Disease Course in Patients With Pentosan Polysulfate Sodium–Associated Maculopathy After Drug Cessation

Key Points

Question  How does the maculopathy associated with pentosan polysulfate sodium evolve after drug cessation?

Findings  In this case series of 11 adults observed for at least 6 months after pentosan polysulfate sodium cessation, there was no evidence of disease regression in any eye. Fundus autofluorescence imaging demonstrated expansion of the area of involved tissue in most eyes, including area of retinal pigment epithelium atrophy, and optical coherence tomography demonstrated collapse of nodular lesions at the level of the retinal pigment epithelium.

Meaning  These findings suggest that the maculopathy associated with pentosan polysulfate sodium may continue to evolve after drug cessation.

Importance  Recent studies have linked a vision-threatening maculopathy with long-term use of pentosan polysulfate sodium (PPS).

Objective  To evaluate the disease course in PPS-associated maculopathy after drug cessation.

Design, Setting, and Participants  In this retrospective case series, patients diagnosed with PPS-associated maculopathy with at least 6 months of follow-up after drug cessation who were treated at the Emory Eye Center, Atlanta, Georgia, or the Casey Eye Institute, Portland, Oregon, were included. Data were collected from April 2014 through November 2019.

Main Outcomes and Measures  Change in visual acuity and retinal imaging characteristics over time.

Results  Of the 11 included patients, all were female, and the median (interquartile range [IQR]) age was 53 (44-63) years. Participants had a baseline visit at a median (IQR) of 2 (0-4) months after drug cessation and were subsequently observed for a median (IQR) of 12 (8-26) months. The median (IQR) cumulative PPS exposure was 1.97 (1.55-2.18) kg. No eyes exhibited a demonstrable improvement in disease after discontinuing PPS. A total of 9 of 11 patients (82%) reported worsening visual symptoms at the final visit. The mean (SD) logMAR visual acuity was 0.14 (0.23) and 0.14 (0.34) at the baseline and final visit, respectively. Visual acuity improved by 2 or more Snellen lines in 1 eye (5%) and declined by 2 or more Snellen lines in 2 eyes of 1 patient (9%). There was evolution in the pattern of fundus autofluorescence changes and/or optical coherence tomography findings in all eyes. A total of 17 eyes (77%) exhibited expansion of the area of involved tissue. A total of 7 eyes (32%) had macular retinal pigment epithelium atrophy at the baseline visit, and atrophy enlarged after discontinuation of PPS in all 7 eyes, with a median (IQR) growth rate of 0.32 (0.13-0.38) mm per year.

Conclusions and Relevance  These retrospective data among 11 patients suggest PPS-associated maculopathy continues to evolve after drug cessation for at least 10 years. In some cases, progressive retinal pigment epithelium atrophy encroaches on the foveal center and thus may pose a long-term threat to central vision.

A 2018 report linked long-term use of pentosan polysulfate sodium (PPS) to a vision-threatening macular disease.¹ Subsequent larger studies have corroborated this finding, demonstrating a strong drug-disease association.^2-4 Affected patients typically report difficulty with reading and problems with dark adaptation. Retinal imaging demonstrates characteristic changes within the retinal pigment epithelium (RPE) and at the RPE-photoreceptor interface, with some patients exhibiting fovea-involving RPE atrophy.^3,5 Because PPS has been widely prescribed since its approval by the US Food and Drug Administration in 1996, thousands of patients are at risk.⁴

Although affected patients are typically advised to discontinue PPS therapy, little is known about the evolution of this newly described retinopathy after drug cessation. The present study is a retrospective evaluation of outcomes after drug cessation in a group of affected individuals across 2 institutions.

This retrospective study was approved by each participating institution’s institutional review board and was conducted at Emory University. Data collection was performed systematically and consistently for each patient across institutions, with the goal of performing a complete and transparent data analysis. Information was gathered and secured in compliance with the Health Insurance Portability and Accountability Act. All data were deidentified and shared securely with the Emory University study center. As this study involved retrospective medical record review with no more than minimal risk to participants, it met all requirements for a waiver of informed consent per institutional policy. A subset of patients at Emory University provided informed consent to participate in a prospective study evaluating long-term outcomes in PPS-associated maculopathy.

Electronic health records were queried for patients with a diagnosis of PPS-associated maculopathy and manually filtered to include only those patients who had reported discontinuation of the medication. Patients with at least 6 months of follow-up after discontinuing PPS and at least 2 visits when not taking the medication were included. Cases were identified at the Emory Eye Center, Atlanta, Georgia, and the Casey Eye Institute, Portland, Oregon.

Each medical record was analyzed for demographic information, visual symptoms, visual acuity, duration of treatment, daily and cumulative PPS exposure, date of and reason for discontinuation of PPS therapy, and follow-up interval after discontinuation. For the purposes of this study, the baseline visit was defined as the clinic visit on the day of drug cessation or the first clinic visit following. Drug exposures were calculated based on patient-reported intake.

Two expert image reviewers (R.S. and N.J.) independently evaluated fundus imaging to assess structural outcomes. All available imaging was assessed, with special attention paid to spectral-domain optical coherence tomography (OCT) (Spectralis HRA+OCT; Heidelberg Engineering), near-infrared reflectance (NIR) imaging (Heidelberg Engineering), and fundus autofluorescence (AF) imaging (California rg/af; Optos). Successive AF images were coregistered semiautomatically using Adobe Photoshop CS6 (Adobe Systems) and the TurboReg plugin for ImageJ using image landmarks, such as vessel branchpoints as anchors, for the registration.⁶ Follow-up OCT and NIR studies for most patients were obtained with the AutoRescan function, and B scans were thus available at the same retinal location on successive imaging sessions to allow for intervisit comparison. Images were assessed for the following changes between the baseline and follow-up visits: evolution of retinal or RPE lesions, change in area of disease involvement, change in area of macular RPE atrophy, change in macular central subfield thickness, change in subfoveal choroidal thickness, and new-onset RPE atrophy, cystoid macular edema (CME), or choroidal neovascularization. Discrepancies between imaging interpretations by the reviewers were resolved by discussion and consensus.

Retinal pigment epithelium atrophy was defined as an area of definitely decreased AF exceeding one-third of a disc diameter in area.³ Area of RPE atrophy was quantified on NIR images in Heidelberg Eye Explorer 2, and the square root transformation was applied to area measurements prior to computing the rate of change.⁷ Macular central subfield thickness was assessed for the central circular area of 1-mm diameter and computed after manual correction of OCT layer segmentations.⁸ Subfoveal choroidal thickness was assessed in ImageJ using enhanced-depth imaging OCT scans, measuring the distance from the Bruchs membrane–RPE complex to the choroidal-scleral interface.

Descriptive statistics were used to summarize demographic characteristics, exposure histories, and imaging findings. Medians are reported with the interquartile range (IQR) unless otherwise specified. Baseline vs final visual acuity and quantitative imaging outcomes were compared with the Wilcoxon signed rank test. Significance level was set at a P value less than .05, using a 2-tailed test. Given the correlation of intereye data among individuals, these data were averaged for each patient prior to comparing the baseline and final outcomes. Analyses were performed with Prism version 8.4 (GraphPad Software).

A total of 11 patients met the eligibility criteria. All 11 patients were female, and the median (range; IQR) age at baseline visit was 53 (37-68; 44-63) years. Patients had baseline visits at a median (range; IQR) of 2 (0-120; 0-4) months after drug cessation and were subsequently observed for a median (range; IQR) of 12 (7-45; 8-26) months (Table). Five patients were observed for at least 1 year. Six patients (55%) had discontinued PPS therapy after learning of its association with their macular disease. Two patients discontinued therapy in the remote past; patient 1 discontinued PPS 3 years prior to presentation and patient 6, 10 years prior to presentation. The median (range; IQR) treatment duration was 15 (3-22; 12-20) years. The median (range; IQR) daily dose was 380 (200-450; 300-400) mg, and the median (range; IQR) cumulative exposure was 1.97 (0.44-2.77; 1.55-2.18) kg (Table).

All patients reported visual symptoms at the baseline visit. Two patients reported first noticing visual symptoms years after discontinuation of PPS. The most common visual complaints were difficulty with near vision and reading (n = 6), prolonged dark adaptation (n = 4), nyctalopia (n = 4), and metamorphopsia (n = 3). Although these symptoms were not robustly characterized in this retrospective study, 9 patients (82%) described continued worsening of symptoms or new symptoms in at least 1 of their eyes, and 2 patients (18%) reported stability of their symptoms at the final visit (Table). No patient reported symptomatic improvement after drug cessation.

Mean (SD) logMAR visual acuities across the 22 eyes in this study at the baseline and final visits were 0.14 (0.23) and 0.14 (0.34), respectively (P = .79). Both eyes of patient 3 demonstrated 2 or more Snellen lines of worsening visual acuity, both in the setting of progressive center-involved RPE atrophy (eFigure in the Supplement). One eye of patient 6 demonstrated 2 or more Snellen lines of improvement in uncorrected visual acuity associated with resolution of CME.

All eyes demonstrated evolution of structural abnormalities in the retina at the final visit compared with baseline. Seventeen eyes (77%) exhibited expansion of the area of retinal changes, and 5 eyes (23%) exhibited no apparent growth in the area of diseased tissue. All eyes manifested subtle evolution in the distribution of hyperautofluorescent and hypoautofluorescent spots, most prominently at the margins of involved tissue, where there tended to be a larger proportion of hyperautofluorescent spots (Figure 1). In patient 1, expansion of the area of involvement occurred 3 years after drug cessation in spite of a low cumulative drug exposure (Figure 1).

All 7 eyes with macular RPE atrophy at baseline demonstrated growth of the area of RPE atrophy. The median (range; IQR) rate of growth of atrophy for these eyes was 0.32 (0.13-0.52; 0.13-0.38) mm per year (eTable in the Supplement). Cases of early or limited atrophy were small and paracentral. With time, coalescing patches of paracentral atrophy encroached on and involved the foveal center (Figure 2).

Serial OCT imaging demonstrated both growth and collapse of nodular lesions at the level of the RPE. In some cases, there was evidence of impending RPE atrophy characterized by attenuation of the outer retinal bands and progressive choroidal hypertransmission (Figure 3). A total of 15 of 17 eyes (88%) with coregistered OCT images sufficient for quantitative analysis had a decline in central subfield thickness, with a mean (SD) thickness of 280.0 (26.8) μm and 271.8 (26.8) μm at the baseline and final visit, respectively (P = .004). A total of 11 of 17 eyes (65%) had a decline in subfoveal choroidal thickness, with a mean (SD) thickness of 213.3 (111.7) μm and 210.5 (98.4) μm at the baseline and final visit, respectively (P = .17) (eTable in the Supplement).

Patient 6, who presented 10 years after drug cessation with new-onset difficulty reading, had bilateral CME that resolved with oral acetazolamide, initially prescribed by her outside ophthalmologist. It is unclear when this patient initially developed CME and if it was related to PPS use, although she had no other identifiable cause for CME. No eye in this small series developed choroidal neovascularization.

These retrospective findings suggest that eyes with PPS-associated maculopathy undergo continued evolution of retinal and RPE changes even after drug cessation. No patient in this series had a demonstrable improvement in disease after discontinuing PPS. Notably, eyes with RPE atrophy developed further enlargement of atrophy, in some cases threatening the foveal center years after drug cessation.

Patients in this study were observed for a minimum of 6 months after drug cessation, with 2 individuals having their baseline visit years after stopping therapy, demonstrating evolution of disease both in the near term and long term. Five individuals were observed for at least 1 year. All eyes exhibited evolution of structural alterations in the retina. Optical coherence tomography imaging demonstrated growth and decline of nodularities at the level of the RPE as well as a statistically significant decline in mean central subfield macular thickness across the cohort. Areas of atrophy grew and coalesced with time, ultimately threatening the foveal center in some eyes.

No patient exhibited substantial improvement in visual function during this study. Two eyes of a single patient developed a 2-line or greater decline in visual acuity in the setting of progressive foveal RPE atrophy. Of note, visual acuity did not appear to be a sensitive measure of visual dysfunction in this population, as it remained relatively normal except in patients with advanced cases with center-involved atrophy.³ Indeed, despite relatively stable visual acuities, nearly all patients expressed an ongoing worsening of visual symptoms at the final visit.

The finding of disease progression after drug cessation is not without precedent. Other medication-related retinopathies, notably toxic effects from hydroxychloroquine, also progress after cessation.^9,10 In the case of PPS-associated maculopathy, where the underlying mechanism of disease remains unclear, the cause for ongoing progression is uncertain. It is possible that there is persistence of a toxic compound within the diseased tissue after cessation. Alternatively, affected eyes may be initiated on a trajectory of progressive degeneration that may be difficult to halt, regardless of the presence of ongoing exposure.

This small study of 11 patients has several limitations. Follow-up intervals were not standardized, and follow-up duration was limited, as this condition was only recently described. The retrospective nature of the investigation introduces several forms of bias, including selection bias, information bias, and ascertainment bias, which in this study at tertiary referral centers may have enriched the sample with relatively severe cases of PPS-associated maculopathy. Another significant weakness was the paucity of visual function testing available. Visual acuity was the primary measure of visual function available across multiple visits, and a standardized testing protocol for best-corrected visual acuity was not used. Additionally, quantitative OCT-based metrics were not corrected for axial length, although no patient in this study had high refractive error.

These data suggest PPS-associated maculopathy continues to evolve after drug cessation. In some cases, progressive RPE atrophy may encroach on the central fovea years after drug cessation. It is possible that with longer-term follow-up, the anatomic progression noted in this series might lead to more significant changes in vision. This small retrospective series highlights the need for a longer prospective study of PPS-associated maculopathy to fully assess the visual impact of this condition. Such a study will help guide management decisions for patients with interstitial cystitis and aid in the counseling of patients affected by PPS-associated maculopathy.

Accepted for Publication: May 10, 2020.

Corresponding Author: Nieraj Jain, MD, Department of Ophthalmology, Emory University School of Medicine, 1365B Clifton Rd, NE, Ste 2400, Atlanta, GA 30322 (nieraj.jain@emory.edu).

Published Online: July 9, 2020. doi:10.1001/jamaophthalmol.2020.2349

Author Contributions: Drs Shah and Jain had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Jain.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Shah.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Shah, Jain.

Obtained funding: Jain.

Administrative, technical, or material support: Lyons, Rao.

Study supervision: Jain.

Conflict of Interest Disclosures: Dr Rao has received grants from the National Institutes of Health and Research to Prevent Blindness as well as research funds from the Leonard G. Miller Endowed Professorship and Ophthalmic Research Fund, Elaine Sandman Research Fund, Grossman Research Fund, and Marek and Maria Spatz Endowed Research Fund. Dr Jain has received grants from Foundation Fighting Blindness. No other disclosures were reported.

Funding/Support: Dr Jain received Career Development Award CD-C-0918-0748-EEC from Foundation Fighting Blindness. This research was supported in part by grant K08EY026654 from the National Eye Institute (Dr Rao) and funding from Research to Prevent Blindness (Dr Rao).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentation: Data contained herein were presented at The Macula Society 2020 Annual Meeting; February 21-22, 2020; San Diego, California.