Page 1 of 9
`
`J Ophthalmic Vis Res. 2011 Jul; 6(3): 192–198.
`
`PMCID: PMC3306104
`
`Dry Eye Syndrome
`Mohammad-Ali Javadi, MD and Sepehr Feizi, MD
`
`Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
`Correspondence to: Mohammad-Ali Javadi, MD. Professor of Ophthalmology, Ophthalmic Research Center, #23 Paidarfard St., Boostan 9
`St., Pasdaran, Tehran 16666, Iran; Tel: +98 21 2258 5952, Fax: +98 21 2259 0607; e-mail:
`moc.oohay@idavaj_am
`
`Received 2011 May 22; Accepted 2011 Jun 8.
`
`Copyright notice
`
`This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
`distribution, and reproduction in any medium, provided the original work is properly cited.
`
`This article has been cited by other articles in PMC.
`
`Abstract
`Our understanding of keratoconjunctivitis sicca (KCS), also known as dry eye syndrome, has been
`changed over recent years. Until lately, the condition was thought to be merely due to aqueous tear
`insufficiency. Today, it is understood that KCS is a multifactorial disorder due to inflammation of the
`ocular surface and lacrimal gland, neurotrophic deficiency and meibomian gland dysfunction. This
`change in paradigm has led to the development of new and more effective medications.
`Keywords: Dry Eye Syndromes, Keratoconjunctivitis Sicca
`
`Go to:
`
`INTRODUCTION
`Dry eye is a disorder of the tear film which occurs due to tear deficiency or excessive tear evaporation;
`it causes damage to the interpalpebral ocular surface and is associated with a variety of symptoms
`1
`reflecting ocular discomfort. Dry eye syndrome, also known as keratoconjunctivitis sicca (KCS), is a
`common condition reported by patients who seek ophthalmologic care and is characterized by
`inflammation of the ocular surface and lacrimal glands.
`
`Go to:
`
`Dry eye symptoms may be a manifestation of a systemic disease, therefore timely detection may lead to
`recognition of a life–threatening condition. Additionally, patients with dry eye are prone to potentially
`2
`blinding infections, such as bacterial keratitis and also at an increased risk of complications following
`common procedures such as laser refractive surgery.
`
`Knowledge of the pathophysiology of dry eye has recently been improved and the condition is now
`understood to be a multifactorial disease, characterized by inflammation of the ocular surface and
`3
`reduction in tear production. This awareness has led to the development of highly effective therapies.
`
`EPIDEMIOLOGY
`Approximately 1 out of 7 individuals aged 65 to 84 years reports symptoms of dry eye often or all of
`4
`5
`the time. Moss et al reported the prevalence of dry eye to be 14.4% in 3,722 subjects aged 48 to 91
`4
`years and noted that the prevalence of the condition doubled after the age of 59. Schein et al , in
`contrast, found no correlation between dry eye and age or sex, while other researchers have reported
`
`Go to:
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/
`
`MYLAN - EXHIBIT 1075
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
`
`

`

`Page 2 of 9
`
`such associations to exist. A study on 926 subjects aged 40 years and older, found a higher prevalence
`6
`of dry eye in women who were also more likely to have a dry eye-related diagnosis or procedure.
`According to another study, women experienced a sharp increase in the prevalence of dry eye earlier
`7
`than men, around the age of 45, roughly at the onset of menopause.
`
`Epidemiological studies on dry eye syndrome suggest vast differences in prevalence. The difficulty in
`determining the extent of the disease stemmed in part from limited understanding of the
`pathophysiology of dry eye. As such, definitions of dry eye syndrome differed from one study to
`8
`another, making results difficult to compare. This is further complicated by the lack of a standardized
`clinical testing protocol to diagnose the condition.
`
`Go to:
`
`CLINICAL TYPES
`The precorneal tear film is an essential component of the ocular surface and can be subdivided into an
`anterior lipid layer, a middle aqueous layer and an innermost mucin layer. These layers are produced by
`2
`the meibomian glands, the lacrimal gland and goblet cells of the conjunctiva, respectively. The tear
`film lubricates the eye, maintains nutrition and oxygenation of ocular structures, acts as a refractive
`component and helps remove debris from the ocular surface. In terms of tear production, dry eye can be
`3
`divided into tear deficient and evaporative types. Tear deficiency dry eye can further be subdivided
`into non-Sjogren syndrome and Sjogren syndrome, which is an autoimmune disease associated with
`lacrimal and salivary gland lymphocytic infiltration. Evaporative dry eye can be divided into
`4,5
`meibomian gland disease (MGD) and exposure-related dry eye.
` In yet another group of patients,
`mucin deficiency due to Stevens-Johnson syndrome or ocular cicatricial pemphigoid is the underlying
`8
`mechanism of dry eye.
`
`Go to:
`
`ETIOLOGY
`Dry eye syndrome is associated with a long list of causes which can be divided into primary and
`secondary. Dry eye may develop secondary to inflammatory disease (e.g. vascular, allergic),
`environmental conditions (e.g. allergens, cigarette smoke, dry climate), hormonal imbalance (e.g.
`perimenopausal women and patients under hormone replacement therapy), and contact lens wear.
`Systemic disorders, such as diabetes mellitus, thyroid disease, rheumatoid arthritis and systemic lupus
`erythematosus can also lead to dry eye. In addition, neurotrophic deficiency, previous eye surgery (such
`as corneal transplantation, extracapsular cataract procedures and refractive surgery), or long-term use of
`medications which create hypersensitivity or toxicity in the eye can predispose to dry eye. Many
`systemic medications, such as diuretics, antihistamines, antidepressants, psychotropics, cholesterol
`9,10
`lowering agents, beta-blockers and oral contraceptives may also be associated with dry eye.
`
`Postmenopausal women may be the largest at risk group; this is due to a decrease in hormonal levels
`9
`leading to loss of anti-inflammatory protection and decreased lacrimal secretion.
`
`Go to:
`
`PATHOGENESIS
`Studies performed on the proteomic profile of the ocular surface comparing dry with normal eyes using
`enzyme-linked immunosorbent assay (ELISA) has revealed a decrease in lactoferrin and epidermal
`growth factor in dry eyes. A protein found in acinar cells of the lacrimal gland, AQP-5, was shown to
`be increased in the Sjogren type of dry eye syndrome, indicating possible leakage of such proteins into
`9
`10
`the tear film due to lymphocytic infiltration of the lacrimal gland. Solomon et al
` found an increase in
`inflammatory cytokines interleukin 1 (IL-1) alpha and IL-1 beta in both MGD and Sjogren syndrome,
`indicating increased protease activity on the ocular surface, mainly in the conjunctival epithelium.
`11
`Apart from IL-1, IL-6 was also increased in Sjogren syndrome,
` indicating an inflammatory process in
`this subgroup of dry eye. Another study investigating sialic acid, a component of mucin in tears, found
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/
`
`

`

`Page 3 of 9
`
`a lower level in dry eye patients compared to controls, indicating a change in quantity and quality of
`12
`tear film glycoproteins in dry eye disease.
` The change in tear protein profile in dry eye syndrome,
`especially in Sjogren disease, has shed light on mechanisms of dry eye.
`
`CLINICAL SYMPTOMS
`Symptoms associated with dry eye may include ocular burning, foreign body sensation, stinging
`9–12
`sensation, pain, photophobia and blurred vision.
`
`Go to:
`
`Go to:
`
`WORKUP
`As dry eye syndrome may be associated with a variety of causes, it is important to perform a
`comprehensive evaluation before proceeding to treatment. A careful history should be obtained with
`particular attention to diabetes, thyroid disease, connective tissue disorders and contact lens wear.
`Previous ocular procedures, such as laser refractive surgery are also important in determining the cause
`of dry eye syndrome. Many medications can affect tear secretion and it is important to review the
`patient’s drug history. A careful clinical examination should include slit lamp biomicroscopy to
`determine ocular surface status and diagnose associated meibomian gland dysfunction, blepharitis or
`meibomian seborrhoea. Examination of the tarsus and fornices for scars and symblepharon is important
`to exclude pre-existing Stevens-Johnson syndrome, other ocular surface inflammatory disease or
`previous infections. A careful look at the conjunctiva and cornea would be helpful to assess the severity
`of dry eye; an increase in staining is observed in more severe cases. Occasionally, corneal filaments and
`edema may be observed in extremely dry eyes. It is important to be thorough in the examination to find
`other areas of involvement. Certain systemic causes of dry eye, such as rheumatoid arthritis and
`systemic lupus erythematosus not only involve the ocular surface but also cause inflammation of the
`episclera or sclera, and occasionally the posterior segment.
`
`DIAGNOSTIC CRITERIA
`9
`Ohashi et al suggested that a combination of (1) dry eye symptoms, (2) suggestive findings on
`Schirmer (< 5 mm wetting after 5 minutes) and fluorescein clearance tests, and (3) fluorescein and Rose
`Bengal staining (> 3+) would verify clinical dry eye. Other authors have devised different diagnostic
`13–15
`criteria and there is no consensus in this regard.
` To further complicate the issue, symptoms and
`14
`signs do not always correlate well with each other in many patients.
`
`Go to:
`
`To confirm a diagnosis of dry eye, certain tests are required in the clinical setting. Tear film stability
`can be assessed with the fluorescein tear break-up time test (TBUT). This measures the interval in
`seconds between a complete blink and the first appearance of a dry spot or discontinuity in the
`precorneal film. Patients with TBUT less than 3 seconds are classified with clinical dry eye. If there is
`aqueous deficiency, the tear meniscus will appear to be thin, less than 1 mm in height. Another clinical
`method for assessing the severity of dry eye is ocular surface dye staining. Fluorescein and Rose Bengal
`stains can be used as diagnostic dyes. Fluorescein staining occurs when the epithelial barrier is
`disrupted and serves as a good test for evaluation of dry eye. Rose Bengal stains devitalized epithelial
`cells on the conjunctiva and serves a similar purpose. However, Rose Bengal causes transient irritation
`after instillation and may be less comfortable. Patients with dry eye syndrome can show signs of
`punctate epitheliopathy and even corneal abrasions.
`
`Another important clinical test is the Schirmer test which measures aqueous tear production. This test is
`easy to perform in clinical settings but may be subject to errors. Strips of filter paper, called Schirmer
`strips, are placed on the lower lid inside the tarsal conjunctiva. The patient is allowed to blink normally
`and the tear strip is scored according to the degree it wets in 5 minutes. There are two ways to perform
`this test: (a) without topical anesthesia (Schirmer test I) which evaluates the ability of the ocular surface
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/
`
`

`

`Page 4 of 9
`
`to respond to surface stimulation; and (b) under topical anesthesia (Schirmer test II) which evaluates
`basal tear secretion. Patients with tear soaking less than 10 mm are considered to have clinical dry eye
`and eyes with less than 5 mm wetting are diagnosed as severely dry. However, it is important to note
`that Schirmer tests are subject to environmental and physiologic changes with varying results over time.
`
`Go to:
`
`MANAGEMENT
`Management of dry eye depends on the cause and severity of the condition. Artificial tears are used to
`replenish the deficient aqueous layer of the tear film and to dilute inflammatory cytokines. Artificial
`tears are available in different viscosities and preserved or non-preserved preparations. If the tear
`deficiency is severe, more viscous agents such as gels or ointments can be used to maintain longer
`protection. Since KCS, including Sjogren syndrome, is associated with inflammation, the use of topical
`steroids or non-steroidal anti-inflammatory medications is sometimes helpful. Topical antibiotics may
`be necessary if the dry eye syndrome is associated with corneal complications. Meibomian gland
`disease warrants prescription of eyelid hygiene and warm lid compresses, together with topical or even
`13,14
`systemic antibiotics such as doxycycline.
`
`For more severe disease, topical immunomodulating agents, such as cyclosporine-A drops, may become
`necessary. Studies have demonstrated an improvement in signs and symptoms of dry eye, together with
`reduction in conjunctival T-cell infiltration and tear cytokine levels following the use of cyclosporine-A
`15,16
`drops.
`
`In very severe cases, frequent topical lubricants may not suffice. Studies have looked into the use of
`autologous serum as topical eye drops for severely dry eyes with improvement reported after prolonged
`treatment regimens ranging from 4 to 6 weeks. Growth factors provided by autologous serum are
`important for epithelial healing. Autologous serum can be prepared by centrifuging venous blood and
`17
`diluting it with balanced salt solution to 20%.
`
`Bandage contact lenses are sometimes useful in dry eyes to minimize the extent of exposure
`keratopathy. Severe dry eye disease with corneal complications may warrant surgical intervention such
`as punctal occlusion. Lacrimal puncta can be plugged temporarily with absorbable collagen plugs or for
`a longer period of time with non-absorbable plugs which need to be removed if problems arise.
`Permanent punctal occlusion can also be performed to prevent tears from draining through the drainage
`system. For patients with dry eye secondary to connective tissue disease, it is important to collaborate
`with internists and optimize treatment for the systemic disorders. In very severe dry eye secondary to
`ocular surface disease (such as chemical injury, Stevens-Johnson syndrome, or ocular cicatricial
`pemphigoid), amniotic membrane transplantation, tarsorrhaphy, keratoplasty, limbal stem cell
`transplantation, or even ocular prostheses, such as rigid scleral contact lenses, may become necessary
`18
`for restoration of vision.
`
`Anti-Inflammatory Therapy
`Before recent findings reframed our understanding of dry eye, treatment was limited to the use of
`artificial tears, ointments, and non-pharmacologic therapies, such as punctal occlusion, environmental
`control, moisture-retaining eyewear, and surgery. Each had limited efficacy and few resulted in long-
`lasting improvement in patients’ quality of life. Today, dry eye can be treated successfully with anti-
`inflammatory agents, the most beneficial of which is topical cyclosporine. Clinical evidence indicates
`that anti-inflammatory therapy inhibits the production of inflammatory mediators and reduces the signs
`and symptoms of KCS.
`
`Corticosteroids are potent anti-inflammatory agents routinely used to control
`Corticosteroids
`inflammation in various organs. Corticosteroids have multiple mechanisms of action. They work
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/
`
`

`

`Page 5 of 9
`
`through traditional glucocorticoid receptor mediated pathways which directly regulate gene expression
`and also by non-receptor pathways that interfere with transcriptional regulators of pro-inflammatory
`genes. Among their multiple biological activities, corticosteroids inhibit the production of inflammatory
`cytokines and chemokines, decrease the synthesis of matrix metalloproteinases and lipid mediators of
`inflammation (e.g. prostaglandins), reduce the expression of cell adhesion molecules (e.g. intercellular
`19–21
`adhesion molecule 1), and stimulate lymphocyte apoptosis.
` Steroids have been reported to decrease
`the production of a number of inflammatory cytokines, including IL-1, IL-6, IL-8, tumor necrosis
`factor-alpha (TNF-α), and granulocyte macrophage colony-stimulating factor (GM-CSF), and matrix
`22
`metalloproteinase 9 (MMP-9) by the corneal epithelium.
` Corticosteroids have been successfully used
`23–25
`for treatment of corneal epithelial disease due to dry eye in several clinical studies.
`
`Cyclosporine A (CsA) is a lipophilic cyclic undecapeptide isolated from the fungus
`Cyclosporine
`26
`Hypocladium inflatum gams.
` It was first introduced for clinical use as an immune-suppressant drug
`for prevention of organ transplant rejection in 1983. The immuno modulatory effect of this agent has
`been proven to be beneficial for treatment of a broad range of disorders such as psoriasis, rheumatoid
`arthritis and ulcerative colitis which have an underlying inflammatory basis. One of its mechanisms of
`action is inhibition of calcineurin, a serine/threonine phosphatase, with subsequent reduction in the
`expression of certain genes involved in T-cell activation such as IL-2, IL-4, IL-12.
`
`The potential of CsA for treating dry eye disease has been demonstrated in several randomized double-
`27–29
`masked clinical trials.
`
`The tetracyclines have anti-inflammatory, as well as antibacterial,
`Tetracyclines and their Derivatives
`properties that may make them useful for management of chronic inflammatory diseases. These agents
`decrease the activity of collagenase, phospholipase A , and several matrix metalloproteinases. They
`2
`also decrease the production of IL-1α and TNF-α in a wide range of tissues, including the corneal
`30–32
`epithelium.
` At high concentrations, tetracyclines inhibit staphylococcal exotoxin-induced cytokines
`33,34
`and chemokines.
` Tetracyclines are also known to inhibit matrix metalloproteinase expression,
`35
`suggesting a rationale for their use in ocular rosacea.
` They can also inhibit angiogenesis, which may
`develop in rosacea.
`
`Doxycycline was discovered in the early 1960s. It is a semisynthetic long-acting tetracycline derivative
`which inhibits bacterial ribosomes in a wide variety of micro-organisms. In subantimicrobial doses it is
`36,37
`also effective as primary treatment for rosacea and sterile corneal ulceration.
` Previous studies using
`experimental dry eye models demonstrated that doxycycline was efficacious in decreasing gelatinolytic
`activity in the ocular surface epithelia, as well as decreasing levels of MMP-9 mRNA transcripts, and
`38
`preventing experimental dry eye-induced increase in IL-1 and TNF-α.
` Doxycycline also improves
`39
`corneal surface regularity and barrier function.
`
`Essential fatty acids are necessary for health. They cannot be synthesized by
`Essential Fatty Acids
`vertebrates and must be obtained from dietary sources. Among the essential fatty acids are the 18
`carbon omega-6 and omega-3 fatty acids. In a typical western diet, omega-6 fatty acids are consumed
`20 to 25 times more than omega-3 fatty acids. Omega-6 fatty acids are precursors of arachidonic acid
`and certain pro-inflammatory lipid mediators such as prostaglandin E and leukotriene B . In contrast,
`2
`4
`certain omega-3 fatty acids, such as eicosapentaenoic acid found in fish oil, inhibit synthesis of these
`40,41
`lipid mediators and also block the production of IL-1 and TNF-α.
` A beneficial clinical effect from
`fish oil omega-3 fatty acids on rheumatoid arthritis has been observed in several double-masked
`42,43
`placebo-controlled clinical trials.
` In a prospective placebo-controlled clinical trial, linoleic acid and
`gamma-linoleic acid administered orally twice a day led to significant improvement in ocular irritation
`symptoms, and a reduction in ocular surface lissamine green staining conjunctival HLA-DR
`44
`reactivity.
` In an animal model of induced dry eye, topical treatment with alpha-linolenic acid
`significantly decreased corneal fluorescein staining as compared to both vehicle and untreated controls,
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/
`
`

`

`Page 6 of 9
`
`decreased CD11b(+) cells and reduced the expression of corneal IL-1α and TNF-α, and conjunctival
`45
`TNF-α.
`
`Go to:
`
`CONCLUSIONS
`Dry eye syndrome consists of a wide spectrum of disorders with different causes. Clinicians should be
`aware of the extent of dry eye symptoms. A thorough history and investigation is necessary to identify
`the cause of dry eye. Useful clinical tests for assessing the severity of the condition include Schirmer,
`fluorescein dye, and tear break up time tests. Management depends on an accurate diagnosis and the
`severity of the condition. Treatments that replenish deficient tears include artificial tears, gels and
`ointments in mild to moderate disease. Other treatment modalities such as topical steroids,
`immunomodulating drugs, antibiotics, bandage contact lenses, autologous serum and amniotic
`membrane transplantation may be used in more severe cases. In severely dry eyes, surgical intervention
`such as punctal occlusion can be employed to minimize tear drainage. Certain conjunctival and lid
`operations can also be performed to treat specific causes.
`
`Footnotes
`Conflicts of Interest
`None.
`
`Go to:
`
`REFERENCES
`1. Lemp MA. Report of the National Eye Institute/Industry workshop on Clinical Trials in Dry Eyes.
`CLAO J. 1995;21:221–232. [PubMed]
`
`Go to:
`
`2. Lemp MA, Chacko B. Diagnosis and treatment of tear deficiencies. In: Tasman W, Jaeger E, editors.
`Duane’s Clinical Ophthalmology. Philadelphia: Harper and Row; 1997.
`
`3. Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC. The pathology of dry eye:
`the interaction between the ocular surface and lacrimal glands. Cornea. 1998;17:584–589. [PubMed]
`
`4. Schein OD, Muñoz B, Tielsch JM, Bandeen-Roche K, West S. Prevalence of dry eye among the
`elderly. Am J Ophthalmol. 1997;124:723–728. [PubMed]
`
`5. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol.
`2000;118:1264–1268. [PubMed]
`
`6. McCarty CA, Bansal AK, Livingston PM, Stanislavsky YL, Taylor HR. The epidemiology of dry eye
`in Melbourne, Australia. Ophthalmology. 1998;105:1114–1119. [PubMed]
`
`7. Yazdani C, McLaughlin T, Smeeding JE, Walt J. Prevalence of treated dry eye disease in a managed
`care population. Clin Ther. 2001;23:1672–1682. [PubMed]
`
`8. Brewitt H, Sistani F. Dry eye disease: the scale of the problem. Surv Ophthalmol. 2001;45:S199
`–S202. [PubMed]
`
`9. Ohashi Y, Ishida R, Kojima T, Goto E, Matsumoto Y, Watanabe K, et al. Abnormal protein profiles
`in tears with dry eye syndrome. Am J Ophthalmol. 2003;136:291–299. [PubMed]
`
`10. Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC. Pro- and anti-inflammatory forms of
`interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis
`Sci. 2001;42:2283–2292. [PubMed]
`
`11. Tishler M, Yaron I, Geyer O, Shirazi I, Naftaliev E, Yaron M. Elevated tear interleukin-6 levels in
`patients with Sjögren syndrome. Ophthalmology. 1998;105:2327–2329. [PubMed]
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/
`
`

`

`Page 7 of 9
`
`12. Jones DT, Monroy D, Ji Z, Atherton SS, Pflugfelder SC. Sjögren’s syndrome: cytokine and Epstein-
`Barr viral gene expression within the conjunctival epithelium. Invest Ophthalmol Vis Sci.
`1994;35:3493–3504. [PubMed]
`
`13. Latkany R. Dry eyes: etiology and management. Curr Opin Ophthalmol. 2008;19:287–291.
`[PubMed]
`
`14. Tuft S, Lakhani S. Medical management of dry eye disease. Dev Ophthalmol. 2008;41:54–74.
`[PubMed]
`
`15. Kymionis GD, Bouzoukis DI, Diakonis VF, Siganos C. Treatment of chronic dry eye: focus on
`cyclosporine. Clin Ophthalmol. 2008;2:829–836. [PMC free article] [PubMed]
`
`16. Jap A, Chee SP. Immunosuppressive therapy for ocular diseases. Curr Opin Ophthalmol.
`2008;19:535–540. [PubMed]
`
`17. Kojima T, Higuchi A, Goto E, Matsumoto Y, Dogru M, Tsubota K. Autologous serum eye drops
`for the treatment of dry eye diseases. Cornea. 2008;27:S25–S30. [PubMed]
`
`18. Geerling G, Brewitt H. Flow chart on surgical approaches to dry eye. Dev Ophthalmol. 2008;41:313
`–316. [PubMed]
`
`19. Dursun D, Kim MC, Solomon A, Pflugfelder SC. Treatment of recalcitrant recurrent corneal
`erosions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids. Am J
`Ophthalmol. 2001;132:8–13. [PubMed]
`
`20. Liden J, Rafter I, Truss M, Gustafsson JA, Okret S. Glucocorticoid effects on NF-kappaB binding
`in the transcription of the ICAM-1 gene. Biochem Biophys Res Commun. 2000;273:1008–1014.
`[PubMed]
`
`21. Aksoy MO, Li X, Borenstein M, Yi Y, Kelsen SG. Effects of topical corticosteroids on
`inflammatory mediator-induced eicosanoid release by human airway epithelial cells. J Allergy Clin
`Immunol. 1999;103:1081–1091. [PubMed]
`
`22. Djalilian AR, Nagineni CN, Mahesh SP, Smith JA, Nussenblatt RB, Hooks JJ. Inhibition of
`inflammatory cytokine production in human corneal cells by dexamethasone, but not cyclosporin.
`Cornea. 2006;25:709–714. [PubMed]
`
`23. Pflugfelder SC, Maskin SL, Anderson B, Chodosh J, Holland EJ, De Paiva CS, et al. A randomized,
`double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic
`suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear
`clearance. Am J Ophthalmol. 2004;138:444–457. [PubMed]
`
`24. Marsh P, Pflugfelder SC. Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis
`sicca in Sjögren syndrome. Ophthalmology. 1999;106:811–816. [PubMed]
`
`25. Wachtel M, Frei K, Ehler E, Fontana A, Winterhalter K, Gloor SM. Occludin proteolysis and
`increased permeability in endothelial cells through tyrosine phosphatase inhibition. J Cell Sci.
`1999;112:4347–4356. [PubMed]
`
`26. Matsuda S, Koyasu S. Mechanisms of action of cyclosporine. Immunopharmacology. 2000;47:119
`–125. [PubMed]
`
`27. Gündüz K, Ozdemir O. Topical cyclosporin treatment of keratoconjunctivitis sicca in secondary
`Sjögren’s syndrome. Acta Ophthalmol (Copenh) 1994;72:438–442. [PubMed]
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/
`
`

`

`Page 8 of 9
`
`28. Laibovitz RA, Solch S, Andriano K, O’Connell M, Silverman MH. Pilot trial of cyclosporine 1%
`ophthalmic ointment in the treatment of keratoconjunctivitis sicca. Cornea. 1993;12:315–323.
`[PubMed]
`
`29. Stevenson D, Tauber J, Reis BL. Efficacy and safety of cyclosporin A ophthalmic emulsion in the
`treatment of moderate-to-severe dry eye disease: a dose-ranging, randomized trial. The Cyclosporin A
`Phase 2 Study Group. Ophthalmology. 2000;107:967–974. [PubMed]
`
`30. Solomon A, Rosenblatt M, Li DQ, Liu Z, Monroy D, Ji Z, et al. Doxycycline inhibition of
`interleukin-1 in the corneal epithelium. Invest Ophthalmol Vis Sci. 2000;41:2544–2557. [PubMed]
`
`31. Li DQ, Luo L, Chen Z, Kim HS, Song XJ, Pflugfelder SC. JNK and ERK MAP kinases mediate
`induction of IL-1beta, TNF-alpha and IL-8 following hyperosmolar stress in human limbal epithelial
`cells. Exp Eye Res. 2006;82:588–596. [PMC free article] [PubMed]
`
`32. Li Y, Kuang K, Yerxa B, Wen Q, Rosskothen H, Fischbarg J. Rabbit conjunctival epithelium
`transports fluid, and P2Y2(2) receptor agonists stimulate Cl(−) and fluid secretion. Am J Physiol Cell
`Physiol. 2001;281:C595–C602. [PubMed]
`
`33. Krakauer T, Buckley M. Doxycycline is anti-inflammatory and inhibits staphylococcal exotoxin-
`induced cytokines and chemokines. Antimicrob Agents Chemother. 2003;47:3630–3633.
`[PMC free article] [PubMed]
`
`34. Voils SA, Evans ME, Lane MT, Schosser RH, Rapp RP. Use of macrolides and tetracyclines for
`chronic inflammatory diseases. Ann Pharmacother. 2005;39:86–94. [PubMed]
`
`35. Stone DU, Chodosh J. Oral tetracyclines for ocular rosacea: an evidence-based review of the
`literature. Cornea. 2004;23:106–109. [PubMed]
`
`36. Akpek EK, Merchant A, Pinar V, Foster CS. Ocular rosacea: patient characteristics and follow-up.
`Ophthalmology. 1997;104:1863–1867. [PubMed]
`
`37. Seedor JA, Perry HD, McNamara TF, Golub LM, Buxton DF, Guthrie DS. Systemic tetracycline
`treatment of alkali-induced corneal ulceration in rabbits. Arch Ophthalmol. 1987;105:268–271.
`[PubMed]
`
`38. De Paiva CS, Corrales RM, Villarreal AL, Farley WJ, Li DQ, Stern ME, et al. Corticosteroid and
`doxycycline suppress MMP-9 and inflammatory cytokine expression, MAPK activation in the corneal
`epithelium in experimental dry eye. Exp Eye Res. 2006;83:526–535. [PubMed]
`
`39. De Paiva CS, Corrales RM, Villarreal AL, Farley W, Li DQ, Stern ME, et al. Apical corneal barrier
`disruption in experimental murine dry eye is abrogated by methylprednisolone and doxycycline. Invest
`Ophthalmol Vis Sci. 2006;47:2847–2856. [PubMed]
`
`40. James MJ, Gibson RA, Cleland LG. Dietary polyunsaturated fatty acids and inflammatory mediator
`production. Am J Clin Nutr. 2000;71:343S–348S. [PubMed]
`
`41. Endres S, Ghorbani R, Kelley VE, Georgilis K, Lonnemann G, van der Meer JW, et al. The effect
`of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and
`tumor necrosis factor by mononuclear cells. N Engl J Med. 1989;320:265–271. [PubMed]
`
`42. James MJ, Cleland LG. Dietary n-3 fatty acids and therapy for rheumatoid arthritis. Semin Arthritis
`Rheum. 1997;27:85–97. [PubMed]
`
`43. Kremer JM. n-3 fatty acid supplements in rheumatoid arthritis. Am J Clin Nutr. 2000;71:349S
`–351S. [PubMed]
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/
`
`

`

`Page 9 of 9
`
`44. Barabino S, Rolando M, Camicione P, Ravera G, Zanardi S, Giuffrida S, et al. Systemic linoleic and
`gamma-linolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea.
`2003;22:97–101. [PubMed]
`
`45. Rashid S, Jin Y, Ecoiffier T, Barabino S, Schaumberg DA, Dana MR. Topical omega-3 and
`omega-6 fatty acids for treatment of dry eye. Arch Ophthalmol. 2008;126:219–225. [PubMed]
`
`Articles from Journal of Ophthalmic & Vision Research are provided here courtesy of Medknow Publications
`
`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3306104/
`
`