PATIENTS: Topical 0.1% tacrolimus eye drops (Senju Pharmaceutical Ltd) is 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 to, and written informed consent was obtained from, all patients before participation in the study. This study was approved by the Institutional Review Board of Shandong Eye Hospital and adhered to the tenets of the Declaration of Helsinki.
106 eyes (106 patients) undergoing high-risk keratoplasty at the Shandong Eye Hospital were recruited on a consecutive basis from Jan 2013 to Jan 2015. Preoperative risk score for all the patients were recorded according to the method reported by Sloper CM et al.14 The patients were divided into two groups in accordance with their own wish, one is the FK506 group treated with 0.1% tacrolimus and corticosteroids eye drops, and the other is CsA group treated with 1% CsA (North China Pharmaceutical Group Corporation, NCPC) and corticosteroids eye drops. Patients with untreated glaucoma, cataract, or retinal detachment were not included.
Diagnosis of immune rejectionon the basis of the following signs and symptoms: (1) ocular pain, photophobia, redness, and tearing; (2) rapid decrease in visual acuity; (3) combined graft edema and opacity, aggravated congestion in the recipient bed, and new blood vessels rapidly entering the graft periphery, or white infiltration at the sutures (negative results in corneal scraping and fungal and bacterial cultures), or effusion at the recipient-host interface in eyes treated by lamellar keratoplasty (LK); (4) endothelial rejection line or keratic precipitates; and (5) increased inflammatory cells in the anterior chamber.15
POSTOPERATIVE THERAPY: The treatment strategy of systemic and topical corticosteroid therapy for all patients were 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 was 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 was administered every night for 6 months and tapered to twice weekly.15-17 In addition, 0.1% tacrolimus eye drops or 1% CsA eye drops was given 4 times per day for 1 month and tapered to three times for 6 months and twice for at least 1 year.
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 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 tapered to twice weekly.15-17 Meanwhile, 0.1% tacrolimus eye drops or 1% CsA eye drops were given 4 times per day.
MAIN OUTCOME MEASURES: Patient history, demographic information, preoperative risk factors, onset time of immune rejection, symptoms, and medication compliance were collected. Complete ocular examinations were performed, including best-corrected visual acuity (BCVA), intraocular pressure and slit-lamp examination.
STATISTICAL ANALYSES: All data were described as mean values ± 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 ranks 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 the graft survival. The influential factors, including age, gender, preoperative risk score (≥ 3 or < 3), surgical treatment (penetrating keratoplasty or keratolimbal allograft), topical immunosuppressants (0.1% tacrolimus eye drops or 1% CsA eye drops), poor medication compliance with 0.1% tacrolimus eye drops or 1% CsA eye drops, type of immune rejection (endothelial and non-endothelial immune rejection) were analyzed using multivariate adjusted logistic regression.