JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 32, Number 3, 2016 ª Mary Ann Liebert, Inc. DOI: 10.1089/jop.2015.0078
Downloaded by Gothenburg University Library from online.liebertpub.com at 09/18/17. For personal use only.
Frequent Dosing of Topical Cyclosporine A for Severe Ocular Surface Disease Anisa I. Gire, Sezen Karakus, Shanna M. Ingrodi, and Esen Karamursel Akpek
Abstract
Purpose: To study the systemic safety and patient tolerability of frequent dosing of cyclosporine A (CsA) 0.05% eyedrops in the treatment of ocular surface disease. This is a retrospective case series. Patients with significant ocular surface diseases who were treated using topical CsA higher than the usual twice daily dosing (3–8 times daily and over a treatment period of 1–70 months). The main outcome measures are plasma levels of CsA and local tolerability. Methods: Symptom assessment, corneal staining using fluorescein, conjunctival staining using lissamine green, tear film breakup time, and other signs according to the disease process were monitored. Discontinuation of treatment due to intolerability was recorded. CsA levels were measured in the plasma at a clinical laboratory. Results: Plasma levels of CsA were below the level of detection (7 ng/mL) in all the 41 patients included. All patients tolerated the treatment well with none discontinuing due to any treatment-related local adverse effects. Conclusions: This study demonstrates that CsA 0.05% ophthalmic emulsion applied more frequently than the usual twice daily dosing was safe and well tolerated in patients with significant ocular surface diseases.
Introduction
D
ry eye affects an estimated 5 million Americans aged 50 years and older.1 It has been defined as a ‘‘multifactorial disease that is caused by a decrease in tear production and/or an increase in tear evaporation and is associated with elevated tear osmolarity, symptoms of ocular irritation, and signs of ocular surface inflammation.’’2 Dry eye has a significant impact on affected patients’ quality of life due to ocular discomfort and visual dysfunction.3–6 It also has a large economic impact not only due to cost of therapy but also its consequent effects on workplace productivity.3,7 The combination of its high prevalence and detrimental effects on the affected patients’ quality of life underscores the importance of effective treatment strategies for dry eye. Irrespective of the presence of any identifiable underlying local or systemic inflammatory disorder, dry eye is invariably associated with chronic inflammation of the ocular surface mediated by lymphocytes.8,9 Cyclosporine A (CsA) 0.05% ophthalmic emulsion (Restasis; Allergan, Inc., Irvine, CA) has been widely used in patients with dry eye since the U.S. Food and Drug Administration (FDA) approved it in 2003. CsA is an immunomodulator that inhibits T-lymphocyte activation and function and apoptosis
of conjunctival epithelial cells.10,11 Systemically administered CsA is known to cause serious side effects, including nephrotoxicity, hypertension, increased risk of opportunistic infections, and hepatotoxicity.10,12 In phase 3 clinical trials, topical CsA at concentrations of 0.05% or 0.1% CsA had negligible plasma levels after 3 years of continuous use at the recommended twice daily dosing. However, local side effects such as burning, stinging, discharge, foreign body sensation, and hyperemia were commonly reported.13 Topical CsA has also been used off-label in the treatment of a variety of other ocular surface conditions, including ocular rosacea, graft-versus-host disease (GvHD), atopic keratoconjunctivitis, and posterior blepharitis.10,11,14–16 It has been the main treatment of severe vernal keratoconjunctivitis in children since 1980s.17 A few studies reported on its use at more frequent doses ranging from 3 to 8 times a day in patients with some of these severe ocular surface diseases.18–20 Currently, whether frequent dosing of topical CsA 0.05% could cause systemic side effects is not known and has been a concern particularly in the pediatric age group. Therefore, we sought to examine the plasma concentration of CsA in patients who received high-frequency topical application of CsA for the treatment of various ocular surface diseases. We also recorded local side effects and the dropout rate due to intolerability to treatment.
Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
150
FREQUENT DOSING OF TOPICAL CSA FOR OSD
Downloaded by Gothenburg University Library from online.liebertpub.com at 09/18/17. For personal use only.
Methods This retrospective medical record review was approved by the Johns Hopkins University Institutional Review Board in accordance with the Declaration of Helsinki. The study was Health Insurance Portability and Accountability Act compliant. Medical records of patients who were evaluated at the Wilmer Eye Institute Ocular Surface Diseases and Dry Eye Clinic, Johns Hopkins University, Baltimore, Maryland, over a period of 6 years (between 2006 and 2012) were reviewed retrospectively. Consecutive patients with various ocular surface diseases who were treated with high doses of topical CsA (ranging from 3 to 8 times a day) and who underwent a blood work-up for plasma CsA level measurement were included in this study. Patients who were on systemic CsA or tacrolimus (e.g., for the treatment of GvHD) were excluded. Clinical assessment of the patients included corneal fluorescein staining, conjunctival lissamine green staining, and tear film breakup time. Other ocular surface findings associated with the underlying disease processes were also monitored. The clinical signs monitored to determine the improvement of the disease process are not included in the Results section due to the variability of the conditions included in this study. Tolerability and local and systemic safety were the main outcomes. Local side effects such as burning, stinging, and discomfort were assessed at every visit. Discontinuation of medication due to local side effects was the main indicator of intolerance. Serum CsA levels were assessed due to concern regarding possible systemic toxicity on consecutive patients who were on CsA 0.05% at higher than the usual twice daily dosing and who were willing to have a blood work-up. Patients were generally tested while they were on their maximum treatment dosing. Determination of serum levels was performed whenever the patients presented to the clinic for a follow-up of their clinical condition but not in any systematic way. In the patients who were on the treatment for only several weeks (n = 12), blood work-up was performed within 30 min after CsA instillation. Laboratory analyses were performed at a CLIA-certified commercial laboratory at the Johns Hopkins Hospital. A minimum of 100 mL of whole blood was drawn and analyzed using the Thermo Scientific TLX liquid chromatography system (Thermo Fisher Scientific, Inc., Waltham, MA) in conjunction with the Thermo Fisher TSQ Quantum Access mass spectrometer (Thermo Fisher Scientific, Inc.) to elute, analyze, and quantitate CsA levels. Values of CsA less than 7 ng/mL were reported as normal with a critical value of 100 ng/mL.
Results Table 1 summarizes demographic information and underlying ocular conditions of 41 consecutive patients included. The majority of patients (33/41, 80.4%) were adult females; one patient was younger than 21 years, a 17-year-old female, with chronic conjunctivitis. Fifteen patients had primary Sjogren’s syndrome and 18 had non-Sjogren’s related dry eye. Three patients had GvHD and 4 had atopic keratoconjunctivitis. Patients with underlying inflammatory systemic diseases were also being treated with various systemic medications, including methotrexate, mycophenolate, or hydroxychloroquine. However, patients who were on oral cyclosporine or tacrolimus were excluded from this study.
151
Table 1. Demographic Characteristics of Patients with Various Ocular Surface Diseases Who Were Treated with Frequent Dosing of Topical CsA 0.05% Emulsion Patient characteristic Gender Male Female Age (years) Range Mean Median Underlying condition Non-Sjogren’s related dry eye Thyroid eye disease Primary Sjogren’s syndrome Atopic keratoconjunctivitis Graft-versus-host disease Sarcoidosis
No. of patients (%) 8 (19.5) 33 (80.4) 17–73 58 60 18 8 15 4 3 1
(43.9) (19.5) (36.6) (9.8) (7.3) (2.4)
CsA, cyclosporine A.
All patients had severe ocular surface disease requiring escalation of treatment due to failure to improve while on CsA twice-a-day regimen. Table 2 summarizes the details of CsA therapy and concurrent topical ophthalmic medications. Frequency of dosing ranged from 3 to 8 times a day with an average of 4.84 times per day. Patients were treated using CsA at frequent dosing over 16 months. Eight patients were treated at 8· daily dosing for 9.3 months. Twenty patients were taking preservative-free artificial tears and 7 also used lubricating ointments. Eleven patients had either a prior punctal plug insertion or cauterization procedure. Fifteen patients were additionally treated with topical tacrolimus 0.03% ointment (Protopic; Astellas Pharma Tech, Toyama, Japan) applied externally on the lids twice a day. One patient was concurrently on treatment with 50% autologous serum tears 4 times a day. Six patients had been treated with topical steroid preparations before initiation of
Table 2. Details of the Treatment in Patients with Various Ocular Surface Diseases Who Were Treated with Frequent Dosing of Topical CsA 0.05% Emulsion Frequency of cyclosporine 0.05% use Range Mean Median Length of cyclosporine 0.05% use Range Mean Median Concurrent topical or local therapy Preservative-free artificial tears Punctal plugs or cauterization Topical steroids Over-the-counter ointment Tacrolimus 0.03% ointment Autologous serum Topical antihistamine/mast cell stabilizers
Times/day 3–8 4.8 4 Months 1–70 16.48 9 No. of patientsa 20 11 7 7 15 1 2
a Total is greater than 41 since some of the patients were on multiple treatments concurrently.
Downloaded by Gothenburg University Library from online.liebertpub.com at 09/18/17. For personal use only.
152
frequent dosing with CsA. Patients had to discontinue topical steroid treatment either for lack of response (n = 5) or because of an increase in intraocular pressure (n = 1). Two patients had never been offered steroid treatment due to a history of steroid use failure, a history of intraocular pressure rise from topical steroids, or hypersensitivity to the several steroid preparations. Seven patients were on topical steroids, as well as frequent CsA drops concurrently. Blood work-up to determine serum CsA levels was performed on an average at 3 months (range, 6 weeks to 6 months) into the treatment. In 12 patients, the plasma levels were measured within 30 min of the last dosing. Plasma levels of CsA were negligible (
Downloaded by Gothenburg University Library from online.liebertpub.com at 09/18/17. For personal use only.
Frequent Dosing of Topical Cyclosporine A for Severe Ocular Surface Disease Anisa I. Gire, Sezen Karakus, Shanna M. Ingrodi, and Esen Karamursel Akpek
Abstract
Purpose: To study the systemic safety and patient tolerability of frequent dosing of cyclosporine A (CsA) 0.05% eyedrops in the treatment of ocular surface disease. This is a retrospective case series. Patients with significant ocular surface diseases who were treated using topical CsA higher than the usual twice daily dosing (3–8 times daily and over a treatment period of 1–70 months). The main outcome measures are plasma levels of CsA and local tolerability. Methods: Symptom assessment, corneal staining using fluorescein, conjunctival staining using lissamine green, tear film breakup time, and other signs according to the disease process were monitored. Discontinuation of treatment due to intolerability was recorded. CsA levels were measured in the plasma at a clinical laboratory. Results: Plasma levels of CsA were below the level of detection (7 ng/mL) in all the 41 patients included. All patients tolerated the treatment well with none discontinuing due to any treatment-related local adverse effects. Conclusions: This study demonstrates that CsA 0.05% ophthalmic emulsion applied more frequently than the usual twice daily dosing was safe and well tolerated in patients with significant ocular surface diseases.
Introduction
D
ry eye affects an estimated 5 million Americans aged 50 years and older.1 It has been defined as a ‘‘multifactorial disease that is caused by a decrease in tear production and/or an increase in tear evaporation and is associated with elevated tear osmolarity, symptoms of ocular irritation, and signs of ocular surface inflammation.’’2 Dry eye has a significant impact on affected patients’ quality of life due to ocular discomfort and visual dysfunction.3–6 It also has a large economic impact not only due to cost of therapy but also its consequent effects on workplace productivity.3,7 The combination of its high prevalence and detrimental effects on the affected patients’ quality of life underscores the importance of effective treatment strategies for dry eye. Irrespective of the presence of any identifiable underlying local or systemic inflammatory disorder, dry eye is invariably associated with chronic inflammation of the ocular surface mediated by lymphocytes.8,9 Cyclosporine A (CsA) 0.05% ophthalmic emulsion (Restasis; Allergan, Inc., Irvine, CA) has been widely used in patients with dry eye since the U.S. Food and Drug Administration (FDA) approved it in 2003. CsA is an immunomodulator that inhibits T-lymphocyte activation and function and apoptosis
of conjunctival epithelial cells.10,11 Systemically administered CsA is known to cause serious side effects, including nephrotoxicity, hypertension, increased risk of opportunistic infections, and hepatotoxicity.10,12 In phase 3 clinical trials, topical CsA at concentrations of 0.05% or 0.1% CsA had negligible plasma levels after 3 years of continuous use at the recommended twice daily dosing. However, local side effects such as burning, stinging, discharge, foreign body sensation, and hyperemia were commonly reported.13 Topical CsA has also been used off-label in the treatment of a variety of other ocular surface conditions, including ocular rosacea, graft-versus-host disease (GvHD), atopic keratoconjunctivitis, and posterior blepharitis.10,11,14–16 It has been the main treatment of severe vernal keratoconjunctivitis in children since 1980s.17 A few studies reported on its use at more frequent doses ranging from 3 to 8 times a day in patients with some of these severe ocular surface diseases.18–20 Currently, whether frequent dosing of topical CsA 0.05% could cause systemic side effects is not known and has been a concern particularly in the pediatric age group. Therefore, we sought to examine the plasma concentration of CsA in patients who received high-frequency topical application of CsA for the treatment of various ocular surface diseases. We also recorded local side effects and the dropout rate due to intolerability to treatment.
Ocular Surface Diseases and Dry Eye Clinic, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.
150
FREQUENT DOSING OF TOPICAL CSA FOR OSD
Downloaded by Gothenburg University Library from online.liebertpub.com at 09/18/17. For personal use only.
Methods This retrospective medical record review was approved by the Johns Hopkins University Institutional Review Board in accordance with the Declaration of Helsinki. The study was Health Insurance Portability and Accountability Act compliant. Medical records of patients who were evaluated at the Wilmer Eye Institute Ocular Surface Diseases and Dry Eye Clinic, Johns Hopkins University, Baltimore, Maryland, over a period of 6 years (between 2006 and 2012) were reviewed retrospectively. Consecutive patients with various ocular surface diseases who were treated with high doses of topical CsA (ranging from 3 to 8 times a day) and who underwent a blood work-up for plasma CsA level measurement were included in this study. Patients who were on systemic CsA or tacrolimus (e.g., for the treatment of GvHD) were excluded. Clinical assessment of the patients included corneal fluorescein staining, conjunctival lissamine green staining, and tear film breakup time. Other ocular surface findings associated with the underlying disease processes were also monitored. The clinical signs monitored to determine the improvement of the disease process are not included in the Results section due to the variability of the conditions included in this study. Tolerability and local and systemic safety were the main outcomes. Local side effects such as burning, stinging, and discomfort were assessed at every visit. Discontinuation of medication due to local side effects was the main indicator of intolerance. Serum CsA levels were assessed due to concern regarding possible systemic toxicity on consecutive patients who were on CsA 0.05% at higher than the usual twice daily dosing and who were willing to have a blood work-up. Patients were generally tested while they were on their maximum treatment dosing. Determination of serum levels was performed whenever the patients presented to the clinic for a follow-up of their clinical condition but not in any systematic way. In the patients who were on the treatment for only several weeks (n = 12), blood work-up was performed within 30 min after CsA instillation. Laboratory analyses were performed at a CLIA-certified commercial laboratory at the Johns Hopkins Hospital. A minimum of 100 mL of whole blood was drawn and analyzed using the Thermo Scientific TLX liquid chromatography system (Thermo Fisher Scientific, Inc., Waltham, MA) in conjunction with the Thermo Fisher TSQ Quantum Access mass spectrometer (Thermo Fisher Scientific, Inc.) to elute, analyze, and quantitate CsA levels. Values of CsA less than 7 ng/mL were reported as normal with a critical value of 100 ng/mL.
Results Table 1 summarizes demographic information and underlying ocular conditions of 41 consecutive patients included. The majority of patients (33/41, 80.4%) were adult females; one patient was younger than 21 years, a 17-year-old female, with chronic conjunctivitis. Fifteen patients had primary Sjogren’s syndrome and 18 had non-Sjogren’s related dry eye. Three patients had GvHD and 4 had atopic keratoconjunctivitis. Patients with underlying inflammatory systemic diseases were also being treated with various systemic medications, including methotrexate, mycophenolate, or hydroxychloroquine. However, patients who were on oral cyclosporine or tacrolimus were excluded from this study.
151
Table 1. Demographic Characteristics of Patients with Various Ocular Surface Diseases Who Were Treated with Frequent Dosing of Topical CsA 0.05% Emulsion Patient characteristic Gender Male Female Age (years) Range Mean Median Underlying condition Non-Sjogren’s related dry eye Thyroid eye disease Primary Sjogren’s syndrome Atopic keratoconjunctivitis Graft-versus-host disease Sarcoidosis
No. of patients (%) 8 (19.5) 33 (80.4) 17–73 58 60 18 8 15 4 3 1
(43.9) (19.5) (36.6) (9.8) (7.3) (2.4)
CsA, cyclosporine A.
All patients had severe ocular surface disease requiring escalation of treatment due to failure to improve while on CsA twice-a-day regimen. Table 2 summarizes the details of CsA therapy and concurrent topical ophthalmic medications. Frequency of dosing ranged from 3 to 8 times a day with an average of 4.84 times per day. Patients were treated using CsA at frequent dosing over 16 months. Eight patients were treated at 8· daily dosing for 9.3 months. Twenty patients were taking preservative-free artificial tears and 7 also used lubricating ointments. Eleven patients had either a prior punctal plug insertion or cauterization procedure. Fifteen patients were additionally treated with topical tacrolimus 0.03% ointment (Protopic; Astellas Pharma Tech, Toyama, Japan) applied externally on the lids twice a day. One patient was concurrently on treatment with 50% autologous serum tears 4 times a day. Six patients had been treated with topical steroid preparations before initiation of
Table 2. Details of the Treatment in Patients with Various Ocular Surface Diseases Who Were Treated with Frequent Dosing of Topical CsA 0.05% Emulsion Frequency of cyclosporine 0.05% use Range Mean Median Length of cyclosporine 0.05% use Range Mean Median Concurrent topical or local therapy Preservative-free artificial tears Punctal plugs or cauterization Topical steroids Over-the-counter ointment Tacrolimus 0.03% ointment Autologous serum Topical antihistamine/mast cell stabilizers
Times/day 3–8 4.8 4 Months 1–70 16.48 9 No. of patientsa 20 11 7 7 15 1 2
a Total is greater than 41 since some of the patients were on multiple treatments concurrently.
Downloaded by Gothenburg University Library from online.liebertpub.com at 09/18/17. For personal use only.
152
frequent dosing with CsA. Patients had to discontinue topical steroid treatment either for lack of response (n = 5) or because of an increase in intraocular pressure (n = 1). Two patients had never been offered steroid treatment due to a history of steroid use failure, a history of intraocular pressure rise from topical steroids, or hypersensitivity to the several steroid preparations. Seven patients were on topical steroids, as well as frequent CsA drops concurrently. Blood work-up to determine serum CsA levels was performed on an average at 3 months (range, 6 weeks to 6 months) into the treatment. In 12 patients, the plasma levels were measured within 30 min of the last dosing. Plasma levels of CsA were negligible (
