Patients who develop maculopathy associated with pentosan polysulfate sodium (PPS) treatment exhibit a number of characteristic findings on multimodal fundus imaging following high cumulative oral exposure, according to research results published in Ophthalmology Retina. According to researchers, these results indicate that standardized ophthalmic screening of PPS-treated patients should be recommended.

Currently, PPS is the only FDA-approved oral treatment for bladder pain associated with interstitial cystitis. In 2018, researchers described a “unique pigmentary maculopathy” in 6 patients, characterized by difficulty reading, prolonged dark adaption, subtle macular pigmentary changes, and pronounced alterations on fundus autofluorescence and near-infrared reflectance imaging, associated with long-term PPS therapy. Subsequent studies have confirmed this association. 

The FDA formally added pigmentary maculopathy as a potential adverse reaction on the medication package insert in June 2020. Due to the high number of interstitial cystitis cases in the US and the frequency of long-term PPS therapy, researchers say it is likely thousands of patients in the US are at risk. 


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Therefore, researchers conducted a multicenter, retrospective case review study to describe the largest series of PPS maculopathy to-date, expanding the clinical understanding of phenotypic manifestations and disease risk factors. 

Between April 2019 and December 2020, both fundus imaging and deidentified clinical data were securely collected. A total of 18 practices — half university based and half retina-only private practices — submitted cases for inclusion in the series. Included cases displayed typical imaging features of PPS maculopathy. 

In total, 105 cases from 18 practices were submitted, of which 74 met inclusion criteria. Median interquartile range of patients from included cases was 62 years (interquartile range [IQR], 56-65.8 years), and 97.3% of patients were women; 91.2% self-identified as White. 

The 3 most common initial referring diagnoses from outside providers to a retinal specialist were age-related macular degeneration (AMD), suspected pentosan polysulfate maculopathy, and inherited retinal disease (54.1%, 16.2%, and 16.2%, respectively). 

At presentation, median exposure duration to PPS was 14 years (IQR, 10.2-18.9 years). Median daily PPS dose was 300.0 mg (IQR, 300.0-400.0), while median cumulative PPS dose was 1.5 kg (0.9-2.4 kg). Median body mass index was 23.2 kg/m2 (IQR, 20.6-27.8), and median cumulative exposure per unit of body mass was 25.7 g/kg (IQR, 14.7-36.7). 

Four cases had less than a 0.66 kg cumulative exposure, and the lowest cumulative exposure was 0.33 kg spanning 3 years. 

The most common symptom was blurry or decreased vision, seen in 66.2% of patients, followed by prolonged dark adaption or nyctalopia (32.4%); 14.9% of patients reported both symptoms. Three patients—4.1%—reported no visual symptoms. 

Median logMAR visual acuity (VA) was 0.2 (IQR, 0.1-0.4). A total of 110 eyes (73.4%) had a logMAR of 0.3 or better, while 7.4% of eyes (n=11) had a logMAR VA of 1.0 or worse. Thirteen patients had a reported history of macular neovascularization, 7 had a reported history of cystoid macular edema, and 48 of 135 eyes that were gradable for atrophy had macular retinal pigment epithelium (RPE) present. 

Fundus imaging generally conformed to prior case descriptions of PPS maculopathy, although 5 patients had unique imaging features that “may represent uncommon manifestations of PPS maculopathy” and included isolated subtle near-infrared reflectance imaging imaging alterations, disease asymmetry between eyes, and large macular vitelliform deposits. 

The current series did not include 4 patients deemed to have “other maculopathies” after initial masked imaging review, 3 of whom represented with unilateral small vitelliform deposit with associate RPE changes. Because these patients had not previously undergone diagnostic genetic testing, it is “unclear if they represented an early manifestation of PPS maculopathy or an unrelated vitelliform maculopathy.” 

Study limitations include the retrospective nature of the research, the contribution of cases by tertiary referral centers which may have selected patients with more advanced disease, variable data methods by center, and a lack of standard protocol for fundus imaging collection. 

“This series of PPS maculopathy cases identified in a range of practice settings largely corroborates findings from prior studies of the condition,” according to the researchers. “This vision-threatening maculopathy is associated with high cumulative PPS exposure and manifests a characteristic constellation of fundus imaging findings in most cases.” 

“Given the potential for severe visual disability, we recommend consideration of implementation of standardized ophthalmic screening programs for patients taking PPS,” researchers conclude.

Reference

Jain N, Liao A, Garg SJ, et al; for the Macula Society Pentosan Polysulfate Maculopathy Study Group. Expanded clinical spectrum of pentosan polysulfate maculopathy: A Macula Society collaborative study. Ophthalmol Retina. Published online July 20, 2021. doi:10.1016/j.oret.2021.07.004