PATIENTS: Topical eye drops containing 0.1% tacrolimus (Senju Pharmaceutical Ltd) are not currently approved for use in the treatment of immune rejection. Accordingly, the potential benefits and complications of off-label topical tacrolimus treatment were fully described, and written informed consent was obtained from all patients before participation in the study. This study was approved by the Institutional Review Board of Eye Hospital of Shandong First Medical University and adhered to the tenets of the Declaration of Helsinki.
A total of 106 eyes (106 patients) undergoing high-risk keratoplasty at Eye Hospital of Shandong First Medical University were recruited on a consecutive basis from Jan 2013 to Jan 2015. The preoperative risk score for all patients was recorded according to the method reported by Sloper CM et al.14 The patients were divided into two groups in accordance with their desired treatment: the FK506 group was treated with 0.1% tacrolimus and corticosteroid eye drops, and the CsA group was treated with 1% CsA (North China Pharmaceutical Group Corporation, NCPC) and corticosteroid eye drops. Patients with untreated glaucoma, cataracts, or retinal detachment were not included.
The diagnosis of immune rejection was based on the following signs and symptoms: (1) ocular pain, photophobia, redness, and tearing; (2) a rapid decrease in visual acuity; (3) combined graft edema and opacity with aggravated congestion in the recipient bed and new blood vessels rapidly entering the graft periphery, with white infiltration into the sutures (negative results of corneal scraping and fungal and bacterial cultures) and effusion at the recipient-host interface in eyes treated by lamellar keratoplasty (LK); (4) endothelial rejection or keratic precipitates; and (5) increases in inflammatory cells in the anterior chamber.15
POSTOPERATIVE THERAPY: The treatment strategy used for systemic and topical corticosteroid therapy for all patients was consistent. All patients received intravenous methylprednisolone (2 mg/kg) daily for 5 days. Oral prednisolone (1 mg/kg) was then started daily and tapered over a period of 2 to 3 months. Topical 1% prednisolone acetate eye drops were used 4 times per day for 1 month. Afterwards, 0.1% fluorometholone was used 4 times daily for 6 months and tapered to 0.02% fluorometholone three times daily for at least 1 year. Tobramycin and dexamethasone ophthalmic ointment were administered every night for 6 months and tapered twice weekly.15-17 In addition, 0.1% tacrolimus eye drops or 1% CsA eye drops were administered 4 times per day for 1 month and then tapered to three times a day for 6 months and twice a day for at least 1 year. For patients with dry eye, 0.3% sodium hyaluronate eye drops or carbomer gel was given accordingly.
ANTIREJECTION THERAPY: When immune rejection occurred, intravenous methylprednisolone (2 mg/kg) was given daily for 5 to 7 days. Oral prednisolone (1
mg/kg) was then started daily and tapered over a period of 1 to 2 months. Tobramycin and dexamethasone eyedrops were administered every 2 hours for the first 3 days and then tapered to 4 times per day for the next 2 to 3 weeks. Afterward, 0.02% fluorometholone eyedrops were applied 4 times daily. Tobramycin and dexamethasone ophthalmic ointment was used every night for 1 month and then tapered to twice weekly use.15-17 Meanwhile, 0.1% tacrolimus eye drops or 1% CsA eye drops were used 4 times per day.
MAIN OUTCOME MEASURES: The patient history, demographic information, preoperative risk factors, onset time of immune rejection, symptoms, and medication compliance were recorded. Complete ocular examinations were performed, including best-corrected visual acuity (BCVA), intraocular pressure and slit-lamp examinations.
STATISTICAL ANALYSES: All data are described as the mean value ± standard deviation. Statistical analyses were performed using SPSS 22.0 (SPSS, Chicago, Illinois, USA). A P value of ≤ 0.05 was considered statistically significant. The demographics and preoperative risk score were compared with the Wilcoxon signed rank test between the two groups. The rejection episodes and irreversible rejection (loss of graft transparency) in each group were analyzed using the Mann-Whitney U test. Kaplan-Meier survival analysis and log rank tests were performed to evaluate graft survival. The most highly influential factors, including age, gender, preoperative risk score (≥ 3 or < 3), surgical treatment (penetrating keratoplasty or keratolimbal allograft), use of topical immunosuppressants (0.1% tacrolimus eye drops or 1% CsA eye drops), poor medication compliance when using 0.1% tacrolimus eye drops or 1% CsA eye drops, and type of immune rejection (endothelial or nonendothelial immune rejection) were analyzed using multivariate adjusted logistic regression.