Purpose
To investigate the efficacy and safety of long-term maintenance treatment with tacrolimus ointment in chronic ocular graft-vs-host disease (GVHD) with ocular surface inflammation.
Design
A retrospective interventional consecutive case series.
Method
Long-term maintenance treatment (≥6 months) with topical 0.02% tacrolimus ointment was applied to patients with chronic ocular GVHD with ocular surface inflammation (at least grade 2 inflammatory score). We evaluated the inflammatory score, steroid score and steroid use period of total duration, and numbers of inflammatory aggravations before and after tacrolimus treatment. The clinical outcomes were assessed by symptom score, ocular surface staining, Schirmer I test, tear break-up time (TBUT), and classification of chronic GVHD conjunctivitis at the initial and final examinations.
Results
Thirteen patients (24 eyes) were treated with tacrolimus ointment for up to 20 months (average 12.2 months). The ocular surface inflammatory score decreased from 2.8 to 0.6 ( P = .001) within 2–8 weeks after starting tacrolimus ointment treatment. The numbers of inflammatory aggravation and the need for steroid treatment also decreased after initiating tacrolimus treatment. At the final follow-up, all patients reported improvement in clinical outcomes, compared to initial findings. Except for blurred vision or mild burning sensation, there were no reported side effects.
Conclusion
Considering the chronic course of GVHD, long-term maintenance treatment with tacrolimus ointment could be useful and safe to locally treat ocular surface inflammation in chronic ocular GVHD.
Chronic ocular graft-vs-host disease (GVHD) occurs in nearly 50% of transplant recipients after hematopoietic stem cell transplantation (SCT). The clinical spectrum of chronic ocular GVHD includes dry eyes, chronic conjunctival inflammation (eg, pseudomembranous and cicatricial conjunctivitis), and blepharitis. Although the pathogenesis of ocular GVHD is still unclear, the inflammatory processes of the lacrimal gland and ocular surface seem to play important roles. Therefore, reducing ocular surface inflammation with supportive lubrication is most important in ocular GVHD treatment.
Topical steroids have been mainly used to treat ocular GVHD accompanied by severe inflammation. However, long-term steroid use can cause undesirable side effects, including steroid-induced intraocular pressure (IOP) elevation, cataract, and superinfection. It is therefore necessary to develop alternative treatments that have more potent anti-inflammatory actions with fewer side effects than steroids.
Tacrolimus is an immunosuppressive drug that inhibits the T cell–mediated immune response and is 10–100 times more potent than cyclosporine. A number of studies have described the effects of topical tacrolimus for treating various immune-mediated ocular diseases. We recently reported that 0.02% tacrolimus ointment was an effective treatment in patients with refractory ocular surface inflammatory diseases, including Stevens-Johnson syndrome, ocular cicatricial pemphigoid, scleritis, and Mooren ulcer, who had previously received topical steroid treatment. This ointment has also been used in the organ-specific treatment of skin and oral GVHD. In ocular GVHD, Tam and associates reported that short-term topical tacrolimus ointment use was safe and effective in 1 patient.
In the present study, we evaluated the efficacy and safety of long-term maintenance treatment with tacrolimus ointment in patients with chronic ocular GVHD with ocular surface inflammation.
Methods
This was a retrospective study of 24 eyes in 13 consecutive patients with chronic ocular GVHD who were treated with topical tacrolimus ointment at Severance Hospital in South Korea between March 1, 2011 and October 15, 2014. The patient characteristics are summarized in Table 1 . A total of 13 patients (7 male and 6 female) were included, and the mean age at ocular GVHD diagnosis was 30.3 ± 15.8 years (range, 5–55 years). The mean time interval between SCT and ocular GVHD diagnosis was 16.8 ± 21.8 months (range, 3–82 months). At the time of diagnosis, all patients had already received systemic immunosuppressive therapy owing to chronic GVHD manifestations in other organs (eg, the lung, skin, mouth, gastrointestinal tract, or liver). Systemic immunosuppression was unchanged or decreased in all patients, and systemic treatment had not been intensified in any patient in the follow-up period after ocular GVHD diagnosis.
| Patient | Sex | Age a | Diagnosis | Stem Cell Source | Onset of Ocular GVHD b | Systemic GVHD c | Systemic Immunosuppressant at Time of Diagnosis of Ocular GVHD | Change of Systemic Immunosuppressant During Study Period |
|---|---|---|---|---|---|---|---|---|
| 1 | F | 55 | AML | Unrelated PBSC | 26 | Lung | PSL | Same |
| 2 | M | 36 | CML | Unrelated PBSC | 14 | Skin, liver | Deflazacort | Taper |
| 3 | F | 21 | ALL | Unrelated PBSC | 8 | Skin, liver, oral | PSL | Taper |
| 4 | M | 43 | AML | Unrelated BM | 82 | Skin, GI | Deflazacort | Same |
| 5 | F | 40 | AML | Related PBSC | 3 | Oral | PSL | Change to deflazacort |
| 6 | F | 20 | ALL | Unrelated PBSC | 6 | Skin, liver, oral | MPD IV d | Change to PO medication, taper |
| 7 | M | 5 | ALL | Unrelated PBSC | 36 | Skin, GI, oral | Tacrolimus, MMF | Same |
| 8 | F | 55 | CML | Related BM + PBSC | 7 | Skin, lung, oral | PSL | Taper |
| 9 | M | 15 | AML | Unrelated PBSC | 12 | Skin, lung | Tacrolimus, MMF | Taper |
| 10 | M | 22 | ALL | Unrelated PBSC | 8 | Skin, lung, oral | PSL, tacrolimus, MMF | Taper |
| 11 | F | 42 | ALL | Unrelated PBSC | 5 | Skin, GI, oral | PSL | Same |
| 12 | M | 19 | ALL | Unrelated PBSC | 8 | Skin | Tacrolimus, MMF | Taper |
| 13 | M | 21 | Anaplastic large cell lymphoma | Unrelated PBSC | 3 | Lung | PSL, tacrolimus, MMF | Taper |
a Age at diagnosis of chronic ocular GVHD (years).
b Time interval from transplantation to diagnosis of ocular GVHD (months).
c GVHD in other organs present before or at the time of ocular GVHD diagnosis.
d Use for treatment of concurrent systemic GVHD, including ocular GVHD.
Topical 0.02% tacrolimus ointment was used in patients with chronic ocular GVHD with ocular surface inflammation (at least grade 2 inflammatory score). This study included patients who were treated with tacrolimus ointment for more than 6 months to evaluate the efficacy and safety of maintenance treatment. The exclusion criteria were any history of previous ocular surgery or trauma, infection, allergy, or autoimmune disease. The left eye of Patient 2 had a history of herpetic keratitis and was therefore excluded. The right eye of Patient 9 with ocular trauma was excluded. Approval was obtained from the Severance Hospital Institutional Review Board, Seoul, South Korea (No 4-2012-0702). The clinical research performed in this study followed the tenets of the Declaration of Helsinki.
Topical 0.02% tacrolimus ointment was applied in the lower conjunctival sac 1–2 times per day, depending on the severity of disease. The commercial tacrolimus ointment (Protopic 0.03%; Fujisawa Healthcare Inc, Munich, Germany) used to treat dermatologic disease is very viscous and inappropriate for direct application into the conjunctival sac. Therefore, a formulation was created by diluting the 0.03% tacrolimus ointment 2:1 by volume with a less viscous lubricating ophthalmic ointment (Duratears; Alcon Laboratories Inc, Fort Worth, Texas, USA) composed of 30 mg anhydrous liquid lanolin per gram of mineral oil base. All patients were also treated with artificial tears for lubrication and lid management, such as warm compression or lid scrub for control ocular surface evaporation.
The definition of the follow-up period was from the diagnosis of chronic ocular GVHD to the final ocular examination. We evaluated the control of ocular surface inflammation, changes in steroid burden, and the numbers of aggravation events before and after tacrolimus treatment.
The ocular surface inflammatory score was modified using the score in refractory ocular surface inflammatory disease, conjunctival injection grading in chronic ocular GVHD, and classification of chronic GVHD conjunctivitis. Ocular surface inflammation was assessed based on hyperemia degree, ocular surface staining, the presence of pseudomembrane, progression of corneal conjunctivalization, and symblepharon. Ocular surface inflammatory scores of 0, 1, and 2 indicated no, mild, and moderate hyperemia, respectively. A score of 3 indicated severe hyperemia with palpebral conjunctival fibrovascular changes and surface staining, and a score of 4 described extensive hyperemia with a pseudomembrane, extensive conjunctival subepithelial fibrosis, and symblepharon formation.
Steroid score and steroid use period of total duration were measured as indicators of severity or progression of the disease. The steroid scores are as follows: 0, no steroids were used; 1, 0.1% topical unpreserved fluorometholone (Fumeron eye drops 0.6 mL; Hanlim Pharm Co, Seoul, South Korea); 2, ophthalmic suspension of loteprednol etabonate 0.5% (Lotemax; Bausch & Lomb Inc, Tampa, Florida, USA); 3, 1% topical unpreserved methylprednisolone solution; and 4, either use of systemic steroids with/without topical steroid use or intensive and frequent use of 1% topical nonpreserved methylprednisolone solution (>6 times per day). The numbers of inflammatory aggravation events were evaluated before and after tacrolimus ointment treatment. An aggravation event was defined as an increase in ocular surface inflammation treated by restarting or increasing steroid use after tapering the initial dose to control the inflammation.
The long-term clinical outcomes at final follow-up after maintenance treatment of tacrolimus ointment were compared with baseline findings at diagnosis of chronic ocular GVHD. The outcomes included visual acuity, symptom score (National Institutes of Health [NIH] eye score), ocular surface staining using the Oxford Scheme 6-point scale, Schirmer I test, and tear break-up time (TBUT), and classification of chronic GVHD conjunctivitis. TBUT was measured by applying a single fluorescein strip (Haag-Streit, Koeniz, Switzerland) to the inferior palpebral conjunctiva after instilling a drop of normal saline. The mean time for 3 attempts was recorded. After measuring TBUT, ocular surface staining was graded from 0 to 5 based on the fluorescein pattern on slit-lamp biomicroscopy. The Schirmer I test was performed without topical anesthesia by placing a standard paper strip in the mid-lateral portion of the lower fornix. Patients were asked to sit quietly with their eyes closed, and the amount of wetting was recorded after 5 minutes. The safety of tacrolimus ointment treatment was investigated by measuring IOP and by recording any side effects, such as blurred vision, burning sensation, development of corneal lesion, infection, and drug-induced conjunctival hyperemia.
Statistical analyses of inflammatory score changes after short-term treatment and comparisons of clinical outcomes before and after long-term maintenance treatment were performed using the Wilcoxon signed rank test. One eye per patient was analyzed when both eyes had different clinical features and treatment course. We selected the eyes with more severe inflammation that was treated with tacrolimus ointment for a longer period. Statistical analyses were performed using the SPSS statistical software package (version 20.0; IBM Corp, Armonk, New York, USA). P values less than .05 were considered to be statistically significant.
Results
Topical 0.02% tacrolimus ointment was initiated for the reasons described in Table 2 , and some eyes were treated with tacrolimus ointment for multiple reasons. In all patients, tacrolimus treatment controlled the ocular surface inflammation with or without topical steroid. The first reason for initiation of tacrolimus ointment treatment was to suppress active and severe inflammation in combination with topical steroid in 2 patients (Patients 1 and 12). After severe inflammation was controlled, maintenance tacrolimus ointment was continued to prevent inflammation aggravation.
| Reason | Number of Patients (% of 13 Patients) |
|---|---|
| To suppress active and severe inflammation in combination with topical steroid | 2 (15.4%) |
| To maintain disease remission after initial control with steroid use | 11 (84.6%) |
| Because of increase in IOP with topical steroid | 6 (46.2%) |
| To control inflammation without steroid use | 2 (15.4%) |
Case 1
A-55-year-old female patient (Patient 1) was diagnosed with chronic ocular GVHD with active and severe ocular surface inflammation 26 months after SCT. Combined 1% topical methylprednisolone and 0.02% tacrolimus ointment were initially used in both eyes. Severe conjunctival hyperemia with fibrovascular changes and a pseudomembrane improved after 2 weeks of treatment, and her inflammatory score decreased from 4 to 1. The topical steroid was tapered and discontinued after 4 months. The tacrolimus ointment treatment was continued for 13 months. Four months after stopping tacrolimus treatment, her ocular surface was stable at final examination ( Figure 1 ).
The second reason for tacrolimus ointment use was to maintain disease remission after achieving initial control with topical steroid use in 11 patients. In 6 patients of them, steroid-induced IOP elevation developed and topical steroids were stopped, and tacrolimus ointment was used. Additional topical tacrolimus treatment facilitated steroid tapering, reduced the remaining inflammation, and maintained disease remission within a normal IOP range.
Case 2
A 21-year-old female patient (Patient 3) presented with pseudomembranous conjunctivitis with epithelial breakdown of both eyes 8 months after SCT. She was initially treated with 0.1% topical unpreserved fluorometholone, and her ocular surface inflammation improved. However, after 13 months of treatment, IOP increased in both eyes, and mild conjunctival hyperemia and subepithelial fibrosis remained. Topical steroid was exchanged for tacrolimus ointment, and IOP subsequently improved. With long-term use of tacrolimus ointment for 16 months since then, there were no signs of inflammatory aggravation and rise of IOP ( Figure 2 ).
The third reason for tacrolimus treatment initiation was to control inflammation in 2 pediatric patients without steroid use. Patients 7 and 13 received tacrolimus ointment for 13 and 14 months, respectively, to initially control ocular surface inflammation. Their symptoms and signs improved after 2 weeks of treatment without disease aggravation or additional steroid use, and there was no disease relapse.
The mean ocular surface inflammatory score decreased from 2.8 ± 0.6 to 0.6 ± 0.5 ( P = .001) in 13 patients 2–8 weeks after starting tacrolimus ointment treatment. However, this treatment was maintained beyond this point. The duration of chronic ocular GVHD before tacrolimus treatment ranged from 0 to 28 months, and the duration of follow-up after tacrolimus treatment ranged from 6 to 20 months. Prior to tacrolimus treatment, patients received different levels of topical steroid (scored 1–4) during 25%–100% of disease duration. After tacrolimus treatment, 7 patients did not use the topical steroid until the final follow-up. Four patients experienced an inflammatory aggravation event that resulted in additional topical steroid use for a 6.7%–20% period of disease duration. Two patients (Patients 1 and 12) were initially treated with tacrolimus ointment and steroid; the steroid was then discontinued, and their symptoms were controlled with maintenance tacrolimus treatment. Therefore, topical tacrolimus ointment enabled the discontinuation or tapering of topical steroid without an increase in relapses. Additional treatments included topical cyclosporine, autoserum eye drops, and punctal plug before or after tacrolimus treatment ( Table 3 ).
| Patient | Before Treatment With Tacrolimus Ointment | After Treatment With Tacrolimus Ointment | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Duration (Months) | Number of Aggravations a | Steroid Score b | Steroid Use Period of Total Duration (%) | Additional Treatment | Duration (Months) | Time to Improvement (Weeks) | Inflammatory Score | Duration of Tacrolimus Therapy (Months) | Number of Aggravations a | Steroid Score b | Steroid Use Period of Total Duration (%) | Additional Treatment | ||
| Before c | After d | |||||||||||||
| 1 | 17 | 2 | 4 | 1 | 13 | 0 | 4 | 23.5% (4/17) | ||||||
| 2 | 24 | 4 | 4 | 75% (18/24) | 20 | 3 | 3 | 1 | 20 | 1 | 1 | 20% (4/20) | Punctal plug | |
| 3 | 13 | 2 | 1 | 30.8% (4/13) | Topical cyclosporin | 16 | 4 | 3 | 1 | 16 | 0 | 0 | 0% (0/16) | |
| 4 | 28 | 3 | 3 | 25% (7/28) | Autoserum | 15 | 4 | 2 | 1 | 8 | 0 | 0 | 0% (0/15) | |
| 5 | 18 | 3 | 4 | 100% (18/18) | 17 | 2 | 3 | 0 | 17 | 1 | 2 | 11.8% (2/17) | ||
| 6 | 5 | 2 | 4 | 100% (5/5) | 6 | 4 | 3 | 1 | 6 | 0 | 0 | 0% (0/6) | ||
| 7 | 13 | 2 | 2 | 1 | 13 | 0 | 0 | 0% (0/13) | ||||||
| 8 | 3 | 1 | 3 | 33.3% (1/3) | Autoserum, punctal plug | 15 | 6 | 3 | 0 | 15 | 1 | 3 | 6.7% (1/15) | Punctal plug |
| 9 | 3 | 1 | 3 | 100% (3/3) | Topical cyclosporin | 11 | 4 | 3 | 0 | 11 | 0 | 0 | 0% (0/11) | |
| 10 | 12 | 2 | 1 | 33.3% (4/12) | 13 | 6 | 3 | 1 | 13 | 1 | 1 | 7.7% (1/13) | ||
| 11 | 4 | 1 | 1 | 100% (4/4) | 6 | 4 | 2 | 0 | 6 | 0 | 0 | 0% (0/6) | ||
| 12 | 7 | 8 | 3 | 1 | 7 | 0 | 3 | 14.3% (1/7) | ||||||
| 13 | 14 | 2 | 2 | 0 | 14 | 0 | 0 | 0% (0/14) | Punctal plug | |||||
a Number of inflammatory aggravations defined as an increase in ocular surface inflammation treated by restarting or increasing steroid use after tapering the initial dose to control the inflammation.
b Steroid scores are as follows: 0, no steroids were used; 1, 0.1% topical unpreserved fluorometholone (Fumeron eye drops 0.6 mL; Hanlim Pharm Co, Seoul, South Korea); 2, ophthalmic suspension of loteprednol etabonate 0.5% (Lotemax; Bausch & Lomb Inc, Tampa, Florida, USA); 3, 1% topical unpreserved methylprednisolone solution; and 4, either use of systemic steroids with/without topical steroid use or intensive and frequent use of 1% topical nonpreserved methylprednisolone solution (>6 times per day).
c Before tacrolimus ointment initiation.
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