Topical tacrolimus has been used successfully as a steroid sparing agent in the treatment of several inflammatory ocular surface diseases.4 We have reported the efficacy of topical tacrolimus in the treatment of vernal keratoconjunctivitis, Thygeson’s Superficial Punctate Keratitis and in keratopathy associated with autoimmune polyglandular syndrome. 7–9 Although the exact pathogenesis of ocular GVHD is still unclear, the T cell mediated inflammation of the ocular surface seems to play an important role. Inhibition of T lymphocytes may therefore ameliorate ocular surface inflammation in patients with ocular GVHD. Tacrolimus is hydrophobic and has a high molecular weight with greater permeation of the conjunctiva than the cornea.4 The conjunctiva is up to 20 times more permeable to lipophilic and high molecular weight drugs than the cornea. This could explain the higher efficacy of tacrolimus in patients with severe conjunctival inflammation associated with ocular GVHD.4 Therefore, topical tacrolimus could be used as a sole therapeutic agent or as an adjunctive therapy in patients with ocular GVHD to minimize the duration and dose of topical steroid.
Patients with ocular GVHD usually suffer from severe symptoms that may interfere with their daily activities. Topical tacrolimus 0.03% was effective in controlling symptoms in 80% of our patients. They reported marked improvement of photophobia and ocular pain. In terms of ocular signs, there was improvement of superficial punctate keratitis in 8(40%) out of the 20 eyes and conjunctival hyperemia in 12 (66%) out of 18 eyes. The improvement of symptoms was more marked than that of signs. These findings are similar to our findings in cases of keratitis associated with Autoimmune Polyglandular Syndrome-1 where improvement of photophobia was much more marked than the keratitis.8 The efficacy of topical tacrolimus for treatment of ocular GVHD has been reported earlier in previous studies. Jung et al. retrospectively studied 24 eyes of 13 patients with GVHD. Patients were treated with tacrolimus 0.02% ointment for up to 20 months.10 The ocular surface inflammatory score decreased and the need for steroid treatment also decreased after initiating tacrolimus treatment. In our 5 patients that were started on combination of topical steroids and tacrolimus, topical steroids were discontinued and the patients were maintained on topical tacrolimus. Ryu and associates reported the therapeutic effect of tacrolimus 0.03% ointment in 14 eyes of 7 patients with refractory anterior segment inflammatory disease associated with GVHD. 11 They noted that significant reduction of inflammation initially appeared at week two for the conjunctiva and at week one for the cornea. In our study, we noted that the response to treatment appeared at an average of 3 weeks (range 1 to 8 weeks) following initiation of therapy. In our study, patients who used concomitant steroids at the initiation of tacrolimus therapy achieved faster response compared to those who did not use topical steroids concomitantly.
Abud et al. found that tacrolimus is a safe and effective therapeutic agent for the treatment of ocular manifestations of GVHD without the known ocular hypertensive effects of topical steroids.12 Tam and associates demonstrated the efficacy of a 1-month use of topical 0.03% tacrolimus ointment in controlling initial inflammation in a single patient with chronic ocular GVHD. 13 Sanz-Marco et al reported efficacy of topical tacrolimus in treating patients with dry eye associated with GVHD.14 In our study, however, topical tacrolimus did not improve dryness as measured by Schirmer test. This could be explained by several factors including: the difference in performing Schirmer test where Sanz-Marco et al tested the basal tear secretion after 5 minutes while we tested the tears after 2 minutes without anesthesia. Furthermore, patients in Sanz-Marco et al study used autologous serum which was not used in our patients. In all previous studies the time to improvement of symptoms and signs ranged from 1 to 8 weeks (table 1). In our study the time to improvement was 1 to 8 weeks (average 3 weeks). This emphasizes the importance of continuing treatment with topical tacrolimus and to avoid premature discontinuation of the drug before its action takes place. Patients with ocular GVHD are more prone to ocular surface irritation following topical use of tacrolimus because of the severe dryness and the severe superficial punctate keratopathy. However, the burning sensation is transient and subsides with continued use of the medication. Burning sensation can be minimized by reducing the concentration of topical tacrolimus until reaching the lowest effective therapeutic concentration. Furthermore, adjunctive short-term use of topical steroids may augment the anti-inflammatory effect on the ocular surface leading to more tolerance to the topical tacrolimus. Burning sensation gradually subsides with further control of inflammation and healing of superficial punctate keratopathy.
Based on our findings in this small cohort of patients we recommend initial adjunctive use of topical steroids to achieve faster response, then the patient can be maintained on topical tacrolimus alone. Our study, however, suffers from certain limitations including retrospective design with its inherent flaws and low number of patients. Further prospective, placebo controlled, randomized clinical studies are needed.
In conclusion, topical tacrolimus is a safe and effective long-term therapy in the treatment of patients with ocular GVHD. Adjunctive short-term use of topical steroids may lead to faster response to topical tacrolimus therapy. Ocular surface irritation following topical tacrolimus in patients with ocular GVHD is common; however, patients should be encouraged to continue use of topical tacrolimus as the burning sensation decreases with continued therapy.