IVT-DI was approved by the patient and an institutional review board approval for the record review was obtained.

The IVT-DI (Ozurdex; Allergan, Inc., Irvine, CA) is a biodegradable, sustained-release implant of 0.7 mg of dexamethasone embedded in a solid polymer drug.¹³ A study on monkeys demonstrates sustained levels of IVT-DI and biological activity for 6 months, with peak levels of drug for the first 2 months¹⁴. It is approved by the United States Food and Drug Administration for the treatment of macular edema secondary to retinal vein occlusion and noninfectious uveitis affecting the posterior segment of the eye.^15–17

All patients had a previous systemic work-up with exclusion of systemic infection. Uveitis etiologies; treatment indications; visual acuity; slit lamp and fundus examination; central retinal thickness (CRT) measured by optical coherence tomography; intraocular pressure (IOP); and systemic, local, and topical treatments were collected. Parameters were analyzed before the injection of a first implant, after 1.5 ± 0.8 months and 4.4 ± 0.9 months for the best corrected visual acuity (BCVA), after 2 ± 1.3 months and 4.6 ± 1.3 months for the ocular coherence tomography (OCT), and after 1.3 ± 0.7 months and 4.4 ± 1 months for the IOP.

One eye had a vitrectomy with epiretinal membrane peeling between the first and the second follow-up. The data of this eye at the second follow-up were thus excluded from the BCVA and OCT analyses.

The primary end point was the evaluation of the BCVA evaluated by Snellen charts and converted to logarithm of the minimum angle of resolution (logMAR) units. The secondary end points were the measure of the IOP obtained by applanation and the evaluation of the CRT measured by SD-OCT (Optovue RTVue 100, Simovison and OCT Spectralis Plus by Heidelberg Engineering). Fifty-two of 60 measurements were performed on OCT Spectralis Plus. The 8 measurements performed on the Optovue RTVue100 were at baseline (5) and after 2 ± 1.3 months (3).

Statistical analysis

Continuous data are presented as mean ± standard deviation and categorical data as numbers or percentage. Changes in BCVA, CRT, and IOP are analyzed using an analysis of variance for repeated measurements with missing data at baseline before the injection, after 1.5 ± 0.8 months and 4.4 ± 0.9 months for the BCVA, after 2 ± 1.3 months and 4.6 ± 1.3 months for the OCT, and after 1.3 ± 0.7 months and 4.4 ± 1 months for the IOP.

The Kaplan–Meier estimate is used to evaluate (1) the cumulative probability of nonimprovement BCVA after a single IVT-DI and (2) the cumulative probability of recurrence of cystoid macular edema (CME) after IVT-DI.

The improvement in BCVA was defined as in the Standardization of Uveitis Nomenclature (SUN) guidelines as ≥0.3 logMAR unit change.¹⁸ Recurrence of CME was defined as a CRT ≥20% from baseline as described in the MUST (Multicenter Uveitis Steroid Treatment) Trial Research Group.¹⁹

A P value <0.05 was considered significant. Analyses were performed by a statistician with Statistix 9.0 (Analytical Sofware, Tallahassee, FL) and Medcalc 11.4 (Medcalc, Oostende, Belgium).

Results

The characteristics of 20 eyes of 14 patients are reported in Table 1. The mean age is 48 years and the majority are women (78%). The anatomical classification of uveitis according to the SUN classification¹⁸ is mostly posterior (64%) but also panuveitis (29%) and intermediate uveitis (7%). There are 57% of unilateral uveitis. The etiologies are mostly idiopathic (71%); birdshot chorioretinitis (14%); presumed tuberculous-related uveitis (7%); and idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis (7%).

Table 1.

Characteristics of Patients and Eyes Treated with the Intravitreal Dexamethasone Implant in Noninfectious Uveitis

Patients	Age, years	Sex	Anatomical	Unilateral or bilateral	Etiology	Indication
1	41	F	Panuveitis	B	Idiopathic	Vasculitis/choroditis
2	30	F	Posterior uveitis	U	Idiopathic	Choroiditis
3	70	M	Posterior uveitis	B	Tuberculous uveitis	Vasculitis
4	46	M	Posterior uveitis	B	Idiopathic	Vasculitis + CME
5	56	F	Posterior uveitis	U	Birdshot	Vasculitis + CME
6	29	F	Panuveitis	U	Idiopathic	CME
7	71	F	Posterior uveitis	U	Idiopathic	Vasculitis + CME
8	38	F	Posterior uveitis	U	IRVAN	Vasculitis + CME
9	60	F	Panuveitis	B	Idiopathic	Vasculitis + CME
10	38	F	Posterior uveitis	B	Idiopathic	Vasculitis + CME
11	55	F	Posterior uveitis	B	Idiopathic	Vasculitis + CME
12	51	M	Panuveitis	U	Idiopathic	Vasculitis + CME
13	32	F	Intermediate uveitis	U	Idiopathic	Vasculitis + CME
14	56	F	Posterior uveitis	U	Birdshot	CME

F, female; M, male; U, unilateral; B, bilateral; IRVAN, idiopathic retinitis, vasculitis, aneurysms, and neuroretinitis; CME, cystoid macular edema.

The indication of treatment is CME associated with inflammatory signs in 78%, active vasculitis in 7%, active choroiditis in 7%, and active vasculitis plus choroiditis in 7%.

The mean BCVA at baseline (before injection) is 0.4 ± 0.5 logMAR, 0.3 ± 0.5 logMAR at 1.5 ± 0.8 months after the IVT-DI, and 0.3 ± 0.5 logMAR at 4.4 ± 0.9 months after the IVT-DI (Fig. 1).

FIG. 1.

Mean initial BCVA in logMAR, at 1.5 ± 0.8 months and at 4.4 ± 0.9 months after IVT-DI. BCVA, best corrected visual acuity; IVT-DI, intravitreal dexamethasone implant.

The improvement of the BCVA between the baseline and 1.5 ± 0.8 months after IVT-DI and between the baseline and 4.4 ± 0.9 months after the IVT-DI is statistically significant (P < 0.05).

A significant decrease of the mean macular thickness measured by OCT in micrometers (Fig. 2) is observed after 2 ± 1.3 months (P = 0.0009) but also 4.6 ± 1.3 months after IVT-DI (P = 0.0232). Statistical analyses were also performed only with the eyes affected with CME at baseline and still showed a significant decrease of macular thickness. As mentioned in the Methods section, all measurements were not performed on the same OCT. However, it has been demonstrated that OCT Optovue RTVue both in normal and pathological edema underestimates the CRT as compared with Spectralis Plus OCT.^20,21

FIG. 2.

Mean initial macular thickness (μm), measured by OCT, at 2 ± 1.3 months and at 4.6 ± 1.3 months after IVT-DI. The horizontal marker corresponding to a 20% CRT reduction from baseline. CRT, central retinal thickness; OCT, ocular coherence tomography.

The Kaplan–Meier survival curve (Fig. 3) of the time to BCVA deterioration after 3.3 months of IVT-DI shows that 17% of the eyes still present a BCVA amelioration that is ≥0.3 logMAR. The Kaplan–Meier survival curve (Fig. 4) of the time to CME recurrence after 6 months of IVT-DI shows that 42% of the eyes present a CME recurrence defined as ≥20% of the baseline CRT.

FIG. 3.

Kaplan–Meier survival curve of the time to BCVA deterioration after IVT-DI. At 100 days (3.3 months) after the IVT-DI, 17% of the eyes still present a BCVA improvement ≥0.3 logMAR.

FIG. 4.

Kaplan–Meier survival curve of the time to CME recurrence after IVT-DI. At 6 months after the IVT-DI, 42% of the eyes present a CME recurrence expressed by an increase ≥20% of baseline CRT. CME, cystoid macular edema.

We found no statistically significant difference between the mean IOP before injection, early after injection (1.3 ± 0.7 months), and late after injection (4.4 ± 1 months). There is no increase in the number of patients using a triple antihypertensive therapy, and no glaucoma surgery, but 28% of the patients required a single or a double antihypertensive therapy in the later follow-up.

We did not note any adverse events because of the surgical intervention itself, such as subconjunctival hemorrhage, retinal detachment, vitreous hemorrhage, endophthalmitis, or implant migration.

Systemic and topical therapies were analyzed before and after IVT-DI (Table 2). Systemic steroids were used for 78.6% of the patients during the entire period before injection (Table 2), for 36% just before implant, and for 28.6% early and late after IVT-DI. Immunosuppressive treatment was used for 64.2% of the patients during all periods before injection (Table 2), for 43% just before implant, for 36% of the patients early after IVT-DI, and for 64.2% of patients late after IVT-DI.

Table 2.

Review of the Systemic, Local, and Topical Therapies of the Patients Previously, Just Before IVT-DI, Early, and Late After IVT-DI

	Previously ^a (%)	Just before IVT-DI (%)	Early post-IVT-DI (%)	Late post-IVT-DI (%)
Systemic
Steroids	78.6	36	28.6	28.6
Immunomodulatory therapy	64.2	43	36	64.2
Methotrexate^a	36	28	21.4	28.6
Azathioprine^a	14	7	7	7
Cyclosporine A^a	14	7	7	28.6
Acétazolamide	36	7	14	14
Other^b	36	14	7	0
Local
Intravitreal triamcinolone acetonide	21.4	0	0	0
Intravitreal anti-VEGF	14	0	0	0
Periocular steroids	7	0	0	0
Topical (%)
NSAID	21.4	7	0	0
Steroids	64.2	21	7	14
Single antihypertensive therapy	7	7	14	21.4
Double antihypertensive therapy	7	7	28.6	14
Triple antihypertensive therapy	21.4	14	7	21.4
SLT	0	0	7	0

From 7 years to 2 days before IVT-DI.

Antibiotics, antiviral, antituberculosis, and anticoagulant.

IVT-DI, intravitreal dexamethasone implant; anti-VEGF, anti-vascular endothelial growth factor; NSAID, nonsteroidal anti-inflammatory drugs; SLT, selective laser trabeculoplasty.

Discussion

Corticosteroids are the first-line treatment for noninfectious uveitis.^10,22,23 There are different forms of administration of corticosteroids: topical, systemic, or local.

Topical steroids penetrate directly into the anterior chamber with minimal systemic absorption, reducing systemic side effects. It can be given at frequent intervals easily. However, topical administration increases the risk of local side effects, including cataract and increased IOP; moreover, it does not penetrate posterior structures of the eye.²⁴

Systemic steroids (oral or intravenous) are generally the first-line therapy for posterior noninfectious uveitis, especially if the ocular disease is bilateral. However, they induce many systemic side effects.²⁵

Local corticosteroid injections (periocular or intravitreal) are used for the treatment of both intermediate and posterior uveitis. Injections provide higher concentration of corticosteroids near the posterior pole for a better treatment of the posterior inflammation than oral treatment and topical drops.^4,23,24 They allow limited systemic absorption and are particularly used when the pathology is unilateral. However, the half-life of local corticosteroid injections is a few months and the patients require repeated injections.^4,13 Periocular injections present risks and side effects (ptosis, extraocular muscle injury, globe penetration, or skin depigmentation), but intravitreal injection also presents side effects (intravitreal hemorrhage, endophthalmitis, and retinal detachment).²⁶ Subconjunctival injections also cause cataract formation and elevated IOP.²⁵ One study found that the IOP of patients who had received ≥1 periocular triamcinolone acetonide 40 mg was ≥24 and ≥30 mmHg in 34.0% and 15%, respectively; glaucoma surgery was performed in 2.4% of eyes. Cataract surgery was performed within 12 months in 13.8% of the initially phakic eyes.²⁷

The IVT-DI releases corticosteroids slowly into the eye, providing a control of the posterior inflammation.^4,13 We can speculate, as suggested in one of the MUST studies,²⁸ that good candidates for local treatment are unilateral or asymmetric uveitis or those with absolute contraindications to immunosuppressive therapy or temporary contraindications (i.e., pregnancy).^11,12 Yet, one other part of the MUST study²⁹ did not demonstrate a clear benefit of the local approach over the systemic approach.

In our retrospective study, our results suggest that a single injection of IVT-DI for the treatment of noninfectious uveitis improves visual acuity and decreases macular thickness. All the positive effects were obtained without uncontrolled IOP or glaucoma surgery during the follow-up.

The effect of the IVT-DI on noninfectious uveitis has been investigated in several studies^30–39 (Table 3); importantly, most studies are retrospective and included only few patients. All studies found a positive effect of the IVT-DI on both visual acuity and macular thickness. In terms of effectiveness, an important issue is the duration of the effect that seems to be around 4 to 6 months. This range has generally been obtained by Kaplan–Meier analysis,^30,31 and our results are in accordance with these data. A few of the mentioned studies have analyzed the effect on the decrease of the dose of the immunosuppressive treatment. Unfortunately, owing to the design of our study, we are also unable to conclude about a possible effect of the injection on the dose of systemic immunosuppressive treatment. Concerning the safety profile, only 3 patients presented an IOP >25 mmHg at 1.3 ± 0.7 months. They were treated with antihypertensive drops and only 1 with an additional selective laser trabeculoplasty whereas no one required a glaucoma surgery. However, 21.4% and 14% of the patients had a triple antihypertensive therapy previously and just before IVT-DI, respectively. A detailed evaluation of the development of cataract was not performed in our retrospective study but none of the eyes needed a cataract surgery during our follow-up. There were no other serious adverse effects. However, this study is not designed to address the effects on cataract and glaucoma, as it typically takes longer than 4–5 months to develop.

Table 3.

Review of the Literature for the Use of the IVT-DI in the Treatment of Noninfectious Uveitis in Adults

Study	Design	No.	Etiologies	Monocentric or multicentric	Mean follow-up time	Visual acuity	Macular thickness	Duration of effect	IOP
Myung et al.³⁹	Case series	6 Eyes, 4 patients, 8 implants	Idiopathic posterior uveitis Sarcoidosis	Monocentric	5.25 Months	NA	Improvement	3–4 Months	No hypertony
			Vogt–Koyanagi–Harada syndrome
Miserocchi et al.³²	Retrospective study	14 Eyes, 12 patients, 15 implants	Idiopathic noninfectious posterior uveitis	Monocentric	9 Months	Improvement	Improvement	NA	3 Eyes developed IOP elevation
			Behçet disease			3.3 lines at the end	Mean retinal thickness
			Sarcoidosis				496 ± 123 μm→226 ± 66 μm at the end
			Rheumatoid arthritis
			HLA-B27
			Multiple sclerosis
Lightman et al.³³	Randomized sham-controlled phase 3 trial	229 Patients	Noninfectious posterior uveitis	Multicentric	26 Weeks	Improvement at 8 weeks:	NA	6 Months	NA
			Noninfectious intermediate uveitis
						0.7 mg: 55% 1–2 lines
						0.35 mg: 60% 1–2 lines
						Sham: 27% 1–2 lines
Zarranz-Ventura et al.³¹	Retrospective study	82 Eyes, 63 patients, 142 implants	Nondifferentiated	Multicentric	35 Months	Improvement	Improvement	6 Months	Hypotensive treatment in 39%
			Birdshot			39% at 1 month	Mean 469 ± 193 μm baseline		Glaucoma surgery in 2.4%
			Sarcoidosis			49% at 3 months	326 ± 81 at 2 weeks
			Mutiple sclerosis			52% at 6 months	267 ± 74 at 1 month
			Juvenile arthritis			58% at 12 months	318 ± 149 at 3 months
			Ankylosing spondylitis				366 ± 140 at 6 months
			HLA-B27 uveitis				355 ± 160 at 12 months
			IRVAN Sympathetic ophthalmia
			Behçet disease
Tomkins-Netzer et al.³⁷	Observational case series	38 Eyes, 27 patients, 61 implants	Noninfectious uveitis	Monocentric	17.3 ± 1.8 Months	Improvement after the first implant from 0.47 ± 0.05logMAR to 0.27 ± 0.07logMAR	Decreased by 263 ± 44.22 μm after the first implantation	6 Months	7 Cases of increased IOP >21 mmHg
Habot-Wilner et al.³⁸	Retrospective study	8 Eyes, 7 patients, 8 implants	Noninfectious uveitis	Monocentric	17.3 Months	BCVA improved by 0.25 logMAR at 3.9 weeks	Improvement from 612 ± 143 to 250 ± 55 μm	4.7 Months	2 Eyes developed IOP elevation
Yap et al.³⁶	Retrospective study	6 Eyes, 4 patients, 6 implants	Idiopathic noninfectious panuveitis	Monocentric	15 Months	Improvement 63–70 letters at 2 weeks	Decreased 556 to 329 μm at 2 weeks	5–6 Months	2 Patients required antiglaucoma therapy
			Idiopathic noninfectious intermediate uveitis
			Birdshot
Rossetto et al.³⁵	Retrospective study	6 Eyes, 5 patients, 6 implants	Noninfectious intermediate uveitis	Monocentric	5 Months	Improvement in 5 eyes: ≥2 lines	Improvement in all eyes	3.6 Months	No hypertony
Ryder et al.³⁴	Retrospective study	22 Eyes, 11 patients, 32 implants	Idiopathic posterior uveitis	Multicentric	23.57 Months	No statistically significant difference at 6 months	No statistically significant difference at 6 months	6 ± 2.39 Months	4 Eyes developed IOP elevation
			Sarcoidosis
			Polyarteritis nodosa-associated posterior uveitis
			Vogt–Koyanagi–Harada syndrome
Khurana et al.³⁰	Retrospective study	18 Eyes, 13 patients, 18 implants	Noninfectious intermediate uveitis	Monocentric	12 Months	Significant improvement at 3 months	Improvement	201 ± 62 days (median time to recurrence of CME)	IOP >25 mmHg in 11% of eyes
			Birdshot				No CME in 89% at 1 month
			Sarcoidosis				No CME in 72% at 3 months

All the studies are retrospective except 1 randomized sham-controlled phase 3 trial to determinate the dose of dexamethasone in the intravitreal implant.

IOP, intraocular pressure.

This study has several weaknesses. It is a retrospective study and few data were missing. In addition, there are multiple etiologies of noninfectious uveitis and the macular thickness is measured by 2 different OCT machines. Indeed, as mentioned in the Methods section, all measurements were not performed on the same OCT. However, it has been demonstrated that OCT Optovue RTVue both in normal and pathological edema underestimates the CRT as compared with Spectralis Plus OCT.^20,21 Since OCT Optovue RTVue measurements were mostly performed at baseline, our findings of a macular thickness decrease are thus at most underestimated but not false.

In addition, follow-up time of each patient slightly differed, which induced some variability in between patients and in the mean evaluation time of visual acuity, macular thickness, and IOP.

In conclusion, in our group of patients with active noninfectious uveitis, the evaluation of a first single dexamethasone implant was found to improve visual acuity and decrease macular thickness without significant increase of IOP, although the effect seems limited in time. It seems to be an interesting adjuvant treatment in noninfectious uveitis already treated by systemic therapies.

Footnotes

Author Disclosure Statement

F.W., L.C., L.P., and X.J. have worked as consultants in advisory board for Allergan. X.J. has received travel refund.

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