Long-term Safety of Topical Pimecrolimus and Topical Tacrolimus in Atopic Blepharoconjunctivitis

Atopic blepharoconjunctivitis (ABC) is an ocular manifestation of atopy with a course similar to that of atopic dermatitis: chronic with exacerbations. Topical corticosteroids are widely used for ABC, but long-term use has a well-established risk of adverse effects: increase of intraocular pressure (IOP) or glaucoma, subcapsular cataract, reactivation of herpes simplex virus, and skin atrophy.^1,2 Some of the adverse effects may manifest in a matter of days in susceptible individuals (IOP increase), while some are relevant in prolonged use (skin atrophy and subcapsular cataract). Topical calcineurin inhibitors pimecrolimus and tacrolimus have shown good long-term safety in the treatment of atopic dermatitis,³ and previous smaller studies of the use of tacrolimus on the eyelids have shown good safety, efficacy, improvement of conjunctival cytology, and a positive effect on IOP.^4-6

We conducted an ethics committee–approved medical record review of ophthalmologist-observed patients with ABC between January 1, 2001, and December 31, 2011, at Helsinki University Skin and Allergy Hospital. Information was collected on topical blepharitis treatments, treatment frequency, conjunctivitis treatments, and follow-up time. Disease characteristics were the severity of symptoms of blepharitis and conjunctivitis, assessed separately on a scale of 0 to 3 (no, marginal, moderate, and severe symptoms) based on the description of symptoms in the medical record. Positive treatment response was defined as a reduced grade of severity. Follow-up started from the induction of topical therapy, and the end point was the last ophthalmologic examination. For the follow-up of malignant neoplasms, the end point was January 31, 2012.

Safety parameters included visual acuity, IOP, corneal and lens status, and data on adverse events. Intraocular pressure was measured with a Goldmann applanation tonometer (Haag-Streit AG). Values of more than 21 mm Hg were considered elevated. A significant rise of IOP was defined as an increase of 6 mm Hg or higher or 20% or more from the baseline (Table 1). Significant use of systemic immunosuppressive medication, concurrent other causes of blepharitis, and other facial dermatoses led to the exclusion of 99 participants.

Of 338 eligible patients, 33 used pimecrolimus, 1%, cream, 297 used tacrolimus ointment (mostly 0.03%) (Table 1), and 8 used topical corticosteroids. The mean follow-up times were 1.5 years for efficacy and 5.7 years (in total, 1945 patient years) for malignant neoplasms (both groups together). No malignant tumors were diagnosed. There were no significant changes in visual acuity and no subcapsular cataract or other treatment-related changes in the lens or the cornea observed. Instead, minor disease-related corneal changes reduced 37.5% with pimecrolimus and 34.6% with tacrolimus. The mean IOP decreased 0.5 to 0.6 mm Hg, and the number of patients with elevated IOP decreased 75% to 80% in both groups (eFigure 1 in the Supplement). In a subgroup of patients with elevated IOP at the baseline, the mean IOP decrease was 6.6 mm Hg (P = .02) in the tacrolimus group and 6.9 mm Hg (P = .18) in the pimecrolimus group (eFigure 2 in the Supplement).

Total discontinuation rates were 56.1% in the pimecrolimus group and 11.0% in the tacrolimus group: 33.3% of pimecrolimus treatments and 9.1% of tacrolimus treatments were discontinued due to patient-reported adverse effects, and lack of treatment response led to discontinuation of 22.8% of started treatments in the pimecrolimus group compared with 1.6% in the tacrolimus group (Table 2).

Treatment response rates for blepharitis were 78.8% with pimecrolimus and 89.9% with tacrolimus (P = .06). In multivariable logistic regression analysis of treatment response, adjusted for confounding factors, tacrolimus seemed more efficacious, with odds ratios of 2.37 (95% CI, 0.90-6.22) for blepharitis and 2.34 (95% CI, 1.02-5.40) for conjunctivitis compared with pimecrolimus (eMethods in the Supplement).

Four patients (12.1%) in the pimecrolimus group and 18 (6.1%) in the tacrolimus group had symptoms of ocular or eyelid herpes simplex virus infection during follow-up, but most of these were confirmed reactivations (Table 2). In a subgroup analysis, there were no infections, no significant changes in IOP or visual acuity in the tacrolimus, 0.1%, subgroup, and no significant difference in efficacy between the tacrolimus, 0.03%, and tacrolimus, 0.1%, groups. Only 1 patient (5.9%) discontinued treatment in the tacrolimus, 0.1%, subgroup.

In previous studies of topical calcineurin inhibitors for ABC, the numbers of patients have been small and the follow-up times limited to a few months. Knowledge of long-term ocular safety is valuable for physicians prescribing tacrolimus ointment to be used in close proximity to the eye. The discrepancy in group sizes and the retrospective setting are limitations of this study.

We conclude that both topical calcineurin inhibitors show good long-term safety profiles. Tacrolimus ointment seems more effective and better tolerated on the eyelid than pimecrolimus cream, and it is efficacious in treating both blepharitis and conjunctivitis. It does not increase IOP or cause glaucoma, subcapsular cataract, or atrophy of the skin, and no malignant neoplasms were detected in exposure areas treated by high UV radiation. Additional prospective studies are needed to address the efficacy compared with topical corticosteroids, but based on our experiences and data, tacrolimus ointment is a possible first-line treatment option in the long-term management of ABC.

Accepted for Publication: July 21, 2013.

Corresponding Author: Ville Kiiski, MD, Skin and Allergy Hospital of Helsinki University Central Hospital, Meilahdentie 2, 00250 Helsinki, Finland (ville.kiiski@helsinki.fi).

Published Online: February 5, 2014. doi:10.1001/jamadermatol.2013.7016.

Author Contributions: Dr Kiiski had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

Acquisition of data: Kiiski, Kari.

Analysis and interpretation of data: Kiiski, Remitz, Reitamo, Kari.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Kiiski.

Obtained funding: Remitz, Reitamo.

Administrative, technical, or material support: Kari.

Study supervision: Remitz, Reitamo, Kari.

Conflict of Interest Disclosures: Dr Reitamo reported serving as a consultant for Astellas Pharma. No other disclosures were reported.

Funding/Support: This study was supported in part by a grant from The Finnish Dermatological Society (Dr Kiiski).

Role of the Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.