Report

Prevalence of Maculopathy Associated with Long-Term Pentosan Polysulfate Therapy

Pentosan polysulfate (PPS; ELMIRON, Janssen Pharmaceuticals, Titusville, NJ) is a U.S. Food and Drug Administration–approved oral medication for interstitial cystitis. Numerous reports have been published detailing retinal toxicity with the use of PPS. Studies characterizing this condition are primarily retrospective, and consequently, alert and screening systems need to be developed to actively screen for this disease. The goal of this study was to characterize ophthalmic monitoring trends of a PPS-using patient sample to construct an alert and screening system for monitoring this condition.

A single-institution retrospective chart review was conducted between January 2005 and November 2020 to characterize PPS use. An electronic medical record (EMR) alert was constructed to trigger based on new PPS prescriptions and renewals offering ophthalmology referral.

A total of 1407 PPS users over 15 years was available for characterization, with 1220 (86.7%) being female, the average duration of exposure being 71.2 ± 62.6 months, and the average medication cumulative exposure being 669.7 ± 569.2 g. A total of 151 patients (10.7%) had a recorded visit with an ophthalmologist, with 71 patients (5.0%) having optical coherence tomography imaging. The EMR alert fired for 88 patients over 1 year, with 34 patients (38.6%) either already being screened by an ophthalmologist or having been referred for screening.

An EMR support tool can improve referral rates of PPS maculopathy screening with an ophthalmologist and may serve as an efficient method for longitudinal screening of this condition with the added benefit of informing pentosan polysulfate prescribers about this condition. Effective screening and detection may help determine which patients are at high risk for this condition.

Le polysulfate de pentosan sodique (PPS; ELMIRON, Janssen Pharmaceuticals, Titusville, New Jersey) est un médicament oral approuvé par la Food and Drug Administration américaine dans le traitement de la cystite interstitielle. Or, de nombreux rapports publiés font état de la toxicité rétinienne du PPS. Les études à ce sujet étant surtout de nature rétrospective, des systèmes d'alerte et de dépistage doivent être mis en place pour surveiller activement l'apparition de cet effet secondaire. Notre étude avait pour objectif de dépeindre les tendances en matière de surveillance ophtalmologique au sein d'un échantillonnage de patients qui reçoivent le PPS afin de mettre sur pied un système d'alerte et de dépistage de cette affection.

Un examen rétrospectif des dossiers médicaux des patients d'un seul établissement a été réalisé entre janvier 2005 et novembre 2020 afin de recenser l'utilisation du PPS. On a ensuite mis au point un système commandant le déclenchement d'une alerte lors de l'ajout de nouvelles ordonnances et de renouvellements d'ordonnances de PPS dans les dossiers médicaux électroniques (DME), de façon à offrir au patient la possibilité de consulter un ophtalmologiste.

Au total, 1407 patients qui ont pris le PPS pendant la période de 15 ans ont servi à décrire le patient type : 1220 sujets (86,7 %) étaient de sexe féminin; la durée moyenne de l'exposition au PPS était de 71,2 ± 62,6 mois; et l'exposition cumulée moyenne a atteint 669,7 ± 569,2 g. Une consultation en ophtalmologie figurait au dossier de 151 patients (10,7 %), et 71 patients (5,0 %) ont subi une tomographie par cohérence optique (OCT). L'alerte DME s'est déclenchée pour 88 patients sur une période de 1 an, dont 34 patients (38,6 %) qui avaient déjà été examinés par un ophtalmologiste ou avaient été dirigés vers un spécialiste en vue d'un dépistage.

Un outil annexé aux DME peut accroître le nombre de patients prenant le PPS qui sont orientés vers un ophtalmologiste en vue du dépistage d'une maculopathie. Cet outil pourrait également être efficace pour réaliser un dépistage longitudinal de cet effet toxique, sans compter qu'il permet d'aviser les prescripteurs de PPS d'un tel risque. Un dépistage efficace pourrait contribuer à identifier les patients qui courent un risque élevé de présenter cette affection.

To investigate the nationwide use of pentosan polysulfate (PPS) and screening practices for PPS maculopathy (PPM), with a focus on the timing and modalities used.

Population-based cohort study.

For evaluation of nationwide usage, 133 762 individuals who received PPS prescriptions between 2012 and 2021 were included. To investigate practice patterns, 55 487 individuals (referred to as overall users) who initiated PPS therapy between 2018 and 2020 were identified using the Health Insurance Review and Assessment database. After excluding patients with ophthalmic diseases before PPS administration, 34 857 PPS users without prior ophthalmic diseases were identified.

Ophthalmic examinations performed after initiating PPS therapy were categorized as baseline and subsequent monitoring examinations. The timing and modalities employed for these examinations were analyzed. The annual trends in PPS utilization and maculopathy screening were evaluated by assessing the number of PPS users and determining the proportion of patients receiving retinal/macular examinations among these users.

Performance of baseline and subsequent monitoring examinations and timing and modalities used for screening.

The number of PPS users dramatically increased annually over the study period from 5494 in 2012 to 40 451 in 2021. However, the majority of PPS users did not undergo baseline or subsequent monitoring examinations for PPM. Only 27.2% and 12.4% of PPS users without prior ophthalmic disease underwent baseline and monitoring examinations, respectively. Funduscopy/fundus photography was the most commonly utilized, whereas OCT and fundus autofluorescence (FAF) were performed in only 45.2% and 5.3% of the PPS users without prior ophthalmic diseases for monitoring, respectively. The performance of the screening examinations differed significantly across the 3 different daily dose and duration groups (all P < 0.05).

This study highlights the lack of performance of baseline and monitoring examinations for maculopathy in most patients taking PPS in South Korea. The limited use of OCT and FAF suggests potential insensitivity in detecting PPM. These findings emphasize the need for improvements in screening practices, including increased awareness and referrals to ophthalmologists, utilization of more sensitive modalities, and regular monitoring to enable early detection of PPM.

The authors have no proprietary or commercial interest in any materials discussed in this article.

To compare choriocapillaris flow deficit (CC-FD) analysis using optical coherence tomography angiography (OCTA) in eyes of patients treated with high cumulative dosages of pentosan polysulfate sodium (PPS) but no signs of retinal toxicity versus healthy age-matched controls.

Retrospective clinical cohort study.

Patients treated with PPS for interstitial cystitis with a cumulative dose of > 1000 g underwent multimodal imaging screening to exclude evidence of PPS maculopathy or other retinal findings. All study patients and age-matched healthy controls completed a 3 × 3 mm macular volume scan OCTA using the SOLIX full-range OCT. En face OCTA images at the level of the CC were exported and CC-FDs were computed and compared between groups.

Fifteen patients treated with PPS and 15 age-matched controls were included. The mean PPS cumulative dose was 1974 ± 666 g over a mean of 17.6 ± 6.8 treatment years. All patients registered a visual acuity of 20/25 or better and normal fundus autofluorescence (FAF), OCT, multicolor, near-infrared reflectance (NIR), and ultra-widefield fundus color and autofluorescence images. The CC-FD was 32.7 ± 3.6% in the PPS group compared with 28.6 ± 4.3% in the control group (P = .023).

Patients treated with PPS long enough to accumulate dosages > 1000 g showed significant CC flow impairment before the development of macular toxicity signs with OCT, NIR, and FAF compared with age-matched normal controls. Thus, the choroid may be the earliest manifestation of ocular toxicity, predating the development of clinically evident retinal pigment epithelium (RPE) injury. The subsequent RPE disruption may be the result of choriocapillaris impairment or primary PPS toxicity. Assessment of the CC on OCTA may be a useful tool for early detection of toxicity, although further longitudinal studies are required.

There is growing evidence of a direct association between pentosan polysulfate (PPS) therapy and the development of macular changes. Using standardized visual acuity (VA) testing and multimodal imaging, we investigated the impact of PPS therapy on vision and described an expanded spectrum of imaging findings among PPS users.

Cross-sectional screening study.

Thirty-nine patients who were current or recent users of PPS.

The participants underwent a brief eye examination and answered a comprehensive medical and ophthalmic history questionnaire. Color fundus photography, fundus autofluorescence (FAF), and spectral-domain OCT (SD-OCT) were performed. The images were evaluated by expert graders at Wisconsin Reading Center. Abnormalities were categorized as definite toxicity (DT) if seen on both FAF and SD-OCT and as questionable toxicity (QT) if seen on either FAF or SD-OCT.

ETDRS and Snellen VA, the dosage and duration of PPS exposure, and the prevalence of retinal toxicity on imaging.

The mean ETDRS and Snellen VA of the study cohort were 85 letters and 20/22, respectively. The mean PPS daily dose was 282 mg (range, 88–400 mg), whereas the mean cumulative dose was 915 g (range, 19–3650 g) over a mean period of 8.8 years (range, 2 months–25 years). There was evidence of retinopathy in 41% of the eyes; DT was identified in 24 eyes (31%) and QT in 8 eyes (10%). Retinal pigment epithelium (RPE) abnormalities (thickening or thinning or both) were present in all eyes with DT. Retinal pigment epithelium atrophy was seen in 7 eyes (9%). In addition to well-established findings, the unique SD-OCT features of this cohort included interdigitation zone abnormalities and the presence of a flying saucer–type defect. Fundus autofluorescence abnormalities were seen in 24 eyes (30.8%), with 20 (66.7%) of these exhibiting abnormalities located outside the central subfield and extending beyond the arcades.

Findings from the masked grading of multimodal imaging at a centralized reading center suggest a wider phenotypic spectrum of structural abnormalities among patients taking PPS. Macular changes selectively involve the RPE and outer retina, with a range of findings often seen beyond the arcades. The subtle and atypical findings in this cohort should prompt clinicians to consider lowering the threshold for diagnosing PPS retinopathy.