CASE REPORT

Long-term Resolution of Immunological Graft Rejection After a Dexamethasone Intravitreal Implant Paolo Vinciguerra, MD,* Elena Albé, MD,* Riccardo Vinciguerra, MD,*† Mario M. Romano, MD,*†‡ Silvia Trazza,* Leonardo Mastropasqua, MD,§ and Daniel Epstein, MD, PhD¶

Purpose: To present the results of the injection of an intravitreal implant of dexamethasone 0.7 mg (DEX 0.7 mg) in 4 patients with an immunologic graft rejection after penetrating keratoplasty.

Methods: Two of the patients received DEX 0.7 mg because inflammation and corneal edema not related to endothelial cell loss persisted despite the administration of topical prednisolone acetate, subconjunctival betamethasone, and systemic methylprednisolone. The other 2 cases received DEX 0.7 mg at the time rejection was diagnosed. Results: At 1 and 6 months after implantation, all rejection episodes resolved with improvement in uncorrected and bestcorrected visual acuity, restoration of graft transparency, reduction of central corneal thickness, and no significant increase in intraocular pressure.

Conclusions: In 4 eyes with an immunologic graft rejection after penetrating keratoplasty, the dexamethasone 0.7 mg intravitreal implant was an effective treatment option, even in cases refractory to standard topical and systemic therapy.

the mainstay of treatment for corneal graft rejection. However, the optimal route of steroid administration remains uncertain. Many approaches have been used, including systemic, topical, subconjunctival, and intraocular corticosteroids, as well as other immunosuppressive agents.6,7 For example, the intracameral application of a corticosteroid such as triamcinolone has been shown to be effective in the treatment of endothelial immune rejections.8,9 We describe the use of an intravitreal implant of dexamethasone 0.7 mg (DEX 0.7 mg) in 4 patients with an immunologic graft rejection after PK, with a complete resolution of the rejection episode in each case.

Setting This study was conduced at the Cornea Unit of the Eye Clinic at Humanitas Research Hospital, Rozzano, Italy, and has been reviewed by the Institutional Review Board at Humanitas Hospital.

CASE REPORT

Key Words: keratoconus, penetrating keratoplasty, immunologic graft rejection, dexamethasone 0.7 mg, Ozurdex (Cornea 2015;34:471–474)

R

ejection of a donor graft is a complex, immune-mediated process and a major complication of penetrating keratoplasty (PK). It can cause corneal decompensation, severe endothelial cell loss, and graft failure.1,2 Risk factors for graft rejection include donor age, graft size, repeated grafts, previous episodes of graft rejection, and corneal vascularization.3 The rate of reversibility after an acute graft rejection varies, ranging from 50% to 94%.4–6 Corticosteroid therapy is

Received for publication July 7, 2014; revision received January 7, 2015; accepted January 7, 2015. Published online ahead of print March 2015. From the *Department of Ophthalmology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy; †Division of Ophthalmology, Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy; ‡Dipartimento di Neuroscienze e Scienze Riproduttive ed Odontostomatologiche, University Federico II, Naples, Italy; §Eye Clinic, University “Gabriele D’Annunzio” Chieti-Pescara, Chieti, Italy; and ¶Eye Research Institute, Bern, Switzerland. The authors have no funding or conflicts of interest to disclose. Reprints: Elena Albé, MD, Department of Ophthalmology, Humanitas Clinical and Research Center, via Manzoni 56, 20089 Rozzano, Milan, Italy (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Cornea  Volume 34, Number 4, April 2015

Case 1 A 28-year-old white man presented with an immunologic endothelial graft rejection in his right phakic eye 5 months after PK after a traumatic corneal perforation. Before graft rejection, at 4 months after PK and with all sutures still intact, his uncorrected visual acuity (UCVA) was 20/50, with best-spectacle corrected visual acuity (BSCVA) 20/25 and a refraction of +0.5 21.5 ·100. Intraocular pressure (IOP) was 15 mm Hg. The endothelial cell count, measured with a Konan Specular Microscope (Konan Medical Inc, Hyogo, Japan) was 2125 cells per square millimeter, and central corneal thickness (CCT) measured with a Scheimpflug camera (Oculus Optikgeräte GmbH, Wetzlar, Germany) was 565 mm. One month later, he presented with acute loss of visual acuity, blurred vision, redness, pain, and foreign body sensation. The slitlamp examination showed flare, endothelial keratic precipitates (KPs), corneal edema, and Descemet folds. No epithelial defects were seen, and no signs of herpetic infection could be detected. BSCVA was 20/ 126, with a refraction of +0.3 23.8 ·180. IOP was 16 mm Hg. After the diagnosis of endothelial graft rejection was made, standard therapy was administered. Prednisolone acetate 1% eye drops were applied hourly for 10 days, and then tapered over several weeks.10 Timolol maleate 0.5% eye drops were used twice a day to reduce the risk of an IOP increase. Treatment with corticosteroids was started 2 days after diagnosis, using oral dexamethasone 25 mg thrice a day. In addition, subtenon betamethasone 4 mg injections were administered every other day for a total of 12 doses.11–15 After 1 www.corneajrnl.com |

471

Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Cornea  Volume 34, Number 4, April 2015

Vinciguerra et al

month of therapy, BSCVA improved to 20/31 with a refraction of 22.0 22.0 ·90. IOP remained stable and below 17 mm Hg. Timolol was therefore discontinued. Despite the increase in visual acuity, the eye still displayed rejection signs such as flare, KPs, corneal edema, and Descemet folds (Fig. 1A). Therefore, 30 days after the last betamethasone injection, an intravitreal implant of DEX 0.7 mg (Ozurdex; Allergan, Inc, Irvine, CA) was administered and both topical and systemic therapy were discontinued. The implant is injected with a 22-gauge needle transconjunctivally through the sclera into the vitreous cavity. It is preloaded with 0.7 mg dexamethasone, and it is administered 4.0 mm from the limbus in phakic eyes and 3.5 mm from the limbus in pseudophakic eyes.16 Suturing of the insertion site is not required. Moxifloxacin and timolol maleate 0.5% eye drops were applied to reduce the risks of infection and increased IOP. Moxifloxacin was discontinued 7 days after the injection of the implant and timolol maleate after 1 month. Blurred vision, ocular tenderness, burning, and foreign body sensation disappeared 3 days after DEX 0.7 mg implantation. All signs of rejection resolved by 1 week after implantation (Fig. 1B). An improvement in BSCVA to 20/25 with a refraction of +1.3 22.3 ·20 was noted 1 month after implantation. The central corneal endothelial cell count decreased to 1956 cells per square millimeter and CCT was 575 mm—a slight increase compared with the prerejection value. IOP was 16 mm Hg. At 6 months after the application of the DEX 0.7 mg implant, BSCVA was stable and the cornea was completely clear.

Case 2 A 73-year-old white woman presented with an immunologic endothelial graft rejection in her right pseudophakic eye that had previously undergone 2 PKs for keratoconus (in 2004 and 2010). Regrafting was performed because of high surgically induced astigmatism secondary to a small graft (7.0 mm diameter). BSCVA (20/40) and manifest refraction (22.0 22.5 ·50) had remained stable for 30 months. IOP was 16 mm Hg. The endothelial cell count was 1847 cells per square millimeter with corneal thickness 582 mm. She presented with acute loss of visual acuity, blurred vision, redness, pain, and foreign body sensation. Her UCVA was counting fingers, and no manifest refraction could be determined. On examination, the single running suture was in place, flare, KPs, corneal edema, neovascularization, and Descemet folds were noted. No epithelial defects were seen and no signs of herpetic infection could be detected. Prednisolone acetate 1% eye drops were administered hourly for 10 days and then tapered over several weeks. Treatment with corticosteroids was started at the time of diagnosis, using oral

dexamethasone 25 mg thrice a day. In addition, subtenon betamethasone 4 mg injections were given every other day for a total of 12 doses.11,17 Timolol maleate 0.5% eye drops were applied twice a day to reduce the risk of an IOP increase. The clinical picture remained unchanged for 1 month. No increase in IOP was noted. Seven days after the last betamethasone injection, a DEX 0.7 mg implant was administered and both topical and systemic therapy were discontinued. Moxifloxacin eye drops were given QID for 1 week after implantation. Timolol maleate 0.5% eye drops were continued for 1 month. At 1 week, all corneal and anterior chamber signs had resolved, and at 10 days, the patient reported less blurred vision, and a decrease in burning and foreign body sensation. No increase in IOP was noted. An improvement in BSCVA to 20/60 with a refraction of 22.5 23.5 ·180 was documented 1 month after implantation. The central corneal endothelial cell count decreased to 1640 cells per square millimeter and CCT was 595 mm—a slight increase compared with the prerejection value. IOP was 18 mm Hg. At 6 months after the application of the dexamethasone 0.7 mg implant, BSCVA was stable and the cornea completely clear.

Case 3 A 91-year-old white man presented with an immunologic endothelial graft rejection in his left pseudophakic eye that had previously undergone cataract extraction after a PK for keratoconus 4 years earlier. Two years after PK, the patient developed immunological rejection, which was treated with our standard therapeutic approach (see Case 1). Thereafter, BSCVA (20/50) and manifest refraction (21.3 26.5 ·60) remained stable. The endothelial cell count was 1526 cells per square millimeter with a CCT of 546 mm. Two years after the first rejection, he presented with a new rejection episode with UCVA at counting fingers and CCT at 1066 mm. DEX 0.7 mg was administered 1 day after diagnosis. Topical timolol maleate 0.5% and moxifloxacin eye drops were used as in the above cases. The symptoms disappeared within 5 days. All signs resolved by 2 weeks after implantation. IOP was 16 mm Hg. An improvement in BSCVA to 20/60 with a refraction of 20.5 25.0 ·80 was noted 1 month after implantation. The central corneal endothelial cell count decreased to 1250 cells per square millimeter, and CCT was 715 mm. At 6 months, BSCVA was stable and the cornea completely clear.

Case 4 A 48-year-old white woman presented with an immunologic endothelial graft rejection in her right phakic eye that had previously

FIGURE 1. Case 1. Right eye unresponsive to systemic, topical, subconjunctival corticosteroids injection administration with persistent endothelial KPs (A). B, Right eye 1 week after Ozurdex implant.

472

| www.corneajrnl.com

Copyright  2015 Wolters Kluwer Health, Inc. All rights reserved.

Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Cornea  Volume 34, Number 4, April 2015

undergone 2 PKs for granular corneal dystrophy (in 1984 and 2004). BSCVA, manifest refraction, and visual acuity remained stable for 10 years at 20/25 with a refraction of 24.5 26.0 ·90. The endothelial cell count was 1847 cells per square millimeter and CCT 582 mm. She presented with a rejection episode decreasing her BSCVA to 20/50 with an unchanged refraction. DEX 0.7 mg was implanted 1 day after diagnosis. Topical timolol maleate 0.5% and moxifloxacin eye drops were used as in the above cases. The symptoms disappeared within 2 days after implantation, and the rejection signs resolved within the first week. There was no increase in IOP. A slight improvement in BSCVA to 20/40 with unchanged refraction was noted at 1 week, remaining stable at the 3-month follow-up examination. The central corneal endothelial cell count decreased to 1640 cells per square millimeter and CCT was 575 mm. At 3 months after the administration of the dexamethasone implant, the BSCVA was stable and the cornea completely clear.

DISCUSSION

To the best of our knowledge, this is the first report on the use of an intravitreal dexamethasone implant in cases of endothelial graft rejection unresponsive to topical and systemic steroid treatment. Our study was reviewed by the hospital’s ethics committee, and each patient read, understood, and signed an informed consent form for treatment with the intravitreal implant. In all 4 cases, the patients described a reduction of symptoms within 7 days after implantation, and all rejection signs also resolved within a week. With the use of topical beta-blockers for as long as 1 month, no IOP increases were observed. In all cases, BSCVA improved and refraction remained stable after a mean follow-up of 4 months. Endothelial cell counts decreased after the rejection episode by a mean of 12%. CCT showed a slight increase at 1 month after implantation. No patient developed a recurrence of the rejection within the first 6 months after implantation. IOP remained normal in all cases, and no lens opacities were seen in any phakic patient at the 6-month follow-up examination. Patients with corneal endothelial rejection typically receive hourly applications of corticosteroid eye drops.6,7 Hudde et al10 reported no statistically significant differences between 2 groups that received either topical corticosteroids alone or topical corticosteroids in combination with a single intravenous pulse of methylprednisolone (500 mg). Costa et al11 reported that subconjunctival triamcinolone in combination with the topical application of prednisolone acetate 1% was more effective in reversing rejection than treatment with a single pulse of methylprednisolone (500 mg) in combination with the topical application of prednisolone acetate. However, in our first 2 patients, signs and symptoms of endothelial rejection were still present despite topical, subconjunctival, and systemic treatment. It has been shown that intracameral injection of triamcinolone maintains therapeutic levels in the aqueous humor for 150 days, inhibits immunologic graft rejection, and increases the chances for a successful treatment with topical corticosteroids.18,19 We decided to adopt a different strategy by inserting a dexamethasone 0.7 mg implant into the vitreous. This vehicle has been shown to continuously release corticosteroids into the eye, providing a therapeutic period of 6 Copyright  2015 Wolters Kluwer Health, Inc. All rights reserved.

Resolution of Immunological Graft Rejection

months after implantation.20 It has also been shown that in the human eye, the sustained-release implant achieves higher and more stable levels of dexamethasone in the vitreous during the initial phase than the subconjunctival,21 periocular,22 topical,23 or oral24 administrations of dexamethasone. The Ozurdex dexamethasone drug delivery system is a biodegradable intravitreal implant made of polymers that deliver a sustained release of 700 mg of preservative-free dexamethasone to the retina and vitreous over prolonged periods.20,25,26 It is approved by the United States Food and Drug Administration as a first-line therapy for the treatment of macular edema after branch or central retinal vein occlusion, as well as for noninfectious posterior uveitis.18,19 However, this intravitreal implant has also been used for the treatment of radiation-induced macular edema following the application of ruthenium-106 plaques in choroidal melanoma, for Irvine-Gass macular edema, and for rhegmatogenous retinal detachment with a high risk of proliferative vitreoretinopathy. Recently, the use of a single-dose subconjunctival 0.7 mg dexamethasone implant for the treatment of nonnecrotizing anterior scleritis was reported.18,19 Implants have many potential advantages over traditional delivery systems. These include drug delivery closer to the target tissue in the posterior segment, adequate and stable concentrations, dose reduction due to delivery at the target tissue (and hence reduced systemic side effects), and fewer complications due to the low frequency of application.18,19 This results in an enhanced efficacy of the treatment. In addition, implants can be beneficial in patients with poor compliance. Because the dexamethasone 0.7 mg implant is biodegradable, it does not require surgical removal. DEX 0.7 mg has been reported to be well tolerated in uveitis and in retinal disorders. The safety profile of the DEX 0.7 mg intravitreal implant has been described as acceptable.27,28 A recent randomized, sham-controlled trial (MEAD Study), including 1048 eyes, reported a 67.9% cataract formation rate in phakic eyes, and 0.6% uncontrolled increases of IOP that required trabeculectomy. No other significant adverse events were reported.27–29 We did not observe any of these complications in the patients reported here. The effect of DEX 0.7 mg in these graft rejection cases was likely because of its potency, stable and sustained therapeutic levels, and extended duration of action. The promising results of DEX 0.7 mg seen in the first 2 cases with rejections unresponsive to standard treatment encouraged us to use it in the other 2 cases without resorting to any initial topical, subconjunctival, or systemic steroid treatment. The short-term follow-up showed good efficacy in reducing rejection symptoms and signs in these cases as well. Our study has several limitations. Only 4 cases are reported, and no data on aqueous humor or vitreous concentration levels are available. Randomized clinical trials, larger sample sizes, and long-term follow-up are needed. Furthermore, it is important to underscore that this use of DEX 0.7 mg implant is “off-label.” Accordingly, users need to ascertain that patients clearly understand this aspect of the informed consent form. In conclusion, the DEX 0.7 mg implant seems to be effective in treating immunological graft rejection refractory www.corneajrnl.com |

473

Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Cornea  Volume 34, Number 4, April 2015

Vinciguerra et al

to topical, periocular, and systemic treatment, and also seems to shorten the duration of treatment. Because of the prolonged therapeutic effect of the implant, it may also decrease the need for systemic steroids or other immunosuppressants. In addition, it could be especially useful in patients with poor compliance.

1. Wilson SE, Kaufman HE. Graft failure after penetrating keratoplasty. Surv Ophthalmol. 1990;34:325–356. 2. Vail A, Gore SM, Bradley BA, et al. Corneal graft survival and visual outcome. A multicenter study. Corneal Transplant Follow-up Study Collaborators. Ophthalmology. 1994;101:120–127. 3. Inoue K, Amano S, Oshika T, et al. Risk factors for corneal graft failure and rejection in penetrating keratoplasty. Acta Ophthalmol Scand. 2001; 79:251–255. 4. Williams KA, Esterman AJ, Bartlett C, et al. How effective is penetrating corneal transplantation? Factors influencing long-term outcome in multivariate analysis. Transplantation. 2006;81:896–901. 5. Tan DT, Dart JK, Holland EJ, et al. Corneal transplantation. Lancet. 2012;379:1749–1761. 6. Ziaei M, Sharif-Paghaleh E, Manzouri B. Pharmacotherapy of corneal transplantation. Expert Opin Pharmacother. 2012;13:829–840. 7. Randleman JB, Stulting RD. Prevention and treatment of corneal graft rejection: current practice patterns 2004. Cornea. 2006;25:286–290. 8. You IC, Yoon KC. Therapeutic effect of intravitreal injection of triamcinolone in the treatment of endothelial graft rejection: a pilot study. Cornea. 2012;31:1135–1140. 9. Athanasiadis Y, Tsatsos M, Sharma A, et al. Subconjunctival triamcinolone acetonide in the management of ocular inflammatory disease. J Ocul Pharmacol Ther. 2013;29:516–522. 10. Hudde T, Minassian DC, Larkin DF. Randomised controlled trial of corticosteroid regimens in endothelial corneal allograft rejection. Br J Ophthalmol. 1999;83:1348–1352. 11. Costa DC, de Castro RS, Kara-Jose N. Case-control study of subconjunctival triamcinolone acetonide injection vs intravenous methylprednisolone pulse in the treatment of endothelial corneal allograft rejection. Eye (Lond). 2009;23:708–714. 12. Qazi Y, Hamrah P. Corneal Allograft Rejection: immunopathogenesis to Therapeutics. J Clin Cell Immunol. 2013;2013(suppl 9). pii: 006. 13. Hamrah P, Mantopoulos D, Akhtar J, et al. Immunologically High-Risk Penetrating Keratoplasty. In: Krachmer J, Mannis MJ, Holland EJ, eds. Cornea. 3rd ed. St. Louis, USA: Mosby; 2010:1495–1510.

14. Hill JC, Maske R, Watson P. Corticosteroids in corneal graft rejection. Oral versus single pulse therapy. Ophthalmology. 1991;98:329–333. 15. Hill JC, Ivey A. Corticosteroids in corneal graft rejection: double versus single pulse therapy. Cornea. 1994;13:383–388. 16. Meyer CH, Liu Z, Brinkmann CK, et al. Penetration force, geometry, and cutting profile of the novel and old Ozurdex needle: the MONO study. J Ocul Pharmacol Ther. 2014;30:387–391. 17. Friedman JN, Kaiser KK. Ocular Pharmacology. In: Friedman JN, Kaiser KK, eds. Essentials of Ophthalmology. Philadelphia, PA: Elsevier Health Sciences; 2007:294. 18. Kompella UB, Kadam RS, Lee VHL. Recent advances in ophthalmic drug delivery. Ther Deliv. 2010;1:435–456. 19. Nascimento H, França M, García LG, et al. Subconjunctival dexamethasone implant for non-necrotizing scleritis. J Ophthalmic Inflamm Infect. 2013;3:7. 20. Chang-Lin JE, Attar M, Acheampong AA, et al. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant. Invest Ophthalmol Vis Sci. 2011;52:80–86. 21. Weijtens O, Feron EJ, Schoemaker RC, et al. High concentration of dexamethasone in aqueous and vitreous after subconjunctival injection. Am J Ophthalmol. 1999;128:192–197. 22. Weijtens O, van der Sluijs FA, Schoemaker RC, et al. Peribulbar corticosteroid injection: vitreal and serum concentrations after dexamethasone disodium phosphate injection. Am J Ophthalmol. 1997;123:358–363. 23. Weijtens O, Schoemaker RC, Romijn FP, et al. Intraocular penetration and systemic absorption after topical application of dexamethasone disodium phosphate. Ophthalmology. 2002;109:1887–1891. 24. Weijtens O, Schoemaker RC, Cohen AF, et al. Dexamethasone concentration in vitreous and serum after oral administration. Am J Ophthalmol. 1998;125:673–679. 25. Short BG. Safety evaluation of ocular drug delivery formulations: techniques and practical considerations. Toxicol Pathol. 2008;36:49–62. 26. Yasukawa T, Ogura Y, Kimura H, et al. Drug delivery from ocular implants. Expert Opin Drug Deliv. 2006;3:261–273. 27. Haller JA, Bandello F, Belfort R Jr, et al; Ozurdex GENEVA Study Group. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology. 2011;118:2453–2460. 28. Yeh WS, Haller JA, Lanzetta P, et al. Effect of the duration of macular edema on clinical outcomes in retinal vein occlusion treated with dexamethasone intravitreal implant. Ophthalmology. 2012;119:1190–1198. 29. Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121:1904–1914.

474

Copyright  2015 Wolters Kluwer Health, Inc. All rights reserved.

REFERENCES

| www.corneajrnl.com

Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

Long-term resolution of immunological graft rejection after a dexamethasone intravitreal implant.

To present the results of the injection of an intravitreal implant of dexamethasone 0.7 mg (DEX 0.7 mg) in 4 patients with an immunologic graft reject...
176KB Sizes 0 Downloads 11 Views