Cyclosporine in Dry Eye: A Review
Gupta S1
1Dr Suruchi Gupta, MS., Associate consultant, Centre for Sight, Jammu, J
& K, India
Address for
Correspondence: Suruchi Gupta, Associate Consultant,
Centre for Sight, Jammu, J & K, India Email:
gupta∙suruchi1@yahoocom
Abstract
Dry eye syndrome (DES) is a multifactorial diseases with varying
prevalence affecting great chunk of population worldwide. Various
environmental, nutritional, hormonal and external factors altering the
functional integrity of the ocular surface components have been
implicated. The imbalance results in changes in epithelium causing
desiccation and setting up an inflammatory cascade which causes
dysregulation of the ocular surface regeneration system. With
increasing knowledge of the etiology and mechanisms involved in the
development of dry eye, role of cyclosporine A has been well
established with numerous clinical studies. This has led to the US Food
and Drug Administration (FDA) approval of the drug for the treatment of
dry eye. This article reviews the pathology of development of dry eye,
pharmacology of cyclosporine, use of cyclosporine A in dry eye
established via various animal and clinical studies.
Key words:
Cyclosporine, Dry Eye, Keratoconjunctivitis Sicca, Sjogren’s
Syndrome
Introduction
Dry eye has been designated as dry eye syndrome (DES). It is a
multifactorial disease of the ocular surface. It is associated with
either increased evaporation of tear film or decrease in the production
of the tears by the meibomian glands. It can result in various ocular
symptoms like discomfort in the form of burning sensation, itching,
redness, stinging, pain and foreign body sensation etc. visual
disturbances and tear film instability. All these things can cause
potential damage to the ocular surface [1]. Various diagnostic tests
are available for confirming the dry eye, however it's mostly a
clinical diagnosis [2]. Tests like schirmer’s test are used
to measure the amount of tears produced. There has been varied reports
on prevalence of dry eyes among populations. In a study on American
population, prevalence was found to be 3.9% in men aging 50-54 years,
up to 7.7% in men aging 80 years or more [3]. In female population, it
was reported to be 5.7% in females less than 50 years and 9.8% in
females aged 75 years or older [4]. DEWS study has provided with an
estimated range of 14% among individuals aging from 65-85 years [5]. In
a study conducted on Indian population, dry eye prevalence was 36.1% in
population above 70 years of age and more in females (22.8%) [6].
Various risk factors associated with dry eye are increasing age [7, 8],
female sex, post menopausal estrogen therapy, connective tissue
diseases, corneal surface procedures like LASIK [9]. Various
environmental factors like contact lens use, low-humidity environments,
air conditioners, high altitudes, more of computer or television use,
medications like antidepressants, anti hypertensive etc. have also been
implicated in aggravating dry eye disease [10-12].
Dry eye can cause a great economic burden by affecting the quality of
life of the individuals suffering from it [13]. This can even cause
negative effects on patients mental state resulting in anxiety or
depression [14]. In a study, it was found that dry eye disease affects
the patient’s ability to perform daily activities [15].
Treatment options for dry eye disease depend upon the severity of the
disease. They can be in the form of environmental modifications or
various medications. Environmental modifications like avoiding air
conditioners etc. to prevent evaporation of tears or stopping
medications that prevent production of tears are useful [16]. Most
common medication used to treat dry eye syndrome is artificial tears or
ocular lubricants. Nowadays nutritional supplementation with omega-3
fatty acids have been implicated [17]. Recent knowledge of the role of
inflammatory molecules like TNF alpha in the pathogenesis of dry eye
has implicated the use of anti-inflammatory molecules like
corticosteroids and cyclosporine [18]. Surgical treatment in the form
of lid surgery, tarsorhaphy or mucus membrane, salivary gland, or
amniotic membrane transplantation might be needed in severe and chronic
dry eye cases [16].
Cyclosporine:
It belongs to immunosuppressant group of drugs. It was first isolated
from a fungus Tolypocladium inflatum. This group of drugs act by
lowering the activity of inflammatory cells i.e. T-cells, thereby
suppressing the immune response generated by these cells. This property
made cyclosporine as the drug available to prevent graft rejection in
transplant patients. Disturbance in various factors like age, hormonal
status, innervation status, immune status, nutrition, pathogens and
environmental stress can disturb the homeostasis in the eye [19]. These
disturbances produce an imbalance between degradation and production of
the various components of the tear film. This causes release of
inflammatory mediators producing a vicious cycle. This warrants the use
of anti inflammatory compounds in dry eye. This anti-inflammatory role
of the cyclosporine founds application in conditions like psoriasis,
rheumatoid arthritis, ulcerative colitis as well as ocular
inflammations [20, 21].
Mechanism of action of cyclosporine: Cyclosporine has chemical formula
of C62H111N11O12 with molecular weight of 120.26 g∕mol. It is a
non-ribosomal peptide that contains one D-amino acid. Its structure is
very rigid because of the hydrogen bonding associated with the cyclic
structure. Cyclosporine has low water solubility with variable
absorption at the cellular level [22].
It belongs the group of Calcineurin inhibitors. It binds to
cyclophillins (lymphocytes) and this complex in turn inhibits
calcineurin, thus, preventing the formation of interleukin-2.
Cyclosporine is a potent inhibitor of T-cell proliferation and thus,
inhibits T-cell mediated immune responses. It might also prevent
mitochondrial permeability transition pore opening [23].
The cyclosporine emulsion has been shown to be an effective therapeutic
agent to treat moderate to severe dry eye disease in various clinical
trials leading to the US Food and Drug Administration (FDA) approval of
the drug in 2003. The exact mechanism of enhanced tear production is
not well delineated, but it is hypothesized that it may be related to
immunmodulatory activity which reduces local inflammation [24].
Results of animal studies: In a study conducted on rabbits with induced
autoimmune dacryoadenitis, it was proved that topical use of
cyclosporine A improved tear production [25]. In another study
conducted on dogs with bilateral keratoconjunctivitis sicca (KCS) the
topical use of cyclosporine A resolved clinical signs of KCS, improved
schirmer's tear test scores and restored normal conjunctival histology
[26].
Adverse effects: Renal toxicity is the main adverse effect observed
with the systemic use of cyclosporine. Neurotoxicity is enhanced if use
along with sirolimus [27]. It is also observed to enhance neoplasm and
can cause neurotoxicity, hypertension, hyperlipidemia and
nephrotoxicity [28].
Ophthalmic uses: Most common clinical ophthalmic use of cyclosporine is
to enhance tear production especially in conditions associated with
ocular inflammation. Topical use is associated with less systemic
adverse effects due to negligible systemic absorption [29]. Earlier
formulations available in oil based vehicles had various adverse
affects. Now an 0.05% aqueous based formulation is available [30]. The
main ocular adverse effects observed are redness, burning sensation and
itching. In a study, 64% of the patients treated with cyclosporine were
free of the adverse events [31]. In another study, it was observed that
even prolonged use of topical cyclosporine for 12 months in patients
with dry eye did not cause substantial changes in corneal endothelium
[32].
Efficacy in dry eye: Various clinical studies have been conducted on
use of 0.05% preparation of cyclosporine in dry eye. In one of the
study conducted on patients with moderate to severe dry eye, it was
observed that most of the patients (72%) were relieved of the symptoms.
Ocular symptoms as well as the schirmer's test scores were improved.
However, adverse effects observed in this study were only ocular
irritation and pain [33].
Role of cyclosporine has been studied even in secondary dry eye states.
In a study conducted in patients with Stevens-Johnson syndrome
significant improvement was observed in dry-eye symptoms, conjunctival
injection, corneal staining, Schirmer I test and fluorescein clearance
test [34].
In another study conducted on patients suffering from dry eye secondary
to ocular graft versus host disease or Sjogren’s syndrome it
was observed that dry eye symptoms were improved in 68.2% whereas
physicians assessment of dry eye improved in 72.7% of the patients
[35]. Efficacy of dry eye in Sjogren’s syndrome was evaluated
in a comparative trial with the observation that the symptoms as well
as the diagnostic parameters were improved after treatment with
cyclosporine [36].
Role of topical cyclosporine therapy has also been implicated in dry
eye states secondary to contact lens wear or ocular surgeries like
cataract surgery or refractive surgery. In a study conducted on dry eye
induced in contact lens wearers, it was observed that topical use of
cyclosporine emulsion 0.05% has positive effect on morphofunctional
parameters of ocular surface and promotes basal tear secretion and
precorneal tear film stability.37 Efficacy of topical cyclosporine has
also been studied in post cataract dry eye. In one study, it was
observed that cyclosporine use in post cataract surgery patients
improved the dry eye symptoms as well as tear film break up time three
months after surgery [38]. Another study proved that topical
cyclosporine A treatment is effective therapy for optimizing patients
for refractive surgery and treatment of new onset or worsened after
refractive surgery [39]. Also, topical use of cyclosporine A has been
proven to be effective in treatment of dry eye, especially for dry eye
states associated with conjunctival injury [40].
Even benefit of topical cyclosporine A therapy was established in dry
eye patients who had discontinued the therapy earlier with repeated
treatment after 3 months for a duration of three months. 80% of the
patients were observed to have clinical benefit from the second course
of treatment [41].
Conclusion
Cyclosporine A 0.05% is the only FDA approved therapy for the treatment
of dry eye syndrome. Most of the studies have shown consistent positive
effects in treatment of DES with cyclosporine A. As topical use is
associated with very few adverse effects, especially with aqueous
preparation of cyclosporine as compared to the systemic use, topical
therapy has gained widespread use in various dry eye states.
Seeing the positive effects of cyclosporine therapy in DES improving
the quality of life of the sufferers, cyclosporine therapy can have
great impact in decreasing the economic and social burden created due
to this disease state.
Funding:
Nil, Conflict of
interest: None initiated.
Permission
from IRB:
Yes
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How to cite this article?
Gupta S. Cyclosporine in Dry Eye: A Review. Int J Med Res
Rev 2015;3(9):1037-1041. doi: 10.17511/ijmrr.2015.i9.190.