Risk and Dose–Response Relationship for Pentosan Polysulfate Sodium Maculopathy

Topic

To determine the pooled relative risk (RR) of pentosan polysulfate sodium maculopathy (PPSM) in patients using pentosan polysulfate sodium (PPS) and model the dose–response relationship of this association from existing literature.

Clinical Relevance

Pentosan polysulfate sodium maculopathy is an acquired, progressive retinal pigmentary disease associated with oral PPS use. Although several observational studies suggest a dose–response relationship of this association, to date, there remains no literature-pooled synthesis on the risk of PPSM across strata of cumulative dose.

Methods

Systematic review and meta-analysis (CRD42024623179). Medline, Embase, and Cochrane Central Register of Controlled Trials were searched from inception to September 15, 2024. We included studies reporting the incidence of PPS-associated maculopathy and including cumulative PPS dose information. Two independent reviewers completed study screening, data extraction, and risk of bias (ROB) assessment using the ROB in nonrandomized studies of exposures tool, and a third reviewer was consulted to resolve conflicts. The primary outcome was the RR of PPSM among patients exposed to PPS compared with nonexposed individuals, stratified by cumulative PPS dose.

Results

We included 5 studies encompassing 141 785 patients and 6432 PPSM cases. The linear dose–response regression model estimated a 0.1% increase in RR of maculopathy per g increase in cumulative PPS dose (log-transformed RR = 0.00101; 95% confidence interval, 0.0005–0.0015; P < 0.0001). Patients with cumulative doses ≥2000 g exhibited an RR of 7.39 (95% confidence interval, 4.17–13.10), while those with a dose between 1 and 500 g had an RR of 1.65 (95% confidence interval, 1.12–2.43) compared with nonexposed individuals. Subgroup analysis excluding high-risk studies demonstrated consistent findings, with reduced heterogeneity (I² = 63.7%).

Conclusion

Moderate certainty evidence supports a dose-dependent relationship between PPS exposure and PPSM risk, whereas higher cumulative doses significantly increase maculopathy risk. This result supports that patients should be tapered to an effective minimal dose and that they should be subject to interval maculopathy screening, especially for patients with greater cumulative dose. Future research should incorporate patient-level data to better control for potential confounding.

Financial Disclosure(s)

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