Corneal Epithelial Toxicity after Intravitreal Methotrexate Injection for Vitreoretinal Lymphoma: Clinical and In Vitro Studies.

Yoon Jeong,Joo Youn Oh,Un Chul Park,Jin Suk Ryu

doi:10.3390/jcm9082672

Abstract

Methotrexate is widely used as an intraocular chemotherapy for vitreoretinal lymphoma (VRL). Although corneal toxicity has been reported in patients after intravitreal methotrexate injections, the incidence, outcome, and mechanism of the toxicity are unclear. Herein, we performed a clinical study to evaluate the incidence, predisposing factors, and treatment outcome of corneal epitheliopathy associated with intravitreal methotrexate injection. In addition, we directly investigated cytotoxic effects and mechanisms of methotrexate in cultures of human corneal epithelial cells (CECs). Medical chart reviews revealed that corneal epitheliopathy occurred in 15 eyes (22.7%, 12 patients) out of 66 eyes (45 patients) after intravitreal methotrexate injections for treatment of VRL. The use of topical anti-glaucoma medication was significantly associated with development of corneal epitheliopathy. The epitheliopathy resolved in all patients 2.4 months after onset. In culture, methotrexate decreased the survival of CECs by inducing apoptosis, increasing oxidative stress, suppressing proliferation, and upregulating inflammatory cytokines. The addition of folinic acid significantly protected the cells from the methotrexate-induced toxicity. Hence, our results suggest that care should be taken to minimize the contact of methotrexate with corneal epithelium during injection, and folic or folinic acid supplementation might be beneficial for preventing corneal complications in patients undergoing intravitreal methotrexate injections.

Highlights

Methotrexate (MTX) is a competitive inhibitor of dihydrofolate reductase (DHFR) and has an anti-neoplastic effect in multiple types of cancers by reducing intracellular folic acid levels and thereby disrupting DNA and RNA synthesis in cancer cells [1,2,3]
Another study by Frenkel et al showed that some form of keratopathy, ranging from mild dryness to severe epitheliopathy, appeared in all vitreoretinal lymphoma (VRL) patients (44 eyes of 26 patients) usually after the third MTX injection [4]
As it has been reported that clinical remission of VRL was achieved after an average 6.4–8.5 intravitreal MTX injections and a maximum of 16 injections per eye [4,7], corneal epitheliopathy would be an inevitable complication following intravitreal MTX injection that can preclude the proper injection schedule for VRL remission

Summary

Introduction

Methotrexate (MTX) is a competitive inhibitor of dihydrofolate reductase (DHFR) and has an anti-neoplastic effect in multiple types of cancers by reducing intracellular folic acid levels and thereby disrupting DNA and RNA synthesis in cancer cells [1,2,3]. MTX-induced cytotoxicity and its mechanisms have been reported in a number of non-cancer cell types such as hepatocytes, alveolar epithelial cells, and intestinal cells [10,11,12]. It is unclear whether MTX has a direct toxic effect on corneal epithelial cells (CECs). We performed a clinical study to evaluate the incidence, risk factors, and treatment outcome of corneal epitheliopathy associated with intravitreal MTX injection in patients with VRL. We carried out an in vitro study to directly analyze the cytotoxic effects of MTX on human CECs and its mechanism of action

Methods

Results

Conclusion