Risk and Dose-Response Relationship for Pentosan Polysulfate Sodium Maculopathy: A Systematic Review and Meta-Analysis.

Abstract

Topic: To determine the pooled relative risk (RR) of Pentosan Phosphate Sodium Maculopathy (PPSM) in patients using PPS and model the dose-response relationship of this association from existing literature.

Clinical relevance: PPSM is an acquired, progressive retinal pigmentary disease associated with oral PPS use. Though several observational studies suggest a dose-response relationship of this association, to-date, there remains no literature-pooled synthesis on risk of PPSM across strata of cumulative dose.

Methods/literature reviewed: Systematic review and meta-analysis (CRD42024623179). Medline, Embase, and CENTRAL 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 Risk of Bias in Non-randomized Studies of Exposures (ROBINS-E) tool, a third reviewer was consulted to resolve conflicts. The primary outcome was the relative risk of PPSM among patients exposed to PPS compared to non-exposed individuals, stratified by cumulative PPS dose.

Results: We included five studies encompassing 141,785 patients and 6,432 PPSM cases. The linear dose-response regression model estimated a 0.1% increase in RR of maculopathy per g increase in cumulative PPS dose (logRR = 0.00101, 95% CI: 0.0005-0.0015, p < 0.0001). Patients with cumulative doses ≥2,000 g exhibited a RR of 7.39 (95% CI: 4.17-13.10), while those with a dose between 1-500 g had a RR of 1.65 (95% CI: 1.12-2.43) compared to non-exposed 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.