Dataset Information

PENTOSAN POLYSULFATE AND VISION: Findings from an International Survey of Exposed Individuals.

ABSTRACT:

Purpose

To investigate patient-reported visual function among individuals taking pentosan polysulfate (PPS) for interstitial cystitis.

Methods

A 27-item online survey was distributed to an international mailing list of individuals with interstitial cystitis in November 2018. Demographic characteristics, PPS exposure history, subjective visual function, and previous macular diagnoses were queried. The impact of PPS use, grouped by tertile of cumulative exposure, on visual function and macular diagnoses was assessed with multivariate logistic regression.

Results

The survey was completed by 912 respondents. Eight hundred and sixty-one (96.4%) were women, and the median age was 55 [interquartile range (IQR), 45-64 years]. Among PPS users, the median exposure was 547.5 g (IQR, 219-1,314 g). Respondents in the highest PPS exposure tertile were more likely to report difficulty with reading small print [adjusted odds ratio 2.29, 95% confidence interval (CI) 1.15-4.57] and to have a diagnosis of macular degeneration and/or pigmentary maculopathy (adjusted odds ratio 2.41, 95% CI 1.44-4.03) than unexposed respondents.

Conclusion

In this large sample of individuals with interstitial cystitis, those in the highest PPS exposure category were more likely to have difficulties reading small print and to report a previous diagnosis of macular disease. Further study of objective measures of visual function in PPS users is warranted.

SUBMITTER: Uner OE

PROVIDER: S-EPMC8200367 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPentosan polysulfate (PPS) is an FDA-approved, oral medication with anti-inflammatory and pro-chondrogenic properties. We have previously shown that animal models of the mucopolysaccharidoses (MPS) exhibit significant inflammatory disease, contributing to cartilage degeneration. Enzyme replacement therapy (ERT) only partly reduced inflammation, and anti-TNF-alpha antibody therapy significantly enhanced clinical and pathological outcomes. Here we describe the use of PPS for the treatment of MPS type VI rats.Methodology/principal findingsTreatment began during prenatal development and at 1 and 6 months of age. All animals were treated until they were 9 months old. Significant reductions in the serum and tissue levels of several inflammatory markers (e.g., TNF-alpha, MIP-1alpha and RANTES/CCL5) were observed, as was reduced expression of inflammatory markers in cultured articular chondrocytes. ADAMTS-5/aggrecanase-2 levels also were reduced in chondrocytes, consistent with an elevation of serum tissue inhibitor of metalloproteinase 1. Marked improvements in motility and grooming behavior occurred, along with a reduction in eye and nasal secretions and a lessening of the tracheal deformities. MicroCT and radiographic analyses further revealed that the treated MPS skulls were longer and thinner, and that the teeth malocclusions, misalignments and mineral densities were improved. MicroCT analysis of the femurs and vertebrae revealed improvements in trabecular bone mineral densities, number and spacing in a subset of treated MPS animals. Biomechanical assessments of PPS-treated spines showed partially restored torsional behaviors, suggesting increased spinal stability. No improvements were observed in cortical bone or femur length. The positive changes in the PPS-treated MPS VI rats occurred despite glycosaminoglycan accumulation in their tissues.ConclusionsBased on these findings we conclude that PPS could be a simple and effective therapy for MPS that might provide significant clinical benefits alone and in combination with other therapies.

Project description:ImportanceCase series have identified a macular condition hypothesized to be associated with the use of pentosan polysulfate sodium (PPS). Observational studies seeking to quantify this association have yielded equivocal results.ObjectiveTo estimate the association between PPS exposure and maculopathy.Design, setting, and participantsThis disproportionality analysis was conducted using the US Food and Drug Administration Adverse Event Reporting System from January 2013 through June 2020.ExposureAdverse event reports for pentosan polysulfate were selected and compared with adverse event reports associated with drugs taken for the following indications: interstitial cystitis, cystitis, bladder disorder, or bladder pain.Main outcome measuresRetinal adverse events were identified using the retinal disorders Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query, which includes conditions associated with retinal damage attributable to blockage of its blood supply, nutritional deficiencies, toxins, and diseases affecting the retina.ResultsThere were 2775 reports available for analysis in the PPS group (of which 1966 were for women [70.9%]) and 6833 reports in the other drugs group (of which 4036 [59.1%] were for women). The proportion of adverse events for any macular event relative to all other events was elevated for the users of PPS compared with those using other interstitial cystitis and bladder pain drugs (proportionate reporting ratio [PRR], 1.21 [95% CI, 1.01-1.44]). With respect to specific retinal conditions, macular degeneration (20 [0.8%] vs 15 [0.2%]), maculopathy (83 [3.4%] vs 2 [0.03%]), retinal dystrophy (3 [0.1%] vs 0), retinal injury (5 [0.2%] vs 0), and retinal toxicity (3 [0.1%] vs 0) were proportionately more common among users of PPS compared with those using other interstitial cystitis and bladder pain drugs, respectively.Conclusions and relevanceThe results of the current study add to the growing evidence that PPS use is associated with an increased risk of maculopathy. Studies that rule out prevalent retinal abnormalities prior to the initiation of PPS would strengthen the current body of literature.

Project description:Importance:A unique pigmentary maculopathy was recently described in 6 patients with long-term exposure to pentosan polysulfate sodium (PPS), a long-standing oral therapy for interstitial cystitis. Objective:To characterize the exposure characteristics and clinical manifestations of PPS-associated maculopathy. Design, Setting, and Participants:In this multi-institutional case series, medical records of patients who exhibited the characteristic maculopathy in the setting of prior PPS exposure were retrospectively reviewed. Data were collected from August 1, 2012, to October 1, 2018, and data were analyzed from October 2018 to January 2019. Main Outcomes and Measures:Drug exposure, visual acuity, and retinal imaging characteristics. Results:Of the 35 included patients (70 eyes), 34 (97%) were female, and the median (range) age was 60 (37-79) years. The median (range) duration of PPS intake was 15 (3-22) years, and the median (range) cumulative exposure was 1.61 (0.44-4.31) kg. The leading visual symptoms were metamorphopsia, blurred vision, and prolonged dark adaptation. Median (range) logMAR visual acuity of all eyes was 0.10 (-0.12 to 1.18). Fundus examination often revealed hyperpigmented macular spots (34 of 64 eyes [53%]) with interspersed pale-yellow deposits, although less commonly in eyes that exhibited retinal pigment epithelial atrophy (6 of 26 eyes [23%]; P?<?.001). Optical coherence tomography showed foci of retinal pigment epithelium elevation or thickening associated with hyperreflectance on near-infrared reflectance imaging. Fundus autofluorescence imaging typically revealed a symmetric, confluent pattern of hyperautofluorescent and hypoautofluorescent spots that involved the fovea in all eyes and extended to the retinal periphery in 24 eyes (36%). Longitudinal evaluation demonstrated dynamic changes in pigmentary abnormalities. Conclusions and Relevance:These findings suggest that PPS-associated maculopathy is a vision-threatening condition that can manifest in the setting of long-term exposure to the drug. Multimodal imaging posits a distinctive clinical phenotype, characterized in this cohort by dynamic alterations within the retinal pigment epithelium and at the retinal pigment epithelium-photoreceptor interface. Ongoing work might explore causality and direct screening guidelines.

Project description:BackgroundWe previously demonstrated the therapeutic benefits of pentosan polysulfate (PPS) in a rat model of mucopolysaccharidosis (MPS) type VI. Reduction of inflammation, reduction of glycosaminoglycan (GAG) storage, and improvement in the skeletal phenotype were shown. Herein, we evaluate the long-term safety and therapeutic effects of PPS in a large animal model of a different MPS type, MPS I dogs. We focused on the arterial phenotype since this is one of the most consistent and clinically significant features of the model.Methodology/principal findingsMPS I dogs were treated with daily oral or biweekly subcutaneous (subQ) PPS at a human equivalent dose of 1.6 mg/kg for 17 and 12 months, respectively. Safety parameters were assessed at 6 months and at the end of the study. Following treatment, cytokine and GAG levels were determined in fluids and tissues. Assessments of the aorta and carotid arteries also were performed. No drug-related increases in liver enzymes, coagulation factors, or other adverse effects were observed. Significantly reduced IL-8 and TNF-alpha were found in urine and cerebrospinal fluid (CSF). GAG reduction was observed in urine and tissues. Increases in the luminal openings and reduction of the intimal media thickening occurred in the carotids and aortas of PPS-treated animals, along with a reduction of storage vacuoles. These results were correlated with a reduction of GAG storage, reduction of clusterin 1 staining, and improved elastin integrity. No significant changes in the spines of the treated animals were observed.ConclusionsPPS treatment led to reductions of pro-inflammatory cytokines and GAG storage in urine and tissues of MPS I dogs, which were most evident after subQ administration. SubQ administration also led to significant cytokine reductions in the CSF. Both treatment groups exhibited markedly reduced carotid and aortic inflammation, increased vessel integrity, and improved histopathology. We conclude that PPS may be a safe and useful therapy for MPS I, either as an adjunct or as a stand-alone treatment that reduces inflammation and GAG storage.

Project description:ImportanceRecent studies have linked a vision-threatening maculopathy with long-term use of pentosan polysulfate sodium (PPS).ObjectiveTo evaluate the disease course in PPS-associated maculopathy after drug cessation.Design, setting, and participantsIn this retrospective case series, patients diagnosed with PPS-associated maculopathy with at least 6 months of follow-up after drug cessation who were treated at the Emory Eye Center, Atlanta, Georgia, or the Casey Eye Institute, Portland, Oregon, were included. Data were collected from April 2014 through November 2019.Main outcomes and measuresChange in visual acuity and retinal imaging characteristics over time.ResultsOf the 11 included patients, all were female, and the median (interquartile range [IQR]) age was 53 (44-63) years. Participants had a baseline visit at a median (IQR) of 2 (0-4) months after drug cessation and were subsequently observed for a median (IQR) of 12 (8-26) months. The median (IQR) cumulative PPS exposure was 1.97 (1.55-2.18) kg. No eyes exhibited a demonstrable improvement in disease after discontinuing PPS. A total of 9 of 11 patients (82%) reported worsening visual symptoms at the final visit. The mean (SD) logMAR visual acuity was 0.14 (0.23) and 0.14 (0.34) at the baseline and final visit, respectively. Visual acuity improved by 2 or more Snellen lines in 1 eye (5%) and declined by 2 or more Snellen lines in 2 eyes of 1 patient (9%). There was evolution in the pattern of fundus autofluorescence changes and/or optical coherence tomography findings in all eyes. A total of 17 eyes (77%) exhibited expansion of the area of involved tissue. A total of 7 eyes (32%) had macular retinal pigment epithelium atrophy at the baseline visit, and atrophy enlarged after discontinuation of PPS in all 7 eyes, with a median (IQR) growth rate of 0.32 (0.13-0.38) mm per year.Conclusions and relevanceThese retrospective data among 11 patients suggest PPS-associated maculopathy continues to evolve after drug cessation for at least 10 years. In some cases, progressive retinal pigment epithelium atrophy encroaches on the foveal center and thus may pose a long-term threat to central vision.

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