CASE SERIES
Long-term results of fluocinolone acetonide intravitreal implant in Behçet intractable posterior uveitis Eun Kyu Oh, MD, Eun Kyoung Lee, MD, Hyeong Gon Yu, MD, PhD ABSTRACT ● RÉSUMÉ Objective: To evaluate the long-term efficacy and safety of the fluocinolone acetonide intravitreal implant in patients with Behçet disease with intractable noninfectious posterior uveitis. Design: Consecutive retrospective analysis. Participants: Eight eyes from 7 patients with Behçet uveitis who did not respond successfully to conventional treatment with topical and systemic steroids and/or systemic steroid-sparing agents were studied. Methods: We performed a chart review of patients who were treated with a 0.59-mg fluocinolone acetonide intravitreal implant at a single centre from September 2007 through June 2009. Snellen visual acuity, control of inflammation, and the development of complications such as infection or uncontrollable intraocular pressure (IOP) elevation were evaluated. Results: Mean age at implant placement was 35.3 (range 17–42) years. Mean follow-up duration was 47.8 (range 39.5–57.6) months. Postoperative visual acuity improved by more than 3 lines in 6 eyes (75%). Five patients were able to discontinue all systemic medications. Six eyes (75%) exhibited postoperative IOP spikes of more than 30 mm Hg. Five patients required glaucoma shunting surgery postoperatively for IOP control. The single phakic eye developed a visually significant posterior subcapsular lens opacification that required cataract extraction. There was 1 case of postoperative cytomegalovirus endothelitis. Infection was controlled with oral valganciclovir and topical antibiotic medication, and the patient did not require implant removal. Conclusions: The fluocinolone implant is effective in the control of intractable inflammation in Behçet uveitis. Elevation of IOP remains a major potential complication, and the possibility of infection should be considered. Objet : Évaluation de l’efficacité à long terme et de la sécurité de l’implant intravitréen de fluocinolone acétonide chez les patients atteints de la maladie de Behçet avec une uvéite postérieure intraitable non infectieuse. Nature : Analyse consécutive rétrospective. Participants : L’étude a porté sur huit yeux de 7 patients atteints d’uvéite Behçet qui n’avaient pas répondu au traitement conventionnel avec stéroïdes topiques et systémiques et/ou agents épargneurs de stéroides. Méthodes : Nous avons revu les dossiers des patients qui avaient été traités avec un implant intravitréen de fluocinolone acétonide de 0.59-mg dans un seul centre, à partir de septembre 2007 et jusqu’à juin 2009. L’acuité visuelle Snellen, le contrôle de l’inflammation et le développement de complications telles l’infection ou la hausse incontrôlable de pression intraoculaire ont été évalués. Résultats : La moyenne d’âge lors du placement de l’implant était de 35.3 (soit 17-42) ans. La durée moyenne de suivi a été de 47.8 (écart, 39.5-57.6) mois. L’acuité visuelle postopératoire s’est améliorée de plus de 3 lignes dans 6 yeux (75%). Cinq patients ont pu discontinuer toute médication systémique. Six yeux (75%) ont présenté des pics de pression intraoculaire postopératoire de >30 mm Hg. Cinq patients eurent besoin d’un implant de glaucome postopératoire pour contrôler la pression intraoculaire. Le seul œil phakique a développé une cataracte sous-capsulaire postérieure importante, requérant l’extraction. Il y eut un cas d’endothéliite à cytomégalovirus postopératoire. L’infection a été contrôlée avec du valganciclovir oral et un traitement antibiotique topique, et le patient n’a pas eu besoin de retrait d’implant. Conclusions : L’implant de fluocinolone est efficace pour contrôler l’inflammation intraitable de l’uvéite Behçet. La hausse de pression intraoculaire demeure une importante possibilité de complication, et la possibilité d’infection devrait être considérée.
Behçet disease is a multisystemic inflammatory disorder with a chronic relapsing course, and ocular Behçet disease is characterized by bilateral intraocular inflammation. The posterior segment of the eye is most commonly affected, resulting in panuveitis, which manifests mainly as retinal vasculitis. The course of the disease is characterized by recurrent explosive attacks of uveitis followed by spontaneous remissions. The initial treatment in Behçet posterior uveitis has been administration of local steroids via topical, periocular, and intravitreal routes. Besides, it typically requires systemic
therapy with oral steroids and steroid-sparing immunosuppressive agents. However, these drugs are often associated with ocular adverse effects or systemic complication, involving the blood and liver.1–5 It is also known that Behçet uveitis is more difficult to treat than other causes of uveitis. Ahn and colleagues6,7 reported that the intraocular infiltration and peripheral expansion of interferon-γ–producing CD56þ T cells contribute to the aggressive and destructive nature of Behçet uveitis. In this backdrop, new treatments are required in patients with Behçet posterior uveitis who are refractory to conventional treatment.
From the Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea
Can J Ophthalmol 2014;49:273–278 0008-4182/14/$-see front matter & 2014 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2014.03.004
Originally received Jul. 10, 2013. Final revision Feb. 24, 2014. Accepted Mar. 16, 2014 Correspondence to Hyeong Gon Yu, MD, Department of Ophthalmology, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea; [email protected]
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Retisert in Behçet intractable posterior uveitis—Oh et al. The 0.59-mg fluocinolone acetonide intravitreal implant (Retisert; Bausch and Lomb, Rochester, N.Y.) was approved by the Food and Drug Administration in April 2005 for the treatment of chronic noninfectious posterior uveitis. This has proved to be a promising therapeutic option for patients with chronic noninfectious uveitis because it enables local release of steroid into the eye for a prolonged period. The Retisert implant is designed to release fluocinolone acetonide, a synthetic steroid, over a 3-year period in a linear fashion.8 Some studies demonstrate the effectiveness of fluocinolone acetonide intravitreal implant for various kinds of uveitis such as Vogt–Koyanagi–Harada disease, serpinginous choroiditis, and sympathetic ophthalmia.9–11 However, there have been few studies that involve fluocinolone acetonide intravitreal implant in patients with Behçet uveitis. The purpose of this study was to evaluate whether the fluocinolone acetonide intravitreal implant in refractory Behçet uveitis patients has a beneficial effect with a tolerable safety and to investigate the treatment outcome in long-term follow-up of at least 3 years.
METHODS A retrospective chart review was performed on 8 eyes of 7 patients who underwent fluocinolone acetonide intravitreal implant insertion from September 2007 through June 20, 2009. All patients had Behçet uveitis. Behçet disease was diagnosed with at least 3 episodes of aphthae over a 12-month period, plus 2 of the 4 major symptoms (genital ulcers, skin lesions, positive pathergy test, and eye lesions).12 Patients who showed active posterior uveitis or panuveitis-associated retinal vasculitis and had experienced prior treatment failure were included. Treatment failure was defined as more than 2 uveitis attacks that involved the posterior segment in the last 6 months, despite treatment with at least 1 conventional immunosuppressive drug—such as azathioprine, cyclosporine, or mycophenolate mofetil—for 6 months, or the patient being unable to taper off oral prednisolone to a dose r10 mg for maintenance therapy for 6 months. Written consent was obtained before implantation. Before beginning the procedure, the implant was prepared on the surgical table by securing double-armed 8-0 Prolene to the implant through a preplaced punch. A localized conjunctival limbal peritomy was created in the inferonasal quadrant, and relaxing incisions enabled retroflexion of the conjunctiva. A microvitreoretinal blade was then used to perform a sclerotomy in the inferonasal quadrant 4 mm away from the limbus. The microvitreoretinal blade was then used to extend the sclerotomy to 3 mm in length with a sawing motion. The implant was inserted into the eye with the tab facing anteriorly and sutured to the sclera with the 8-0 Prolene suture (Fig. 1).
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Fig. 1 — A, Gonioscopic examination reveals that fluocinolone acetonide implant is inserted in proper position. B, 10-0 Prolene suture is buried under the conjunctiva.
Tight sclerotomy closure was ensured because of possible delayed wound healing caused by the steroid implant. The sclerotomy was closed with 8-0 Prolene suture. Watertight closure was confirmed by drying the closure site with a spear-shaped cellulose sponge. The conjunctiva was then closed with 8-0 Vicryl suture. Postoperative treatment of the operative eye comprised 1 drop of prednisolone acetate 1% 4 times daily (tapered over 4 weeks), 1 drop of a broad-spectrum antibiotic 4 times daily for 4 weeks, and 1 drop of homatropine 1% twice daily for 1 week. Primary outcomes of this study were postimplant control of inflammation, changes in visual acuity, changes of intraocular pressure (IOP), and development of adverse events. Postimplant control of inflammation was measured by the ability to taper systemic steroids and the number of times that active uveitis recurred. Active anterior uveitis relapse was defined as anterior chamber cells increasing from 0 or 0.5þ to Z1þ, as defined by the standardization of uveitis nomenclature criteria.13 Active posterior uveitis relapse was defined as an increase in or the development of vitreous haze, the emergence of inflammatory sheathing of retinal vessels, vascular occlusion, retinal hemorrhages, retinal infiltrates, macular edema, or papillitis. IOP was
Retisert in Behçet intractable posterior uveitis—Oh et al. Table 1—Patients demographics Sex/Age, y
FU, mo
Preoperative Phakic Status
Concomitant Cataract surgery
Previous Intraocular Surgery or Procedures
OD OS OS OD
M/30 M/30 F/17 M/40
48.8 45.3 57.6 51.9
Phakia Phakia Pseudophakia Phakia
Yes Yes No Yes
Patient 4 OD Patient 5 OS
M/40 M/42
48.5 44.2
Phakia Pseudophakia
No No
Patient 6 OD Patient 7 OS
M/42 F/41
46.4 39.5
Phakia Phakia
Yes Yes
None Ahmed implant PE and PCL Subtenon TA injection (1 time), intravitreal TA injection (4 times) None Intravitreal TA injection (1 time) Intravitreal dexamethasone injection (1 time) PE and PCL None Subtenon dexamethasone injection (1 time)
Patient Patient Patient Patient
1 1 2 3
FU, follow-up; PE and PCL, phacoemulsification and posterior chamber lens implantation; TA, triamcinolone acetate.
monitored at preoperative day 1 and postoperative months 1, 3, 6, 9, and 12, and then every 6 months until 3 years. Adverse events that were monitored were development of cataract, postoperative infection, and postoperative hypotony.
RESULTS This study included 8 eyes of 7 patients. Mean age at fluocinolone acetonide intravitreal implant insertion was 35.3 (range 17–42) years. There were 5 males and 2 females, and all patients were Korean. Mean follow-up duration was 47.8 (range, 39.5–57.6) months. Two eyes had undergone previous cataract extraction and intraocular lens (IOL) implantation, and 1 eye had undergone previous Ahmed glaucoma device implantation. Five of the study eyes underwent cataract extraction and IOL implantation at the time of fluocinolone acetonide intravitreal insertion because of lens opacity that had developed as a result of chronic inflammation and topical steroid use (Table 1). All eyes exhibited persistent intraocular inflammation that was not controlled with periocular steroids, oral steroids, or oral steroid-sparing agents. Previous treatments included azathioprine, cyclosporine, and Z10 mg oral prednisolone (3 patients, 4 eyes); azathioprine, mycophenolate mofetil, and Z10 mg oral prednisolone (1 patient,
1 eye); cyclosporine and Z10 mg oral prednisolone (1 patient, 1 eye); cyclosporine, mycophenolate mofetil, and Z10 mg oral prednisolone (1 patient, 1 eye); and repetitive intravitreal triamcinolone acetate injections following abdominal discomfort with oral prednisolone and azathioprine (1 patient, 1 eye). After fluocinolone acetonide intravitreal implant insertion, intraocular inflammation was controlled in 5 patients without oral medication (after 13.4 months, on average), but the remaining 2 patients continued oral medication for inflammation of the contralateral eye. The mean number of times anterior uveitis recurred during the follow-up period was 0.25 time/eye in study eyes compared with 2.17 times/eye in contralateral eyes. No posterior uveitis recurrence was observed in study eyes (Table 2). Preoperative Snellen visual acuity ranged from 20/2000 to 20/40 (Fig. 2). At final visit, 6 eyes (75%) showed postoperative vision improvement of more than 3 lines (after 48.6 months, on average), and 1 eye (Patient 6 OD), in which inflammation was successfully controlled but visual acuity was limited by IOL opacification, showed improved visual acuity from 20/300 to 20/200 (after 46.4 months). The single eye (Patient 5 OS) with worsening of vision deteriorated from 20/100 before the implant to 20/ 2000 at the final follow-up approximately 2 years after implant placement. Three months after implantation, this patient experienced development of corneal edema. Polymerase chain reaction analysis of aqueous humor detected
Table 2—Postimplant control of inflammation No. of Times That Active Uveitis Recurred (Study Eye)
Patient Patient Patient Patient Patient Patient Patient Patient
1 1 2 3 4 5 6 7
OD OS OS OD OD OS OD OS
No. of Times That Active Uveitis Recurred (Contralateral Eye)
Previous Systemic Therapy for Inflammation
Anterior
Posterior
Anterior
Posterior
Final Systemic Therapy for Inflammation
AZA, CSA, oral PD AZA, CSA, oral PD CSA, MMF, oral PD None* CSA, oral PD AZA, CSA, oral PD AZA, CSA, oral PD AZA, MMF, oral PD
0 0 0 0 2 0 0 0
0 0 0 0 0 0 0 0
0 0 6 0 5 0 1 1
0 0 0 0 0 0 0 0
None None CSA None CSA, CCC, oral PD None None None
AZA, azathioprine; CSA, cyclosporin A; PD, prednisolone; MMF, mycophenolate mofetil; CCC, colchicine. n
Patient 3 was treated with repetitive intravitreal triamcinolone acetate injections because of abdominal discomfort with oral prednisolone and azathioprine.
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Fig. 2 — Bar graph presenting preoperative and final visual acuities in logMAR. Visual acuities improved more than 3 lines in Snellen chart in all study eyes, except eyes that experienced development of cytomegalovirus endothelitis (Patient 5 OS) or intraocular lens opacification (Patient 6 OD). Final visual acuities were 0 logMAR in Patient 3 OD, Patient 4 OD, and Patient 7 OS.
3.9 104 copies/mL cytomegalovirus (CMV) DNA. After treatment with oral valganciclovir, CMV DNA nearly disappeared, but visual outcome was poor because of corneal decompensation resulting from severe endothelial cell loss.14 Patients were closely monitored postoperatively for the development of any adverse events. An IOP spike was defined as a pressure surge in the postoperative period more than 10 mm Hg greater than preoperative baseline. Six eyes of 5 patients were found to have IOP spikes: greater than 50 mm Hg in 2 eyes, greater than 40 mm Hg but less than 50 mm Hg in 1 eye, and greater than 30 mm Hg but less than 40 mm Hg in 3 eyes (Fig. 3). All 6 eyes needed glaucoma surgery to control IOP. Of the 2 eyes (Patient 1 OD, Patient 2 OS) with IOP greater than 50 mm Hg, one was successfully controlled with trabeculectomy and the other with trabeculectomy followed by additional Ahmed glaucoma device implantation. The eye with IOP greater than 40 mm Hg, but less than 50 mm
Hg (Patient 1 OS), had received previous Ahmed glaucoma device implantation for uveitic glaucoma. Ahmed tube exposure developed after fluocinolone acetonide intravitreal implantation, although this phenomenon had no evidence that related with fluocinolone acetonide intravitreal implantation. The exposed Ahmed glaucoma device was removed; subsequently, IOP increased to 44 mm Hg. Thus, Ahmed glaucoma device reimplantation was performed and IOP stabilized. Two of the 3 eyes with IOP greater than 30 mm Hg, but less than 40 mm Hg, required Ahmed glaucoma device implantation, and the other eye required trabeculectomy (Table 3). Before fluocinolone acetonide intravitreal implantation, 2 of the study eyes had undergone previous cataract extraction with IOL implantation. Five eyes underwent phacoemulsification and primary IOL implantation at the time of fluocinolone acetonide intravitreal implantation. Therefore, only 1 eye was monitored for cataract development. This eye had a visual acuity as good as 20/20 at 1year follow-up. However, visual acuity deteriorated to 20/ 30 by 14-month follow-up with the development of posterior subcapsular opacity. This eye underwent cataract extraction and IOL implantation, and visual acuity recovered to 20/20. There were no complications related to the surgical procedure in any of the operated eyes. There were no instances of vitreous hemorrhage, retinal detachment, or hypotony. There were also no instances of implant dislocation or sclerotomy dehiscence (Table 3).
DISCUSSION Behçet disease is classified among the vasculitides. Major manifestations of the disease are oral aphthosis, genital aphthosis, skin manifestations, and ocular lesions. Mucocutaneous lesions usually resolve without permanent sequelae after a short course of attack followed by healing,
Fig. 3 — Polygonal line graph showing fluctuations of intraocular pressure. In every eye, intraocular pressure reached its peak level in postoperative month 18. Intraocular pressures were maintained in tolerable range 3 years after surgery, and glaucoma surgery was required in 6 eyes.
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Retisert in Behçet intractable posterior uveitis—Oh et al. Table 3—Elevation of intraocular pressure and adverse events Postoperative IOP Spike Patient Patient Patient Patient Patient Patient Patient Patient
1 1 2 3 4 5 6 7
OD OS OS OD OD OS OD OS
Yes Yes Yes Yes Yes
(57 mm (44 mm (51 mm (34 mm (38 mm No No Yes (35 mm
Hg) Hg) Hg) Hg) Hg)
Hg)
Surgical Intervention
Other Adverse Events
TLE Ahmed reimplantation TLE, Ahmed implant Ahmed implant Ahmed implant None None TLE
None None None None Cataract formation Cytomegalovirus endothelitis None None
TLE, trabeculectomy.
but ocular lesions often result in severe permanent visual loss with a protracted healing process.15 Behçet disease is essentially a T-cell–mediated disease. T cells play a pivotal role in uveitis and are found in high levels in serum and aqueous humor. Consequently, T cells have been used as targets in the treatment of ocular manifestations of Behçet disease. Systemic therapy with oral steroids and steroid-sparing agents are very effective in suppression of T lymphocyte function and are the mainstay of long-term control of uveitis in Behçet disease. Although there are no consistent recommendations regarding treatment of choice for refractory Behçet uveitis, several promising agents have been reported. Gueudry and coworkers16 reported good results of interferon-alpha-2a in 32 patients with Behçet uveitis who did not respond positively to previous immunosuppressive and corticosteroid therapy. In addition, there are studies on favourable treatment results of infliximab in refractory Behçet uveitis.17,18 However, infliximab and interferon treatments have the following disadvantages: Gueudry and coworkers16 concluded that, although treatment was efficient and safe for the control of Behçet uveitis, relapse occurrence increased after discontinuation of interferon-alpha. Tognon and coworkers18 remarked that ocular and systemic manifestations tended to recur after infliximab treatment was discontinued or when the interval between infliximab infusions was longer than 8 weeks. Thus, frequent visits and expense are ongoing problems. Our case series shows promising results for the use of the fluocinolone acetonide intravitreal implant in refractory Behçet uveitis. Six of the 8 study eyes showed significant improvement in vision at the final follow-up. In addition, all treated eyes had improved control of intraocular inflammation, allowing for the discontinuation of all oral steroid or steroid-sparing medications and the weaning off of all topical steroids. Further, the fluocinolone acetonide intravitreal implant appears to last at least 3 years. Elevated IOP and cataract development are both wellknown complications of chronic steroid exposure, and the development of both of these has been reiterated in the multicentre fluocinolone acetonide implant study. In our series, 6 eyes had postoperative IOP spikes. Four of these eyes required glaucoma valve placement for adequate IOP
control, and 2 eyes required trabeculectomy. These data are encouraging because there were no intractable cases of glaucoma that required fluocinolone acetonide intravitreal implant removal. Ahn and colleagues19 reported that elevated IOP is common after therapeutic vitrectomy, concomitant with intravitreal triamcinolone acetate injection in Behçet uveitis. However, in most cases, IOP was stabilized on postoperative 1 month. In our study, IOP of some study eyes reached its peak level even after postoperative year 1. This phenomenon can be explained by sustainability of triamcinolone acetonide implant. Of the 8 study eyes, 2 had undergone cataract extraction before fluocinolone acetonide intravitreal implantation because of the development of a visually significant cataract from uveitis and steroid therapy, and 5 underwent cataract extraction at the time of fluocinolone acetonide intravitreal implantation. The single eye that was phakic did develop a visually significant cataract postoperatively that required cataract extraction. Although CMV endothelitis infection occurred in 1 eye, we did not remove the implant even after identification of CMV in the aqueous humor. Valganciclovir treatment was effective in reducing the viral load despite the presence of the working implant in the vitreous, which enabled successful control of inflammation for a year without immunosuppressants. In a previous report, a patient who experienced development of CMV retinitis after intravitreal triamcinolone injection for Behçet uveitis was treated successfully with interferon-alpha and ganciclovir without recurrence of Behçet uveitis, and complete resolution of CMV retinitis occurred.20 Therefore, removal of the implant and switching to interferonalpha for control of Behçet uveitis could have been considered together with antiviral treatment. This study showed that fluocinolone acetonide intravitreal implantation is a useful treatment method in controlling refractory, recurrent Behçet uveitis. Whereas infliximab or interferon treatment requires repetitive treatment and uveitis recurrence is common after cessation of treatment, the effect of the fluocinolone acetonide intravitreal implant persists for about 3 years and is associated with a low recurrence rate and improved visual acuity. Elevation of IOP is common but can be controlled with glaucoma surgery or topical antiglaucoma agents. In conclusion, fluocinolone acetonide intravitreal implant CAN J OPHTHALMOL — VOL. 49, NO. 3, JUNE 2014
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Retisert in Behçet intractable posterior uveitis—Oh et al. insertion is an effective treatment method in refractory Behçet uveitis; IOP and opportunistic infection should be monitored carefully.
Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. REFERENCES 1. Castellarin A, Pieramici DJ. Anterior segment complications following periocular and intraocular injections. Ophthalmol Clin North Am. 2004;17:583-90. 2. Carnahan MC, Goldstein DA. Ocular complications of topical, periocular and systemic corticosteroids. Curr Opin Ophthalmol. 2000;11: 478-83. 3. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina. 2004;24:676-98. 4. Moshfeghi DM, Kaiser PK, Scott IU, et al. Acute endophthalmitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol. 2003;136:791-6. 5. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492-513. 6. Ahn JK, Seo JM, Yu J, et al. Down-regulation of IFN-γ–producing CD56þ T cells after combined low-dose cyclosporine/prednisone treatment in patients with Behçet’s uveitis. Invest Ophthalmol Vis Sci. 2005;46:2458-64. 7. Ahn JK, Chung H, Lee DS, et al. CD8brightCD56þ T cells are cytotoxic effectors in patients with active Behçet’s uveitis. J Immunol. 2005;175:6133-42. 8. Jaffe GJ, Yang CH, Guo H, et al. Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device. Invest Ophthalmol Vis Sci. 2000;41:3569-75.
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9. Yousuf K, Allison RL, Nisha RA. Fluocinolone acetonide intravitreal implants in Vogt-Koyanagi-Harada disease. Ocul Immunol Inflamm. 2009;17:431-3. 10. Rajeev KS, Paul AG. Treatment of serpiginous choroiditis with intravitreous fluocinolone acetonide implant. Ocul Immunol Inflamm. 2008;16:103-5. 11. Vinit BM, Karen MG, Debra AG, et al. Management of sympathetic ophthalmia with the fluocinolone acetonide implant. Ophthalmology. 2009;116:552-7. 12. Gold DH. Ocular manifestations of connective tissue (collagen) diseases. In: Tasman W, Jaeger AE, eds. Duane’s Clinical Ophthalmology. Philadelphia: J.B. Lippincott 1989:17-9 13. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140: 509-16. 14. Unchul P, Sangjin K, Hyeonggon Y. Cytomegalovirus endotheliitis after fluocinolone acetonide (Retisert) implant in a patient with Behçet uveitis. Ocul. Immunol. Inflamm. 2011;19:282-3. 15. Davatchi F, Shahram F, Chams-Davatchi C, et al. How to deal with Behcet’s disease in the daily practice. Int J Rheum Dis. 2010;13: 105-16. 16. Gueudry J, Wechsler B, Terrada C, et al. Long-term efficacy and safety of low-dose interferon alpha-2a therapy in severe uveitis associated with Behçet disease. Am J Ophthalmol. 2008;146: 837-44. 17. Niccoli L, Nannini C, Benucci M, et al. Long-term efficacy of infliximab in refractory posterior uveitis of Behçet’s disease: a 24month follow-up study. Rheumatology. 2007;46:1161-4. 18. Tognon S, Graziani G, Marcolongo R. Anti-TNF-alpha therapy in seven patients with Behçet’s uveitis: advantages and controversial aspects. Ann N Y Acad Sci. 2007;1110:474-84. 19. Ahn JK, Chung H, Yu HG. Vitrectomy for persistent panuveitis in Behcet’s disease. Ocul Immunol Inflamm. 2005;13:447-53. 20. Tugal-Tutkun I, Araz B, Cagatay A. CMV retinitis after intravitreal triamcinolone acetonide injection in a patient with Behcet’s uveitis. Int Ophthalmol. 2010;30:591-3.
Long-term results of fluocinolone acetonide intravitreal implant in Behçet intractable posterior uveitis Eun Kyu Oh, MD, Eun Kyoung Lee, MD, Hyeong Gon Yu, MD, PhD ABSTRACT ● RÉSUMÉ Objective: To evaluate the long-term efficacy and safety of the fluocinolone acetonide intravitreal implant in patients with Behçet disease with intractable noninfectious posterior uveitis. Design: Consecutive retrospective analysis. Participants: Eight eyes from 7 patients with Behçet uveitis who did not respond successfully to conventional treatment with topical and systemic steroids and/or systemic steroid-sparing agents were studied. Methods: We performed a chart review of patients who were treated with a 0.59-mg fluocinolone acetonide intravitreal implant at a single centre from September 2007 through June 2009. Snellen visual acuity, control of inflammation, and the development of complications such as infection or uncontrollable intraocular pressure (IOP) elevation were evaluated. Results: Mean age at implant placement was 35.3 (range 17–42) years. Mean follow-up duration was 47.8 (range 39.5–57.6) months. Postoperative visual acuity improved by more than 3 lines in 6 eyes (75%). Five patients were able to discontinue all systemic medications. Six eyes (75%) exhibited postoperative IOP spikes of more than 30 mm Hg. Five patients required glaucoma shunting surgery postoperatively for IOP control. The single phakic eye developed a visually significant posterior subcapsular lens opacification that required cataract extraction. There was 1 case of postoperative cytomegalovirus endothelitis. Infection was controlled with oral valganciclovir and topical antibiotic medication, and the patient did not require implant removal. Conclusions: The fluocinolone implant is effective in the control of intractable inflammation in Behçet uveitis. Elevation of IOP remains a major potential complication, and the possibility of infection should be considered. Objet : Évaluation de l’efficacité à long terme et de la sécurité de l’implant intravitréen de fluocinolone acétonide chez les patients atteints de la maladie de Behçet avec une uvéite postérieure intraitable non infectieuse. Nature : Analyse consécutive rétrospective. Participants : L’étude a porté sur huit yeux de 7 patients atteints d’uvéite Behçet qui n’avaient pas répondu au traitement conventionnel avec stéroïdes topiques et systémiques et/ou agents épargneurs de stéroides. Méthodes : Nous avons revu les dossiers des patients qui avaient été traités avec un implant intravitréen de fluocinolone acétonide de 0.59-mg dans un seul centre, à partir de septembre 2007 et jusqu’à juin 2009. L’acuité visuelle Snellen, le contrôle de l’inflammation et le développement de complications telles l’infection ou la hausse incontrôlable de pression intraoculaire ont été évalués. Résultats : La moyenne d’âge lors du placement de l’implant était de 35.3 (soit 17-42) ans. La durée moyenne de suivi a été de 47.8 (écart, 39.5-57.6) mois. L’acuité visuelle postopératoire s’est améliorée de plus de 3 lignes dans 6 yeux (75%). Cinq patients ont pu discontinuer toute médication systémique. Six yeux (75%) ont présenté des pics de pression intraoculaire postopératoire de >30 mm Hg. Cinq patients eurent besoin d’un implant de glaucome postopératoire pour contrôler la pression intraoculaire. Le seul œil phakique a développé une cataracte sous-capsulaire postérieure importante, requérant l’extraction. Il y eut un cas d’endothéliite à cytomégalovirus postopératoire. L’infection a été contrôlée avec du valganciclovir oral et un traitement antibiotique topique, et le patient n’a pas eu besoin de retrait d’implant. Conclusions : L’implant de fluocinolone est efficace pour contrôler l’inflammation intraitable de l’uvéite Behçet. La hausse de pression intraoculaire demeure une importante possibilité de complication, et la possibilité d’infection devrait être considérée.
Behçet disease is a multisystemic inflammatory disorder with a chronic relapsing course, and ocular Behçet disease is characterized by bilateral intraocular inflammation. The posterior segment of the eye is most commonly affected, resulting in panuveitis, which manifests mainly as retinal vasculitis. The course of the disease is characterized by recurrent explosive attacks of uveitis followed by spontaneous remissions. The initial treatment in Behçet posterior uveitis has been administration of local steroids via topical, periocular, and intravitreal routes. Besides, it typically requires systemic
therapy with oral steroids and steroid-sparing immunosuppressive agents. However, these drugs are often associated with ocular adverse effects or systemic complication, involving the blood and liver.1–5 It is also known that Behçet uveitis is more difficult to treat than other causes of uveitis. Ahn and colleagues6,7 reported that the intraocular infiltration and peripheral expansion of interferon-γ–producing CD56þ T cells contribute to the aggressive and destructive nature of Behçet uveitis. In this backdrop, new treatments are required in patients with Behçet posterior uveitis who are refractory to conventional treatment.
From the Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea
Can J Ophthalmol 2014;49:273–278 0008-4182/14/$-see front matter & 2014 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcjo.2014.03.004
Originally received Jul. 10, 2013. Final revision Feb. 24, 2014. Accepted Mar. 16, 2014 Correspondence to Hyeong Gon Yu, MD, Department of Ophthalmology, Seoul National University College of Medicine, 101, Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea; [email protected]
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Retisert in Behçet intractable posterior uveitis—Oh et al. The 0.59-mg fluocinolone acetonide intravitreal implant (Retisert; Bausch and Lomb, Rochester, N.Y.) was approved by the Food and Drug Administration in April 2005 for the treatment of chronic noninfectious posterior uveitis. This has proved to be a promising therapeutic option for patients with chronic noninfectious uveitis because it enables local release of steroid into the eye for a prolonged period. The Retisert implant is designed to release fluocinolone acetonide, a synthetic steroid, over a 3-year period in a linear fashion.8 Some studies demonstrate the effectiveness of fluocinolone acetonide intravitreal implant for various kinds of uveitis such as Vogt–Koyanagi–Harada disease, serpinginous choroiditis, and sympathetic ophthalmia.9–11 However, there have been few studies that involve fluocinolone acetonide intravitreal implant in patients with Behçet uveitis. The purpose of this study was to evaluate whether the fluocinolone acetonide intravitreal implant in refractory Behçet uveitis patients has a beneficial effect with a tolerable safety and to investigate the treatment outcome in long-term follow-up of at least 3 years.
METHODS A retrospective chart review was performed on 8 eyes of 7 patients who underwent fluocinolone acetonide intravitreal implant insertion from September 2007 through June 20, 2009. All patients had Behçet uveitis. Behçet disease was diagnosed with at least 3 episodes of aphthae over a 12-month period, plus 2 of the 4 major symptoms (genital ulcers, skin lesions, positive pathergy test, and eye lesions).12 Patients who showed active posterior uveitis or panuveitis-associated retinal vasculitis and had experienced prior treatment failure were included. Treatment failure was defined as more than 2 uveitis attacks that involved the posterior segment in the last 6 months, despite treatment with at least 1 conventional immunosuppressive drug—such as azathioprine, cyclosporine, or mycophenolate mofetil—for 6 months, or the patient being unable to taper off oral prednisolone to a dose r10 mg for maintenance therapy for 6 months. Written consent was obtained before implantation. Before beginning the procedure, the implant was prepared on the surgical table by securing double-armed 8-0 Prolene to the implant through a preplaced punch. A localized conjunctival limbal peritomy was created in the inferonasal quadrant, and relaxing incisions enabled retroflexion of the conjunctiva. A microvitreoretinal blade was then used to perform a sclerotomy in the inferonasal quadrant 4 mm away from the limbus. The microvitreoretinal blade was then used to extend the sclerotomy to 3 mm in length with a sawing motion. The implant was inserted into the eye with the tab facing anteriorly and sutured to the sclera with the 8-0 Prolene suture (Fig. 1).
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Fig. 1 — A, Gonioscopic examination reveals that fluocinolone acetonide implant is inserted in proper position. B, 10-0 Prolene suture is buried under the conjunctiva.
Tight sclerotomy closure was ensured because of possible delayed wound healing caused by the steroid implant. The sclerotomy was closed with 8-0 Prolene suture. Watertight closure was confirmed by drying the closure site with a spear-shaped cellulose sponge. The conjunctiva was then closed with 8-0 Vicryl suture. Postoperative treatment of the operative eye comprised 1 drop of prednisolone acetate 1% 4 times daily (tapered over 4 weeks), 1 drop of a broad-spectrum antibiotic 4 times daily for 4 weeks, and 1 drop of homatropine 1% twice daily for 1 week. Primary outcomes of this study were postimplant control of inflammation, changes in visual acuity, changes of intraocular pressure (IOP), and development of adverse events. Postimplant control of inflammation was measured by the ability to taper systemic steroids and the number of times that active uveitis recurred. Active anterior uveitis relapse was defined as anterior chamber cells increasing from 0 or 0.5þ to Z1þ, as defined by the standardization of uveitis nomenclature criteria.13 Active posterior uveitis relapse was defined as an increase in or the development of vitreous haze, the emergence of inflammatory sheathing of retinal vessels, vascular occlusion, retinal hemorrhages, retinal infiltrates, macular edema, or papillitis. IOP was
Retisert in Behçet intractable posterior uveitis—Oh et al. Table 1—Patients demographics Sex/Age, y
FU, mo
Preoperative Phakic Status
Concomitant Cataract surgery
Previous Intraocular Surgery or Procedures
OD OS OS OD
M/30 M/30 F/17 M/40
48.8 45.3 57.6 51.9
Phakia Phakia Pseudophakia Phakia
Yes Yes No Yes
Patient 4 OD Patient 5 OS
M/40 M/42
48.5 44.2
Phakia Pseudophakia
No No
Patient 6 OD Patient 7 OS
M/42 F/41
46.4 39.5
Phakia Phakia
Yes Yes
None Ahmed implant PE and PCL Subtenon TA injection (1 time), intravitreal TA injection (4 times) None Intravitreal TA injection (1 time) Intravitreal dexamethasone injection (1 time) PE and PCL None Subtenon dexamethasone injection (1 time)
Patient Patient Patient Patient
1 1 2 3
FU, follow-up; PE and PCL, phacoemulsification and posterior chamber lens implantation; TA, triamcinolone acetate.
monitored at preoperative day 1 and postoperative months 1, 3, 6, 9, and 12, and then every 6 months until 3 years. Adverse events that were monitored were development of cataract, postoperative infection, and postoperative hypotony.
RESULTS This study included 8 eyes of 7 patients. Mean age at fluocinolone acetonide intravitreal implant insertion was 35.3 (range 17–42) years. There were 5 males and 2 females, and all patients were Korean. Mean follow-up duration was 47.8 (range, 39.5–57.6) months. Two eyes had undergone previous cataract extraction and intraocular lens (IOL) implantation, and 1 eye had undergone previous Ahmed glaucoma device implantation. Five of the study eyes underwent cataract extraction and IOL implantation at the time of fluocinolone acetonide intravitreal insertion because of lens opacity that had developed as a result of chronic inflammation and topical steroid use (Table 1). All eyes exhibited persistent intraocular inflammation that was not controlled with periocular steroids, oral steroids, or oral steroid-sparing agents. Previous treatments included azathioprine, cyclosporine, and Z10 mg oral prednisolone (3 patients, 4 eyes); azathioprine, mycophenolate mofetil, and Z10 mg oral prednisolone (1 patient,
1 eye); cyclosporine and Z10 mg oral prednisolone (1 patient, 1 eye); cyclosporine, mycophenolate mofetil, and Z10 mg oral prednisolone (1 patient, 1 eye); and repetitive intravitreal triamcinolone acetate injections following abdominal discomfort with oral prednisolone and azathioprine (1 patient, 1 eye). After fluocinolone acetonide intravitreal implant insertion, intraocular inflammation was controlled in 5 patients without oral medication (after 13.4 months, on average), but the remaining 2 patients continued oral medication for inflammation of the contralateral eye. The mean number of times anterior uveitis recurred during the follow-up period was 0.25 time/eye in study eyes compared with 2.17 times/eye in contralateral eyes. No posterior uveitis recurrence was observed in study eyes (Table 2). Preoperative Snellen visual acuity ranged from 20/2000 to 20/40 (Fig. 2). At final visit, 6 eyes (75%) showed postoperative vision improvement of more than 3 lines (after 48.6 months, on average), and 1 eye (Patient 6 OD), in which inflammation was successfully controlled but visual acuity was limited by IOL opacification, showed improved visual acuity from 20/300 to 20/200 (after 46.4 months). The single eye (Patient 5 OS) with worsening of vision deteriorated from 20/100 before the implant to 20/ 2000 at the final follow-up approximately 2 years after implant placement. Three months after implantation, this patient experienced development of corneal edema. Polymerase chain reaction analysis of aqueous humor detected
Table 2—Postimplant control of inflammation No. of Times That Active Uveitis Recurred (Study Eye)
Patient Patient Patient Patient Patient Patient Patient Patient
1 1 2 3 4 5 6 7
OD OS OS OD OD OS OD OS
No. of Times That Active Uveitis Recurred (Contralateral Eye)
Previous Systemic Therapy for Inflammation
Anterior
Posterior
Anterior
Posterior
Final Systemic Therapy for Inflammation
AZA, CSA, oral PD AZA, CSA, oral PD CSA, MMF, oral PD None* CSA, oral PD AZA, CSA, oral PD AZA, CSA, oral PD AZA, MMF, oral PD
0 0 0 0 2 0 0 0
0 0 0 0 0 0 0 0
0 0 6 0 5 0 1 1
0 0 0 0 0 0 0 0
None None CSA None CSA, CCC, oral PD None None None
AZA, azathioprine; CSA, cyclosporin A; PD, prednisolone; MMF, mycophenolate mofetil; CCC, colchicine. n
Patient 3 was treated with repetitive intravitreal triamcinolone acetate injections because of abdominal discomfort with oral prednisolone and azathioprine.
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Fig. 2 — Bar graph presenting preoperative and final visual acuities in logMAR. Visual acuities improved more than 3 lines in Snellen chart in all study eyes, except eyes that experienced development of cytomegalovirus endothelitis (Patient 5 OS) or intraocular lens opacification (Patient 6 OD). Final visual acuities were 0 logMAR in Patient 3 OD, Patient 4 OD, and Patient 7 OS.
3.9 104 copies/mL cytomegalovirus (CMV) DNA. After treatment with oral valganciclovir, CMV DNA nearly disappeared, but visual outcome was poor because of corneal decompensation resulting from severe endothelial cell loss.14 Patients were closely monitored postoperatively for the development of any adverse events. An IOP spike was defined as a pressure surge in the postoperative period more than 10 mm Hg greater than preoperative baseline. Six eyes of 5 patients were found to have IOP spikes: greater than 50 mm Hg in 2 eyes, greater than 40 mm Hg but less than 50 mm Hg in 1 eye, and greater than 30 mm Hg but less than 40 mm Hg in 3 eyes (Fig. 3). All 6 eyes needed glaucoma surgery to control IOP. Of the 2 eyes (Patient 1 OD, Patient 2 OS) with IOP greater than 50 mm Hg, one was successfully controlled with trabeculectomy and the other with trabeculectomy followed by additional Ahmed glaucoma device implantation. The eye with IOP greater than 40 mm Hg, but less than 50 mm
Hg (Patient 1 OS), had received previous Ahmed glaucoma device implantation for uveitic glaucoma. Ahmed tube exposure developed after fluocinolone acetonide intravitreal implantation, although this phenomenon had no evidence that related with fluocinolone acetonide intravitreal implantation. The exposed Ahmed glaucoma device was removed; subsequently, IOP increased to 44 mm Hg. Thus, Ahmed glaucoma device reimplantation was performed and IOP stabilized. Two of the 3 eyes with IOP greater than 30 mm Hg, but less than 40 mm Hg, required Ahmed glaucoma device implantation, and the other eye required trabeculectomy (Table 3). Before fluocinolone acetonide intravitreal implantation, 2 of the study eyes had undergone previous cataract extraction with IOL implantation. Five eyes underwent phacoemulsification and primary IOL implantation at the time of fluocinolone acetonide intravitreal implantation. Therefore, only 1 eye was monitored for cataract development. This eye had a visual acuity as good as 20/20 at 1year follow-up. However, visual acuity deteriorated to 20/ 30 by 14-month follow-up with the development of posterior subcapsular opacity. This eye underwent cataract extraction and IOL implantation, and visual acuity recovered to 20/20. There were no complications related to the surgical procedure in any of the operated eyes. There were no instances of vitreous hemorrhage, retinal detachment, or hypotony. There were also no instances of implant dislocation or sclerotomy dehiscence (Table 3).
DISCUSSION Behçet disease is classified among the vasculitides. Major manifestations of the disease are oral aphthosis, genital aphthosis, skin manifestations, and ocular lesions. Mucocutaneous lesions usually resolve without permanent sequelae after a short course of attack followed by healing,
Fig. 3 — Polygonal line graph showing fluctuations of intraocular pressure. In every eye, intraocular pressure reached its peak level in postoperative month 18. Intraocular pressures were maintained in tolerable range 3 years after surgery, and glaucoma surgery was required in 6 eyes.
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Retisert in Behçet intractable posterior uveitis—Oh et al. Table 3—Elevation of intraocular pressure and adverse events Postoperative IOP Spike Patient Patient Patient Patient Patient Patient Patient Patient
1 1 2 3 4 5 6 7
OD OS OS OD OD OS OD OS
Yes Yes Yes Yes Yes
(57 mm (44 mm (51 mm (34 mm (38 mm No No Yes (35 mm
Hg) Hg) Hg) Hg) Hg)
Hg)
Surgical Intervention
Other Adverse Events
TLE Ahmed reimplantation TLE, Ahmed implant Ahmed implant Ahmed implant None None TLE
None None None None Cataract formation Cytomegalovirus endothelitis None None
TLE, trabeculectomy.
but ocular lesions often result in severe permanent visual loss with a protracted healing process.15 Behçet disease is essentially a T-cell–mediated disease. T cells play a pivotal role in uveitis and are found in high levels in serum and aqueous humor. Consequently, T cells have been used as targets in the treatment of ocular manifestations of Behçet disease. Systemic therapy with oral steroids and steroid-sparing agents are very effective in suppression of T lymphocyte function and are the mainstay of long-term control of uveitis in Behçet disease. Although there are no consistent recommendations regarding treatment of choice for refractory Behçet uveitis, several promising agents have been reported. Gueudry and coworkers16 reported good results of interferon-alpha-2a in 32 patients with Behçet uveitis who did not respond positively to previous immunosuppressive and corticosteroid therapy. In addition, there are studies on favourable treatment results of infliximab in refractory Behçet uveitis.17,18 However, infliximab and interferon treatments have the following disadvantages: Gueudry and coworkers16 concluded that, although treatment was efficient and safe for the control of Behçet uveitis, relapse occurrence increased after discontinuation of interferon-alpha. Tognon and coworkers18 remarked that ocular and systemic manifestations tended to recur after infliximab treatment was discontinued or when the interval between infliximab infusions was longer than 8 weeks. Thus, frequent visits and expense are ongoing problems. Our case series shows promising results for the use of the fluocinolone acetonide intravitreal implant in refractory Behçet uveitis. Six of the 8 study eyes showed significant improvement in vision at the final follow-up. In addition, all treated eyes had improved control of intraocular inflammation, allowing for the discontinuation of all oral steroid or steroid-sparing medications and the weaning off of all topical steroids. Further, the fluocinolone acetonide intravitreal implant appears to last at least 3 years. Elevated IOP and cataract development are both wellknown complications of chronic steroid exposure, and the development of both of these has been reiterated in the multicentre fluocinolone acetonide implant study. In our series, 6 eyes had postoperative IOP spikes. Four of these eyes required glaucoma valve placement for adequate IOP
control, and 2 eyes required trabeculectomy. These data are encouraging because there were no intractable cases of glaucoma that required fluocinolone acetonide intravitreal implant removal. Ahn and colleagues19 reported that elevated IOP is common after therapeutic vitrectomy, concomitant with intravitreal triamcinolone acetate injection in Behçet uveitis. However, in most cases, IOP was stabilized on postoperative 1 month. In our study, IOP of some study eyes reached its peak level even after postoperative year 1. This phenomenon can be explained by sustainability of triamcinolone acetonide implant. Of the 8 study eyes, 2 had undergone cataract extraction before fluocinolone acetonide intravitreal implantation because of the development of a visually significant cataract from uveitis and steroid therapy, and 5 underwent cataract extraction at the time of fluocinolone acetonide intravitreal implantation. The single eye that was phakic did develop a visually significant cataract postoperatively that required cataract extraction. Although CMV endothelitis infection occurred in 1 eye, we did not remove the implant even after identification of CMV in the aqueous humor. Valganciclovir treatment was effective in reducing the viral load despite the presence of the working implant in the vitreous, which enabled successful control of inflammation for a year without immunosuppressants. In a previous report, a patient who experienced development of CMV retinitis after intravitreal triamcinolone injection for Behçet uveitis was treated successfully with interferon-alpha and ganciclovir without recurrence of Behçet uveitis, and complete resolution of CMV retinitis occurred.20 Therefore, removal of the implant and switching to interferonalpha for control of Behçet uveitis could have been considered together with antiviral treatment. This study showed that fluocinolone acetonide intravitreal implantation is a useful treatment method in controlling refractory, recurrent Behçet uveitis. Whereas infliximab or interferon treatment requires repetitive treatment and uveitis recurrence is common after cessation of treatment, the effect of the fluocinolone acetonide intravitreal implant persists for about 3 years and is associated with a low recurrence rate and improved visual acuity. Elevation of IOP is common but can be controlled with glaucoma surgery or topical antiglaucoma agents. In conclusion, fluocinolone acetonide intravitreal implant CAN J OPHTHALMOL — VOL. 49, NO. 3, JUNE 2014
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Retisert in Behçet intractable posterior uveitis—Oh et al. insertion is an effective treatment method in refractory Behçet uveitis; IOP and opportunistic infection should be monitored carefully.
Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article. REFERENCES 1. Castellarin A, Pieramici DJ. Anterior segment complications following periocular and intraocular injections. Ophthalmol Clin North Am. 2004;17:583-90. 2. Carnahan MC, Goldstein DA. Ocular complications of topical, periocular and systemic corticosteroids. Curr Opin Ophthalmol. 2000;11: 478-83. 3. Jager RD, Aiello LP, Patel SC, Cunningham ET Jr. Risks of intravitreous injection: a comprehensive review. Retina. 2004;24:676-98. 4. Moshfeghi DM, Kaiser PK, Scott IU, et al. Acute endophthalmitis following intravitreal triamcinolone acetonide injection. Am J Ophthalmol. 2003;136:791-6. 5. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492-513. 6. Ahn JK, Seo JM, Yu J, et al. Down-regulation of IFN-γ–producing CD56þ T cells after combined low-dose cyclosporine/prednisone treatment in patients with Behçet’s uveitis. Invest Ophthalmol Vis Sci. 2005;46:2458-64. 7. Ahn JK, Chung H, Lee DS, et al. CD8brightCD56þ T cells are cytotoxic effectors in patients with active Behçet’s uveitis. J Immunol. 2005;175:6133-42. 8. Jaffe GJ, Yang CH, Guo H, et al. Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device. Invest Ophthalmol Vis Sci. 2000;41:3569-75.
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