The current study investigated the long-term safety of topical tacrolimus treatment in pediatric patients with inflammatory ocular surface disease that was refractory to conventional treatment. The results of our analyses showed that majority of patients tolerated the treatment, showed improved symptoms and clinical signs, and required less concurrent steroid therapy. Over 12 months of follow-up, no adverse reaction was noted.
The largest study to date to have investigated topical tacrolimus use in pediatric patients included only 45 patients. However, this study had limited the patient population to those diagnosed with VKC and the follow-up period was on average 8 months . In contrast, our study included patients with follow-up period of 12 months or longer, where the average follow-up period reached 23.12 ± 19.07 (range, 12 to 98) months. In addition to VKC, this study included a variety of severe disease, such as GVHD, OCP, SJS, AKC, and PKC.
The absence of serious side effects in pediatric patients during the study period of 12 months emphasizes the safety of the prolonged use of the topical 0.02% tacrolimus ointment. Irritation upon application with complaints of transient burning sensation was the only side effect noted and the sole reason for treatment termination in six patients. No case of keratitis, IOP elevation, and infection related to topical tacrolimus was reported. These results suggest topical tacrolimus ointment as an efficient and safe treatment choice for ocular surface inflammation in pediatric patients.
The application of topical tacrolimus is effective in treating various T-cell-mediated ocular diseases . T helper 2 (Th2) cells play a vital role in the pathogenesis of VKC. The Th2-derived cytokines such as interleukin (IL)-3, IL-4, IL-5 and IL-13 are found to be increased in patients with the disease . In AKC, both Th1 and Th2 cytokines are expressed in the irritated conjunctiva with possible Th1-mediated mechanisms . Chronic ocular GVHD occurs in the near half of transplant recipients after hematopoietic stem cell transplantation. The inflammatory processes by reactive T cell of the lacrimal gland and ocular surface are thought to play vital roles in its pathogenesis . OCP is a type of progressive cicatrizing conjunctivitis that results in fornix foreshortening and symblepharon . By secreting cytokines that stimulate fibroplasia, T cells in conjunction with other forms of inflammatory cells are responsible for producing conjunctival scarring . SJS lesions are produced by the migration of skin-homing cytotoxic T lymphocytes that release cytotoxic proteins to stimulate keratinocyte apoptosis . PKC is an ocular immunological disorder, characterized by an allergic response in the conjunctiva and/or cornea [18, 19]. The pathogenesis of PKC is delayed-type hypersensitivity to foreign microbial proteins .
Tacrolimus is an effective steroid-sparing agent. While both steroids and tacrolimus inhibit inflammatory cells, tacrolimus is believed to be approximately 100 times more powerful than betamethasone valerate at inhibiting human epidermal Langerhans cell stimulatory function . In the current study, patients were initially prescribed 0.02% tacrolimus ointment in combination with topical steroids during the active phase because topical tacrolimus requires several weeks to reach the treatment concentration in eyes. On the other hand, topical steroids are fast-acting and promptly relieve symptoms [22–24]. Therefore, topical steroids help resolve inflammation in the cornea and conjunctiva immediately until tacrolimus becomes effective.
Tacrolimus is hydrophobic. Therefore, in theory, the drug should permeate conjunctiva better than cornea because conjunctiva is more permeable to lipophilic drugs compared to cornea. This characteristic of tacrolimus may explain the higher efficacy of tacrolimus in patients with ocular GVHD with severe conjunctival inflammation .
The major side effects of topical tacrolimus are eye irritation, blurring, itching, chemosis, transient burning sensation, conjunctival hyperemia, and conjunctival chemosis . Burning sensation, which was the reason behind treatment cessation in our study population, has been documented in previously published reports using higher concentrations (0.01%) but not in those using lower concentrations (0.005%). Hence, it is possible that this side effect is dependent on the drug concentration [17, 26, 27]. In terms of adverse effects, renal toxicity, hyperglycemia, and hypertension have been reported . However, because of the limited amount of tacrolimus used during topical treatment, the risk of these adverse effects is negligible. A study that investigated the blood concentration profile of tacrolimus following topical application, its systemic exposure was reported to be minimal and temporary . There have also been reports of complications such as blood dyscrasias, malignancies and outbreaks of infection including herpes simplex as well as organ damage with the use of tacrolimus. Such complications are thought occur more frequently in children, but no systemic complications were noted in our study. to be greater in children. A possible local adverse effect of topical tacrolimus is an increased predisposition to infections . A study has shown that its long-term usage increases the risk of corneal infections . The prevalence of corneal infections in a large cohort of patients treated with topical tacrolimus was 0.35% . However, no ocular complications were observed during our study.
The study has several limitations. The majority of patients (80%) were diagnosed with VKC and AKC patients. And because of that, the number of patients who finally maintained treatment for more than 12 months was relatively small. Although no major complications arose from the continuous use of topical tacrolimus for more than 12 months in pediatric patients in our study, adverse reactions might have been observed with a larger number of subjects. Despite these limitations, however, we believe that our long-term observation proved tacrolimus as an effective and safe treatment option in pediatric patients with inflammatory ocular surface disease.