Pentosan polysulfate sodium (PPS) is a semi-synthetic sulfated polysaccharide that is the only FDA-approved oral treatment for interstitial cystitis (IC) dating back almost three decades. ^,,,,,,,,,,, Despite its widespread use, emerging data over the past several years indicate that PPS can be associated with a remarkable retinal toxicity ^{,,,,,,,,,,,,,} and, more recently, toxicity of the gastrointestinal (GI) tract. ^,,

PPS toxic retinopathy, first described by Pearce and Jain et al. in 2018, is characterized by a signature speckled autofluorescent maculopathy, with atrophy in the more severe stage, that is centered on the fovea and optic disc and that often progresses in a centrifugal direction, even after drug cessation. The prevalence of the characteristic maculopathy is as high as 15%, and toxicity strongly correlates with cumulative dosage and duration of PPS exposure. ^{,,,,,,,,,,,,,} Prevalence rates increase to 45% with cumulative dosages greater than 1500 grams. ^,

Of great concern, recent investigations suggest that PPS may also exert toxic effects on the colon. ^,, Case series and cohort studies have identified a novel drug-induced colopathy associated with chronic PPS exposure, manifesting as chronic mucosal inflammation, crypt architectural distortion, and, in some cases, dysplasia and colonic polyposis. ^,, While some authors postulate that the underlying inflammatory state of IC may contribute to both macular and GI manifestations, the ever-growing body of evidence indicates that PPS causes tissue-specific damage to the retina and colon and underscores the need for heightened clinical vigilance of patients being treated with this potentially harmful drug. ^,,

While the retina community and beyond is becoming more and more knowledgeable of the manifestations of PPS macular toxicity, recognition of the spectrum of toxic effects of PPS on the colon remains limited and incompletely characterized. More robust investigation of the nature of the colopathy associated with PPS is necessary to better understand the scope of toxicity. In this study, we report a series of 8 patients with confirmed PPS maculopathy who also developed significant GI pathology, including severe adenomatous polyposis and colitis-associated dysplasia, with the goal of expanding the clinical spectrum of colopathy associated with PPS maculopathy, raising awareness about this important association, and underscoring the importance of colonoscopy screening in patients exposed to PPS.

The electronic medical records of 8 patients diagnosed with PPS maculopathy with concomitant GI toxicity, evaluated by a single retina specialist (D.S.) between 2019 and 2025, were reviewed.

Institutional review board (IRB) was obtained from the University of California, Los Angeles IRB Office of Human Protection for this retrospective review (IRB#12-001006 and IRB#14-001080). The study was conducted in accordance with the Health Insurance Portability and Accountability Act of 1996 and the tenets of the Declaration of Helsinki. This study was exempted from the requirement to obtain informed consent because of its retrospective nature and the exclusion of any personal information that could lead to the identification of patients.

Patients with a diagnosis of PPS maculopathy were included in the study. Exclusion criteria were as follows: (1) Subjects younger than 18 years old; (2) Other etiologies of maculopathy, including, but not limited to AMD and genetic disorders such as Stargardt’s disease, late-onset retinal degeneration (LORD), Sorsby’s fundus dystrophy, pseudoxanthoma elasticum (PXE), and mitochondrial syndromes; and (3) Poor quality of images.

Demographic and clinical data, including age, sex, ethnicity, medical and ocular history, Snellen visual acuity, PPS administration, duration of PPS use and cumulative dosage, were recorded. Multimodal retinal imaging was performed in all cases and included cross-sectional and en face spectral domain optical coherence tomography (SD-OCT) (Heidelberg Spectralis OCT; Heidelberg Engineering Inc, Heidelberg, Germany) and OCT angiography (OCTA) (Optovue RTVue XR Avanti or Solix; Optovue Inc/Visionix, Fremont, CA, USA; or PLEX Elite 9000, Carl Zeiss Meditec, Inc, Dublin, CA, USA). Additional imaging included ultra-widefield fundus photography (UWF CFP), fundus autofluorescence (UWF FAF), and fluorescein angiography (UWF FA) using Optos devices (Optos, Inc, Marlborough, MA, USA). Truecolor fundus photography (CFP) was also acquired with the iCare EIDON system (iCare, Italy), and short-wavelength FAF was obtained with the Heidelberg Spectralis. Full field electroretinography (ERG) (VERIS 4.8 clinic system) and genetic testing (Quest Diagnostics, Helsinki, Finland) were performed in selected cases. All patients also underwent colonoscopy, and histopathologic analysis was performed in selected cases. For all cases with relevant histopathology, the reports and histological images were retrospectively collected and reviewed with an expert gastrointestinal pathologist (W.T.C.).

PPS maculopathy was classified into 3 stages according to the Wang et al.’s classification system :

• •

  Stage 1 (mild): Presence of a speckled pattern of hypo- and/or hyperautofluorescence centered on the fovea, without any signs of well-demarcated atrophy on FAF or complete retinal pigment epithelium and outer retinal atrophy (cRORA) on SD-OCT.

• •

  Stage 2 (moderate): Presence of well-demarcated, nummular, hypoautofluorescent atrophic lesions on FAF corresponding to cRORA on SD-OCT in the macula without foveal involvement.

• •

  Stage 3 (severe): Presence of geographic atrophy and cRORA involving the fovea.

All retinal images were evaluated by experienced and independent graders (A.F., M.M.P., S.F., T.E.L., A.I.M., P.T.) and in case of any discrepancies, the senior retinal specialist (D.S.) was consulted to provide final determination.

Multiple OCT parameters were also recorded, which were defined as follows:

• •

  Macular atrophy was defined as a well-demarcated hypoautofluorescent area of nonspecific diameter on FAF, corresponding to the presence of cRORA on OCT.

• •

  Outer retinal tubulations were defined as ovoid structures with hyperreflective rings at the level of the outer nuclear layer (ONL) and present in areas of atrophy or fibrosis on OCT. ^,

• •

  Acquired vitelliform lesions (AVL) were defined as homogeneous or heterogenous yellowish lesions in the subretinal space on clinical exam or CFP, corresponding to a focal area of subretinal hyperreflective material (SHRM) on OCT and hyperautofluorescence on FAF. ^,,,

• •

  Epiretinal membrane (ERM) on OCT was diagnosed by the presence of hyperreflective lines above the inner retinal surface, resulting in tangential retinal traction. ^,

Genetic testing was performed using the Invitae Inherited Retinal Disorders Panel (Invitae, San Francisco, CA, USA), which included both sequence analysis and deletion/duplication testing of 330 genes associated with inherited retinal diseases. Genomic DNA was extracted from saliva samples and enriched for targeted regions through a hybridization-based protocol. Sequencing was carried out on an Illumina platform, with all targeted regions covered at a minimum depth of ≥ 50 × or supplemented with additional analysis to ensure complete coverage. In selected cases, genetic testing was also performed using a next-generation sequencing (NGS)-based multigene hereditary cancer panel (including the APC gene), supplemented with deletion/duplication analysis to detect large rearrangements. Variants were annotated according to HGVS nomenclature and classified based on ACMG/AMP criteria.

Eight patients (16 eyes) were included in the study. The summary of the demographic, clinical, imaging, and GI characteristics of the entire cohort is shown in Table 1 .

Table 1

Summary of the Demographic, Clinical, Ocular, and Gastrointestinal Characteristics of Patients With Pentosan Polysulfate Sodium (PPS) Maculopathy and Associated Gastrointestinal Disease

Pat- ient	Gen- der	Age (years) at first referral	Eye	Follow-up (months)	Pento- san administration	Duration of PPS use (years)	Cumu- lative dosage (grams)	Family history and/or genetic testing	Systemic medical history	Ocular history	PPS maculopathy stage at baseline	PPS maculopathy stage at last available follow-up	Additional OCT and OCTA findings	GI findings	Mode of diagnosis of GI disease and surgery	Time to diagnosis of GI disease after PPS initiation (years)	Histopa- thology	Baseline VA	Last available VA	Symptoms	Treatment
1	F	61	OD	56	Oral	15	1679	Negative genetic testing for FAP	Interstitial cystitis	LASIK OU	1 (Mild)	3 (Severe)	Develop- ment of foveal cRORA after collapse of subfoveal SHRM and SRF Progressive CC flow deficits	Severe polyposis with tubular adenomas	Colonoscopy; partial colectomy	13	Innumer- able ill-defined mucosal areas with neoplastic changes (tubular adenomas), mainly from splenic flexure to cecum	20/20	20/20	Blurred vision	Observation
			OS						1 (Mild)	1 (Mild)	Progre- ssive CC flow deficits					20/50	20/20	Blurred vision	Observation
2	F	67	OD	62		15	1800	Negative family history	Interstitial cystitis	Unrema- rkable	1 (Mild)	2 (Moderate)	Outer retinal tubulations Progre- ssive CC flow deficits	Chron’s disease diagnosed 11 years after initiation of PPS therapy	Colonoscopy; Ileostomy	11	No	20/20	20/25	Blurred vision	Observation
			OS		Oral				1 (Mild)	2 (Moderate)	Outer retinal tubulations Progre- ssive CC flow deficits					20/40	20/25	Blurred vision	Observation
3	M	72	OD	72	Subcutaneous (0.7 mL, i.e. 70 units, weekly of 125 mg/mL)	10	45.5	Negative family history	Osteoart- hritis, ankylosing spondylitis	Cataract extraction OU	2 (Moderate)	2 (Moderate)	Pericentral areas of cRORA	Microscopic colitis	Colonoscopy	1	No	20/25	20/25	Blurred vision, metamorp- hopsia	1 intravitreal aflibercept injection
			OS						2 (Moderate)	2 (Moderate)	Pericentral areas of cRORA					20/25	20/25	Blurred vision, metamorphopsia	3 intravitreal avacincaptad pegol injections
4	M	72	OD	39		25.8	3723	Negative family history	Interstitial cystitis, hypercholesterolemia, kidney stones, benign prostatic hyperplasia	Cataract extraction OU	1 (Mild)	2 (Moderate)	Pericentral areas of cRORA Grade 3 ERM Progre- ssive CC flow deficits	Ulcerative colitis and severe polyposis	Colonoscopy	9	No	20/30	20/30	Blurred vision	Observation
			OS		Oral				1 (Mild)	3 (Severe)	Develo- pment of foveal cRORA after collapse of subfoveal SHRM and SRF Grade 2 ERM Type 2 MNV Progre- ssive CC flow deficits					20/50	20/1600	Blurred vision	5 intravitreal aflibercept injections
5	F	49	OD	53	Oral	26.1	2798	Low penetrance variant in APC gene: c.3920T > A ( p .lle1307Lys) which is not associated with FAP in Ashkenazi Jewish population (the patient with Ashkenazi Jewish). Negative family history	Interstitial cystitis	Oculodermal melanocytosis with periocular and scleral pigmentation OU	2 (Moderate)	2 (Moderate)	Increase in peripheral CHRPE lesions Grade 2 ERM	Ulcerative colitis and massive polyposis with tubular interstitial adenomas	Colonoscopy (widespread polyps especially in the proximal colon, with associated neovascularization suggestive of prior inflammation)	10	Patchy low-grade dysplasia, chronic colitis (including crypt architectural distortion), and tubular adenomas	20/20	20/25	Blurred vision	Observation
			OS						2 (Moderate)	2 (Moderate)	Increase in peripheral CHRPE lesions					20/25	20/25	Blurred vision	Observation
6	F	72	OD	6	Oral	30	3300	VUS in CACNA1F gene : c.812G > A – associated with X-linked congenital stationary night blindnes Risk variant in ABCA4 gene : c.5603A > T – autosomal recessive inheritance VUS in CNGB3 gene : c.1982_1984dup– autosomal recessive inheritance	Interstitial cystitis, triple negative breast cancer in full remission	Unrema- rkable	2 (Moderate)	2 (Moderate)	Pericentral areas of cRORA	Severe polyposis with tubular adenomas	Colonoscopy; total colectomy		Tubular adenomas in the cecum, ascending colon, and hepatic flexure	20/25	20/25	Blurred vision	Observation
			OS						3 (Severe)	3 (Severe)	Foveal cRORA			22		20/20	20/20	Blurred vision	Observation
7	F	64	OD	33	Oral	32.4	4672	Negative family history.	Interstitial cystitis, ductal carcinoma in situ of the right breast, migraine, irritable bowel syndrome	Unrema- rkable	1 (Mild)	1 (Mild)	Progre- ssive CC flow deficits	Severe polyposis with tubular adenomas (colonoscopy)	Colonoscopy; endoscopic mucosal resection and polypectomy	32	Tubular adenomas (cecum, transverse) and mild hyperplastic changes (descending colon)	20/20	20/20	Blurred vision	Observation
			OS						1 (Mild)	1 (Mild)	Progre- ssive CC flow deficits					20/20	20/20	Blurred vision	Observation
8	F	72	OD	47	Oral	19	3006	Negative family history and genetic testing for IRDs	Interstitial cystitis	Unrema- rkable	1 (Mild)	1 (Mild)	Progre- ssive CC flow deficits	Severe polyposis with tubular adenomas (colonoscopy)	Colonoscopy; endoscopic mucosal resection and polypectomy	9	Tubular adenomas in the hepatic flexure and proximal sigmoid colon	20/40	20/30	Blurred vision	Observation
			OS						1 (Mild)	3 (Severe)	Foveal cRORA Outer retinal tubulations Progres- sive CC flow deficits					20/70	20/100	Blurred vision	Observation

Only gold members can continue reading. Log In or Register to continue

Share this:

• X
• Facebook

Related

Related posts:

1. Outcomes and Risk Factors for Failure After PRESERFLO™ MicroShunt Implantation in a Multicenter Japanese Cohort
2. Quantifying Orbital Segmentation in Thyroid Eye Disease- Fat to Muscle Ratio Correlates With Restrictive Strabismus
3. Forecasting the Workforce of Uveitis Specialists
4. Concomitant Tarsorrhaphy During Penetrating Keratoplasty for Promoting Epithelial Healing in Neurotrophic Keratopathy

Stay updated, free articles. Join our Telegram channel

Join