Pentosan polysulfate maculopathy: clinical considerations, pathobiology, and causality

Pentosan polysulfate (PPS) maculopathy is a progressive, vision-threatening retinal disorder linked to prolonged use of PPS, a heparin-like sulfated polysaccharide prescribed for interstitial cystitis/bladder pain syndrome. Affected individuals often experience impaired dark adaptation and progressive central vision loss. Fundus imaging commonly reveals hyperpigmented macular clumps at the level of the retinal pigment epithelium (RPE), and a distinctive pattern of autofluorescence abnormality in the posterior fundus. This degenerative maculopathy may continue to progress even after drug cessation, with some patients developing macular atrophy years later. While the underlying pathogenic mechanism remains unclear, mounting evidence supports a causal relationship between PPS use and the macular pathology. Studies have repeatedly demonstrated the strength of the association; the dose-response relationship; and the lack of confounding by indication. Furthermore, laboratory studies demonstrate that such a toxicity is biologically plausible, suggesting a direct toxicity to the RPE and/or choroid. Given the widespread use of PPS over many decades, tens of thousands of individuals are already at risk for toxicity, with no known treatment available. However, screening rates remain low; prescribing rates continue to rise in certain regions; and novel applications for the drug, such as subcutaneous injection for osteoarthritis, are under clinical investigation. Consequently, there is a pressing need for increased recognition of PPS toxicity and further understanding of disease mechanisms. This review summarizes the clinical characteristics of PPS maculopathy, evaluates its public health impact, explores potential pathogenic mechanisms, and presents a compelling case for causality using clinical, laboratory, and epidemiological evidence.