A Clinical Trial Comparing the Safety and Efficacy of Topical Tacrolimus versus Methylprednisolone in Ocular Graft-versus-Host Disease

Abstract

Purpose: To evaluate the safety and efficacy of topical tacrolimus 0.05% versus topical methylprednisolone 0.5% in patients with ocular graft-versus-host disease (GVHD).

Design: Phase 1/2 prospective, randomized, double-masked clinical trial.

Participants: Eighty eyes of 40 patients diagnosed with chronic ocular GVHD were enrolled.

Methods: Forty patients with ocular GVHD were randomized; 24 patients were treated with topical tacrolimus 0.05% and 16 patients were treated with topical methylprednisolone 0.5% twice daily for 10 weeks, in addition to continuing their baseline treatment regimen.

Main outcome measures: Safety was evaluated based on occurrence of adverse events. Tolerability was assessed based on subject reports of discomfort after drop instillation. Intraocular pressure (IOP) was monitored. The main efficacy end points were corneal fluorescein staining (CFS), tear film break-up time (TBUT), Schirmer test results, and expression of the ocular surface inflammatory markers human leukocyte antigen-DR (HLA-DR) and intercellular adhesion molecule-1 (ICAM-1). Symptoms were evaluated using the Ocular Surface Disease Index (OSDI).

Results: After 10 weeks of treatment, no major adverse events occurred in either treatment group, and there was no significant difference in the composite tolerability scores between the 2 groups (P = 0.06). However, burning sensation was more pronounced with tacrolimus (P = 0.002). Topical tacrolimus was more effective than methylprednisolone in reducing the CFS score at week 10 (55% vs. 23% reduction, respectively; P = 0.01) and achieved significant improvement in TBUT when compared with baseline (P < 0.001). Reduction in OSDI score achieved statistical significance with tacrolimus (27% reduction; P = 0.02), but was marginal with methylprednisolone (32% reduction; P = 0.06). Expression of ICAM-1 by ocular surface epithelium decreased significantly in both groups (tacrolimus, P = 0.003; methylprednisolone, P = 0.008), whereas HLA-DR expression decreased significantly only in the tacrolimus group (P = 0.03). Schirmer test scores did not change significantly in either group during the study; IOP increased significantly with methylprednisolone at week 10 (P = 0.04).

Conclusions: Topical tacrolimus 0.05% is safe, generally well tolerated, and effective for the treatment of ocular GVHD without the hypertensive effects of topical corticosteroids.

Figure 1

Randomization scheme. Subjects who met the general inclusion/exclusion criteria (n=32) were randomized in a 1:1 ratio to the two treatment groups using a permuted-block design. Patients with history of intraocular pressure >22 mmHg or glaucoma in first-degree relatives (n=8) were allocated in the tacrolimus arm.

Figure 2

Drug instillation-induced discomfort, burning sensation, and intraocular pressure induced by topical tacrolimus and methylprednisolone in patients with ocular GVHD. (A) Discomfort score, (B) burning sensation score, and (C) intraocular pressure after drug instillation. The mean intraocular pressure increased in patients treated with methylprednisolone at week 5 (P = 0.04) and week 10 (P = 0.04), when compared to baseline. The mean intraocular pressure did not change significantly in the patients treated with tacrolimus at week 5 (P = 0.50) or week 10 (P =0.20). *P <0.05 compared to baseline; GVHD, graft-versus-host disease.

Figure 3

Tacrolimus significantly reduced corneal fluorescein staining in patients with ocular GVHD at weeks 5 and 10 when compared to baseline (P = 0.02 and P < 0.001, respectively). Methylprednisolone significantly reduced corneal fluorescein scores at week 5 (P = 0.02) but not at week 10 (P = 0.09), when compared to baseline. Tacrolimus achieved more reduction in corneal fluorescein staining after 10 weeks when compared to methylprednisolone (P = 0.01). *P <0.05 compared to baseline; GVHD, graft-versus-host disease.

Figure 4

(A) Tacrolimus decreased symptoms (OSDI) in patients with ocular GVHD at week 5 (P = 0.35) and week 10 (P = 0.02) when compared to baseline. Methylprednisolone decreased the OSDI score at week 5 (P = 0.004) and week 10 (P = 0.06) when compared to baseline. (B) Percentage change in the OSDI score at week 5 and week 10 compared to baseline. Tacrolimus reduced OSDI by 10% at week 5 (P = 0.35) and 27% at week 10 (P = 0.02). Methylprednisolone reduced OSDI by 27% at week 5 (P = 0.004) and 32% (P = 0.06) at week 10. OSDI, Ocular Surface Disease Index. *P < 0.05 compared to baseline; GVHD, graft-versus-host disease.

Figure 5

Tacrolimus increased the mean TBUT after 5 weeks (P = 0.49) and 10 weeks (P = 0.003) in patients with ocular GVHD, when compared to baseline. Methylprednisolone did not affect TBUT at week 5 or 10 when compared to baseline (P = 0.09 and P = 0.42, respectively). TBUT, tear break-up time. *P < 0.05 compared to baseline; GVHD, graft-versus-host disease.

Figure 6

Expression of inflammatory surface markers at baseline and week-10 in patients with ocular GVHD treated with topical tacrolimus and methylprednisolone. Topical tacrolimus and methylprednisolone significantly reduced the frequencies of ICAM-1 positive cells (P = 0.003 and P = 0.008, respectively). Only topical tacrolimus reduced significantly the frequencies of HLA-DR positive cells (P = 0.03). GVHD, graft-versus-host disease; HLA-DR, human leucocyte antigen-DR; ICAM-1, intercellular adhesion molecule-1.