Abstract
Purpose:
To report the practices and outcomes of ophthalmic evaluations for pentosan polysulfate sodium (PPS) maculopathy at a single institution.
Methods:
This study was conducted on patients of Massachusetts Eye and Ear who had documented PPS exposure and an ophthalmic encounter from 2019 through 2022. The main outcomes were examination components performed and identification of PPS maculopathy. Image analysis confirmed findings.
Results:
Thirty-seven patients were included. Of the initial encounters, optical coherence tomography (OCT) was documented for 29 (78.4%) patients, fundus autofluorescence (FAF) for 13 (35.1%), and color fundus photography (CFP) for 12 (32.4%). Four cases (10.8%) of PPS maculopathy were observed. Mean (range) duration of exposure was 17 (15–20), and mean (range) cumulative exposure was 2418 (2190–2628) mg. Maculopathy did not occur until after 15 years of exposure and greater than 2000 mg of cumulative exposure. Three cases (8.1%) of PPS maculopathy were evaluated following drug cessation over a mean of 18.3 months. Two cases (5.4%) of PPS maculopathy progression post-cessation over durations of 1.1 and 4.3 years were described.
Conclusion:
We found inadequate imaging and documentation of OCT, CFP, and FAF to evaluate for toxicity in patients with a history of current or past PPS exposure. This study contributes four cases of PPS maculopathy to the growing literature reporting the phenotypic spectrum of toxicity, including two cases of maculopathy progression following drug cessation. There is a need for evaluations post-cessation due to possible progression of maculopathy, so patients are not treated inappropriately for differential diagnoses.
Plain language summary
We conducted a retrospective study to assess evaluation practices for pentosan polysulfate use. We found that providers may be underutilizing retinal imaging. We found low rates of toxic maculopathy and high mean exposures for the development of maculopathy. Finally, we report two cases of disease progression post-drug cessation.
Introduction
Recent studies have highlighted maculopathy as a potential consequence of prolonged pentosan polysulfate sodium (PPS; Elmiron®; Janssen Pharmaceuticals, Titusville, NJ, USA) use.1,2 PPS is the only medication approved by the Food and Drug Administration (FDA) to treat interstitial cystitis (IC). Reported visual symptoms may include nyctalopia, blurred vision, and metamorphopsia, with characteristic retinal findings of retinal pigment epithelium (RPE) changes.1–3 After these discoveries, the FDA updated the PPS label in June 2020 to include an adverse effect of retinal pigmentary changes.
While the risk of PPS maculopathy has been demonstrated to increase with higher cumulative exposure, duration of use, and daily dosages, the thresholds remain unclear. 4 Ophthalmologists at the Emory Eye Center, as well as The Macula Society, recommend that all patients initiating treatment of PPS should undergo annual comprehensive retinal screening evaluations, including color fundus photography (CFP), fundus autofluorescence (FAF), optical coherence tomography (OCT), and near-infrared reflectance (NIR).4,5 A study by Wang et al. recommends screening evaluations within 6 months of PPS initiation and annual screenings as patients approach 500 g of cumulative exposure, that is, approximately 4.6 years if the patient is taking the standard 300 mg daily dose. 3
To date, major ophthalmology organizations, including the American Academy of Ophthalmology, have not published rigorous, standardized screening guidelines. As a result, more data is necessary to estimate the prevalence of PPS maculopathy and to assess the appropriate evaluation modalities for the disease.
This study aims to report the examination practices and outcomes of ophthalmic evaluations for PPS maculopathy at a single academic institution.
Methods
This retrospective study was conducted at Massachusetts Eye and Ear (MEE). The study conformed to the tenets of the Declaration of Helsinki and was approved by the Mass General Institutional Review Board (protocol #2022P003082).
The Partners Research Patient Data Registry (RPDR) is the centralized clinical data warehouse at the Mass General Brigham integrated healthcare system. The RPDR was used to obtain a list of all patients with electronic health records (EHRs) within the Mass General Brigham network with documented prescriptions of PPS from the earliest date available to the date of data retrieval. The RPDR generated a detailed patient dataset that captured data on demographics, including age, gender, race, ethnicity, as well as clinical encounter details, diagnoses, and PPS exposure.
We isolated a subset of patients within the study period, January 1, 2019 to 1 January 1, 2023 who had (1) a documented encounter with an MEE ophthalmologist, and (2) an ophthalmic encounter with the linked ICD code Z79.899, defined as “high-risk medication use.”
A retrospective chart review on this subset was completed by two study authors (D.H. and E.W.). Additional variables captured included encounter characteristics, specialty of ophthalmologist, PPS exposure (dosage, duration, cumulative dosage, cessation), exposure to other medications associated with retinal toxicity, diagnoses, visual symptoms, tests (Humphrey’s visual field, OCT, OCT with angiogram, fluorescein angiography, FAF, CFP, and ERG), findings, assessments, visual acuity (VA) converted to Logarithm of the Minimum Angle of Resolution (logMAR), and follow-up encounters.
Ophthalmic evaluation for PPS use was defined as an encounter with an ophthalmologist for which the risk for PPS toxicity or maculopathy was explicitly mentioned in the encounter documentation. The initial encounter was defined as the first encounter that met the definition for an ophthalmic evaluation for PPS. Inclusion criteria were patients who had an ophthalmic evaluation for PPS use within the study period. Exclusion criteria were patients for whom the purpose of the ophthalmic encounter was to evaluate for toxicity associated with non-PPS medications, including hydroxychloroquine. 6
PPS maculopathy was determined by explicit chart documentation and verified with image analysis. For all patients with unclear PPS maculopathy, subsequent image analysis was conducted to confirm diagnoses and characterize findings. Snellen VA was converted to logMAR. 7 For non-Snellen equivalents, counting fingers was assigned a logMAR of 2.1. 8 There were no patients for whom VA was worse than counting fingers. For the reporting of patients with PPS maculopathy, visits that occurred after the study period were included in the analysis to capture longitudinal findings.
Image analysis
All available retinal imaging was reviewed by an expert reviewer (M.K.) to confirm the diagnosis of PPS maculopathy. Testing included color and non-color fundus photography (Spectralis® (Heidelberg Engineering®); Topcon®), OCT (Spectralis®; Cirrus® 5000 and 6000 (Carl Zeiss Meditec®)), FAF (California® (Optos®); Spectralis®), and NIR imaging (Spectralis®).
Image analysis included characterization of macular involvement, severity, symmetry, and progression. Disease progression was defined as an increase in affected retinal area on subsequent imaging that was visually detectable by the expert reviewer (M.K.). The analysis included the degree of RPE changes, including atrophy, pattern of pigmentation, and involvement of the vascular arcades and fovea. FAF analysis included hyper- and hypo-autofluorescence (AF) patterns, and involvement of the arcades and fovea.
Disease staging was categorized according to two systems described in previous literature. Hanif et al. categorized mild, moderate, and severe disease as “disease contained within the vascular arcades and lacking atrophy,” “disease reaching but not extending more than two disc diameters beyond the temporal vascular arcades, or the presence of noncentral RPE atrophy” and “disease extending greater than two disc diameters beyond the temporal vascular arcades or the presence of RPE atrophy involving the foveal center,” respectively. 2 Wang et al. categorized mild, moderate, and severe disease as “no atrophy,” “discrete areas of atrophy,” and “diffuse atrophy,” respectively. 3
Primary outcome measures were examination components of the ophthalmic evaluation and detection of PPS maculopathy. Secondary outcomes were characteristics of PPS maculopathy.
Descriptive statistics, including mean with standard deviation for continuous variables, and percentages for categorical variables, were used to analyze all data collected. Analysis was performed using Microsoft® Excel® (2024).
Results
The RPDR yielded 530 patients who (1) received an ophthalmic visit within the study period, and (2) had PPS documented on their medication history. Sixty-five of these patients (12.3%) had the ICD code Z79.899 linked to an ophthalmic encounter. Eighteen patients (3.4%) were excluded for receiving hydroxychloroquine screening in the encounter assessments. Ten patients (1.9%) were excluded due to a lack of documentation of PPS retinal toxicity or for its mention in encounter assessments that occurred outside the study period. Thirty-seven patients (7.0%) met the inclusion criteria for receiving an ophthalmic evaluation for PPS.
Demographics and PPS exposure
The demographic data is reported in Table 1. Fourteen patients (37.8%) were still taking PPS at the first visit. Four patients (10.8% 9 ) stopped taking PPS during the study period in response to an ophthalmic encounter, and five (13.5%) reduced or attempted to decrease the dosage of PPS due to long term resolution of IC symptoms and to minimize risk for maculopathy. The remaining five (13.5%) continued taking the medication without changing the dose. For the 23 patients (62.2%) who had ceased PPS use prior to the initial encounter, the median duration since last dose was 15.5 months.
Characteristics of patients taking pentosan polysulfate sodium.
Race not reported for one patient without PPS maculopathy.
BMI data unavailable for eight patients.
PPS, pentosan polysulfate sodium.
PPS exposure data were not explicitly detailed for one patient (2.7%). For the remaining 36 patients (97.3%), the median duration of PPS use at the first encounter was 13 years. The median daily PPS dosage was 300 mg. The median cumulative PPS exposure was 1168 g.
Prior ophthalmic diagnosis
Twenty-seven of the 37 evaluated patients (73%) had existing ophthalmic diagnoses before the initial encounter. Twelve (32.4%) had prior vitreoretinal diagnoses, including three patients (8.1%) with dry AMD.
Ophthalmic evaluations for PPS
The evaluation characteristics are displayed in Table 2. Fourteen patients (37.8%) self-reported PPS use leading to the initial evaluation. Referrals for PPS to ophthalmic providers were made for 20 (54.1%) patients: internal medicine (9), ophthalmology (5), optometry (4), and other (2). For seven patients (18.9%), PPS exposure was identified during a routine ophthalmic encounter. Twenty-three patients (62.3%) were evaluated by retina specialists. Eleven patients (29.6%) were enrolled in a prospective study evaluating PPS maculopathy (unpublished data).
Characteristics of ophthalmic evaluations.
CFP, color fundus photography; FAF, fundus autofluorescence; OCT, optical coherence tomography.
Median follow-up interval for the 32 patients (86.5%) with scheduled follow-up was 12 months. Median follow-up interval if scheduled was 6 months for the four patients (10.8%) with PPS maculopathy, 12 months for the 28 patients (75.7%) without PPS maculopathy, 9 months for the 10 patients (27%) who continued taking PPS with or without dose reduction, and 12 months for the 18 patients (48.6%) who had ceased PPS use before the initial encounter. Five of the 23 patients who had ceased PPS use (21.7%) before the initial encounter had no scheduled follow-up encounter. One of the ten patients (10%) who continued PPS use had a follow-up interval scheduled for every 2 years. Mean duration within study period per patient was 1.6 years (standard deviation, 1.1 years; range, 0.1–4.3 years).
The most common visual symptoms reported were difficulty reading (32.4%), blurry vision (32.4%), and floaters (24.3%).
All patients received a baseline eye exam during their initial encounter. At the initial encounter, OCT of the retina was documented for 29 patients (78.4%), FAF for 13 (35.1%), color fundus photography (CFP) for 12 (32.4%), and NIR was not explicitly documented for any patients. ERG (19%), Humphrey’s visual field (35%), and OCT with angiogram (8%) were not routinely performed for all patients evaluated.
Five patients (13.5%) were observed to have macular pathologies not attributed to PPS, including retinal ischemia, cellophane retinopathy, RPE mottling, vitreomacular adhesion, and dry AMD.
PPS maculopathy
Four of the 37 evaluated patients (10.8%) were diagnosed with PPS maculopathy (Table 3). The mean (range) age at the initial encounter was 71 (54–85) years. The mean (range) number of years on PPS at first visit was 17 (15–20). The mean (range) daily dosage was 371.4 (300–400) mg. The mean (range) of cumulative PPS exposure was 2418 (2190–2628) mg. Three patients had prior diagnoses of dry AMD. Three patients were evaluated following cessation of PPS over a mean (range) of 25.8 (13.2–51.6) months.
Characteristics of patients with PPS maculopathy.
Exam obtained at initial evaluation.
Disease staging by both Hanif et al. and Wang et al. correlated in severity for each patient.
We observed PPS maculopathy in patients with cumulative exposures of greater than 2000 g. No maculopathy was observed for the 25 patients with cumulative exposures up to 2000 g. Of the five patients with cumulative exposures from 2001 to 2500 g, two (40%) had PPS maculopathy. For the six patients with cumulative dosages greater than 2500 g, two (33.3%) had PPS maculopathy.
We found PPS maculopathy in patients with 15 years of use or more. No maculopathy was observed for the 25 patients with exposure durations up to 15 years. For the five patients with exposure durations from 15 to 20 years, two (40%) had PPS maculopathy. For the seven patients with exposure durations from 21–25 years, two (28.6%) had PPS maculopathy.
We noted PPS maculopathy in patients with daily dosages of 300 mg or greater. No maculopathy was observed in the two patients with daily dosages of 100 mg. No maculopathy was observed for the five patients with daily dosages of 200 mg. Of the 24 patients with daily dosages of 300 mg, three (12.5%) had PPS maculopathy. Of the three patients with daily dosages of 400 mg, one (33.3%) had maculopathy. No maculopathy was found in the two patients with daily dosages of 600 mg.
Disease stages correlated between the Hanif et al. and Wang et al. systems were mild in both eyes for three patients ((Table 3) patients 1, 3, 4). One patient was observed with moderate stage in the right eye and severe in the left eye ((Table 3) patient 2). Disease progression was observed on longitudinal follow-up over a mean duration of 2.7 years for two of the four patients, as characterized below ((Table 3) patients 1 and 2).
Patient 1
Sixty-seven-year-old woman presented for a new diagnosis of dry AMD. Her IC was actively being treated with PPS. She complained of scotoma and delayed dark adaptation. Subsequently, the patient reported worsening VA, diplopia, metamorphopsia, and abnormal color perception. PPS exposure, VA, and ancillary exams are in Table 3. Images are displayed in Figure 1.
Patient 1 FAF, CFP, and OCT at Initial and Latest Encounters. Row 1: Right Eye Initial. Row 2: Right Eye Latest. Row 3: Left Eye Initial. Row 4: Left Eye Latest.
Patient 2
Seventy-seven-year-old woman presented for evaluation of retinal atrophy. Past medical history revealed dry AMD. Her IC was treated with PPS, which she self-discontinued 22 years prior. She complained of photophobia and reported stable vision at subsequent encounters. PPS exposure, VA, and ancillary exams are in Table 3. Image findings are displayed in Figure 2.
Patient 2 FAF, CFP, and OCT at Initial and Latest Encounters. Row 1: Right Eye Initial. Row 2: Right Eye Latest. Row 3: Left Eye Initial. Row 4: Left Eye Latest.
The summary of findings is displayed in Table 4.
Summary of Findings.
CFP, color fundus photography; FAF, fundus autofluorescence; OCT, optical coherence tomography.
Discussion
This retrospective study describes ophthalmic evaluation practices and outcomes for PPS use. We found that many patients had not been documented with retinal evaluations that align with previous recommendations. Of the patients evaluated for PPS maculopathy, four (11%) had PPS maculopathy with high cumulative exposures. Three were diagnosed post-PPS cessation. Two were observed to have progression of PPS maculopathy on longitudinal follow-up.
With 37.8% of patients self-reporting PPS use leading to initial evaluation, prescribers of PPS and ophthalmologists may be under-evaluating or under-documenting its use. Only three of 38 patients with a diagnosis of AMD from the initial patient set prior to exclusions who had a documented history of PPS and an ophthalmic encounter also had a documented evaluation for PPS. PPS maculopathy may be underrepresented in the differential diagnoses for RPE changes, including AMD, pattern dystrophy, and other macular dystrophies. 4 Our findings support the previously reported need for increased retinal evaluation for all patients with a history of PPS use.4,10
This study does not report screening practices, as our definition of ophthalmic evaluation may not meet the clinical intention nor adhere to recommendations for screening.3,4
Our findings may further contribute to the development of screening guidelines. Past studies have recommended yearly exams with CFP, FAF, OCT, and NIR. 4 While we found that providers obtain OCT for the majority of the patients evaluated, 100% of patients should obtain OCT. Providers may also be underutilizing or under-documenting FAF. However, FAF and NIR may have been captured as part of the OCT imaging modality, Spectralis®, and were not explicitly noted. Clinically, we have found FAF to be the most sensitive to retinal change for our PPS patients, although OCT and CFP are still important components of a retinal evaluation. The documented imaging available may reveal underperformance for PPS retinal evaluations, a trend previously observed at other institutions.10,11 We recommend that ophthalmologists minimally obtain FAF and OCT at every evaluation or refer the patient to a facility that can perform the necessary imaging. Additional tests, including NIR and multifocal ERG, can be performed at the discretion of the ophthalmologist.3,4
This study contributes data to the association between PPS and the development of maculopathy. In a review of nine studies evaluating PPS toxicity in 84 patients, Myers, Hanif, and Jain found that the mean (SD) duration of the drug use was 15 years (5.7) and the mean (SD) cumulative exposure was 1824 g (1042).2–4,10,12–17 We found higher mean duration (17 years) and cumulative exposure (2418 g) for the diagnosis of PPS-related maculopathy. The absence of PPS maculopathy in patients with <2000 g cumulative exposure and less than 16 years of use provides data regarding risk thresholds, although toxicity might still occur at lower cumulative doses.
This study contributes four cases to the phenotypic spectrum of PPS retinal toxicity, including two cases of maculopathy progression after more than 3 years of cessation. We found that visual symptoms and VA loss may progress even if exam findings remain stable, and vice versa. Previous reports have demonstrated that PPS maculopathy may progress for ten years following cessation, but the exposure threshold for toxicity progression is unclear.16–20 Providers should inquire about PPS use for patients with a history of IC who present with atypical RPE changes, even if the patient is no longer taking the drug. Likewise, prescribers of PPS should be aware of possible retinal toxicity and refer the patients for screening.
Initial retinal evaluation for PPS maculopathy after drug cessation is important in the context of evolving treatment approaches to differential diagnoses, including AMD with geographic atrophy, which may now be treated with complement inhibitors, including pegcetacoplan (Syfovre®; Apellis Pharmaceuticals, Inc.®). 9 As cystoid macular edema (CME) and choroidal neovascularization (CNV) may be treatable manifestations of severe retinal toxicity, there is utility in continued monitoring for PPS maculopathy after drug cessation, with follow-up interval determined by the severity and stability of the condition.5,21 Besides drug cessation, there are no current treatments that may reverse PPS maculopathy without CME or CNV. In addition, there are no recommendations for screening for PPS toxicity post-drug cessation. In our study, we find that providers may or may not schedule follow-up after initial encounter if patients had ceased PPS use and had no evidence of toxicity on evaluation. In the context of possible disease progression, we recommend that patients continue receiving annual evaluation post-cessation, even if the initial exam reveals no definitive retinal toxicity.
Limitations
The retrospective nature of this study presented inherent limitations, including dependency on accurate coding, written documentation, and image access. We were not able to retrieve significant granularities regarding drug use, clinical decision-making, and encounter details with providers not affiliated with Mass General Brigham. In this context, we were unable to report a reliable evaluation rate or confidently capture all initial and follow-up exams performed. Furthermore, data, including evaluations, exam findings, presence of PPS maculopathy, and visual symptoms relied on encounter notes, but relevant details may have varied. The documentation may not have explicitly described the clinical decision-making process and may likely have excluded nuances in the patient-provider discussions that may influence evaluation practices.
The study may be subject to ascertainment bias, as patients referred to the institution for evaluation may have different risk factors or phenotypic severity of maculopathy than previously published cohorts.
PPS exposure relied on explicit mention if available, and otherwise, data were calculated from prescription history within the EHR. Patients who took PPS inconsistently may have falsely elevated exposure history within our study.
For three of the four patients with maculopathy, evaluations occurred following cessation of the drug. It was unclear at which point in their course of PPS use those retinal changes developed. This study included patients who had prior ophthalmic diagnoses. Evaluation practices, disease presentations, and retinal findings differed by patient with varying ophthalmic co-diagnoses.
This study was limited to the patients of a single institution. The sample size was limited and did not allow for more in-depth analysis beyond descriptive statistics.
Conclusion
We present a retrospective study highlighting the evaluation practices and findings for PPS maculopathy at a single institution. The study supports the need for increased ophthalmic evaluation with OCT, CFP, and FAF for patients with a history of PPS exposure and adds to the growing literature reporting the phenotypic spectrum of retinal toxicity. We found a 10.8% prevalence of PPS maculopathy among patients who had a history of PPS use and were evaluated by an ophthalmologist. In our small cohort of patients, PPS maculopathy occurred only in patients with greater than 15 years of use and greater than 2000 g of cumulative exposure. We report two cases of PPS maculopathy progression post-cessation of PPS. Accurate diagnosis and management of PPS maculopathy after drug cessation are important in the context of evolving treatment approaches to differential diagnoses, including AMD with geographic atrophy, which may now be treated with intravitreal injections.
Supplemental Material
sj-docx-1-oed-10.1177_25158414251364944 – Supplemental material for Evaluating for pentosan polysulfate maculopathy at a single academic institution
Supplemental material, sj-docx-1-oed-10.1177_25158414251364944 for Evaluating for pentosan polysulfate maculopathy at a single academic institution by Daniel J. Hu, Emily Wang, Sophia Ghauri, Sandra Hoyek, Dean Eliott, Nimesh A. Patel, Rachel M. Huckfeldt and Magdalena G. Krzystolik in Therapeutic Advances in Ophthalmology
Footnotes
References
Supplementary Material
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