### Patient Information
This report summarizes a multi-institutional retrospective case series involving three patients treated at centers in Miami, Florida; Los Angeles, California; and Sydney, Australia between September 2024 and July 2025. All patients were adults diagnosed with osteoarthritis or inflammatory arthritis and had undergone subcutaneous administration of pentosan polysulfate sodium (PPS) for arthritis management.
– Patient 1: Middle-aged adult with osteoarthritis.
– Patient 2: Adult diagnosed with inflammatory arthritis.
– Patient 3: Adult with osteoarthritis.
All patients presented with visual complaints after prolonged treatment periods ranging between 7 to 10 years. The cumulative subcutaneous PPS doses ranged from 45.5 g to 96 g, notably lower than cumulative doses typically associated with retinal toxicity in oral administration.
### Diagnosis
Multimodal retinal imaging in all three cases revealed characteristic features consistent with pentosan polysulfate maculopathy (PPM). Key clinical findings included:
– Distinctive pigmentary changes in the macula.
– Disruption of retinal pigment epithelium (RPE) visualized on optical coherence tomography (OCT).
– Fundus autofluorescence patterns correlating with toxicity.
The diagnosis was confirmed based on clinical history of PPS exposure via subcutaneous route, characteristic imaging findings, and exclusion of alternative causes. The temporal correlation between PPS treatment duration and retinal changes strengthened the causative association.
### Differential Diagnosis
Other retinal conditions considered included:
– Age-related macular degeneration (AMD): Ruled out due to younger age of patients and imaging features inconsistent with drusen or neovascular changes.
– Pattern dystrophies: Excluded based on distinct pigment distribution and clinical progression.
– Drug-induced retinal toxicity from other agents: No other medications with known retinal toxicity at significant exposure levels were reported.
– Inflammatory or infectious maculopathies: Absent systemic or ocular inflammatory signs.
### Treatment and Management
Upon diagnosis, all patients underwent discontinuation of subcutaneous PPS administration to prevent further retinal damage.
Management consisted primarily of:
– Regular ophthalmologic monitoring, including multimodal imaging at intervals to track disease progression.
– Patient education regarding visual symptoms requiring urgent evaluation.
– Supportive care for visual function; no specific reversal treatment for PPM currently exists.
Decision-making emphasized early recognition of toxicity to minimize additional drug exposure. Referral to retinal specialists was essential for ongoing care.
### Outcome and Prognosis
Despite cessation of PPS, maculopathy progression was noted in at least some cases, reflecting the persistent toxicity effects documented in literature.
Visual acuity varied but showed a trend of gradual decline, underscoring the importance of early diagnosis. Long-term prognosis remains guarded due to the chronic and potentially progressive nature of toxicity.
### Discussion
This case series is the first to directly associate subcutaneous PPS administration with retinal toxic effects, demonstrating that maculopathy can occur at substantially lower cumulative doses than previously reported for oral formulations. This finding likely relates to substantially increased bioavailability—approximately 10-fold higher—when PPS is administered subcutaneously.
The implications are clinically profound:
– Retinal toxicity risk extends beyond oral administration.
– Patients receiving subcutaneous PPS for arthritis require proactive ophthalmic monitoring.
– Multimodal imaging is imperative for early detection and differentiation from other maculopathies.
– Clinicians should exercise caution prescribing subcutaneous PPS, balancing therapeutic benefits with ocular risks.
Moreover, the progression of maculopathy post-drug cessation highlights possible irreversible damage, reinforcing the priority of early recognition and limiting exposure. This aligns with prior reports of PPS-induced maculopathy and expands understanding to alternate administration routes.
This series underscores the need for updated guidelines and vigilance in prescribing and monitoring PPS therapy across all routes. Further research is warranted to elucidate pharmacokinetics, mechanisms of retinal toxicity with subcutaneous administration, and potential protective strategies.
### References
1. Fung AT, Sarraf D, Carrillo JM, et al. Pentosan Polysulfate Maculopathy Following Subcutaneous Injections for Arthritis. JAMA Ophthalmol. 2025 Dec 11:e255069. doi:10.1001/jamaophthalmol.2025.5069. Epub ahead of print. PMID: 41379439; PMCID: PMC12699400.
2. Pearce WA, Lopez AM. Drug-Induced Retinal Toxicity. In: Yanoff M, Duker JS, editors. Ophthalmology. 6th ed. Elsevier; 2020.
3. Olsen TW, Mariani AF. Pentosan polysulfate sodium and associated pigmentary maculopathy. Retina Today. 2022.
