Meera S. Ramakrishnan
During the last 2 years, a novel maculopathy has emerged that has been linked to chronic exposure to pentosane polysulfate sodium (PPS) (Elmiron; Janssen Pharmaceuticals, Beerse, Belgium). PPS is a semisynthetic heparin-like macromolecule used to treat interstitial cystitis (IC), a chronic, incurable bladder pain syndrome manifesting as relentless bladder or pelvic pain, incontinence, and dyspareunia. PPS is the only oral option of the two U.S. Food and Drug Administration (FDA)-approved therapies for IC. It is estimated that IC affects more than 1 million individuals in the United States, predominantly women.1,2 Since compassionate use in 1986 and regulatory approval in 1996, PPS has been prescribed by urologists and gynecologists to hundreds of thousands of patients with IC.3,4
First reported in 2018 by Pearce et al. after remarkable diagnostic sleuthing, PPS exposure for treatment of IC was identified as the common thread linking six patients (six white women; median age: 60 years; age range: 37 to 62 years) reporting difficulty reading, paracentral scotomas, and prolonged dark adaptation despite relatively preserved visual acuity (VA).5 These patients were found to have retinal pigment epithelium (RPE) hyperpigmentation surrounded by subtle vitelliform-like deposits with highly irregular appearances on fundus autofluorescence (FAF) and near-infrared reflectance (NIR) imaging. Genetic screening and evaluation for hereditary retinal dystrophies and mitochondrial cytopathies were negative.
Subsequent case series and cohort studies demonstrated a pattern of PPS exposure characteristics and clinical features.6–8 In these studies, affected patients tended to be white women with a median age of 60 years (range: 37 to 79 years). Symptoms most commonly reported were blurred vision, prolonged dark adaptation, and metamorphopsia. The most common presenting diagnoses for these cases were macular or pattern dystrophy and age-related macular degeneration. VA correlated with degree of foveal atrophy, and in some cases, cystoid macular edema (CME) or choroidal neovascularization.6,9 There is one case of CME that was responsive to anti-vascular endothelial growth factor (VEGF) therapy.10
Clinical features of PPS maculopathy are quite distinct from other macular dystrophies or toxicity.5,6,11 These include 1) bilateral symmetric pathology centered on and frequently involving the fovea, 2) macular hyperpigmented spots, yellow-orange deposits, and/or patchy RPE atrophy, with 3) densely packed hyper- and hypoautofluorescent spots on FAF, and 4) focal RPE thickening on OCT with hyperreflectance on NIR imaging. In particular, a peripapillary hypoautofluorescent halo can be useful in distinguishing PPS maculopathy from ARMD and hereditary dystrophies that are usually peripapillary-sparing (Figure 1).11
Typical presentation of pentosane polysulfate sodium maculopathy. (A) Color fundus photos show bilateral hypopigmented spots and patchy retinal pigment epithelium (RPE) atrophy. (B) Near-infrared reflectance imaging highlights atrophy as areas of hyperreflectance and depicts the overall pigment disturbance, and (C) optical coherence tomography shows perifoveal areas of outer retinal and RPE atrophy with overlying intraretinal cysts (asterisk) and focal RPE thickening (arrows).
Pathogenesis remains unclear. Based on the prolonged exposure time and cumulative dose, the mechanism is potentially related to toxic PPS metabolites accumulating in the RPE, thereby disrupting processing of photoreceptor outer segments or the interphotoreceptor matrix.6 Another proposed mechanism involves fibroblast growth factor signaling pathways that affect retinal integrity and have been implicated in other retinal toxicity.12
The key question lies in identifying risk factors for developing maculopathy, especially the relationship to extent of cumulative drug exposure.
We evaluated the prevalence of PPS maculopathy in our population of 4.3 million patients in the Kaiser Permanente Northern California service areas.13 Among the patients studied, 2,510 (0.6%) carried a diagnosis of IC, of whom, 475 (0.01%) took PPS. Of the 138 patients who had cumulative exposure of at least 500 g, 85% underwent retinal imaging and were classified as definite, probable, or no PPS maculopathy. Twenty-seven (23%) patients had definite signs of maculopathy. A dose response was seen with definite maculopathy in 13% of patients taking 500 g to 999 g PPS daily and 42% of those taking more than 1,500 g PPS daily. Patients with maculopathy had mean cumulative drug exposure of 1,350 g compared with 1,040 g in those without maculopathy.
Other Findings in the Literature
The prevalence of maculopathy in patients taking PPS is estimated to be 20% to 25%.13,14 In a cohort of 219 patients with IC, patients with PPS exposure had an odds ratio (OR) of 11.25 for developing an unspecified pigmentary maculopathy, and all 14 patients with definite clinical characteristics of PPS maculopathy had exposure to PPS.7 No other IC therapy demonstrated a significant association with maculopathy. Patients with maculopathy reported duration of PPS intake ranging from 3 to 22 years (median: 16 to 17 years).5–7,13,14 Signs of PPS toxicity presented with cumulative drug exposures greater than 500 g, with more severe maculopathy after more than 1,500 g.13,14 A retrospective cohort study by Jain et al. involving a large U.S. claims database found that by 7 years, PPS users had significantly increased odds (OR: 1.41) of developing maculopathy compared with matched controls.15
In aggregate, these findings are potentially alarming and possibly represent a major patient safety issue. Many patients with PPS exposure may have been previously misdiagnosed with age-related macular degeneration or retinal dystrophies, which may have led to preventable, irreversible vision loss or misguided genetic counseling. Formal screening guidelines have yet to be developed but current findings suggest a baseline ophthalmologic evaluation prior to starting PPS therapy with FAF, NIR, and OCT. Retina imaging should likely be repeated annually, or at least once cumulative drug exposure approaches 500 g, and prescribers should be aware of the higher risk as cumulative dosage reach 1,000 g to 1,500 g.14 It remains unclear whether discontinuing PPS will halt or alter the course of maculopathy. Concerning new reports show progression and expansion of RPE atrophy even after drug cessation for a median of 12 months and up to 10 years.16,17
Discussion with urology and gynecology colleagues is key to raise awareness and inform their patients of risk of PPS toxicity.18,19 The FDA has now issued a warning based on these findings. Because of the severely debilitating pain IC patients experience, asking them to stop using PPS may also cause significant morbidity. Further investigation is warranted to explore pathogenesis and inform screening guidelines for this sight-threatening condition.
- Parsons CL. Evidence-based strategies for recognizing and managing IC. Contemp Urol. 2003;15(2):22–35.
- Curhan GC, Speizer FE, Hunter DJ, Curhan SG, Stampfer MJ. Epidemiology of interstitial cystitis: a population based study. J Urol. 1999;161(2):549–552. doi:10.1016/S0022-5347(01)61947-5 [CrossRef] PMID:9915446
- Kivlin D, Lim C, Ross C, Whitmore K, Schellato T. The Diagnostic and Treatment Patterns of Urologists in the United States for Interstitial Cystitis/Painful Bladder Syndrome. Urol Pract. 2016;3(4):309–314. doi:10.1016/j.urpr.2015.08.005 [CrossRef]
- Davis NF, Brady CM, Creagh T. Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and evidence-based treatment options. Eur J Obstet Gynecol Reprod Biol. 2014;175(4):30–37. doi:10.1016/j.ejogrb.2013.12.041 [CrossRef] PMID:24480114
- Pearce WA, Chen R, Jain N. Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium. Ophthalmology. 2018;125(11):1793–1802. doi:10.1016/j.ophtha.2018.04.026 [CrossRef] PMID:29801663
- Hanif AM, Armenti ST, Taylor SC, et al. Phenotypic spectrum of pentosan polysulfate sodium-associated maculopathy. JAMA Ophthalmol. 2019;137(11):1275–1282. doi:10.1001/jamaophthalmol.2019.3392 [CrossRef] PMID:31486843
- Hanif AM, Shah R, Yan J, et al. Strength of Association between pentosan polysulfate and a novel maculopathy. Ophthalmology. 2019;126(10):1464–1466. doi:10.1016/j.ophtha.2019.04.024 [CrossRef] PMID:31004677
- Vora RA, Patel AP, Yang SS, Melles R. A case of pentosan polysulfate maculopathy originally diagnosed as stargardt disease. Am J Ophthalmol Case Rep. 2020;17:100604. doi:10.1016/j.ajoc.2020.100604 [CrossRef] PMID:32043016
- Mishra K, Patel TP, Singh MS. Choroidal neovascularization associated with pentosan polysulfate toxicity. Ophthalmol Retina. 2020;4(1):111–113. doi:10.1016/j.oret.2019.08.006 [CrossRef] PMID:31570285
- Larochelliere ED, Bourgault S. Pentosan polysulfate sodium-induced pigmentary maculopathy with non-leaking cystoid macular edema successfully treated with anti-VEGF therapy. Retin Cases Brief Rep. 2020Jun5. doi:10.1097/ICB.0000000000001013 [CrossRef]. Online ahead of print. 10.1097/ICB.0000000000001013 PMID:32541441
- Barnes AC, Hanif AM, Jain N. Pentosan polysulfate maculopathy versus inherited macular dystrophies. Ophthalmol Retina. 2020;S2468–6530(20)30200–1. doi:10.1016/j.oret.2020.05.008 [CrossRef] PMID:32446908
- Greenlee T, Hom G, Conti T, Babiuch AS, Singh R. Re: Pearce et al.: Pigmentary maculopathy associated with chronic exposure to pentosan polysulfate sodium (Ophthalmology. 2018;125:1793–1802). Ophthalmology. 2019;126(7):e51. doi:10.1016/j.ophtha.2018.12.037 [CrossRef] PMID:31229012
- Vora RA, Patel AP, Melles R. Prevalence of maculopathy associated with long-term pentosane polysulfate therapy. Ophthalmology. 2020;127(6):835–836. doi:10.1016/j.ophtha.2020.01.017 [CrossRef] PMID:32085877
- Wang D, Au A, Gunnemann F, et al. Pentosan-associated maculopathy: prevalence, screening guidelines, and spectrum of findings based on prospective multimodal analysis. Can J Ophthalmol. 2020;55(2):116–125. doi:10.1016/j.jcjo.2019.12.001 [CrossRef] PMID:31973791
- Jain N, Li AL, Yu Y, VanderBeek BL. Association of macular disease with long-term use of pentosan polysulfate sodium: findings from a US cohort. Br J Ophthalmol. 2020;104(8):1093–1097. doi:10.1136/bjophthalmol-2019-314765 [CrossRef] PMID:31694837
- Shah R, Simonett JM, Lyons RJ, Rao RC, Pennesi ME, Jain N. Disease course in patients with pentosan polysulfate sodium-associated maculopathy after drug cessation. JAMA Ophthalmol. 2020;138(8):894–900. doi:10.1001/jamaophthalmol.2020.2349 [CrossRef] PMID:32644147
- Huckfeldt RM, Vavvas DG. Progressive maculopathy after discontinuation of pentosan polysulfate sodium. Ophthalmic Surg Lasers Imaging Retina. 2019;50(10):656–659. doi:10.3928/23258160-20191009-10 [CrossRef] PMID:31671200
- Wein AJ. Re: pigmentary maculopathy associated with chronic exposure to pentosane polysulfate sodium. J Urol. 2020;203(2):259–260. doi:10.1097/01.JU.0000614920.84680.c7 [CrossRef] PMID:31721679
- Lyons RJ, Ahmad S, Ansari S, Foote JE, Jain N. Pentosan-polysulfate associated macular disease in patients with interstitial cystitis. Obstet Gynecol. 2020;135(5):1091–1094. doi:10.1097/AOG.0000000000003794 [CrossRef] PMID:32282604