May 2013, Issue 57

Nonsteroidal Anti-inflammatory Drugs for Age-Related Macular Degeneration

Stephen J. Kim, MD Vanderbilt Eye Institute Vanderbilt University Medical Center Nashville, Tennessee

Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively in ophthalmology for pain and photophobia after photorefractive surgery and to reduce inflammation and cystoid macular edema following cataract surgery. In recent years, the U.S. Food and Drug Administration has approved new topical NSAIDs and previously approved NSAIDs have been reformulated. These changes may allow for greater drug penetration into the retina and therapeutic inhibition of retinal prostaglandins.

Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed classes of medications and are employed for their analgesic, antipyretic, and anti-inflammatory properties. A growing body of scientific evidence indicates that inflammation contributes to the pathogenesis of age-related macular degeneration (AMD)^1-3 and prostaglandins (PGs) are an important class of inflammatory mediators that are biosynthesized from arachidonic acid by the cyclooxygenase (COX) enzyme.⁴ NSAIDs are potent inhibitors of COX enzyme and thereby the synthesis of all downstream PGs. Within the eye, PGs increase vascular dilation, disrupt the blood-ocular barrier, and facilitate leukocyte migration.⁴ Consequently, their inhibition may have favorable effects on both intraocular inflammation and macular edema.⁵ There is increasing evidence that PGs play a role in the pathogenesis of AMD and, in recent years, there have been more studies examining the therapeutic application of NSAIDs for this condition.

Nonsteroidal Anti-Inflammatory Drugs
NSAIDs are a class of medications that lack a steroid nucleus and inhibit COX enzyme. COX enzyme catalyzes the production of five classes of PGs: PGE2, PGD2, PGF2α, PGI2, and Thromboxane A2. Two main isoforms of COX, COX-1 and COX-2, exist. COX-1 contributes to normal physiological processes while COX-2 is mainly upregulated during inflammatory responses. There are several topical NSAIDs that are commercially available for ophthalmic use, including ketorolac, diclofenac, nepafenac, bromfenac, and flurbiprofen. Ketorolac is reported to be the most potent inhibitor of COX-1, while bromfenac and amfenac are the most potent inhibitors of COX-2.^4,5 The relative importance of COX-1 versus COX-2 inhibition in ocular disease, however, remains unclear.

Age-Related Macular Degeneration
AMD is the leading cause of blindness in the United States; it is estimated that AMD will affect nearly 8 million Americans by 2020.⁶ Choroidal neovascularization (CNV) is the most common cause of severe vision loss in patients with neovascular AMD.^6-8 It is now firmly established that vascular endothelial growth factor (VEGF) is a principle mediator of CNV, but while VEGF inhibitors have been an important advance in treating neovascular AMD, they do not slow down the underlying disease process. Moreover, VEGF is essential for normal homeostasis of retinal cells and its chronic inhibition may, therefore, be undesirable.⁹ For example, chronic VEGF inhibition may potentially promote geographic atrophy.¹⁰ Consequently, it is clear that strictly inhibiting VEGF neither addresses the multifactorial pathogenesis of CNV nor the underlying cause of VEGF upregulation. An accumulating body of scientific evidence indicates that inflammation plays a central role in CNV.^1-3 An improved understanding of inflammatory mediators involved in VEGF induction may provide an opportunity to develop preventative strategies.

In this regard, COX-2 can be detected in human choroidal neovascular membranes¹¹ and considerable scientific evidence indicates that COX is a promoter of angiogenesis.^12-14 Patients who regularly take NSAIDs have a 40-50% reduction in mortality from colorectal cancer and a distinguishing feature of colorectal tumors is high expression of COX.¹⁴ Pharmacologic inhibition of COX appears to reduce VEGF expression in cultured human retinal pigment epithelium cells and suppresses VEGF in both trauma- and ischemia-induced models of retinal angiogenesis.^15-17 Furthermore, animal studies have consistently shown that pharmacologic inhibition of COX reduces CNV.^18-21 Finally, mice with genetic deletion of COX-2 have significantly less CNV in response to laser rupture of Bruch's membrane due to decreased retinal VEGF.²¹

Emerging clinical evidence also supports a potential therapeutic role of NSAIDs for AMD. A prospectively followed cohort of patients with rheumatoid arthritis had a low prevalence of AMD,²² and it was hypothesized that long-term anti-inflammatory treatment may have been responsible. In support of this, two recent prospective, randomized, controlled clinical studies reported favorable effects of topical bromfenac with respect to retinal thickness and reduced number of anti-VEGF treatments.^23,24 Flaxel and colleagues investigated combination treatment with topical bromfenac 0.09% for exudative AMD.²³ Patients received monthly intravitreal ranibizumab (IVR) for four months, followed by as needed treatment and were randomized to either combination treatment with IVR and bromfenac or IVR monotherapy. There was no observed difference with regards to vision or number of injections between groups, but there was a significantly greater reduction in central macular thickness (CMT) in the combination group (-82 microns) when compared to eyes treated with IVR monotherapy (-43 microns). In an independent study by Gomi and colleagues,²⁴ combination treatment with bromfenac 0.1% and IVR for exudative AMD significantly reduced the number of anti-VEGF injections needed compared to IVR monotherapy. Moreover, there was a trend of greater reduction of CMT in the combination group that almost reached the level of statistical significance (P = 0.06).

Conclusions
It is well established that inflammation plays a pathogenic role in AMD, and anti-inflammatory based therapies have great promise for delaying disease progression. Emerging clinical evidence indicates a potential therapeutic role for NSAIDs in AMD but more compelling clinical data is needed before routine application can be recommended.

Supported by an unrestricted grant from Research to Prevent Blindness to the Vanderbilt University School of Medicine Department of Ophthalmology and Visual Sciences.

Conflicts of Interest: None

REFERENCES
1. Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004;122:598-614.
2. Patel M, Chan CC. Immunopathological aspects of age-related macular degeneration. Semin Immunopathol. 2008;20:97-110.
3. Kim SJ, Toma HS. Inhibition of choroidal neovascularization by intravitreal ketorolac. Arch Ophthalmol. 2010;128(5):596-600.
4. Kim SJ, Flach AJ, Jampol LM. Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol. 2010;55:108-133.
5. Reddy R, Kim SJ. Critical appraisal of ophthalmic ketorolac (Acuvail) in the treatment of pain and inflammation following cataract surgery. Clinical Ophthalmology. 2011;5:751-58.
6. Friedman DS, O'Colmain BJ, Munoz B, et al. Prevalence of age-related macular degeneration in the United States. Archives of Ophthalmology. 2004; 122:564-572.
7. Brown GC, Brown MM, Sharma S, et al. The burden of age-related macular degeneration: a value-based medicine analysis. Transactions of the American Ophthalmological Society. 2005;103:173-184.
8. Folk JC, Stone EM. Ranibizumab therapy for neovascular age-related macular degeneration. New England Journal of Medicine. 2010;363:1648-55.
9. Yourey PA, Gohari S, Su JL, Alderson RF. Vascular endothelial cell growth factors promote the in vitro development of rat photoreceptor cells. Journal of Neuroscience. 2000; 20(18): 6781-88.
10. Saint-Geniez M, Kurihara T, Sekiyama E, Maldonado AE, D'Amore PA. An essential role for RPE-derived soluble VEGF in the maintenance of the choriocapillaris. Proc Natl Acad Sci USA.2009;106(44):18751-6.
11. Maloney SC, Fernandes BF, Castiglione E, et al. Expression of cyclooxygenase-2 in choroidal neovascular membranes from age-related macular degeneration patients. Retina. 2009; 29(2):176-180.
12. Monnier Y, Zaric J, and Ruegg C. Inhibition of angiogenesis by non-steroidal anti-inflammatory drugs: from the bench to the bedside and back. Current Drug Targets: Inflammation and Allergy.2005; 4(1):31-8.
13. Gately S, Kerbel R. Therapeutic potential of selective cyclooxygenase-2 inhibitors in the management of tumor angiogenesis. Progress in Experimental Tumor Research. 2003; 37:179-92.
14. Wu WK, Sung JJ, Lee CW, Yu J, Cho CH. Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms. Cancer Letters. 2010; 295:7-16.
15. Yanni SE, Barnett JM, Clark ML, Penn JS. The role of PGE2 receptor EP4 in pathologic ocular angiogenesis. Investigative Ophthalmology & Visual Science. 2009; 50:5479-86.
16. Amrite AC, Ayalasomayajula SP, Cheruvu NP, Kompella UB. Single periocular injection of celecoxib-PLGA microparticles inhibits diabetes-induced elevations in retinal PGE2, VEGF, and vascular leakage. Investigative Ophthalmology & Visual Science. 2006; 47:1149-60.
17. Takahashi K, Saishin Y, Saishin Y, et al. Topical nepafenac inhibits ocular neovascularization. Investigative Ophthalmology & Visual Sciences. 2003;44:409-15.
18. Hu W, Criswell MH, Ottlecz A, et al. Oral administration of lumiracoxib reduces choroidal neovascular membrane development in the rat laser-trauma model. Retina. 2005; 25:1054-64.
19. Takahashi H, Yanagi Y, Tamaki Y, Uchida S, Muranaka K. COX-2-selective inhibitor, etodolac, suppresses choroidal neovascularization in a mice model. Biochemical and Biophysical Research Communications. 2004; 325: 461-66.
20. Kim SJ, Toma HS, Barnett JM, Penn JS. Ketorolac inhibits choroidal neovascularization by suppression of retinal VEGF. Exp Eye Res. 2010; 91(4):537-43.
21. Rezaei KA, Toma HS, Cai, J, Penn JS, Sternberg P, Kim SJ. Reduced choroidal neovascular membrane formation in cyclooxygenase-2 deficient mice. Invest Ophthalmol Vis Sci. 2011;52(2):701-7.
22. McGeer PL, Sibley J. Sparing of age-related macular degeneration in rheumatoid arthritis. Neurobiolog of Aging. 2005; 26:1199-1203.
23. Flaxel C, Schain MB, Hamon SC, Francis PJ. Prospective randomized controlled trial of combination ranibizumab (Lucentis) and bromfenac (Xibrom) for neovascular age-related macular degeneration. Retina. 2012; 32:417-23.
24. Gomi F, Sawa M, Tsujikawa M, Nishida K. Topical bromfenac as an adjunctive treatment with Intravitreal ranibizumab for exudative age-related macular degeneration. Retina. 2012;32:1804-10.