REVIEW

CURRENT OPINION therapy and ocular surface disease: current literature and recommendations

Zane Anwara,b, Sarah R. Wellika,b, and Anat Galora,b

Purpose of review To provide an update on clinical and experimental literature for ocular surface effects of glaucoma therapy and to provide practical guidelines for ophthalmologists treating glaucoma patients with ocular surface disease (OSD). Recent findings Preservatives, notably benzalkonium chloride (BAK), continue to contribute to OSD and demonstrate a variety of toxic ocular effects both in-vitro, and in animal/human studies. Recent literature frequently compares BAK with Polyquad, SofZia, and preservative-free therapies. Some clinical benefit has been demonstrated with newer BAK-free alternatives. Summary BAK-free and preservative-free therapies are becoming available but are not always a feasible alternative. It is important to recognize different clinical manifestations of allergy and chronic inflammation and to discuss options for patients experiencing OSD. Keywords benzalkonium chloride, glaucoma, ocular surface disease, preservatives, recommendations

INTRODUCTION , and distorted vision [3]. OSD primar- Over 60 million individuals worldwide suffer from ily manifests in the and as glaucoma, projected to increase to almost 80 million superficial punctate (SPK), tear-film insta- in 2020 [1]. Up to 40% of the glaucoma population bility, and allergic manifestations. in the USA requires more than one agent to effec- tively lower (IOP) [2]. Ocular Superficial punctate keratitis surface disease (OSD) and (DES) are present in 15% of the elderly population and SPK encompasses lesions of the corneal epithelium have been reported in several studies to be more that are classified by morphology, and include common in patients with glaucoma. Using the punctate epithelial erosions (Fig. 1), fine and ocular surface disease index (OSDI) score, it has been coarse punctate epithelial keratitis, areolar punctate shown that up to 60% of glaucoma patients have keratitis, and filamentary keratitis. Keratoepithelial OSD, both of which can independently impact chemical toxicity leading to SPK has been of particu- quality of life and compliance [3,4&&,5]. It has lar interest in glaucoma therapy, most commonly been postulated that multiple, daily exposures associated with topical prostaglandin analogs, beta- of the ocular surface to active compounds and blockers, and cholinergics [6]. Early studies esti- preservatives can worsen the burden of OSD in mated a prevalence of 44–46% of SPK in glaucoma this population.

aMiami Veteran Affairs Medical Center and bDepartment of Ophthal- mology, Bascom Palmer Eye Institute, University of Miami, Miami, Florida, CLINICAL MANIFESTATIONS OF OCULAR USA SURFACE DISEASE FROM Correspondence to Sarah R. Wellik, MD, Bascom Palmer Eye Institute, ANTIGLAUCOMA THERAPIES 900 NW 17th Street, Miami, FL 33136, USA. Tel: +1 305 326 6000; fax: The clinical presentation of OSD varies in severity +1 305 575 3312; e-mail: [email protected] and includes symptoms of dryness, redness, Curr Opin Ophthalmol 2013, 24:136–143 tearing, irritation, burning, foreign body sensation, DOI:10.1097/ICU.0b013e32835c8aba

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[3,14&,15,18&&]. Hyperosmolarity is likely an import- KEY POINTS ant factor, but as yet understudied due to its  OSD secondary to glaucoma therapy commonly inability to be readily obtained clinically [19]. manifest as SPK, allergy, and tear-film instability.  Recent in-vivo and animal studies continue to Allergic manifestations demonstrate the toxic effects of preservatives, mainly Allergy induced by topical glaucoma treatment is BAK, through various mechanisms. primarily seen in the conjunctiva and periorbital  Although many crossover clinical trials show benefit to areas as conjunctival hyperemia, chemosis, lid preservative-free therapies, there are multiple studies edema, periorbital erythema or eczema, and itching that show no improvement of OSD after crossover. [20]. These symptoms are mediated through IgE  In patients with medication related OSD (but not type I hypersensitivity or delayed type IV hyper- allergy), artificial tears, anti-inflammatory therapy, and sensivity which resolve after withdrawal of the BAK-free or preservative-free therapy can be used if offending agent. Clinical presentation from an feasible for the patient. allergic reaction can vary between a typical peri- orbital dermatitis and papillary to more subtle allergic [21]. Drug-induced allergic reactions occur due patients on [7,8]. More recently, large to both active compounds and preservatives and multicenter studies from Europe found a SPK preva- differences are seen between the classes of therapy lence of 18–31% and smaller studies from Japan [20,22,23]. and dermatitis have found SPK to be present in 20–54% of patients to prostaglandin analogs are relatively rare and are on antiglaucoma therapies [9&,10–12]. Furthermore, reported at 1.5% in patients on [20]. the European studies found a significant difference Beta-blockers, however, have been shown to cause of SPK in patients on preservative versus nonpreser- contact dermatitis in 11–13% of patients [24] and vative topical antiglaucoma therapy (25 versus 9% dorzolamide has reported rates of 3% dermatitis and and 19% versus 9%) [11,12]. 4% conjunctivitis [6]. Ocular allergy to brimonidine has been reported at 9 and 11.5% in two separate long-term studies [25,26]. Tear-film instability The disruptive effects of topical glaucoma medi- cations on tear film integrity are well known Other manifestations [13,14&,15–17]. Objective measures of tear-film A variety of other clinical manifestations of break-up time (TBUT), Schirmer’s test, osmolarity, topical glaucoma treatments are possible. Pseudo- and meibomian gland score have been used to assess pemphigoid is a cicatrizing conjunctivitis that tear-film functionality of patients on long-term mimics ocular mucous membrane pemphigoid and short-term therapy. It is reported that TBUT (MMP) in presentation and is distinguished by con- and Schirmer values are abnormal in over 60% of junctival biopsy. A 2004 study from Thorne et al. glaucoma patients in addition to significant tear- [27] evaluating MMP and pseudopemphigoid found film hyperosmolarity and meibomian gland loss that the most common associated diagnosis of the

FIGURE 1. Superficial punctate keratitis identified in the left eye of a patient with primary open angle glaucoma on travoprost preserved with Sofzia (in comparison to the patient’s right eye on no topical therapy).

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pseudopemphigoid cohort was glaucoma with long- proposed to promote drug transmission into the term topical treatment (28%), and that most of anterior chamber. these patients were receiving multiple agents BAK has been under much scrutiny due to its (97%) including a beta-blocker (87%). Recurrent toxic effects on ocular tissues. Recent reviews secondary to latanoprost, have demonstrated the large body of literature on , and travoprost has also been described effects of BAK on a variety of clinically relevant in case reports. It has been suggested that the ocular tissues [21,32]. Table 1 summarizes the most prostaglandin analogs promote viral shedding in recent in-vitro and animal studies [33,34&,35,36&, ganglion cells leading to flare-ups directly associated 37–39,40&,41&,42&&,43–45]. Most of the in-vitro with the prostaglandin use in these patients literature has studied corneal and conjunctival [28,29]. In addition, corneal decompensation after epithelial cell viability with BAK exposure from 5– dorzolamide use has been reported in two series. 30 min. BAK-preserved antibiotics have been shown A presumed decreased in endothelial function to significantly decrease in the tear film starting at from previous intraocular surgery was thought to 30 s, thus, challenging the clinical value of the many potentiate the toxic effects of dorzolamide [30,31]. studies with relatively long exposure times [46]. To date, vernal-like charac- Polyquarternium-1 (Polyquad) is another qua- terized by tarsal or limbal papillae has not been ternary ammonium preservative considered to be reported in the literature as a secondary effect of less toxic to the ocular surface based on studies antiglaucoma therapy. Figure 2 demonstrates a examining toxicity to corneal and conjunctival patient seen in our clinic with primary open angle epithelial cells. A newer generation preservative glaucoma on brimonidine who presented with SofZia (Alcon, Fort Worth, Texas, USA) functions superior limbal Horner Trantas Dots and superior as a microbicidal agent through oxidative pro- tarsal follicles that resolved after discontinuation perties. This ionic buffer solution, comprised of of brimonidine (Wellik S, Galor A, personal borate, propylene glycol, sorbitol, and zinc chloride, communication). converts to nontoxic byproducts after contact with ocular surface cations. More recently, several formulations of pre- EFFECT OF PRESERVATIVES ON OCULAR servative-free glaucoma topical medications have SURFACE DISEASE come to market. Preservative-free timolol has been Benzalkonium chloride (BAK) was one of the available for several years in the USA and Europe. first preservatives introduced in the 1950s and Preservative-free dorzolamide/timolol combination remains the most common ophthalmic preservative (Cosopt PF; Merck, Whitehouse Station, New Jersey, today. Its effective antimicrobial properties as a cell USA) and preservative-free prostaglandin analog, wall and cytoplasmic membrane detergent prevent (Zioptan; Merck, Whitehouse Station, microbial contamination in multidose containers. New Jersey, USA) have recently been released in BAK’s cationic quaternary ammonium structure the United States as well. The concern of ocular allows it to act as a surfactant by which it has been surface damage from preservatives, especially BAK, has prompted the shift towards entirely preserva- tive-free medications in single unit dose containers.

Studies on corneal and conjunctival epithelium Initial studies on ocular surface epithelium and preservatives identified abnormal rabbit corneal cell morphology after BAK exposure using electron microscopy [47]. More recent in vivo animal studies on corneal epithelia observed inflammatory cell infiltrates and overall ocular toxicity evaluated by confocal microscopy, scoring greatest in BAK- preserved therapy [45]. Comparing three preservatives, Ammar and associates observed conjunctival cell survival in decreasing order from Polyquad (101 Æ 8%), SofZia- FIGURE 2. Vernal keratoconjunctivitis with superior limbal preserved (68 Æ 8%), and BAK-preserved (54 Æ 9%) Horner-Trantas dots in a patient on brimonidine. travoprost with a similar trend in corneal epithelial

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Table 1. Recent in-vitro and animal studies on preservative toxicity

Authors Year Cell Type(s) Description Preservatives Exposure

In-vitro studies Paimela et al. [33] 2012 Cornea Cell viability, apoptosis, BAK, PQ 5/15/30 min and inflammatory markers (NF-KB, IL-6, IL-8) Clouzeau et al. 2012 Conjunctiva Hyperosmolarity and BAK 24/48 h [34&] BAK toxicity Pellinen et al. [35] 2012 In-vitro and in-vivo Increased cytotoxicity of BAK, BAK 14 days topical daily rabbit cornea and BAK with increasing homologs conjunctiva alkyl chain length (C12–C16) Ye et al. [36&] 2011 Cornea DNA strand breaks and BAK 30 min BAK toxicity Ammar et al. [37] 2011 Trabecular cell BAK, PQ 25 min viability with BAK and PQ Ammar et al. [38] 2011 Trabecular and ciliary Trabecular meshwork cell BAK, PQ, SZ 10 min and ciliary epithelial cell viability with BAK, PQ, SZ Liang et al. [39] 2011 Cornea BAK toxicity on a three- BAK 24 h dimensional environment: inflammation, tight junctions, cell viability, proliferation Ammar et al. [40&] 2011 Cornea, conjunctiva Cell viability of corneal and BAK, PQ 25 min conjunctival cells to BAK and PQ Animal studies Li et al. [41&] 2012 In-vivo rabbit cornea In-vivo dry animal eye model BAK 2 to 5 weeks topical daily and conjunctiva with prolonged BAK exposure Sarkar et al. [42&&] 2012 In-vivo mouse cornea Corneal neurotoxicity, BAK 1 week topical daily inflammation, and tear production with BAK exposure Pellinen et al. [35] 2012 In-vitro and in-vivo Increased cytotoxicity of BAK, BAK 14 days topical daily rabbit cornea and BAK with increasing alkyl homologs conjunctiva chain length (C12–C16) Uematsu et al. [43] 2011 In-vivo rabbit cornea Modulators of acute corneal BAK, SZ 60 s dysfunction measured by transepithelial electrical resistance Kim et al. [44] 2011 In-vivo rabbit cornea Effect of BAK on schirmer test, BAK 14 days topical and conjunctiva rose-begal staining, and four times / day goblet cell density in vivo Liang et al. [45] 2011 In-vivo rabbit cornea In-vivo confocal microscopy BAK, PQ 15 times, and conjunctiva findings on in-vivo rabbit 5 min intervals ocular surface cells with BAK and PQ.

Corneal and conjunctival cell types for in-vivo studies are epithelial cells unless otherwise stated. BAK, benzalkonium chloride; PQ, polyquad; SZ, SofZia. cells, but more pronounced BAK toxicity (Polyquad and severe DES (300.8 Æ 7.8, 315.5 Æ 10.4, and 80 Æ 15%, SofZia 72 Æ 7%, and BAK 14 Æ 5% cell 336.7 Æ 22.2 mOsm) [49]. Tear-film and cell mor- survival) [48]. More recently, a hyperosmolar phology abnormalities have been shown to persist environment was found to potentiate the cyto- up to 2 weeks after last use in an animal dry eye toxicity of BAK in conjunctival cells, consistent with model with 5-week daily BAK exposure [41&]. its independent role in ocular surface inflammation Two large multicenter European clinical trials in DES [34&]. The osmolarities in this study, how- observed the frequency of ocular surface damage ever, were at elevated levels (400, 425, 500 mOsm) in patients on preservative and preservative-free compared with those seen in mild, moderate, glaucoma drops. The initial French study with over

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4000 patients found preservative-free formulations In the anterior chamber, inflammation had reduced subjective complaints of irritation secondary to BAK has recently been demonstrated and discomfort upon and between instillations, using a flare meter [52&&]. In 28 patients, BAK- and decreased frequencies of abnormal slit-lamp preserved timolol was administered in one eye findings such as hyperemia, follicles, SPK, and and preservative-free timolol in the fellow eye. Flare palpebral signs [12]. This study was extended to meter increases were seen in both eyes, greater in more than 9000 European patients with similar the BAK exposed eye. The increases were hypo- findings [11]. thesized to be secondary to both decreased aqueous humor production from timolol and BAK-induced subclinical inflammation. Corneal neurotoxicity The neurotoxic effect of BAK on the ocular surface has been shown in animal and human in-vivo Crossover clinical trials (benzalkonium studies. In a mouse model, inflammatory cell infil- chloride to benzalkonium chloride free or trate in BAK exposed eyes was accompanied by preservative free) significant decreases in stromal nerve fiber density. Crossover studies represent the majority of recent Recuperation of axonopathy by retaining original clinical trials studying preservatives (Table 2 [9&, nerve patterns and by regeneration of new nerve 18&&,52&&,53&&,54]) with all recent studies switching patterns was seen in the recovery period [42&&]. from BAK to preservative-free or SofZia-preserved Clinical neurotoxicity of BAK to the ocular surface therapies. Three recent trials have studied the two was demonstrated in a study with 84 patients preservative-free therapies approved in the USA, [50]. In the BAK-exposed groups, decreases in preservative-free tafluprost and dorzolamide- corneal sensitivity were detected by esthesiometry timolol. Two of the trials switched patients from and reduction in sub-basal nerves observed by BAK-preserved latanoprost to preservative-free microscopy in comparison to preservative-free tafluprost for 3 months. Between both of these trials patients. there were significant decreases in subjective symp- toms and tear film abnormalities (osmolarity, TBUT, Schirmer’s test) [18&&,55]. The third trial, a 2010 Other cell lines and findings German study, transitioned over 2000 patients from The damaging effects of preservatives on trabecular various BAK-preserved therapies to preservative-free meshwork cells are not as prominent, with relatively dorzolamide/timolol and found 80% of the patients similar cell viabilities after exposure to BAK- had improvement of local intolerability [56]. preserved (83%), SofZia-preserved (97%), and Poly- quad-preserved (97%) prostaglandin analogs. In nonpigmented ciliary epithelial cells, no difference Benzalkonium chloride: the whole story? was found in cell viabilities between preservatives Although most in-vitro studies demonstrate signifi- [37]. Corneal endothelial cells, although, have cant ocular toxicity from BAK and to a lesser degree shown decreased survival in BAK-preserved thera- Polyquad and SofZia, it is not as clear and consistent pies (travoprost, latanoprost) compared with in clinical trials. Whitson et al. [57] randomized preservative-free and SofZia-preserved timolol and 106 patients from BAK-preserved latanoprost to dorzolamide [51]. This toxicity diminished when either BAK-preserved latanoprost, bimatoprost, or therapies were diluted 100-fold, wherein all cell SofZia-preserved travoprost for 3 months and found viabilities were more than 80% with the exception no differences in conjunctival hyperemia and tear- of preservative-free dorzolamide (71%). This is film abnormalities. This was followed by a study consistent with the clinical rarity of endothelial wherein 678 patients on BAK-preserved latanoprost toxicity wherein cells encounter diluted BAK with OSD (OSDI 13) were randomized to continue and the suggested association of dorzolamide with on BAK-preserved latanoprost or switch to SofZia- corneal decompensation. preserved travoprost, wherein improvement was DNA damage as a molecular mechanism under- only seen in the mild OSDI group but no statistically lying BAK toxicity has been proposed by Ye et al., significant difference when all patients were who found a dose-dependent relationship with examined (mild, moderate and severe OSD) [58]. single and double-strand DNA breaks [36&]. The Furthermore, a 2012 study with 353 patients inflammatory mechanisms of Polyquad were also on either BAK-preserved travoprost or Polyquad- recently studied. Increases in NF-kB associated preserved travoprost were found to have no differ- inflammation and mediators IL-6 and IL-8 were seen ences in subjective symptoms, SPK, or conjunctival from Polyquad therapies greater than BAK [33]. hyperemia [53&&].

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Quality of life OSD and glaucoma are both known to affect quality of life [1,59]. Pouyeh et al. [59] found ocular surface symptoms determined by the Dry Eye Question- PQ-travoprost BAK-travoprost or N/A N/A naire five to correlate with a decrease in the ability to perform daily activities, ability to work, and emotional well being. In 61 patients with glaucoma and DES, number of instillations was found to significantly impact quality of life [60]. This was followed by a recent study with 124 patients, half with OSD by OSDI score. This study found that patients with OSD had a poorer quality of life by the GQL-15 scale. The strongest predictors of OSD were daily BAK more than four drops and more than prostaglandin analogs, adrenergic agonists Timolol-PF or BAK-Travoprost/ Timolol two topical glaucoma medications, whereas daily dose BAK more than three drops was an independ- ent predictor of OSDI score [4&&]. include irritation, burning, dry eye sensation, foreign body sensation; SZ, CONCLUSION With the multiple, daily topical instillations of medication for glaucoma treatment, a balance must be struck between microbiological safety and 3 month3 month 30 353 BAK-Latanoprost Various beta-blockers, PF-Tafluprost 6 week 372 PQ-Travoprost/Timolol iatrogenic OSD. Increasing options in glaucoma therapy are becoming available to ophthalmo- logists, and with them decisions on when to switch therapies based on class and preservative. Patients with OSD need to be addressed with a stepladder approach. After recognition of the problem, use of artificial tears is essential with lubricating gel and ointment added if needed. Short-term use of mild corticosteroids should be considered, although being watchful for steroid- induced elevation in IOP. Use of topical 0.05% cyclosporine should also be considered although fluorescein staining, TBUT, subjective symptoms adverse events: subjective symptoms, ocular hyperemia, SPK drug reactions: subjective symptoms, ocular hyperemia, conjunctival hyperemia not well studied in patients with glaucoma related OSD. When treatment of OSD is not showing clinical improvement, there must be a high index of suspicion for ocular allergy that should be treated with discontinuation and subsequent trial of a different class of active compound, keeping in mind cross-reactivity. Allergy to BAK should be suspected when there is documented intolerance of multiple medication classes, and, in these cases, a BAK-free or preservative-free medication prescribed. The increased cost of BAK-free and preservative- 2012 Crossover Tear osmolarity, corneal 2011 Prospective Secondary endpoints of adverse free medications can be prohibitive for many patients though. Generic, BAK-preserved glaucoma drugs may cost 2–10 times less than available pres- ] 2012 Observational Secondary endpoints of

] 2012 Observational Flare meter values 1 monthervative-free 28 Timolol-BAK and options. The most extreme example && &&

] 2012 Crossoveris SPK, conjunctivalthe hyperemia case 12month of timolol, 67 in BAK-Latanoprost which preservative- SZ-Travoprost & [53 [52 ] [9 free individual dose ampules cost approximately && et al. et al. 27 times more than the generic, BAK-preserved et al. [18 et al. counterpart (1 month supply of twice daily dosing [54] et al. with costs obtained from Epocrates www.drugstore. Table 2. Recent clinical trials studying preservative toxicity Kitazawa AuthorsStevens Year Type of trial Endpoints (in addition to IOP) Time N Initial Therapy Crossover therapy Januleviciene Gandolfi Aihara

BAK, benzalkonium chloride; mo,Sofia. months; PF, preservative free; PQ, polyquad; SPK, superficial punctate keratitis; Subjective symptoms generally com; san Mateo, California, USA). The same search

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for generic prostaglandin analog reveals an annual 9. Aihara M, Otani S, Kozaki J, et al. Long-term effect of BAK-free travoprost on & ocular surface and intraocular pressure in glaucoma patients after transition cost of approximately US$275, whereas the BAK-free from latanoprost. J Glaucoma 2012; 21:60–64. This crossover study evaluated SPK in patients who were transitioned to alternative prostaglandin analog cost is over preservative-free therapy who were followed up to 12 months. US$1100 annually. Costs for the newer, completely 10. Inoue K, Okugawa K, Kato S, et al. Ocular factors relevant to antiglaucoma- tous eyedrop-related keratoepitheliopathy. J Glaucoma 2003; 12:480– preservative-free prostaglandin analog as well as 485. preservative-free dorzolamide/timolol are more 11. Jaenen N, Baudouin C, Pouliquen P, et al. Ocular symptoms and signs with preserved and preservative-free glaucoma medications. Eur J Ophthal- difficult to find, however, information from both mol 2007; 17:341–349. the manufacturer and phone calls to local pharma- 12. Pisella PJ, Pouliquen P, Baudouin C. Prevalence of ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J cies found the cost to be similar to the brand, BAK- Ophthalmol 2002; 86:418–423. preserved alternatives (US$90–130 for a 1 month 13. Arici MK, Arici DS, Topalkara A, Guler C. Adverse effects of topical anti- glaucoma drugs on the ocular surface. Clin Experiment Ophthalmol 2000; supply). 28:113–117. Costs aside, some patients with severe OSD may 14. Arita R, Itoh K, Maeda S, et al. Effects of long-term topical antiglaucoma & medications on meibomian glands. Graefes Arch Clin Exp Ophthalmol 2012; not be able to tolerate any topical medication 250:1181–1185. regardless of preservative. 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