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Dogma vs Data: Prostaglandin Use in Glaucoma Patients With Uveitis

Do prostaglandins increase risk of uveitis flares, macular edema, and herpetic keratouveitis?

By: Debra A. Goldstein, MD, Jennifer Lee, MD
Glaucoma Physician September 1, 2020 Vol Ophthalmology Management 24, Issue September 2020 Page(s): 40, 41, 46

Related

Glaucoma is a common complication of uveitis. Thirty percent to 78% of uveitis patients develop elevated intraocular pressure (IOP) at some point in their disease course, and up to 23% develop glaucomatous damage.1-7 Elevated IOP may be a result of the inflammation itself, as well as a consequence of steroid treatment.4-8 Uveitic glaucoma cases are therapeutic challenges, and patients face a higher risk of blindness.2 Medical management is typically the first-line therapy; however, many clinicians are biased against using prostaglandin analogs (PGA). This practice is likely based on the early literature, which suggested a causal relationship between PGA and ocular inflammation.

The initial concerns regarding PGA-associated inflammation were based on rabbit data, which demonstrated increase blood–aqueous barrier (BAB) permeability with exogenous PGA.9,10 Subsequent data on humans treated with PGA revealed increased BAB breakdown as measured by anterior chamber (AC) flare.11 Later, retrospective data of 94 patients using latanoprost found a 6.4% incidence of iritis.12 Case reports also linked uveitis to bimatoprost13,14 and latanoprost.15 To support the hypothesis that PGA were the source of inflammation, AC cells were noted to resolve with discontinuation and recur with rechallenge testing.12,15 There was also evidence suggesting that PGA use resulted in macular edema (ME). Case series, retrospective data, and prospective data found clinically significant ME as well as angiographic edema in studies of pseudophakic and aphakic eyes.11,12,16-18 These findings portrayed PGA as proinflammatory, and investigators advised against using PGA in the setting of inflammation.

Challenging the Data on PGA in Uveitis

Taking a closer look at this literature suggesting that PGA be avoided in uveitis patients, there are significant flaws in the studies on which this recommendation was based. First, rabbit models are poor predictors of the human response to PGA. Rabbits have an evolutionarily advantageous labile BAB compared to primates.19 Investigators cautioned against PGA use in uveitis based on flare/BAB breakdown data. However, flare (increased aqueous protein) and cells (leukocytes) are independent, but related, processes,20 and the limited available animal data did not show an increase in cells with PGA.21

At the time, no controlled studies were done on the risk of anterior uveitis with PGA. In all patients who had reactivation of uveitis (increased cells) with rechallenge testing, their ocular histories were complicated by intraocular surgery, laser procedures, and/or history of uveitis.12,15 In a major review, the data demonstrating the risk of ME were also confounded by coexisting risk factors for ME: recent postoperative status, complicated intraocular surgery, posterior capsule rupture, retinal disease (eg, vein occlusion, epiretinal membrane), vitreous loss, underlying uveitis, aphakia, and diabetes status. No cystoid ME or increased aqueous flare were found in phakic eyes in these studies.22,23 Although increased central macular thickness measured by optical coherence tomography was observed in a study of phakic eyes, these changes were not clinically significant, and no patients progressed to develop intraretinal fluid, subretinal fluid, or changes in vision.24

More recent comparative studies of PGA, specifically in uveitic eyes, have also challenged the long-held dogma. Retrospective analyses found no significant difference in inflammatory relapses or ME in patients with a history of uveitis on PGA compared to those receiving other antiglaucoma agents.22,25-27 Also, the use of latanoprost did not worsen disease activity in patients with active uveitis.28 Large randomized multicenter trials have also failed to show increase risk of uveitis with 5 years of follow-up in patients receiving PGA compared to other agents.29

Herpetic Eye Disease

Classic teaching is that PGA should also be avoided in patients with herpetic eye disease. The purported risk of herpetic keratouveitis reactivation with the use of PGA was based on anecdotal case reports30,31 as well as rabbit models.32 However, the evidence should be questioned, because none of the rabbit models and only 1 out of 4 total patients had culture- or PCR-proven herpetic disease.30-32 This is especially problematic because PGA are ocular irritants with a well-documented history of causing pseudodendrites or medicamentosa-induced epitheliopathy.33 Again, no causal relationship was proved in a controlled manner. In general, patients with herpetic keratitis or keratouveitis are at risk of recurrence, independent of PGA use. A large claims-based study evaluating the association between ocular herpes simplex virus (epithelial, stromal, uveitis) and antiglaucoma agents found similar prevalence of herpetic disease in the group using latanoprost (0.11%) compared to other antiglaucoma agents (0.09%-0.16%) and compared to the general population (0.15%).34

Conclusion

Worsening anterior uveitis, herpetic keratouveitis, and ME are not proven side effects of PGA. Prostaglandin analogs are effective in lowering IOP, and they should remain a treatment option for uveitis patients. As a caveat, there are no data on PGA in active herpetic disease or active ME. Any patient starting PGA should be followed carefully, especially if there are risk factors for inflammation. The data are reassuring for patients who do flare on PGA; the uveitis is typically a mild anterior uveitis, and both AC inflammation and ME respond to discontinuation of PGA alone,12,13,16 a short course of steroids,12,14,16,23,27 or nonsteroidal agents.11,12,16-18 GP

Jennifer Lee, MD, completed a uveitis fellowship and Debra A. Goldstein, MD, is the Magerstadt Professor of Ophthalmology and director of the Uveitis Service in the Department of Ophthalmology at Northwestern University Feinberg School of Medicine in Chicago, Illinois. The authors report no relevant disclosures. Reach Dr. Goldstein at debra.goldstein@northwestern.edu.

References

  1. Herbert HM, Viswanathan A, Jackson H, Lightman SL. Risk factors for elevated intraocular pressure in uveitis. J Glaucoma. 2004;13(2):96-99.
  2. Moorthy RS, Mermoud A, Baerveldt G, Minckler DS, Lee PP, Rao NA. Glaucoma associated with uveitis. Surv Ophthalmol. 1997;41(5):361-394.
  3. Takahashi T, Ohtani S, Miyata K, Miyata N, Shirato S, Mochizuki M. A clinical evaluation of uveitis-associated secondary glaucoma. Jpn J Ophthalmol. 2002;46(5):556-562.
  4. Friedman DS, Holbrook JT, Ansari H, et al. Risk of elevated intraocular pressure and glaucoma in patients with uveitis: results of the multicenter uveitis steroid treatment trial. Ophthalmology. 2013;120(8):1571-1579.
  5. Goldstein DA, Godfrey DG, Hall A, et al. Intraocular pressure in patients with uveitis treated with fluocinolone acetonide implants. Arch Ophthalmol. 2007;125(11):1478-1485.
  6. Callanan DG, Jaffe GJ, Martin DF, Pearson PA, Comstock TL. Treatment of posterior uveitis with a fluocinolone acetonide implant: three-year clinical trial results. Arch Ophthalmol. 2008;126(9):1191-1201.
  7. Jaffe GJ, Martin D, Callanan D, et al. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology. 2006;113(6):1020-1027.
  8. Rush RB, Goldstein DA, Callanan DG, Meghpara B, Feuer WJ, Davis JL. Outcomes of birdshot chorioretinopathy treated with an intravitreal sustained-release fluocinolone acetonide-containing device. Am J Ophthalmol. 2011;151(4):630-636.
  9. Camras CB, Bito LZ, Eakins KE. Reduction of intraocular pressure by prostaglandins applied topically to the eyes of conscious rabbits. Invest Ophthalmol Vis Sci. 1977;16(12):1125-1134.
  10. Bhattacherjee P. Prostaglandins and inflammatory reactions in the eye. Methods Find Exp Clin Pharmacol. 1980;2(1):17-31.
  11. Arcieri ES, Santana A, Rocha FN, Guapo GL, Costa VP. Blood-aqueous barrier changes after the use of prostaglandin analogues in patients with pseudophakia and aphakia: a 6-month randomized trial. Arch Ophthalmol. 2005;123(2):186-192.
  12. Warwar RE, Bullock JD, Ballal D. Cystoid macular edema and anterior uveitis associated with latanoprost use. Experience and incidence in a retrospective review of 94 patients. Ophthalmology. 1998;105(2):263-268.
  13. Parentin F. Granulomatous anterior uveitis associated with bimatoprost: a case report. Ocul Immunol Inflamm. 2003;11(1):67-71.
  14. Packer M, Fine IH, Hoffman RS. Bilateral nongranulomatous anterior uveitis associated with bimatoprost. J Cat Refract Surg. 2003;29(11):2242-2243.
  15. Fechtner RD, Khouri AS, Zimmerman TJ, et al. Anterior uveitis associated with latanoprost. Am J Ophthalmol. 1998;126(1):37-41.
  16. Moroi SE, Gottfredsdottir MS, Schteingart MT, et al. Cystoid macular edema associated with latanoprost therapy in a case series of patients with glaucoma and ocular hypertension. Ophthalmology. 1999;106(5):1024-1029.
  17. Miyake K, Ota I, Maekubo K, Ichihashi S, Miyake S. Latanoprost accelerates disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema in early postoperative pseudophakias. Arch Ophthalmol. 1999;117(1):34-40.
  18. Yeh PC, Ramanathan S. Latanoprost and clinically significant cystoid macular edema after uneventful phacoemulsification with intraocular lens implantation. J Cataract Refract Surg. 2002;28(10):1814-1818.
  19. Bito LZ. Species differences in the responses of the eye to irritation and trauma: a hypothesis of divergence in ocular defense mechanisms, and the choice of experimental animals for eye research. Exp Eye Res. 1984;39(6):807-829.
  20. Bhattacherjee P, Hammond B, Salmon JA, Stepney R, Eakins KE. Chemotactic response to some arachidonic acid lipoxygenase products in the rabbit eye. Eur J Pharmacol. 1981;73(1):21-28.
  21. Kulkarni PS, Srinivasan BD. The effect of intravitreal and topical prostaglandins on intraocular inflammation. Invest Ophthalmol Vis Sci. 1982;23(3):383-392.
  22. Schumer RA, Camras CB, Mandahl AK. Latanoprost and cystoid macular edema: is there a causal relation? Curr Opin Ophthalmol. 2000;11(2):94-100.
  23. Arcieri ES, Pierre Filho PT, Wakamatsu TH, Costa VP. The effects of prostaglandin analogues on the blood aqueous barrier and corneal thickness of phakic patients with primary open-angle glaucoma and ocular hypertension. Eye (Lond). 2008;22(2):179-183.
  24. Selen F, Tekeli O, Yanik O. Assessment of the anterior chamber flare and macular thickness in patients treated with topical antiglaucomatous drugs. J Ocul Pharmacol Ther. 2017;33(3):170-175.
  25. Fortuna E, Cervantes-Castaneda RA, Bhat P, Doctor P, Foster CS. Flare-up rates with bimatoprost therapy in uveitic glaucoma. Am J Ophthalmol. 2008;146(6):876-882.
  26. Markomichelakis NN, Kostakou A, Halkiadakis I, Chalkidou S, Papakonstantinou D, Georgopoulos G. Efficacy and safety of latanoprost in eyes with uveitic glaucoma. Graefes Arch Clin Exp Ophthalmol. 2009;247(6):775-780.
  27. Chang JH, McCluskey P, Missotten T, Ferrante P, Jalaludin B, Lightman S. Use of ocular hypotensive prostaglandin analogues in patients with uveitis: does their use increase anterior uveitis and cystoid macular oedema? Br J Ophthalmol. 2008;92(7):916-921.
  28. Smith SL, Pruitt CA, Sine CS, Hudgins AC, Stewart WC. Latanoprost 0.005% and anterior segment uveitis. Acta Ophthalmol Scand. 1999;77(6):668-672.
  29. Goldberg I, Li XY, Selaru P, Paggiarino D. A 5-year, randomized, open-label safety study of latanoprost and usual care in patients with open-angle glaucoma or ocular hypertension. Eur J Ophthalmol. 2008;18(3):408-416.
  30. Kroll DM, Schuman JS. Reactivation of herpes simplex virus keratitis after initiating bimatoprost treatment for glaucoma. Am J Ophthalmol. 2002;133(3):401-403.
  31. Wand M, Gilbert CM, Liesegang TJ. Latanoprost and herpes simplex keratitis. Am J Ophthalmol. 1999;127(5):602-604.
  32. Kaufman HE, Varnell ED, Thompson HW. Latanoprost increases the severity and recurrence of herpetic keratitis in the rabbit. Am J Ophthalmol. 1999;127(5):531-536.
  33. Sudesh S, Cohen EJ, Rapano CJ, Wilson RP. Corneal toxicity associated with latanoprost. Arch Ophthalmol. 1999;117(4):539-540.
  34. Bean G, Reardon G, Zimmerman TJ. Association between ocular herpes simplex virus and topical ocular hypotensive therapy. J Glaucoma. 2004;13(5):361-364.

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