Purpose
To evaluate topical tacrolimus ointment for treating Thygeson’s superficial punctate keratitis (Thygeson SPK).
Design
Retrospective interventional case series.
Methods
setting : Institutional practice. patient population : The medical records of 14 patients (9 women; age range, 9–65 years) with Thygeson SPK were reviewed retrospectively. Diagnosis was based on the history and clinical examination. intervention : Patients were treated with tacrolimus 0.03% eye ointment instilled into the lower fornix twice daily for the first 2 weeks, followed by nocturnal application. The clinical signs and symptoms were assessed after 1 month of treatment. The drug was tapered with disease improvement. main outcome measure(s) : Treatment efficacy and side effects.
Results
All patients had bilateral disease (average duration, 6 years). All patients, except 2 who used the medication irregularly, had improved visual acuity (VA), symptoms, and signs as long as the medication was applied. Before treatment 28.57% of patients had VA between 20/30 and 20/50, with improvement after treatment to 20/25 or 20/20. Attempts to withdraw the medication resulted in recurrent disease, and, therefore, treatment was not curative during the study period. No significant local medication side effects were reported.
Conclusion
Tacrolimus eye ointment 0.03% was effective for controlling Thygeson SPK for a long period with good patient tolerance and no noticeable local or systemic side effects. During the average 6-year follow-up, treatment was not curative. Randomized studies are difficult to conduct because of the disease rarity.
Phillip Thygeson originally described Thygeson’s superficial punctate keratitis (Thygeson SPK) in 1950 as a chronic, bilateral punctate epithelial keratitis of long duration (from months to years) with exacerbations and remissions; eventual healing without scars; lack of response to systemic and topical antibiotics, sulfonamides, and removal of corneal epithelium; and a striking symptomatic response to topical steroids.
The main disease symptoms are photophobia, tearing, and irritation; patients generally have good vision. Slit-lamp examination shows focal epithelial keratitis with variable shapes, whitish gray in color, and slightly raised. The lesions tend to accumulate centrally in the cornea and there is no associated conjunctival or stromal inflammation.
Since Abbott and Forster in 1979 and more recently Fintelmann and associates in 2012 described that chronic corneal inflammation in Thygeson SPK can lead to corneal scarring, treatment is needed not just for patient comfort and temporary visual improvement but also to reduce the risk of corneal scarring.
Use of topical lubricants, topical antiviral drugs, bandage contact lenses, and photorefractive keratectomy or phototherapeutic keratectomy, among others, are options for medical management of Thygeson SPK, but these options usually are unsatisfactory. The therapy of choice is topical corticosteroid, which is associated with risks and severe side effects of chronic use, such as secondary infections, cataract, and glaucoma. Topical immunomodulatory agents such as cyclosporine A and tacrolimus seem appropriate for treating Thygeson SPK because of its characteristic long duration and marked response to corticosteroids. In fact, topical use of both drugs, cyclosporine A and tacrolimus, has already been a frequent alternative for treating several chronic ocular surface diseases in general, including Thygeson SPK.
Methods
This retrospective interventional case series included 14 patients diagnosed with Thygeson SPK who were treated with topical ophthalmic tacrolimus eye ointment 0.03%. The Federal University of São Paulo, São Paulo, Brazil Review Board prospectively approved the study (#19771113.3.0000.5505).
The diagnosis of Thygeson SPK was based on history, symptoms, and typical clinical signs observed during the slit-lamp examination. Age, sex, disease duration, treatment duration, best-corrected visual acuity (BCVA) before and after treatment, symptoms, and signs before and after treatment were assessed.
The tacrolimus eye ointment 0.03% was formulated without preservatives at a compounding pharmacy (Eye Pharma Ophthalmos, São Paulo, Brazil) using the following components: tacrolimus 0.03% on solid petrolatum (70.0%), liquid petrolatum (27.5%), and liquid lanolin (2.5%). Tacrolimus ointment was applied in the lower fornix twice daily for 2 weeks followed by once daily at night before bed. The medication regimen was tapered based on the response until discontinuation. If the patient had recurrent disease, the medication was reintroduced at the same frequency as at the initiation of the treatment, followed by new tapering.
The patients were examined every month for the first 3 months of use and then every 3 months or depending on the individual clinical complaints and findings. During visits, patients were asked about symptoms of the disease and medication side effects such as foreign body and burning sensations and blurred vision. Slit-lamp examination was used for signs of disease and medication toxicity (hyperemia, papillary or follicular conjunctival reaction, and toxic punctate keratitis). We also looked for signs of herpes simplex keratitis or malignancies of the ocular surface during the use of topical tacrolimus.
The treatment was considered successful when there was symptom improvement, absence of or significant reduction in corneal lesions, and improved BCVA.
A “good, fair, and bad” methodology was used to evaluate the tolerance to the use of topical tacrolimus in the different published studies. These studies were read and ranked in 3 groups: good, authors described good medication tolerance; fair, authors described that patients experienced some burning and foreign body sensation and blurred vision, which did not preclude use of the medication; and bad, authors described that patients were intolerant of the medication.
Results
All patients had a history of chronic bilateral corneal disease with an average duration of 6 years (range, 2–14 years), with main complaints of photophobia, foreign body and burning sensations, blurred vision, and tearing. Patients also had a long history of use of topical corticosteroid, lubricant, and antiviral medications. The patients’ ages ranged from 9 to 65 years. Nine were female.
Slit-lamp examination showed typical focal epithelial keratitis in the central area of the cornea with a positive staining with fluorescein ( Figure ). The remainder of the eye examination was normal, including the intraocular pressure values before and after treatment.
The average treatment period with tacrolimus was 3.2 years (range, 1–6 years) to the last follow-up evaluation. All patients, except 2 who used the drug irregularly, had improved visual acuity (VA), symptoms, and signs as long as the medication was applied. Before treatment, 28.57% of patients had a VA between 20/30 and 20/50; and all improved to 20/25 or 20/20 during treatment ( Table 1 ).
| Patient No. | Age/Sex | ΔT DI (Years) | Previous Treatments | ΔT TC (Years) | SS Last Visit a | Tacrolimus D90 | Side Effects a | BCVA OD, OS Before Treatment | BCVA OD, OS After Treatment |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 9/M | 3 | Topical corticosteroid, lubricants | 3 | − | QD | – | 20/40, 20/30 | 20/20, 20/20 |
| 2 | 17/F | 9 | Topical corticosteroid, antiviral, lubricants | 2 | − | QD | – | 20/20, 20/20 | 20/20, 20/20 |
| 3 | 18/F | 2 | Topical lubricants | 2 | − | QD | – | 20/40, 20/30 | 20/20, 20/20 |
| 4 | 21/M | 4 | Topical corticosteroid, lubricants | 4 | − | QD | – | 20/20, 20/20 | 20/20, 20/20 |
| 5 | 27/F | 5 | Topical corticosteroid, lubricants | 4 | − | QD | – | 20/50, 20/40 | 20/25, 20/20 |
| 6 | 29/M | 4 | Topical corticosteroid, lubricants, cyclosporine | 4 | + | QD b | FBS | 20/20, 20/20 | 20/40, 20/40 |
| 7 | 33/M | 5 | Topical lubricants | 4 | − | QD | – | 20/20, 20/20 | 20/20, 20/20 |
| 8 | 33/F | 5 | Topical corticosteroid, lubricants, cyclosporine, BCL | 3 | − | BID | BS | 20/25, 20/20 | 20/20, 20/20 |
| 9 | 35/F | 11 | Topical corticosteroid, lubricants | 6 | − | QD | – | 20/20, 20/20 | 20/20, 20/20 |
| 10 | 36/M | 7 | Topical corticosteroid, antiviral, lubricants | 6 | − | QD | – | 20/20, 20/20 | 20/20, 20/20 |
| 11 | 44/F | 4 | Topical corticosteroid, lubricants | 3 | + | QD b | – | 20/20, 20/20 | 20/20, 20/20 |
| 12 | 50/F | 9 | Topical corticosteroid, lubricants | 1 | − | Q2D | BS | 20/20, 20/20 | 20/20, 20/20 |
| 13 | 53/F | 14 | Topical corticosteroid, lubricants | 1 | − | Q1W | – | 20/25, 20/25 | 20/20, 20/20 |
| 14 | 65/F | 2 | Topical lubricants | 2 | − | QD | – | 20/30, 20/30 | 20/20, 20/20 |
a A “+” indicates present; “−” indicates absent.
b Patients 6 and 11 have reported irregular use of tacrolimus.
No significant local side effects such as foreign body and burning sensation, blurred vision, or signs of hyperemia, papillary or follicular conjunctival reaction, and toxic punctate keratitis were observed during the study period, and all patients tolerated the drug well during the treatment. No herpes simplex keratitis or malignancies of the ocular surface developed during the use of topical tacrolimus.
Attempts to withdraw the medication resulted in recurrent disease, and, therefore, treatment was not curative during the study period.
Review of the literature on the use of topical tacrolimus for treating ocular surface diseases showed that the drug was efficacious in most studies. Topical use of tacrolimus was well tolerated except for a slight burning sensation and blurred vision in some patients upon drug instillation, mainly in the first weeks of treatment ( Table 2 ).
| Disease | Tacrolimus Formulation | Regimen | Effectiveness | Tolerance a | Reference/First Author/Year |
|---|---|---|---|---|---|
| Diverse | Dermatologic ointment 0.03% (Protopic) | BID | Effective b | Good | 9/Joseph/2005 |
| VKC, AKC, graft rejection | Dermatologic ointment 0.1% (Protopic) | BID | Effective | Good | 10/Abeysiri/2010 |
| GVHD | Dermatologic ointment 0.03% (Protopic) | BID | Effective | Good | 19/Tam/2010 |
| VKC | Dermatologic ointment 0.03% (Protopic) | BID | Effective | Good | 21/Muller/2014 |
| AKC | Dermatologic ointment 0.03% (Protopic) | BID | Effective | Good | 23/Garcia/2011 |
| GPC | Dermatologic ointment 0.03% (Protopic) | BID | Effective | Good | 24/Kymionis/2008 |
| VKC, PAC | Dermatologic ointment 0.03% (Protopic) | BID | Effective | Good | 26/Attas-Fox/2008 |
| AKC | Dermatologic ointment 0.03% (Protopic) | BID | Effective | Good | 27/Tzu/2012 |
| SLK | Dermatologic ointment 0.03% (Protopic) | BID | Effective | Good | 32/Kymionis/2013 |
| Phlyctenular keratoconjunctivitis | Dermatologic ointment 0.03% (Protopic) | BID | Effective | Good | 33/Kymionis/2012 |
| OCP | Dermatologic ointment 0.03% (Protopic) | BID | Effective | Good | 34/Michel/2006 |
| VKC | Ophthalmic ointment 0.1% | BID | Effective | Fair | 16/Labcharoenwongs/2012 |
| GVHD | Ophthalmic ointment 0.02% | QD/BID | Effective | Fair | 39/Jung/2015 |
| Refractory allergic conjunctivitis | Ophthalmic suspension, 0.1% | BID | Effective | Fair | 20/Fukushima/2014 |
| AKC | Ophthalmic suspension 0.1% | BID | Effective | Good | 28/Wakamatsu/2011 |
| Severe VKC and AKC | Ophthalmic suspension 0.1% | BID | Effective | Fair | 38/Ebihara/2012 |
| VKC, AKC | Ophthalmic suspension 0.1% | BID | Effective | Fair | 29/Ohashi/2010 |
| CLPC | Ophthalmic suspension 0.05% | BID | Effective | Fair | 30/Diao/2012 |
| Dry eye | Ophthalmic suspension 0.03% | BID | Effective | Fair | 17/Moscovici/2012 |
| Dry eye in GVHD | Ophthalmic suspension 0.03% | QD | Effective | Fair/bad | 18/Sanz-Marco/2013 |
| Adenoviral corneal SEI | Ophthalmic suspension 0.03% | BID/TID | Effective | Fair | 31/Ghanem/2014 |
| VKC | Ophthalmic suspension 0.005% | QID | Effective | Good | 22/Kheirkhah/2011 |
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