• Cornea/External Disease

    Corneal transplantation is one of the most frequently performed tissue transplantations worldwide, with an estimated 40,000 corneal transplant operations performed each year in the United States.1,2 Immunologic transplant rejection represents one of the main causes for corneal graft failure among patients with negative prognostic factors. High-risk corneal graft patients have been defined as having 2 quadrants of stromal vascularization, or a history of previous graft rejection (Ophthalmology. 1994;101(9):1536–1547). Additional risk factors for corneal graft failure include previous grafts, quadrants of anterior synechiae, anterior segment surgery, and preoperative glaucoma. In high-risk grafts, reported failure rates are between 60%–90%.3-6 Additionally, in some patients, topical steroids do not prevent rejection or cannot be administered as they cause unacceptable elevation of intraocular pressure (IOP) in steroid-responder patients (Graefe’s Arch Clin Exp Ophthalmol. 1997;135(9):553–557). To address this problem, the use of tacrolimus 0.03% topical ointment (Protopic; Fujisawa Health, Inc., Deerfield, IL) as an immunosuppressive agent in high-risk corneal grafts has been proposed. This article presents 4 cases of high-risk corneal grafts treated with topical tacrolimus 0.03% ointment, demonstrating safe and effective use in all patients and suggesting that tacrolimus may be an effective alternative to topical steroids in certain high-risk corneal transplantations.

    Tacrolimus: Background and Use

    Tacrolimus, also known as FK 506, is a macrolide with potent immunosuppressive activity and is isolated from the soil fungus Streptomyces tsukubaensis(Ophthalmology. 2001;108(10):1838–1844). The mechanism of action is similar to that of cyclosporine: It binds to a specific cytosolic binding protein and inhibits the T-cell receptor–mediated signal transduction necessary for the transcription of interleukin-2 and other lymphokines (Br Med J. 1999;318(7191):1104–1107). Tacrolimus is used systemically for prophylaxis of allograft rejection in liver, kidney, and heart transplantation and in dermatological topical ointment form for atopic eczema. 10,11 Topical tacrolimus (Protopic) ointment is currently available in two concentrations, 0.1% and 0.03%. The ointment has been FDA-approved for cutaneous application in moderate to severe atopic dermatitis (Cornea. 2005;24(4):417–420). In March 2005, the FDA required a “Black Box” warning of cancer risks, including lymphoma, for tacrolimus topical ointment.

    Tacrolimus is a very hydrophobic macrolide lactone, and because of this characteristic and its relatively large molecular size, it should penetrate the corneal epithelium with some difficulty and accumulate in the corneal stroma, resulting in low intraocular drug levels (Invest Ophthalmol Vis Sci. 1993;34(12):2737–2742). The medication has been found to prevent or delay corneal graft rejection in rabbit models, including models of high-risk grafts (Cornea. 1995;14(2):157–160). The immunosuppressive effect of FK 506 has also been used in allogeneic and xenogeneic rat corneal transplantation models.15,16 Additionally, Sloper et al reported a case series using systemic tacrolimus in the management of high-risk corneal and limbal grafts. Data from this study showed that tacrolimus is effective in preventing graft rejection in high-risk grafts.

    Case Series

    Four patients underwent high-risk penetrating keratoplasty (PKP). The Institutional Review Board granted its approval, and the off-label use of Protopic ointment 0.03% was discussed with the patients. Prior to treatment with tacrolimus ointment 0.03% twice daily, 3 patients experienced acute corneal graft rejection; 1 of these patients was a known steroid responder, and 1 additional patient became a steroid responder. The results are described in Table 1 below.

    Table 1. Four cases of high-risk corneal grafts treated with topical tacrolimus 0.03% ointment.

    CASE 1

    50-year-old man

    CASE 2

    56-year-old woman

    Presentation and History

    Known steroid responder receiving second penetrating keratoplasty.

    Progressive decrease in vision, worse in the left eye, secondary to keratoconus. Contact lens–intolerant. Nuclear sclerotic cataracts and central corneal scarring in both eyes.

    Treatment and Responses

    Patient received a prior corneal graft to treat a dense disciform scar after herpes simplex virus (HSV) infection in left eye.

    Patient had multiple episodes of rejection postoperatively while on cyclosporine 1% drops. Short-term steroids with close monitoring were used to treat the rejection after increased frequency of drops showed no benefits.

    Patient received prior combined PKP with cataract extraction and IOL implant in the left eye. Prednisolone acetate 1% was administered 6 times daily in left eye with topical ophthalmic antibiotics.

    Patient was found to be a steroid responder after initial surgery. IOP increased to 40 mm Hg at 3 weeks postoperatively. Topical steroid was tapered and discontinued; cyclosporine 0.05% emulsion was started.

    Corneal punctuate erosions and striae seen at 8 weeks postoperatively. Early rejection with a Khodadoust line noted in left eye. Rejection could not be reversed with the cyclosporine drops.

    Tacrolimus Regimen

    Upon regraft, patient was educated on the off-label use of tacrolimus 0.03% and the risk of recurring HSV despite antiviral medication. Tacrolimus 0.03% ointment was started after second transplant.

    Tacrolimus 0.03% was started while cyclosporine was discontinued. Reversal of graft rejection and a clear cornea after 2 weeks of tacrolimus therapy.

    Patient’s Current Status

    No episodes of rejection or HSV reactivation and a clear corneal graft at 2 years posttreatment. Patient continues prophylactic valacyclovir HCl 500 mg QD with no adverse events. Patient is comfortable with UCVA of 20/50 in left eye.

    No signs of rejection or adverse effects at 12 months posttreatment. Patient has UCVA of 20/70 and IOP of 18 mm Hg in the left eye.

    CASE 3

    53-year-old woman

    CASE 4

    52-year-old woman

    Presentation and History

    Opaque cornea with a corneal ulcer. Decreased VA to hand motion in right eye after poor response to conventional topical antibiotic therapy. Ulcer progressed; VA of light perception without pain.

    Corneal dystrophy and history significant for primary open-angle glaucoma and cataracts in both eyes. Diagnosed with Fuchs corneal endothelial dystrophy and corneal edema.

    Treatment and Responses

    Patient underwent a PKP. Acanthamoeba cysts noted in the corneal button. Appropriate antiamoebic medications were used, but the first 2 corneal transplants failed. Acanthamoeba cysts noted in the edge of the excised corneal buttons.

    Patient’s final corneal graft showed early signs of rejection 1 month postoperatively despite the use of topical and oral steroids and topical antiamoebic medications.

    Patient had received combined PKP with cataract extraction and IOL implant in the left eye 4 months earlier. Prednisolone acetate 1% topical suspension was administered 5 times daily in the left eye. Early rejection noticed 3 weeks postoperatively.

    Prednisolone acetate was increased to 8 times daily with subsequent elevation in IOP from 21 to 36 mm Hg in the left eye despite optimizing topical antiglaucoma medications.

    Tacrolimus Regimen

    Tacrolimus 0.03% was started in right eye while topical steroids were tapered. Reversal of graft rejection achieved after 1 month of tacrolimus therapy.

    Tacrolimus 0.03% was started while topical steroids were tapered. Patient experienced an episode of early rejection with keratic precipitates. Tacrolimus ointment was increased to qid with successful reversal.

    Patient’s Current Status

    No signs of rejection or adverse effects at 14 months posttreatment. Patient is comfortable and pleased with UCVA of 20/80 in the right eye.

    Clear corneal graft with the use of tacrolimus ointment tid in the left eye. Patient has UCVA of 20/100 in the left eye.

    Summary and Discussion

    We used the lower concentration of commercially available tacrolimus 0.03% twice daily in our 4 study patients. Patient 1 has a history of herpes simplex keratitis and previous graft failure. Patient 2 experienced immunologic rejection, not responding to topical steroids or topical cyclosporine. Patient 3 has a history of 3 failed grafts. Patient 4 is a steroid responder with a history of moderately advanced open-angle glaucoma. The 3 patients with graft rejection showed reversal of the rejection and improvement in vision. Patient 4, who was a steroid responder, showed a clear corneal graft and an IOP of 18 mm Hg. The longest duration of treatment and follow up has been 2 years and the shortest has been 6 months (mean follow-up time of 14 months).

    All 4 patients have clear corneal grafts to date and continue to receive tacrolimus therapy. One patient developed early signs of rejection, which were reversed successfully by increasing tacrolimus to 4 times a day. Currently, she is on tacrolimus 0.03% ointment 3 times a day with a clear graft and no signs of rejection.

    None of our patients developed punctuate keratopathy or other signs of corneal or conjunctival toxicity. None of our patients developed lymphadenopathy, tumors, or other adverse ocular effects. Tacrolimus, like any immunosuppressive agent, may cause a recurrence of herpes simplex virus infection. We continue the systemic antiviral prophylaxis therapy in our patient with a history of HSV keratitis to prevent reactivation of his disease while he uses topical tacrolimus ointment.

    Our small case series demonstrated safe and effective use of topical tacrolimus ointment in this group of high-risk corneal graft patients. Tacrolimus topical ointment may prove to be an effective modality in the management of high-risk corneal grafts and may also be considered as an immunosuppressive agent in corneal graft patients for whom steroids are not an option. The optimum length of treatment, however, is not yet known, nor is it possible at the present time to compare tacrolimus to other immunosuppressive agents used in patients with high-risk corneal grafts. Further research is necessary to evaluate the ocular use of this promising medication.

     

    References

    1. Reis A, Reinhard T, Sundmacher R, et al. A comparative investigation of FK506 and cyclosporine A in murine corneal transplantation.Graefes Arch Clin Exp Ophthalmol. 1998;236(10):785–789.
    2. Cumming CE. Corneal Graft Statistics. Washington, D.C.: Eye Bank Association of America. 1992.
    3. Maguire MG, Stark WJ, Gottsch JD, et al. Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies. Collaborative Corneal Transplantation Studies Research Group. Ophthalmology. 1994;101(9):1536–1547.
    4. Hill JC. Systemic cyclosporine in high-risk keratoplasty: short- versus long-term therapy.Ophthalmology. 1994;101(1):128–133.
    5. Hill JC. Immunosuppression in corneal transplantation.Eye. 1995;9(pt 2):247–253.
    6. Fine M, Stein M. The role of corneal vascularisation in human corneal graft reactions. In: Corneal Graft Failure. Amsterdam: Elsevier, 1973;193–204. Ciba Foundation Symposium 15 Series.
    7. Reinhard T, Kallmann C, Cepin A, et al. The influence of glaucoma on graft survival after penetrating keratoplasty.Graefe’s Arch Clin Exp Ophthalmol. 1997;135(9):553–557.
    8. Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the management of high-risk corneal and limbal grafts.Ophthalmology. 2001;108(10):1838–1844.
    9. Knoll GA, Bell RC. Tacrolimus versus cyclosporine for immunosuppression in renal transplantation: meta-analysis of randomized trials.Br Med J. 1999;318(7191):1104–1107.
    10. Crespo-Leiro MG. Tacrolimus in heart transplantation.Transplant Proc. 2003;35(5):1981–1983.
    11. Bhorade SM, Jordan A, Villanueva L, et al. Comparison of three tacrolimus-based immunosuppressive regimens in lung transplantation.Am J Transplant. 2003;3(12):1570–1575.
    12. Joseph MA, Kaufman HE, Insler M. Topical tacrolimus ointment for treatment of refractory anterior segment inflammatory disorders.Cornea. 2005;24(4):417–420.
    13. Pleyer U, Lutz S, Jusko WJ, et al. Ocular absorption of topically applied FK506 from liposomal and oil formulations in the rabbit eye.Invest Ophthalmol Vis Sci. 1993;34(12):2737–2742.
    14. Mills RA, Jones DB, Winkler CR, et al. Topical FK-506 prevents experimental corneal allograft rejection.Cornea. 1995;14(2):157–160.
    15. Starzl T, Murase N, Demetris AJ, et al. Allograft and xenograft acceptance under FK-506 and other immunosuppressant treatment.Ann NY Acad Sci. 1993;685:46–51.
    16. Celli S, Valdivia J, Fung J, et al. Long-term survival of heart and liver xenografts with splenectomy and FK-506. Transplant Proc. 1993;25:647f.

    Author Disclosure

    The authors disclose that their research is supported by a grant from the Alliance for Vision Research, Inc. They have no financial relationship with the manufacturer or provider of any product or service discussed in this article or with the manufacturer or provider of any competing product or service.