Case Report

Corneal transplant rejection after initiation of systemic antineoplastic agents

Rohr, Ashley MD; Fridman, Gabrielle MD; Sengillo, Jesse D. BS; Schrier, Amilia MD*

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Journal of Cataract and Refractive Surgery Online Case Reports: July 2018 - Volume 6 - Issue 3 - p 37-39
doi: 10.1016/j.jcro.2018.02.004
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Abstract

Over 40 000 corneal graft transplants have been performed annually since 2008 in the United States. Penetrating keratoplasty (PKP) and endothelial keratoplasty make up the majority of these surgeries, followed by anterior lamellar keratoplasty.1 Graft rejection is the most common cause of corneal graft failure, and it is a feared complication regardless of the type of procedure.2,3 Graft survival has been calculated predominantly from registry data and varies depending on the indication for surgery.3 Five-year cumulative incidence of graft rejection is approximately 22% in low-risk transplants and 37% in high-risk transplants among PKP and lamellar keratoplasty.4 Lamellar keratoplasty boasts lower rates of graft rejection compared with PKP; however, it still has a 10% 3-year cumulative incidence of rejection episodes.5,6

Although prompt treatment with corticosteroids reduces the risk for graft failure,7 identifying risk factors for graft rejection are important for preventing consequent blindness. Donor factors contributing to rejection include the degree of human leukocyte antigen and ABO blood type compatibility.8–10 Graft storage duration and method of storage have also been shown to affect rejection; however, there is contradictory evidence provided by the 1994 Collaborative Corneal Transplantation Studies Research Group, which found no significant effect of graft preservation on outcome.8 A range of host factors for rejection include but are not limited to: vascularization, number of previous grafts, ocular surface disease, young age, active inflammation, anterior synechiae, preoperative glaucoma, previous anterior segment surgery, and postoperative loose suturing.8–13 Vascularization is considered the largest host risk factor for rejection and is possibly a result of increased exposure of the corneal layers to immune cells.8

Iatrogenic causes of graft rejection are of particular interest. Influenza vaccine and excimer laser phototherapeutic keratectomy, for example, have been reported to trigger corneal graft rejection episodes.14–17 In this case series of 3 patients, we describe several antineoplastic drugs as potential risk factors for corneal graft rejection. To our knowledge, no other published studies or case reports document a relationship between antineoplastic therapy and corneal graft rejection.

CASE REPORTS

Case 1

This was an 85-year-old woman with an ocular history of pseudoexfoliation glaucoma that was well-controlled with brimonidine and latanoprost, and Descemet-stripping automated endothelial keratoplasty (DSAEK) in the right eye 3 years previously for pseudophakic bullous keratopathy. She presented with decreased visual acuity in the right eye. She was started on systemic chemotherapy 28 days previously, specifically platinum taxane compounds and doxorubicin for metastatic ovarian cancer.

On examination, her visual acuity was 20/150 and slitlamp evaluation revealed 3+ corneal edema. Given the extensive corneal edema, it was difficult to detect any potential anterior chamber reaction. Of note, 3 months earlier, her vision was 20/50 and she exhibited a clear DSAEK graft on examination. Before the presentation she was using maintenance dose prednisolone acetate 1.0% twice daily. She was subsequently diagnosed with corneal transplant rejection and her topical steroids were increased to 4 times daily dosing and later to every 2 hours dosing. She was also treated with sodium chloride 5.0% eyedrops (Muro 128) 3 to 4 times daily. This patient continued to receive monthly chemotherapy during her treatment period. Her rejection ultimately led to DSAEK failure and need for repeat DSAEK graft 6 months later.

Case 2

This was 60-year-old woman with a past ocular history of PKP in the left eye for keratoconus 18 years earlier. She presented reporting irritation in the left eye. Two weeks previously she was started on immunotherapy (ipilimumab).

On examination, her visual acuity was 20/40 in the left eye and slitlamp evaluation revealed trace cell and keratic precipitates. At an examination 5 months earlier, her visual acuity was 20/30 with a clear graft and a quiet anterior chamber. At the time of presentation, she was taking maintenance dose prednisolone acetate 1.0% every other day. The patient was diagnosed with corneal transplant rejection and her topical steroids were increased to 4 times daily dosing. Her rejection episode resolved after 2 weeks of therapy. She had no known risk factors for transplant rejection.

Case 3

This was a 68-year-old woman with a history of bilateral PKPs for keratoconus approximately 30 years ago with a repeat PKP after graft failure in the left eye 6 years earlier. She presented after 1 month of hormonal therapy with tamoxifen for breast cancer complaining of bilateral decreased vision.

On examination, her visual acuity was found to be 20/500 and 20/70 in the right and left eyes, respectively, and slitlamp evaluation revealed bilateral stromal opacification with an anterior chamber reaction. At this patient's examination 6 months earlier, her baseline visual acuity was 20/80 and 20/50 in the right and left eyes, respectively, and anterior segment examination demonstrated clear grafts and quiet anterior chambers bilaterally. At the time of presentation, she was taking prednisolone acetate 1.0% once daily in the left eye alone. Her known risk factor for rejection was a history of repeat grafts in the left eye. The patient was subsequently diagnosed with simultaneous corneal transplant rejection and treated with increased prednisolone acetate 4 times daily in both eyes. Her rejection episodes eventually resolved by a 3-month follow-up. During this period, she was switched from tamoxifen to anastrazole.

DISCUSSION

We have described 3 patients, a total of 4 eyes, with corneal transplant rejection episodes including 1 DSAEK and 3 PKPs. All patients had recent initiation of various systemic antineoplastic agents within 4 weeks of presentation. The proximity between cancer treatment and graft rejection in each case leads us to question whether antineoplastic agents are a newly identified risk factor for graft rejection.

The cornea is often described as a site of “immune privilege,” meaning it elicits a significantly weaker immune response to new antigens. Immune privilege is maintained by lack of vasculature, lymphatics, antigen-presenting cells, and immunomodulatory factors in the vitreous humor.6,18 This immune isolation can be compromised by trauma and inflammation, which can cause neovascularization in the cornea. Neovascularization can lead to an increased number of immune cells and major histocompatibility antigen expression leading to recognition of foreign antigens by the host immune system; thus, a T cell-mediated immune cascade ensues.6,18 If antineoplastic agents are a risk factor for graft rejection, in might be attributable to a common mechanism, such as increasing corneal susceptibility to immune injury.

Interestingly, it has been reported that 5 post-keratoplasty patients developed central subepithelial opacification in cases where the individuals providing the donor cornea had received a full course of systemic antimetabolite therapy within 8 weeks of death. Three of those patients subsequently required repeat grafts.19

The chemotherapeutic agents used by our patients included platinum taxane-derived compounds, doxorubicin, ipilimumab, and tamoxifen. Platinum taxane-derived therapies affect cell division by inhibiting microtubule formation. Microtubule formation is vital in the transport of new epithelial cells onto the donor corneal basement membrane and could be adversely affected by drugs which impair their function.19 Doxorubicin is a topoisomerase inhibitor shown to have the side effect of excessive lacrimation and conjunctivitis in approximately 25% of patients.20 Ipilimumab is a monoclonal antibody that targets CTLA-4, a protein receptor that downregulates inhibitory mechanisms of the immune system allowing cytotoxic T cells to function; it is associated with various forms of ocular inflammation including conjunctivitis, scleritis, anterior uveitis, and vitreous hemorrhaging.21 It can be hypothesized that these agents might cause subclinical inflammation of the corneal layers leading to increased exposure to the immune system and subsequent graft rejection. Tamoxifen is unlike the others in that it has not been associated with inflammatory conditions of the anterior eye, but instead with corneal deposits that are reversible with discontinuation of the drug. Tamoxifen has also been linked to posterior subcapsular cataract formation, optic nerve swelling, and more rarely, retinopathy.22

Although our observations shed light on a potentially new risk factor for graft rejection, our findings are only descriptive in nature and confirming such an association requires a well-powered study with proper controls. Furthermore, each of our patients were on a different regimen for their cancer treatment, thus complicating the interpretation of our findings. To this end, the data presented herein are certainly not robust enough to alter the standard of care for patients with corneal grafts requiring antineoplastic therapy, but rather to prompt further investigation among colleagues to assess whether this population is at greater risk for rejection episodes.

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