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INTRODUCTION

For all forms of glaucoma, the only currently known modifiable risk factor is the lowering of intraocular pressure (IOP). This may be accomplished through topical or systemic therapy, laser treatment to the trabecular meshwork via argon or selective laser trabeculoplasty, or laser treatment to the ciliary body through transscleral or endoscopic cyclophotocoagula-tion. Finally, as a last resort, incisional surgery can be considered. There has been some controversy regard-ing the use of prostaglandin analogs (PGA) in patients with uveitic glaucoma. This paper briefly describes the mechanism of glaucoma in uveitis, the background of PGA, their mechanism of action, the side-effects that have been seen in patients treated with PGA, and the effect these factors have on PGA use in uveitic patients.

UVEITIC GLAUCOMA

There are many mechanisms that produce elevated IOP in patients with uveitis. Trabeculitis causes high pressures from a direct effect by inflammatory cells on the outflow capacity of the trabecular meshwork. Additionally, the development of peripheral anterior synechiae with angle closure can decrease outflow.

Also, the development of posterior synechiae may eventually produce pupillary block. Finally, patients with uveitis may be on long-term steroid treatment to help control intraocular inflammation. A steroid response mechanism may then lead to an elevation of IOP. Prostaglandins have been shown to be effica-cious in lowering IOP in uveitic patients even when concurrently on steroid treatment.1-3

BACKGROUND ON THE PROSTAGLANDIN ANALOGS

Prostaglandins like travoprost and latanoprost are autocoids, or substances that are produced and released locally within tissues and act upon the prostanoid FP receptors. They are members of a larger family of substances called eicosanoids, which includes thromboxane and leukotrienes. It is argued that bimatoprost is derived from the endocannabinoid family and has a mechanism that mimics another autocoids group called pros-tamides. Therefore, to include both the prosta-glandin group and prostamide group, this class of ocular hypotensive agents have adopted broader terms such as hypotensive lipids or prostanoids to designate any substance that has prostaglandin agonist-like activity.

Seminars in Ophthalmology, 26(4-5), 285–289, 2011Copyright © 2011 Informa Healthcare USA, Inc.ISSN: 0882-0538 print/ 1744-5205 onlineDOI: 10.3109/08820538.2011.588650

Received 24 February 2011; accepted 15 March 2011

Correspondence: Michael B. Horsley, M.D.; Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02114. Email: mailto:horsley@sweye.com

24 February 2011

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15 March 2011

© 2011 Informa Healthcare USA, Inc.

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The Use of Prostaglandin Analogs in the Uveitic PatientMichael B. Horsley and Teresa C. Chen

Glaucoma Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA

ABSTRACT

Glaucoma is a disease process characterized by progressive optic nerve damage and corresponding visual field loss. It may be further categorized into either primary open-angle glaucoma or secondary glaucoma. These secondary glaucomas include glaucomas associated with uveitis and inflammation. Prostaglandin ana-logs (PGA) have been used to help lower intraocular pressure (IOP) in these often difficult to manage eyes. However, controversy exists concerning their use in uveitic patients due to the theoretically higher risk of anterior uveitis, development of cystoid macular edema (CME), and reactivation of herpes simplex keratitis (HSK). There is little evidence that PGA disrupt the blood-aqueous barrier and only anecdotal evidence sug-gesting an increased risk of these rare findings. PGA may be used in uveitic glaucoma when other topical treatments have not lowered IOP to the patient’s target range.

Keywords: prostaglandin analogs, uveitis, cystoid macular edema, Herpes simplex keratitis

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Isopropyl unoprostone or UF-021 (Rescula) was introduced in October 1994 in Japan and became the first prostaglandin that was used internationally. It was derived from the pulmonary metabolite prostaglandin F2 and is a docosanoid or 22-carbon molecule. It is a prodrug that lowers IOP in a dose-dependent fashion with twice daily dosing.

Introduced in June 1996, latanoprost 0.005%, or PhXA41 (Xalatan, Pharmacia & Upjohn, Kalamazoo, MI), was the first topical prostaglandin analog that was approved by the United States Food and Drug Administration (FDA). Latanoprost is an isopropyl ester prodrug of 17-phenyl substituted prostaglandin F2a. It is converted in the cornea to its active form. In its initial trials, latanoprost 0.005% reduced IOP by 25–35% with a single daily dose.4 One study showed that once daily dosing in the evening was more effective than twice daily dosing of timolol.5 Although Xalatan more recently has been marketed by Pfizer (New York, NY), generic latanoprost became available in the United States in 2011.

Bimatoprost 0.03% (Lumigan, Allergan Inc., Irvine, CA) is another prostaglandin F2a analog that was intro-duced in 2001. Structurally it is similar to latanoprost, but with a neutral ethylamide replacing the carboxylic acid. This agent has a minimal effect on prostaglandin F2a receptors. Its pressure-lowering effect is related to both the uveoscleral as well as the pressure-sensitive outflow pathways.6 As with latanoprost, when used once daily, it produces a flatter diurnal curve when compared to timolol alone or to a timolol and dorzol-amide combination.7 One meta-analysis revealed that bimatoprost seemed to improve IOP control by about 1-1.5 mmHg over latanoprost.8Noecker et al. compared each of the prostanoid agents over a six-month time-frame and found a small advantage for bimatoprost over both latanoprost and travoprost.9 In August 2010, the FDA approved Lumigan 0.01% as first-line therapy for the reduction of intraocular pressure. Although not without some controversy, it seems reasonable to institute a trial of bimatoprost if latanoprost is not effective.

Travoprost (Travatan, Alcon Laboratories, Fort Worth, TX) was introduced in 2001 and is an isopropyl ester of a potent prostaglandin F2a, which is highly selective for the prostaglandin FP receptor. Like latano-prost, its main mechanism of action is through increas-ing outflow facility. However, it is not clear how much is through the trabecular meshwork or the uveoscleral pathway.10 Compared to latanoprost, travoprost shows similar IOP level reduction over a 24-hour period but may have a longer duration of action.11Travatan Z, approved in September 2006, is preserved with SofZia and currently the only prostaglandin analog that does not include the preservative benzalkonium chloride (BAK), which has been shown to increase ocular sur-face disease.12

PROSTAGLANDIN ANALOG MECHANISM OF ACTION

It was first thought that prostaglandins were up-regu-lators of inflammation in the eye and other tissues. It was initially found that high doses of prostaglandins in rabbits were associated with significant hyper-emia, breakdown of the blood-aqueous barrier, and increased IOP.13Later studies have relegated low-dose prostaglandins to a minor and mostly regulatory role in ocular inflammation with some anti-inflammatory action.14,15

The main intraocular pressure-lowering effect of the PGA relies on increasing uveoscleral outflow.16 This is accomplished through activation of the FP receptor. Upon activation of this receptor by the PGA, the ciliary body relaxes, thus facilitating aqueous outflow. In addi-tion to increasing outflow, prostaglandins alter struc-ture. This remodeling may be related to latanoprost’s up-regulation of matrix metalloproteinase (MMP) I activity in the non-pigmented epithelium of the ciliary body.17 MMPs are neutral zinc-dependent endoprotei-nases which are involved in the normal remodeling of the trabecular meshwork. Their upregulation by PGA results in widening of connective tissue-filled spaces in the ciliary body as well as loss of trabecular meshwork extracellular matrix, leading to increased outflow in an animal model.18–20

Although the structural change described may be the most logical reason prostaglandins have a pressure-lowering effect, other recently described intracellular metabolic changes may contribute.21,22 Travoprost and latanoprost both seem to work directly on the FP receptors. However, some controversy remains as to the exact mechanism of bimatoprost. In addition to potentially working on the FP receptor, bimatoprost may also down-regulate enzymes that metabolize prostaglandins.23

PROSTAGLANDIN SIDE-EFFECTS

Each PGA is very effective in lowering intraocular pressure. In general, they are all very well tolerated systemically. But there are common ocular side-effects. The most frequently encountered side-effects of PGA include conjunctival hyperemia, ocular pruritis, peri-orbital skin pigmentation, iris color change, periorbital fat atrophy, and eyelash elongation.24 The XLT study compared latanoprost, bimatoprost, and travoprost and concluded that latanoprost had the best ocular tolerability while maintaining equal efficacy in lower-ing IOP.25

Other, more serious, side-effects have been reported with the use of PGA. These include intraocular inflam-mation, cystoid macular edema (CME), and reactivation of herpes simplex keratitis.

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Intraocular Inflammation

It has been established that high-dose prostaglandins play a role in mediating ocular inflammation. One theory of this up-regulation in inflammation focuses on prostaglandin-F2alpha stimulating the release of prostaglandin-E2, which then increases arachidonic acid release through phospholipase A2.26 There is debate concerning whether the use of PGA in patients with uveitis can reactivate inflammation due to the potential deleterious effect on the blood-aqueous barrier.27 Initial reports have implicated each PGA in blood-aqueous barrier disruption in pseudopha-kic and aphakic patients through higher mean flare values for each, as measured by a laser flare meter in the anterior chamber.28However, more recent stud-ies show no change in the blood-aqueous barrier in human subjects after using latanoprost.29 In addition, latanoprost or other PGA have not been shown to produce chemotaxis, a hallmark of inflammation, in experimental studies.30

Smith et al. described a group of patients who devel-oped uveitis while on latanoprost therapy.31 In their retrospective review of 527 patients who were treated with latanoprost, 5/505 (1.0%) of patients with no prior history of uveitis developed ocular inflammation after beginning treatment and 3/13 (23.1%) of patients who had a history of prior uveitis but it was inactive at the time of starting latanoprost developed a mild uveitis. In their final group, there was no increase of inflammation in patients with pre-existing cell and flare (0/9 patients). Another retrospective review of 94 patients revealed 6.4% (6/94 patients) had the development of anterior uveitis while on latanoprost.32 Each of these patients’ uveitis resolved upon cessation of latanoprost. There have been several other case series and case reports implicating travoprost, latanoprost, and bimatoprost with the development of anterior uveitis.33–36

Recently, Foster et al. studied flare-up rates with bimatoprost therapy in 42 patients (59 eyes) with uveitis.37They concluded that bimatoprost did not increase the rate of uveitis flare-ups in patients with uveitic glaucoma. In addition, they did not associate the use of bimatoprost with an increase likelihood of uveitis recurrence.

Finally, Chang et al. retrospectively compared 163 eyes with uveitis that had been treated with a prosta-glandin analog.2 In their series, they found that prosta-glandins reduced IOP significantly in this subtype of glaucoma and that there was no difference in the fre-quency of reactivation of anterior uveitis in those uveitis patients treated with prostaglandins versus other topi-cal hypotensive agents.

From these reports, it appears that there may be a relationship between PGA use and the rare devel-opment of anterior uveitis. There has been specula-tion that some individuals may be more sensitive to PGA leading to an increase in arachidonic acid and

eicosanoid production. The clinician should be aware of this relationship and monitor the uveitic patient accordingly for exacerbation of the uveitis after the initiation of PGA treatment.

Cystoid Macular Edema

The development of cystoid macular edema (CME) after cataract surgery (Irvin-Gass syndrome) is felt to be due to anterior segment inflammation with release of endogenous inflammatory mediators including prostaglandins. There is an increased risk of CME development in patients with diabetes, patients who have had laser capsulotomy, patients with posterior capsular rents during cataract extraction, patients who are aphakic, patients with a uveitis history, patients with retinal inflammatory disease or vascu-lar disease, and patients on chronic topical glaucoma medications.38–40 Since endogenous prostaglandins are associated with increased inflammation and the development of CME post-surgically, there is some controversy regarding the use of topical PGA for patients with uveitic glaucoma.

The overall incidence of CME in pseudophakic and aphakic eyes using PGA is estimated at 1-2%.30For high-risk patients who have aphakia or an absent or open posterior capsule and who are on latanoprost, Wand et al. estimated the overall incidence as 5%.41

There have been a number of reports of CME in patients receiving latanoprost, travoprost, and bimatoprost.41–47 Many of these patients had other risk factors for CME. Specifically, in the report by Lima et al., of the 185 patients treated with latanoprost after cataract surgery, only 4/185 (2.16%) of these patients had visual reduction from CME, and all of these patients had ruptured posterior capsules requiring anterior vitrectomy.48

There is controversy as to whether or not a true cause-and-effect relationship does exist between the development of CME in patients taking PGA. A sug-gested pathophysiological mechanism appears to sur-round the breakdown of the blood-aqueous barrier, thus allowing inflammatory mediators to reach the macula. Therefore, in uveitic patients they are more prone to have a break-down in this barrier due to inflammation. PGA may further provoke the formation of CME. However, a recent report specifically studying the development of CME in uveitic patients treated with prostaglandin analogs did not find an increased risk of its development.2 Interestingly, all 69 patients in this study with uveitis and no previous history of CME did not develop CME when treated with a PGA.

Herpes Simplex Virus

There are a few reports of reactivation of latent herpes simplex virus with the use of PGA.49Keratouveitis,

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pseudodendrites, and dendrites have been anecdotally reported.50 This seems to be a rare complication but has been replicated in an animal model with latanoprost.51,52 One retrospective study evaluated nearly 100,000 glau-coma patients treated with PGAs, and 411 of these patients had a previous history of herpes simplex keratitis (HSK).53 They determined the rate of HSK in this group (0.11%) to reflect the normal population (0.15%)54and not correlated with an increased risk from the use of PGA. However, based on a few anecdotal reports, caution must be taken when starting PGA in patients with a previous history of HSK.

SUMMARY

The use of prostaglandin analogs in uveitic patients remains controversial. A causal relationship has yet to be established between prostaglandins and the reacti-vation of anterior uveitis, the development of cystoid macular edema, or the reactivation of HSK.

Due to the efficacy of prostaglandins in lowering IOP in patients with uveitis and the small likelihood of developing these rare complications, prostaglandin analogs should remain in the treatment algorithm of uveitic glaucoma patients.

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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