Advancements in anti-inflammatory therapy for dry eye syndrome

Transcription

1 Optometry (2009) 80, Advancements in anti-inflammatory therapy for dry eye syndrome Erin McCabe, O.D., and Srihari Narayanan, O.D., Ph.D. Pennsylvania College of Optometry at Salus University, Elkins Park, Pennsylvania. KEYWORDS Inflammation; Cytokines; Therapeutics; Corticosteroids; Immunomodulation; Fatty acids; Androgens; Oral antibiotics Abstract PURPOSE: The goal of this literature review is to discuss recent discoveries in the pathophysiology of dry eye and the subsequent evolution of diagnostic and management techniques. The mechanisms of various anti-inflammatory treatments are reviewed, and the efficacy of common pharmacologic agents is assessed. Anti-inflammatory therapy is evaluated in terms of its primary indications, target population, and utility within a clinical setting. METHODS: The Medline PubMed database and the World Wide Web were searched for current information regarding dry eye prevalence, pathogenesis, diagnosis, and management. After an analysis of the literature, major concepts were integrated to generate an updated portrayal of the status of dry eye syndrome. RESULTS: Inflammation appears to play a key role in perpetuating and sustaining dry eye. Discoveries of inflammatory markers found within the corneal and conjunctival epithelium of dry eye patients have triggered recent advancements in therapy. Pharmacologic anti-inflammatory therapy for dry eye includes 2 major categories: corticosteroids and immunomodulatory agents. Fatty acid and androgen supplementation and oral antibiotics have also shown promise in dry eye therapy because of their anti-inflammatory effects. CONCLUSIONS: Anti-inflammatory pharmacologic agents have shown great success in patients with moderate to severe dry eye when compared with alternative treatment modalities. A deeper understanding of the link between inflammation and dry eye validates the utilization of anti-inflammatory therapy in everyday optometric practice. Optometry 2009;80: A PubMed query containing the short term, dry eye, returns well over 2,000 research articles dating back to 1952, and the numbers only continue to climb. Dry eye syndrome (DES) is essentially the common cold of the optometric and ophthalmologic fields. The syndrome affects millions of people around the world. Despite abundant research, a panacea for the average case of dry eye ceases to surface. Dry eye is the shared manifestation Corresponding author: Srihari Narayanan, O.D., Ph.D., Pennsylvania College of Optometry at Salus University, 8360 Old York Road, Elkins Park, Pennsylvania srihari@salus.edu of numerous and varied causes. Because many perpetrators may be operating simultaneously to elicit the symptomatology of dry eye, it often is unrealistic to definitively pinpoint a single cause for DES. Within the last decade, advancements in the understanding of the pathophysiology of DES have underscored inflammation as a common thread linking most presenting cases of dry eye. Inflammation often plays a key role in propagating and sustaining the disorder, regardless of the cause of the ocular surface disease. These discoveries have triggered the development of a new line of successful anti-inflammatory treatments. It remains to be determined whether anti-inflammatory therapy will become a forerunner in the clinical management of /09/$ -see front matter Ó 2009 American Optometric Association. All rights reserved. doi: /j.optm

2 556 Optometry, Vol 80, No 10, October 2009 DES. The purpose of reviewing anti-inflammatory therapy as a contemporary treatment modality of DES is 3-fold: 1) to highlight the latest findings in the pathophysiology of dry eye and uncover the evidence supporting the use of antiinflammatory therapy in the treatment for dry eye, 2) to examine the pharmacology and the efficacy of anti-inflammatory agents indicated for DES, and 3) to assess clinical utilization of anti-inflammatory therapy and to evaluate which subpopulations of dry eye patients will theoretically benefit the most. Prevalence and incidence A general definition for dry eye characterizes the syndrome as a tear film abnormality caused by tear deficiency or excessive tear evaporation, which often causes ocular surface damage and ocular irritation. 1 DES covers a wide range of ocular surface disturbances and affects a broad spectrum of patients. Women and the elderly seem to be the most frequent target of dry eye disease. A recent cross-sectional prevalence survey found that 5.7% of women younger than 50 years old and 9.8% of women older than 75 years reported clinically diagnosed DES or severe dry eye symptoms. 2 DES, therefore, afflicts around 3.2 million middle-age to older American women. Another study found that incidence in male and female patients age 43 to 84 years reached 13.3% over a 5-year period and correlated significantly with age. 3 Besides gender and age, other factors associated with increased incidence and prevalence of dry eye include a history of diabetes, allergies, and the use of certain medications. 2,4,5 Dry eye and the use of artificial tears in diabetics over the age of 50 were significantly higher when compared with that in nondiabetics. 6 The relationship held after being controlled for age, sex, and place of residence. Frequency of ocular lubricant use was directly proportional to increases in hemoglobin A1c levels. Because both the elderly and diabetic populations in the United States are growing, the prevalence of dry eye can be expected to climb even higher. The high prevalence of DES is reflected in the economy. 7 Pharmacologic and surgical management of DES drives costs the most, but other factors such as office visits, diagnostic tests, complementary and alternative treatment, and decreased patient productivity have economic implications as well. From the patient s perspective, DES decreases vitality, increases bodily pain, and imparts physical constraints as measured by the SF-36 general health questionnaire, and these factors likely impact workplace efficiency. 8 As management of DES makes use of more complex pharmaceuticals, costs will continue to escalate. Evolution of dry eye management The ubiquitous nature of DES, along with its economic burdens and its deleterious effects on patient quality of life, necessitates more efficient and effective treatment strategies. Palliative therapies, namely artificial tears or rewetting agents, are currently the most common choice of treatment but have failed to yield high success rates. Albietz and Bruce 9 concluded that preserved topical tear replacements increased expression of conjunctival inflammatory markers and reduced goblet cell density in patients with DES. They also showed that treatment with nonpreserved rewetting agents did not decrease the levels of inflammatory markers as well as did not increase goblet cell density in DES. 9 Likewise, an 8-year prospective study examining a broad range of dry eye patients treated with tear substitutes found that although symptoms and lubricant use diminished over time, alterations in conjunctival morphology attributed to dry eye persisted. 10 Aims to improve rewetting agent formulations focus mainly on viscosity and composition. 11 The viscosity of tear replacements influences duration of action, but longer-lasting, higher-viscosity formulas can temporarily disturb vision after instillation. Although ocular surface lubricating ointments may provide relief from ocular irritation symptoms for several hours, their effect on vision precludes them from being used in the waking hours. Some tear substitutes attempt to mimic natural tear composition by containing lipid, aqueous, and mucin components. Despite these attempts, rewetting agents fail to yield the same benefits as natural tears because of the complexity of the composition and dynamics of the tear film. Some evidence exists that rewetting agents containing sodium hyaluronate might improve a dry eye condition. One small study 12 done several years ago found that nonpreserved 0.1% sodium hyaluronate eye drops improved tear breakup time in 10 dry eye patients. In another study, 13 sodium hyaluronate eye drops did not improve subjective symptoms in 104 dry eye patients, whereas it did improve fluorescein staining scores in these patients. This was followed by several other recent studies that showed that hyaluronate eye drops were useful in improving subjective symptoms as well as the ocular health of dry eye patients, treating lipid tear-deficient patients, 17 and treating Sjogren s syndrome patients. 18 Sodium hyaluronate also seemed to have protective effects on the corneal epithelium. 19 Although preservative-free rewetting agents decrease corneal toxicity, single dosing and cost limit their clinical use, so that less toxic preservative-containing versions are more commonly prescribed. 20 For similar reasons (singledosing and cost), autologous serum eye drops have not become maintstream in the treatment of dry eye. Autologous serum drops, derived from blood serum, provide essential naturally nonallergenic nutrients, such as growth factors, fibronectin, and vitamin A, to the tears. Although these eye drops have been shown to improve ocular inflammation and symptoms of ocular surface disorders, more research with larger study populations is needed to establish the risks, standards, and indications for autologous eye drop treatment. 21 Furthermore, because of the high costs of production, this treatment is unlikely to become widespread in the treatment of mild to moderate dry eye. Although

3 McCabe and Narayanan Issue Highlight 557 autologous serum eye drops have shown superior efficacy in treating severe dry eye when compared with conventional rewetting agents, the ease of use and low cost of conventional therapy likely contribute to its long-standing popularity. 22 Rewetting agents attempt to replace tear volume. Other palliative treatments for DES, such as moisture aid treatments, strive to reduce tear evaporation. Wet gauze eye masks and humidifying goggles, for example, can effectively treat dry eye by increasing periocular humidity, but feasibility and patient compliance with these techniques is low. 7,20 Eye care providers often reserve nonpharmacologic punctal occlusion for patients with moderate to severe DES. Punctal plugs block nasolacrimal drainage to increase moisture at the ocular surface. The majority of patients who undergo punctal occlusion report symptomatic improvements, but cost of the procedure is high, and followup care because of poor plug retention and possible infection is required. 7,23 Punctal occlusion remains an option for patients who are noncompliant with pharmacologic agents or tear substitutes, but this management technique still fails to address the underlying cause of dry eye. Interestingly, it has been suggested that punctal occlusion may aggravate a dry eye condition by reducing tear clearance and corneal sensation after the procedure. Reduction in the rate of tear clearance will lead to stagnation of tears and any inflammatory components present in the tear fluid. 24 Application of punctal plugs may alter the ocular surface lacrimal gland interactive feedback mechanism. 25 This implies that punctal occlusion has the potential to worsen a dry eye condition. Patients undergoing punctal occlusion must be monitored carefully for worsening of ocular irritation symptoms or increase in corneal staining. Although punctal occlusion certainly conserves tears, concurrent topical anti-inflammatory therapy must be considered to prevent worsening of the disease. Lackluster success of tear substitutes and moisture aid treatments for DES surely promoted the quest to find a pharmacologic agent that would address the underlying cause as opposed to the symptoms of DES. To effectively review the recent pursuits to understand and manage DES, dry eye classification categories are clarified here. Next, current concepts in the pathophysiology of DES are discussed, and several anti-inflammatory therapies are evaluated in terms of their mechanisms, success rates, and clinical utility. Classification and diagnosis The National Eye Institute introduced a classification schema for dry eye based on 2 major categoriesdteardeficient dry eye and evaporative dry eye. 1 Common features of dry eye include interpalpebral surface damage, tear instability, tear hyperosmolarity, and symptoms of ocular irritation. Diagnostic tests for dry eye evaluate these characteristics, but confirming a diagnosis does not require the presence of all 4 features. Some patients with DES, for instance, may experience ocular discomfort but may not exhibit ocular surface damage as measured by current diagnostic tests. A Delphi panel of several international dry eye experts has made several recommendations to current classification and treatment paradigms for this disease. An important recommendation of this panel was to initiate topical immunomodulatory therapy at early stages of dry eye disease (severity level 2). 26 The International Dry Eye Workshop 27 report classifies those with severity level 2 as patients who have moderate subjective discomfort, annoying visual symptoms, variable corneal staining, decreased tear meniscus, tear breakup times %10 seconds, and Schirmer scores of %10 mm wetting in 5 minutes. Tear-deficient dry eye results from lacrimal gland malfunction or a disruption in the path of tears through the lacrimal ducts to the conjunctival sac. Patients with teardeficient dry eye lack sufficient tear flow and experience decreases in tear volume and secreted lacrimal proteins. Types of tear-deficient dry eye include, but are not limited to, Sjögren s syndrome, lacrimal disease, lacrimal obstructive disease, and reflex hyposecretion. Sjögren s syndrome, an autoimmune disease, is characterized by a lymphocytic infiltration and consequent destruction of exocrine glands, including the salivary and lacrimal glands. Systemic autoimmune connective tissue disease, including rheumatoid arthritis, polyarteritis, and systemic lupus erythematosus, accompanies secondary Sjögren s syndrome. The autoimmune nature of Sjögren s syndrome and its systemic associations provided the foundation for considering inflammation as a factor in the pathogenesis of DES. 28 Reflex hyposecretion, one type of non-sjögren s tear-deficient dry eye, can result from decreased corneal sensation associated with a variety of causes such as contact lens wear, diabetes mellitus, and use of certain medications. 1 In contrast to tear-deficient dry eye, evaporative dry eye occurs despite normal lacrimal function and sufficient tear volume caused by periocular disorders that interfere with the integrity of the tear film. Blepharitis, meibomian gland disease, and abnormalities with blinking or lid/globe congruity may result in evaporative tear loss. Increased levels of inflammatory markers also have been noted on the ocular surface of patients with rosacea, which causes severe evaporative dry eye. Current challenges in dry eye diagnosis lie in the observation that patient symptoms rarely correlate with clinical findings. 29 Although tear stability and osmolality tend to correlate best with reported patient symptoms, a detailed patient history may prove to be the most valuable tool in the diagnosis of dry eye. 30 Furthermore, Nichols et al. 29 found that many clinically used diagnostic techniques lack repeatability. Tear breakup time and symptom assessment have been shown to yield the most repeatable results. Tests for tear hyperosmolarity are highly sensitive and specific for DES but are not practical for the clinical setting. 1,30 Most studies examining novel anti-inflammatory treatment for DES select patients based on outcomes of Schirmer

4 558 Optometry, Vol 80, No 10, October 2009 testing, tear film breakup time, tear fluorescein clearance, or staining techniques, and at least one measure of subjective patient-reported symptoms such as the Ocular Surface Disease Index. 31 A detailed assessment of a patient s symptoms, systemic conditions, medications, and work environment, along with a careful slit lamp examination, will be sufficient in most cases to draw the distinction between tear deficient and evaporative dry eye. The practitioner can then begin to formulate a management strategy for the dry eye patient. Although anti-inflammatory therapy represents the latest in dry eye treatment, 32 it is not indicated for all types of dry eye. Anti-inflammatory therapy can be initiated when level-1 dry eye therapy fails to improve the patient s condition. 27 Level-1 therapies consist of environmental/dietary modifications, use of rewetting agents, and elimination of systemic medications that cause dry eye. An accurate diagnosis of the type of presenting ocular surface disease, along with an assessment of patient motivation and compliance, allows the practitioner to accurately select appropriate candidates for anti-inflammatory dry eye treatment. Pathophysiology Normal physiology of tear production In the healthy individual, the ocular surface, tear secreting glands, and interconnecting neural reflex loops function as an integrated unit. 33 Alteration of any one component of this unit will disrupt tear homeostasis. The ocular surface includes the tear film, corneal and conjunctival epithelia, conjunctival goblet cells, meibomian glands, and accessory lacrimal glands. 28 The highly dynamic tear film maintains the refractive quality of the ocular surface and rapidly responds to stresses caused by microorganisms, foreign bodies, and shear forces. 33 Because the ocular surface must react to environmental elements and initiate the reflex loop for tear production, it receives a vast innervation. Afferent stimulation at the cornea and conjunctiva transmit signals, via the ophthalmic division of the trigeminal nerve, to the spinal trigeminal nucleus in the medulla of the brainstem. 28 The message is relayed to the lacrimal nucleus of the pons, where efferent parasympathetic preganglionic nerve fibers arise. These fibers synapse at the pterygopalatine ganglion, and the lacrimal nerve then carries the impulse to the acinar cells of the lacrimal gland. The pons also stimulates sympathetic preganglionics of the spinal cord, which synapse at the superior cervical ganglion before innervating the acinar cells. The lacrimal gland receives mostly parasympathetic stimulation from acetylcholine and vasoactive intestinal peptide neurotransmitters. 34 Acetylcholine primarily causes water and electrolyte release, whereas vasoactive intestinal peptide encourages protein secretion. 20 Sensory nerves and androgens also participate in lacrimal support and regulation. The tears produced by the lacrimal gland enter the conjunctival sac through a series of lacrimal ducts to complete the reflex loop of tear production. Pathogenesis of dry eye syndrome The ocular surface, lacrimal gland, and the central nervous system form an integrated unit providing appropriate feedback to maintain ocular surface wetting. 28 In dry eye patients, a reduction in lacrimal gland tear flow slows the rate of tear turnover at the ocular surface. 20 Although the exact mechanism of this delayed tear clearance is unknown, it has been well documented in the literature. 24,35 Decreased tear turnover, known as delayed tear clearance, increases tear osmolarity, which activates inflammatory pathways at the ocular surface. The inflammation decreases corneal sensitivity, which disrupts the neural feedback mechanism between the ocular surface and lacrimal glands and further impedes tear flow and tear clearance. Thus, the cycle of ocular surface inflammation continues. A variety of factors may initiate the dry eye cycle by targeting the lacrimal gland, the ocular surface, or the central nervous system. Lacrimal dysfunction can occur with autoimmune disease such as Sjögren s syndrome, viral disease, loss of androgen or growth factor support, neurogenic inflammation, or decreased neural stimulation. 20,36 Medications, including diuretics and anticholinergic drugs, often reduce parasympathetic innervation to the lacrimal gland. Lacrimal deficiency or obstruction of the lacrimal ducts will directly reduce tear output. The eye responds by delaying tear clearance through a poorly elucidated mechanism, which allows surface debris, bacteria, and inflammatory cytokines to linger. Other factors can independently impede tear clearance, such as ectropion, decreased frequency of blinking, conjunctivochalasis, nasal allergy, and punctal plugs. The cycle of dry eye as described above is not strictly limited to aqueous tear deficiencies. Evaporative dry eye causes an increase in tear osmolarity and impairs tear stability and will ultimately perpetuate inflammation and DES as well. Song et al. 37 found many of the properties of dry eye pathology by depriving mice of neurturin, a neurotrophic factor that aids in the development of specific postganglionic parasympathetic neurons and trigeminal sensory nerves. Neurturin-deficient mice exhibit poor parasympathetic lacrimal innervation as well as fewer trigeminal nerves. Neurturin-deficient mice showed significant reductions in aqueous tear production, tear fluorescein clearance, and corneal sensation compared with age-matched neurturin-positive mice. These mice underwent further analysis to confirm the presence of concomitant ocular inflammatory markers. Hallmarks of inflammation The efficacy of novel therapies for dry eye can be assessed by their action on various inflammatory markers characteristic of DES. The experiment by Song et al. 37 was useful not only because it devised an accurate murine

5 McCabe and Narayanan Issue Highlight 559 keratoconjunctivitis sicca model for future studies, but also because it measured dry eye using a vast array of techniques. This allowed the researchers to compare a wide selection of inflammatory markers present on a cellular level with characteristics such as tear clearance and corneal sensation. The corneal epithelia of neurturin-deficient mice expressed high levels of matrix metalloproteinase (MMP)- 9, interleukin (IL)-1b, tumor necrosis factor alpha (TNF-a), macrophage inflammatory protein-2, and neutrophil chemoattractant mrna. Mucin and goblet cell density in the conjunctiva of neurturin-deficient mice were also significantly lower than that in neurturin-normal mice, which correlates with squamous metaplasia of the corneal and conjunctival epithelium. 38 Patients with moderate to severe dry eye express many of the same pro-inflammatory cytokines and chemokines. One of the first inflammatory signs measured in dry eye patients was human leukocyte antigen (HLA)-DR. Human leukocyte antigen-dr processes and presents antigens to T-cells, promoting lymphocyte infiltration of conjunctival epithelium. 39 The expression of HLA-DR by lymphocytes and conjunctival epithelial cells has been detected in dry eye patients with and without Sjögren s syndrome. Furthermore, more severe cases of dry eye correlate with higher HLA-DR expression. These findings indicate that the ocular surface itself plays an active role in promoting inflammation, regardless of whether an autoimmune condition already exists. 40 CD40, a cell surface receptor responsible for lymphocyte stimulation, chronic inflammation, and apoptosis, demonstrates a similar upregulation within the conjunctival epithelium of dry eye patients. 41 CD11a and intercellular adhesion molecule-1 work together to promote cell communication and attract lymphocytes to surrounding tissue; both of these molecules proliferate during inflammatory conditions as well. 41 The last important class of molecules that mediate inflammation are the cytokines, which include the ILs, TNFs, and interferons (IFN). Cytokines enhance the immune response to inflammation by activating and amplifying T cell response and promoting cell cell interaction. Solomon et al. 42 noted an increase in proinflammatory IL-1a and mature IL-1b molecules in patients with meibomian gland disease and Sjögren s syndrome. Interleukin-1Ra, an anti-inflammatory molecule, also increased in dry eye participants, but the IL-1Ra to IL-1a ratio was significantly lower in dry eye patients compared with the control group. Of recent interest is the production of the protease MMP-9 and cytokines such as IL-1 and TNF via mitogenactivated protein kinase (MAPK) signaling pathways. 43,44 The increased expression of cytokines and MMP-9 in dry eye patients perpetuates MAPK pathways on the ocular surface. Matrix metalloproteinases lyse components of the corneal epithelium may contribute to the irregularities observed in dry eye corneal structure. 44 Li et al. 45 linked tear hyperosmolarity to an increase in production of inflammatory cytokines and chemokines by human limbal epithelial cells via MAPK signaling pathways. Mitogen-activated protein kinase inhibitors, in addition to other anti-inflammatory agents, successfully suppressed the expression of these pro-inflammatory molecules. 45 Within the last decade, dry eye research has increasingly used techniques aimed at analyzing inflammatory markers of DES in hopes of further formulating and evaluating anti-inflammatory therapies. Anti-inflammatory therapy In light of the consistent research findings of inflammatory mediators in DES, the use of anti-inflammatory therapy has been gaining popularity. 32 The major anti-inflammatory agents currently in use include topical corticosteroids and immunomodulatory agents. Androgen therapy, tetracycline antibiotics, and nutritional supplements also show promise in treating the inflammatory component of DES. Cyclosporine A (CsA), an immunomodulator approved in 2002 by the Federal Drug Administration for treatment of ocular conditions, surfaced in response to knowledge concerning the pathogenesis of DES. Several older studies observing corticosteroid treatment, on the other hand, provided substantial evidence for further investigation into the role of inflammation in DES. To evaluate the clinical use of these anti-inflammatory agents, the mechanisms, efficacy, indications, advantages, and disadvantages of each type of therapy are assessed. Topical corticosteroids Several studies have found that topical corticosteroids effectively treat dry eye. 32 Corticosteroids interfere with expression and transcription of pro-inflammatory genes by targeting receptor and nonreceptor-mediated pathways, respectively. As a result, these drugs inhibit cytokine and chemokine production, decrease the synthesis of matrix metalloproteinases and arachidonic acid derivatives, suppress the expression of cell adhesion molecules, and induce lymphocyte apoptosis. Corticosteroid treatment has provided significant evidence for the involvement of inflammation in the pathogenesis of DES. 46,47 Prabhasawat and Tseng 46 examined 70 patients who had delayed tear clearance, despite normal tear production and absence of punctal obstruction. After the administration of 1% nonpreserved methylprednisolone 3 times per day for 3 weeks, 80% of the patients showed improvement in their condition based on subjective and objective measures of dry eye. Additionally, 87% of patients had accelerated dye clearance indicated by the fluorescein clearance test. The treatment effect of the corticosteroid in this study is questionable because no control group was utilized. In a more recent pilot study, 64 patients suffering from delayed tear clearance and who had keratoconjunctivitis sicca were randomly assigned to treatment with either the corticosteroid loteprednol etabonate 0.5% or a

6 560 Optometry, Vol 80, No 10, October 2009 placebo at 1 drop 4 times daily for 4 weeks. 48 Patients of both treatment groups improved subjectively and objectively after 2 to 4 weeks of therapy. Objective signs, however, including central corneal fluorescein staining and conjunctival hyperemia, improved significantly only in the corticosteroid group in patients with moderate to severe dry eye. Although the magnitude of the loteprednol treatment effect was less than that observed in previous studies with methylprednisolone therapy, it showed a more favorable safety profile. Over the course of 1 month of treatment, no significant changes in intraocular pressure or cataract formation were noted. Despite the relatively small sample size and the loose selection criteria for study participants, this study was well designed and laid a foundation for future research comparing corticosteroids with placebo in the treatment of moderate to severe dry eye. Fluorometholone 0.1%, like loteprednol etabonate, has a good safety profile and was used to treat patients with moderate to severe dry eye who did not experience relief from artificial tears alone. 49 After 1 week of using fluorometholone 0.1% 4 times daily, symptoms improved in all patients, and by the end of 1 month, significant improvement in objective signs of dry eye occurred as well. Objective measures included tear breakup time, Schirmer I scores, conjunctival hyperemia, and corneal fluorescein staining. Faults of this study include a small sample size and the lack of a control group. The findings, however, reinforce those noted in the loteprednol study regarding a significant treatment effect of corticosteroids in a subset of patients suffering from moderate to severe dry eye. Interestingly, Afonso et al. 50 correlated delayed tear clearance with increased concentrations of the pro-inflammatory cytokine IL-1 and enhanced MMP-9 activity in patients with ocular irritation associated with meibomian gland dysfunction. Similar results have been observed in murine models of dry eye. 37,44 Put together, these results suggest that the success of corticosteroid therapy in patients sustaining delayed tear clearance likely stems from the drug s action on the concurrent ocular inflammation. In a retrospective study, 21 patients with Sjögren s syndrome, 47 experiencing persistent dry eye despite trying treatments such as rewetting agents and punctal plugs, were treated with 1% nonpreserved methylprednisolone 3 to 4 times a day for 2 weeks. After the 2 weeks, they discontinued treatment or continued treatment at a lower frequency (typically 1 drop per day) or dose (0.1% to 0.5%) on a case-by-case basis. All patients reported symptomatic improvement after the initial 2 weeks of therapy. Corneal fluorescein staining scores decreased in all patients. Many patients noted diminished ocular irritation weeks to months after cessation of treatment, which suggests that corticosteroids may treat causative factors of dry eye instead of merely alleviating symptoms. A separate Sjögren s study group underwent topical methylprednisolone 1% treatment 4 times a day. 51 Patients were reassessed at 2-week intervals. Those who were symptom-free and showed no corneal fluorescein staining continued therapy at half the original frequency. All other patients continued with treatment at the same frequency. The tapering schedule continued until patients reached once-daily dosing. If they remained disease-free after 2 weeks of once-daily dosing, use of the drop was discontinued. 51 All patients used artificial tears concurrently on an hourly basis. Both objective and subjective symptoms improved in all patients after approximately 8 weeks of treatment, and the effects of the steroid lasted an average of 56.6 weeks. Around 21% of patients experienced recurrence of the dry eye after the first pulse dose. After a second pulse dose of methylprednisolone, however, mean improvement extended to 72.4 weeks. Only 1 patient had a relapse after the second dose. A short pulse of corticosteroids for this population of Sjögren s patients provided long-lasting relief, and no adverse side effects caused by the treatment were noted. This study had a good sample size for a Sjögren s syndrome population, but did not compare the treatment group to a non-sjögren s syndrome control group or a placebo group. Avunduk et al. 52 broadened the scope of corticosteroid research by including impression cytology techniques in the analysis of moderate to severe dry eye patients. Examining the quantity of HLA-DR positive cells, goblet cells, and Apo 2.7 positive cells in the conjunctiva epithelium after corticosteroid treatment helps to elucidate the effect of the drug on the actual inflammatory markers associated with dry eye. The study found that patients treated with fluorometholone topical corticosteroid drops and artificial tear substitute displayed significantly lower symptom severity scores, decreased corneal staining scores, and fewer HLA-DR positive cells compared with patients taking nonsteroidal anti-inflammatory drops with artificial tear substitutes or artificial tear substitutes alone. The corticosteroid group also had higher numbers of goblet cells. The researchers speculate that corticosteroids downregulate cytokines, such as IFN-g and TNF-a, which encourage HLA-DR expression. Because nonsteroidal anti-inflammatory drugs do not affect cytokine production, their limited effect on HLA-DR expression was to be expected. The study did not find any correlations between treatment and numbers of apoptotic cells, as indicated by the Apo 2.7 cell analysis. Because corticosteroids actually promote apoptosis, the decrease in inflammation-stimulated apoptosis may have balanced the amount of drug-stimulated apoptosis. Later studies found that both dexamethasone and methylprednisolone were capable of suppressing cytokines, namely TNF-a and a variety of ILs, in experimental dry eye. 43,45 In addition, methylprednisolone decreased the expression of MMP-9 and stifled MAPK activation. Recall that MMP-9s and MAPK pathways disrupt the corneal epithelial barrier. This research suggests that corticosteroids can restore the disrupted corneal epithelium of dry eye patients. 43 As previously discussed, researchers have found that inflammation does, in fact, cause dry eye to persist despite palliative treatment, which is why corticosteroids often prove successful when other methods fail. Long-term

7 McCabe and Narayanan Issue Highlight 561 methylprednisolone therapy is associated with the risk of ocular hypertension, posterior subcapsular cataracts, delayed corneal epithelial healing, and microbial keratitis. 46,47 The less potent 0.5% corticosteroid solutions induce minimal, if any, adverse effects, as shown in trials using them for no longer than 1 month. 48,52 Sound evidence supporting the use of corticosteroids for mild cases of dry eye has not yet emerged. As of now, corticosteroid treatment for DES is indicated more so for patients with Sjögren s syndrome or moderate to severe disease. Because of the possible serious side effects of prolonged corticosteroid use and the need for frequent monitoring by the eye care professional, this class of drugs will likely continue to be reserved for more severe cases of dry eye until further research on less potent corticosteroids is complete. Topical immunomodulatory agents In December 2002, Allergan, Inc (Irvine, California) received approval from the Food and Drug Administration for RestasisÒ, a CsA ophthalmic emulsion indicated for patients with suppressed tear production associated with dry eye. 53 The mechanism of CsA in increasing tear production is not yet fully understood, but the drug seems to have partial immunomodulatory effects that reduce inflammation. CsA is used widely as an immunosuppressive therapy during organ transplantation and has been shown to increase lacrimation upon systemic administration in patients with no pre-existing autoimmune lacrimal disease. 54 Upon detecting its lacrimomimetic qualities, and after a series of initial studies using canine keratoconjunctivitis sicca models, researchers initiated attempts at creating an ophthalmic immunomodulatory CsA emulsion that would limit the systemic effects of the drug. 55 Cyclosporine A binds to nuclear proteins required for T-cell activation, which results in a decrease in T-cell stimulated inflammatory cytokines. 56 The drug also has the ability to block c-jun NH2-terminal kinase and p38 MAPK cascades, which contribute to T-cell activation. 57 Lastly, conjunctival epithelial apoptosis may decrease in response to CsA administration, although these findings have varied among dry eye studies. 39,58,59 CsA suppression of T-cell induced inflammatory cytokines mitigates dry eye by improving lacrimation and decreasing the effects of ocular surface inflammation. A multicenter study using various doses of a specially formulated CsA ophthalmic emulsion (Restasis) began in the mid 1990s. 60 Study subjects had keratoconjunctivitis sicca with or without Sjögren s syndrome and were unable to obtain relief with standard dry eye treatment. One hundred twenty-nine patients were treated with various doses of CsA (0.05%, 0.1%, 0.2%, or 0.4%) twice daily for 3 months, whereas 33 patients were administered the vehicle only. Patients were observed for 1 month after discontinuation of treatment. Treatment effects were assessed using rose bengal staining, superficial punctate keratitis, Schirmer testing, symptoms of ocular discomfort, and Ocular Surface Disease Index scores. The CsA 0.1% treatment group showed the most consistent success in objective measures, including significant improvements in rose bengal staining, superficial punctate keratitis, and tear film debris. Measures of patient symptoms, however, improved the most in the CsA 0.05% treatment group. The effects noticed in the CsA treatment groups exhibited mainly within-group significance due to favorable findings within the vehicle group as well. No dose response relationship was observed. This phase 2 pilot study was followed by an even larger phase 3 study, with 877 patients and lasting 6 months duration. 61 This study focused primarily on safety and efficacy of twice-daily dosing of CsA 0.05% and 0.1% emulsion when compared with the vehicle alone. Follow-up was conducted at months 1, 3, 4, and 6. Findings indicated that the CsA treatment groups excelled over the vehicle group in corneal staining and Schirmer testing scores. The vehicle group, however, still exhibited significant decreases in corneal staining and actually showed a comparable amount of improvement in conjunctival staining as the CsA treatment groups. All treatment groups significantly raised their Schirmer test scores measured without anesthesia, but only the CsA groups improved upon Schirmer scores measured with anesthesia. These results suggest that CsA actually increases basal tear production from the lacrimal gland. Symptoms of dryness, sandy/gritty feeling, itching, photophobia, burning, stinging, and pain significantly declined in both the treatment groups and the vehicle group. Blurred vision was the one symptom that showed a statistically significant difference between the vehicle group and the treatment groups. Patients treated with 0.05% CsA emulsion showed significant improvements in blurred vision at all follow-up visits when compared with the vehicle group. Very few adverse effects and little systemic absorption were observed in patients taking CsA. The most commonly reported complaint was mild ocular burning upon instillation. 62 Reasons for discontinuation of CsA included burning and stinging eyes, conjunctival hyperemia, cataract, and eye pain. Several studies examining actual markers of inflammation used subsets of participants of the large phase 3 study. One analysis found that conjunctival epithelium levels of IL-6 decrease with 0.05% CsA treatment. 63 Kunert et al. 41 found the inhibitory effect of CsA on T-cells by noting decreased numbers of conjunctival cells expressing CD11a and HLA-DR. Levels of CD31, CD 41, and CD81, however, did not significantly change within the greater patient population. CsA, therefore, likely suppresses T-cell activity rather than eliminating T-cells altogether. A later small study using the same participants also found an increase in goblet cell number within the conjunctiva, which promotes mucin production, and a decrease in epithelial proliferation, which preserves conjunctival and goblet cell integrity. 64 Further research comparing CsA with rewetting agent therapy supported these findings. 65 After 6 weeks of therapy, goblet cell density in the inferior bulbar conjunctiva significantly increased from baseline only in

8 562 Optometry, Vol 80, No 10, October 2009 the CsA treatment group. At 12 weeks, the CsA-treated patients demonstrated an increase in goblet cell density in the temporal bulbar conjunctiva as well. 65 Contradictory to animal studies on CsA treatment, apoptosis has been shown to increase in CsA-treated dry eye patients, as indicated by the cell marker Apo ,59,66 This finding and its associated hypotheses are consistent with those observed with corticosteroid use. An increase in apoptosis in epithelial cells may help to restore and repair the deformed epithelium initially, but with prolonged use of CsA, one would expect the apoptosis to diminish. 66 Mice with dry eye treated with CsA showed decreased rates of apoptosis within the conjunctival epithelium, but dry eye was induced for only 12 days before the analysis took place. 59 The shorter duration of inflammatory insult to the eye may have contributed to the absence of initial apoptosis. Cyclosporine, like corticosteroids, has shown the greatest efficacy within moderate to severe dry eye patients. Restasis is indicated for patients with suppressed tear production associated with inflammation caused by dry eye and is a novel therapy for patients who have failed to respond to the standard palliative dry eye treatments. It has shown excellent safety because of its vehicle, which allows limited delivery of CsA to the systemic circulation but allows the drug enough time to act appropriately at the level of the eye. 67 The most common adverse reaction is ocular burning and stinging upon instillation. Although the beneficial effects of this drug for dry eye patients do not occur instantaneously, subjective symptomatic improvement seems to occur earlier than the resolution of objective clinical signs. 61 Trattler et al. 68 surveyed 0.05% CsA-treated patients regarding compliance and onset of symptom relief. Seventy percent of noncompliant patients and 73% of compliant patients noted relief of dry eye symptoms within a 5-week period. Patients who reported good compliance, however, noted significantly higher rates of satisfaction than those who missed half or more of the prescribed dose. Eighty-three percent of the patients surveyed intended to continue using CsA. Stonecipher et al. 69 reported similar findings among another subset of dry eye patients treated with 0.05% CsA. After just 3 weeks of use, 73% of patients noted significant decreases in symptom severity and the effect of dry eyes on everyday activities. Artificial tear use also declined among the majority of patients. Whether long-term resolution of DES is attained with a course of CsA therapy has yet to be determined. One study found that only 3.9% of patients who instilled 0.05% CsA twice daily for a course of at least 6 months enjoyed a diseasefree state for a year or more afterward. 70 Further studies are necessary to delineate the appropriate time course of CsA therapy necessary to achieve lasting effects. The significant cost of Restasis (approximately $115 for 32 vials) could pose a financial burden on patients and managed care considering that 2 doses per day for an indefinite period is the standard patient regimen. 7 Insurance providers (including Medicare) help patients cover the cost of Restasis. A large retrospective analysis of patients who had undergone CsA therapy found that most patients only used about 1 vial of CsA per day, suggesting that the cost to managed care may be less than would be expected based on the 2-vial-per-day dosing recommendations. 71 Still, considering the cumulative cost of the drug, possible burning with instillation, twice-a-day dosing for an indefinite period of time, and the lag in onset of the therapeutic effect, Restasis may not be ideal for all dry eye candidates. Nonetheless, Restasis has enjoyed much success, and new research continues to provide evidence for the utilization of the CsA ophthalmic formula for many inflammatory ocular conditions other than DES, including vernal and atopic keratoconjunctivitis, Thygeson s superficial punctate keratitis, superior limbic keratoconjunctivitis, and noninfectious keratitis. 72 Androgens, tetracyclines, and fatty acid supplements Several other agents show promise for treating the inflammatory component of DES. Krenzer et al. 73 observed 15 patients who had been on antiandrogen therapy for 3 or more months. 73 Although the study was small, significant increases in tear film debris and corneal staining were observed as well as decreases in tear film breakup time. Other measures were highly indicative of meibomian gland deficiency, including an abnormal lipid profile of the tear film. Although androgens also affect lacrimal gland functioning, androgen deficiency has not been shown experimentally to cause aqueous tear deficiency in patients without preexisting autoimmune disease, such as Sjögren s syndrome. 74 Nevertheless, meibomian gland disease and evaporative dry eye can still lead to inflammation of the ocular surface, and androgen deficiency in postmenopausal women and older individuals may contribute to the high prevalence of dry eye in these populations. 20 Because androgens share an intimate connection with both the lacrimal glands and the ocular surface, therapy taking advantage of their widespread targets could generate a broad therapeutic effect. Little research on the effect of androgen treatment on dry eye has been performed, but the notion of topical androgen therapy has been suggested and will likely continue to be researched in the future. 31,75 Tetracycline antibiotics, specifically doxycycline, mediate matrix metalloproteinase activity of the ocular surface. Doxycycline administration to cultured human corneal epithelial cells inhibits hyperosmolarity induced by MMP production and MAPK activity. 76,77 Furthermore, doxycycline reduced transcription of MMP-9 and TNF-a and decreased MAPK activation in experimental murine dry eye. 43 Tetracyclines have already shown success in treating inflammatory conditions such as blepharitis, periodontitis, rheumatoid arthritis, and acne. 78 At concentrations incapable of significantly affecting Propionibacterium acnes growth, tetracycline still shows the ability to inhibit

9 McCabe and Narayanan Issue Highlight 563 inflammatory neutrophil chemotactic factors and reactive oxygen species at the site of infection. 79 Tetracycline treatment of ocular surface inflammatory diseases improves surface irritation and results in an increase in tear film stability, but it has not yet been indicated for the management of dry eye. Lastly, emerging research observing the effects of essential fatty acid (FA) intake on ocular inflammation may lead to dietary supplements and new topical formulations for DES. FA supplementation has already been shown to effectively mediate inflammation in systemic conditions such as rheumatoid arthritis and irritable bowel syndrome. 80 Two subclasses of essential FAs exist. The omega-3 group consists of the essential FA alpha-linolenic acid (ALA) and its derivatives, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The omega-6 group includes the essential FA linoleic acid (LA) and its derivatives, gamma-linolenic acid (GLA), dihomogamma-linolenic acid (DGLA), and arachidonic acid (AA). 81 FAs, namely AA, which are the most abundant FA in phospholipid membranes, serve as precursors for eicosanoid synthesis. Eicosanoids include prostaglandins, thromboxanes, and leukotrienes. They control the duration and intensity of immune responses via pro- and anti-inflammatory actions. The key to enhancing the anti-inflammatory effects of FAs lies in increasing the phospholipid membrane concentration of those FAs that compete with and limit the effect of the mostly pro-inflammatory AA pathway. Eicosapentaenoic acid is mainly derived from oily fish and competes with AA to form less biologically active eicosanoids. Additionally, both EPA and DHA produce more anti-inflammatory mediators compared with those synthesized from AA. 80 When the ratio of omega-6 to omega-3 is around 4:1 or lower, a reduction in the conversion of LA and DGLA to AA occurs. 82 Barabino et al. 83 conducted a small study in which patients were administered tablets twice daily containing 28.5 mg LA and 15 mg GLA along with a tear substitute. Another group of patients received a placebo tablet and a tear substitute. The treatment group significantly improved in subjective symptoms, lissamine green staining, and ocular surface inflammation as measured by HLA-DR levels compared with the control group. Gamma-linolenic acid is a precursor to DGLA, which is responsible for prostaglandin-e1 production. Prostaglandin-E1 combats ocular inflammation by inhibiting TNF, IL-1b, IL-6, and superoxide. Supplementation with oral LA and GLA in 40 patients with primary Sjögren s syndrome showed similar results. 84 After 1 month of treatment, a significant improvement in symptom severity, corneal staining, and prostaglandin-e1 concentration in tears was noted in the treated group compared with placebo. FA treatments currently on the market claim to decrease inflammation, limit apoptosis, and increase tear secretion, but scientific studies observing the efficacy of omega-3 supplements in treating dry eye are scarce. 85 An analysis of surveys from more than 30,000 women between 45 and 84 years of age led Miljanovic et al. 82 to draw several statistically significant relationships between essential FA intake and the prevalence of DES. Findings showed that women with diets high in omega-3 FAs, specifically DHA, showed lower risk for development of DES. Tuna fish consumption was inversely correlated with DES. In contrast, participants whose diets had a high omega-6 to omega-3 ratio (.15:1) were more than twice as likely to have DES. These relationships held after controlling for systemic conditions, such as connective tissue disorders, diabetes, and hypertension. Only one study to date has examined the effects of a topical FA formulation on the inflammatory component of DES. 81 Dry eye induced mice received a topical dose of 0.2% LA, 0.2% ALA, 0.1%LA to 0.1% ALA, or vehicle alone once daily. Only the group treated with ALA formulation showed significant and sustained improvements in corneal fluorescein staining and conjunctival and corneal expression of TNF-a and IL-1a. Further research examining the specific effects of individual FAs at the ocular surface is needed to substantiate existing evidence for the use of omega-3 and omega-6 FAs in the treatment of DES. Because of the complex interplay of pro- and anti-inflammatory actions of the various essential FAs and their derivatives, future studies will likely focus on determining which FA formulations and concentrations best suppress the inflammatory mediators of DES. Although oral supplementation with FAs has resulted in few adverse effects among study participants, more research assessing the safety profile and drug interactions of FAs is needed. Conclusions The evolution of anti-inflammatory therapy for dry eye has only just begun. Although the pathogenesis of DES is much better understood, the complete cycle of aqueous and evaporative tear deficiencies and their relationships with each other are still under investigation. The fact that inflammation plays a role in perpetuating DES is now universally accepted, and this knowledge alone will spur researchers to continue devising potential therapies that will actually address the cause instead of the symptoms of dry eye. As a norm, optometry and ophthalmology offices still use artificial tear substitutes as a first line of defense for the average case of DES. If tear substitutes provide no subjective or objective relief for the patient, many eye care professionals may now prescribe an anti-inflammatory agent. To appropriately diagnose and select ideal candidates for anti-inflammatory therapy, today s eye care professional must integrate clinical findings with the patient s symptoms and assess the patient s motivation and willingness to comply with pharmacologic therapy. Attempts to treat ocular surface inflammation before resorting to surgical procedures, such as punctal occlusion, may more effectively address the underlying etiology of the stubborn chronic case of dry eye.