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Asia-Pacific Journal of Ophthalmology...Pentosan polysulfate (PPS) sodium (Elmiron) is the only Food and Drug Administration (FDA)-approved oral medication to treat interstitial cystitis, also known as bladder... (Review)
Review
Pentosan polysulfate (PPS) sodium (Elmiron) is the only Food and Drug Administration (FDA)-approved oral medication to treat interstitial cystitis, also known as bladder pain syndrome. A symptomatic pigmentary maculopathy associated with PPS was reported in 2018. Since then, recognition of this unique drug toxicity has increased rapidly. This potentially sight-threatening side effect prompted the FDA in June 2020 to update the label for PPS to warn about "retinal pigmentary changes." A challenging feature of pentosan maculopathy is its ability to mimic many other retinal conditions, including inherited retinal dystrophies such as pattern dystrophy, mitochondrially inherited diabetes and deafness, and Stargardt disease, and age-related macular degeneration. In this review, we discuss the history of PPS maculopathy and its implications for thousands of at-risk interstitial cystitis patients. We use published literature and an illustrative case from our institution to highlight the importance of diagnosing PPS maculopathy. We also compare PPS maculopathy to age-related macular degeneration, explain why differentiating between the 2 is clinically important, and highlight avenues for further research. Finally, we highlight the paucity of data on patients of color and why this lack of understanding may impact patient care.
Topics: Anticoagulants; Cystitis, Interstitial; Female; Humans; Macular Degeneration; Male; Pentosan Sulfuric Polyester; Retinal Dystrophies
PubMed: 35533330
DOI: 10.1097/APO.0000000000000504 -
Seminars in Immunopathology Jan 2018Complement turnover is tightly regulated throughout the human body in order to prevent over-activation and subsequent damage from inflammation. In the eye, low-level... (Review)
Review
Complement turnover is tightly regulated throughout the human body in order to prevent over-activation and subsequent damage from inflammation. In the eye, low-level complement activation is maintained to provide immune tolerance in this immune privileged organ. Conversely, the complement system is suppressed in the cornea to protect it from continuous immunological insult. Over-activation of the complement cascade has been implicated in the disease progression of glaucoma and diabetic retinopathy and is now known to be a central driver in the pathogenesis of age-related macular degeneration (AMD). Indeed, it is with AMD where the most recent and exciting work has been carried out with complement-based therapies entering into clinical trials. However, the success of these trials will depend upon delivering the therapeutics to the correct anatomical sites within the eye, so a full understanding of how complement regulation is compartmentalized in the eye is required, a topic that will be highlighted in this review.
Topics: Animals; Clinical Trials as Topic; Complement Activation; Complement System Proteins; Disease Susceptibility; Eye Diseases; Humans; Macular Degeneration; Molecular Targeted Therapy; Treatment Outcome
PubMed: 28948331
DOI: 10.1007/s00281-017-0649-6 -
CMAJ : Canadian Medical Association... Jul 2021
Review
Topics: Humans; Macular Degeneration; Pentosan Sulfuric Polyester
PubMed: 34312174
DOI: 10.1503/cmaj.201900-f -
Clinical Interventions in Aging 2008Age-related macular degeneration (AMD) is an ocular disease that causes damage to the retinal macula, mostly in the elderly. Normal aging processes can lead to... (Review)
Review
Age-related macular degeneration (AMD) is an ocular disease that causes damage to the retinal macula, mostly in the elderly. Normal aging processes can lead to structural and blood flow changes that can predispose patients to AMD, although advanced age does not inevitably cause AMD. In this review, we describe changes that occur in the macular structure, such as the retinal pigment epithelium and Bruch's membrane, with advancing age and in AMD. The role of genetics in AMD and age-related changes in ocular blood flow that may play a role in the pathogenesis of AMD are also discussed. Understanding the pathophysiology of AMD development can help guide future research to further comprehend this disease and to develop better treatments to prevent its irreversible central vision loss in the elderly.
Topics: Aged; Aging; Blood Flow Velocity; Disease Progression; Humans; Macula Lutea; Macular Degeneration
PubMed: 18982917
DOI: 10.2147/cia.s2777 -
Archives of Ophthalmology (Chicago,... Mar 2010Age-related macular degeneration (AMD) is one of the most well-characterized late-onset, complex trait diseases. Remarkable advances in our understanding of the genetic... (Review)
Review
Age-related macular degeneration (AMD) is one of the most well-characterized late-onset, complex trait diseases. Remarkable advances in our understanding of the genetic and biological foundations of this disease were derived from a recent convergence of scientific and clinical data. Importantly, the more recent identification of AMD-associated variations in a number of complement pathway genes has provided strong support for earlier, paradigm-shifting studies that suggested that aberrant function of the complement system plays a key role in disease etiology. Collectively, this wealth of information has provided an impetus for the development of powerful tools to accurately diagnose disease risk and progression and complement-based therapeutics that will ultimately delay or prevent AMD. Indeed, we are poised to witness a new era of a personalized approach toward the assessment, management, and treatment of this debilitating, chronic disease.
Topics: Complement System Proteins; Genetic Techniques; Humans; Macular Degeneration
PubMed: 20212207
DOI: 10.1001/archophthalmol.2010.18 -
Clinical Chemistry and Laboratory... May 2017Advanced age-related macular degeneration (AAMD) is a complex sight-threating disease of public health significance. Micro RNAs (miRNAs) have been proposed as biomarkers... (Review)
Review
Advanced age-related macular degeneration (AAMD) is a complex sight-threating disease of public health significance. Micro RNAs (miRNAs) have been proposed as biomarkers for AAMD. The presence of certain single nucleotide polymorphisms (SNPs) may influence the explanatory value of these biomarkers. Here we present findings from an integrated approach used to determine whether AAMD-associated SNPs have the capacity to influence miRNA-mRNA pairing and, if so, to what extent such pairing may be manifested in a discrete AAMD transcriptome. Using a panel of 8854 SNPs associated with AAMD at p-values ≤5.0E-7 from a cohort of >30,000 elderly people, we identified SNPs in miRNA target-encoding constituents of: (1) regulator of complement activation (RCA) genes (rs390679, CFHR1, p≤2.14E-214 | rs12140421, CFHR3, p≤4.63E-29); (2) genes of major histocompatibility complex (MHC) loci (rs4151672, CFB, p≤8.91E-41 | rs115404146, HLA-C, p≤6.32E-12 | rs1055821, HLA-B, p≤1.93E-9 | rs1063355, HLA-DQB1, p≤6.82E-14); and (3) genes of the 10q26 AAMD locus (rs1045216, PLEKHA1, p≤4.17E-142 | rs2672603, ARMS2, p≤7.14E-46). We used these findings with existing data on AAMD-related retinal miRNA and transcript profiles for the purpose of making inferences on SNP-mRNA-miRNA-AAMD relationships. Four of 12 miRNAs significantly elevated in AAMD retina (hsa-miR-155-5p, hsa-let-7a-5p, hsa-let-7b-5p hsa-let-7d-5p) also showed strong pairing capacity (TarBase 7.1 context++ score <-0.2, miRanda 3.3 pairing score >150) with miRNA target transcripts encoded by AAMD-associated SNPs resident in HLA-DQB1 (rs1063355, hsa-miR-155-5p) and TGFBR1 (rs868, hsa-let-7). Three of the 12 miRNAs overexpressed in AAMD retina are inducible by NFkB and have high affinity targets in the complement factor H (CFH) mRNA 3' UTR. We used ENSEMBL to identify polymorphic regions in the CFH mRNA 3' UTR with the capacity to disrupt miRNA-mRNA pairing. Two variants (rs766666504 and rs459598) existed in DNA sequence encoding the seed region of hsa-miR-146a-5p in the CFH mRNA 3' UTR - as this miRNA is also elevated in both vitreous and serum of people with AAMD, it shows great value as a biomarker. Our findings suggest that knowledge on the nature of DNA sequence variation may increase the explanatory power of miRNA biomarkers in genetically diverse populations, while yielding information with which to develop: (1) mechanistic tests on processes implicated in AMD pathogenesis; and, (2) site-specific small molecules (synthetic mimetics or anti-miRNAs) with preventive or therapeutic efficacy for AAMD.
Topics: Gene Expression Regulation; Humans; Macular Degeneration; MicroRNAs; Polymorphism, Single Nucleotide; Retina; Vitreous Body
PubMed: 28343170
DOI: 10.1515/cclm-2016-0898 -
BMC Ophthalmology Dec 2021Age-related macular degeneration (AMD) is a disease that causes damage in the macular region of the retina, leading to irreversible blindness. This study aims to... (Observational Study)
Observational Study
BACKGROUND
Age-related macular degeneration (AMD) is a disease that causes damage in the macular region of the retina, leading to irreversible blindness. This study aims to understand the profile and care of patients with AMD and its cost at the Brazilian public health system to identify AMD-care needs.
METHODS
This is a retrospective observational study of AMD with real-world data from the Brazilian public healthcare system, using DATASUS claim databases. Patients with AMD were selected from 01/Jan/2014 to 31/Jan/2020; had at least one claim of ICD10 code H35.3 (Degeneration of macula and posterior pole), and were submitted to one of two procedures exclusively available for AMD patients - optical coherence tomography (OCT) and medical treatment of retinal disease (antiangiogenic); aged ≥18 years at first ICD10 claim, and presenting at least 1 year of follow-up in the database. We described patients' characteristics, healthcare resource utilization and cost, and the antiangiogenic intravitreal treatment received by AMD patients, including the number of doses and interval time between them.
RESULTS
Patients searching for AMD treatment since 2014 were mostly females (59%), white (61%), and a mean age of 72 years. They were mainly located in the Southeast (87%), and few patients were found in the North (1%) and Central-West (1.5%) regions, probably reflecting where the Brazilian guideline to treat AMD (Protocolo Clínico e Diretrizes Terapêuticas - PCDT) was incorporated as routine care for AMD. The average antiangiogenic dose of 2.5 antiangiogenic therapies within a year was below the expected. Most injections had an interval time of 20 to 40 days between doses, although some patients were treated more than 100 days. Another setback is that patients traveled longer distances for OCT and antiangiogenic treatment than overall AMD-healthcare, between 10 and 100 km.
CONCLUSIONS
AMD patients seem to be undertreated, as they receive a mean of 2.5 doses of antiangiogenic treatment within a year. Inequalities among regions are evident, as the Southeast and South regions comprise almost all patients receiving the treatment from the public health system, probably reflecting the region with more access to AMD care according to PCDT recommendations.
Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Delivery of Health Care; Female; Humans; Macular Degeneration; Male; Retrospective Studies; Tomography, Optical Coherence
PubMed: 34903203
DOI: 10.1186/s12886-021-02181-1 -
Drug Discovery Today Nov 2023The complement system is involved in the pathogenesis of several ocular diseases, providing a rationale for the investigation of complement-targeting therapeutics for... (Review)
Review
The complement system is involved in the pathogenesis of several ocular diseases, providing a rationale for the investigation of complement-targeting therapeutics for these conditions. Dry age-related macular degeneration, as characterised by geographic atrophy (GA), is currently the most active area of research for complement-targeting therapeutics, with a complement C3 inhibitor approved in the United States earlier this year marking the first approved therapy for GA. This review discusses the role of complement in ocular disease, provides an overview of the complement-targeting agents currently under development for ocular conditions, and reflects on the lessons that can be learned from the preclinical investigations and clinical trials conducted in this field to date.
Topics: Humans; Macular Degeneration; Eye; Geographic Atrophy
PubMed: 37657753
DOI: 10.1016/j.drudis.2023.103757 -
American Journal of Ophthalmology Aug 2023To report the incidence and risk factors for fibrosis at 10 years in a large cohort of persons with neovascular age-related macular degeneration (nAMD).
PURPOSE
To report the incidence and risk factors for fibrosis at 10 years in a large cohort of persons with neovascular age-related macular degeneration (nAMD).
DESIGN
Retrospective, multicenter, cohort study.
METHODS
We included 225 naive nAMD eyes that underwent intravitreal anti-vascular endothelial growth factor treatment over 10 years of follow-up at two Italian referral centers. Demographic and clinical data were reviewed at baseline and on an annual basis. Onset of fibrosis was defined by clinically assessing photographs, fundus descriptions, or fluorescein angiograms. Optical coherence tomography (OCT) scans of fibrosis were inspected by an external reading center and graded as subretinal pigment epithelium (RPE), mixed, or subretinal.
RESULTS
The mean age at baseline was of 72.1 ± 6.9 years. The incidence rate of fibrosis was estimated to be 8.9 per 100 person-years, with a cumulative incidence of 62.7% at 10 years. Fibrotic lesions were sub-RPE in 46.1%, mixed in 29.8%, and subretinal in 22.7%. Independent factors associated with fibrosis included the following: larger central subfield thickness variation (P < .001), submacular hemorrhages (P = .008), higher number of injections (P = .01), and worse baseline visual acuity (VA) (P = .03). Type 2 macular neovascularization was significantly associated with mixed and subretinal fibrosis. VA significantly declined over 10 years (-16.4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters), particularly in eyes with mixed and subretinal fibrosis (P < .001).
CONCLUSIONS
We identified a 62.7% cumulative incidence of fibrosis in a large nAMD cohort at 10 years. Fibrosis was more common with frequent reactivations and lower baseline VA; its onset had a significant impact on final VA. This supports the hypothesis that nAMD patients should be promptly treated with proactive regimens.
Topics: Humans; Aged; Angiogenesis Inhibitors; Ranibizumab; Incidence; Cohort Studies; Vascular Endothelial Growth Factor A; Retrospective Studies; Fibrosis; Risk Factors; Macular Degeneration; Intravitreal Injections; Wet Macular Degeneration; Tomography, Optical Coherence
PubMed: 37030492
DOI: 10.1016/j.ajo.2023.03.033 -
Investigative Ophthalmology & Visual... Dec 2013Age-related macular degeneration is the leading cause of irreversible visual dysfunction in individuals over 65 in Western Society. Patients with AMD are classified as... (Review)
Review
Age-related macular degeneration is the leading cause of irreversible visual dysfunction in individuals over 65 in Western Society. Patients with AMD are classified as having early stage disease (early AMD), in which visual function is affected, or late AMD (generally characterized as either "wet" neovascular AMD, "dry" atrophic AMD or both), in which central vision is severely compromised or lost. Until recently, there have been no therapies available to treat the disorder(s). Now, the most common wet form of late-stage AMD, choroidal neovascularization, generally responds to treatment with anti-vascular endothelial growth factor therapies. Nevertheless, there are no current therapies to restore lost vision in eyes with advanced atrophic AMD. Oral supplementation with the Age-Related Eye Disease Study (AREDS) or AREDS2 formulation (antioxidant vitamins C and E, lutein, zeaxanthin, and zinc) has been shown to reduce the risk of progression to advanced AMD, although the impact was in neovascular rather than atrophic AMD. Recent findings, however, have demonstrated several features of early AMD that are likely to be druggable targets for treatment. Studies have established that much of the genetic risk for AMD is associated with complement genes. Consequently, several complement-based therapeutic treatment approaches are being pursued. Potential treatment strategies against AMD deposit formation and protein and/or lipid deposition will be discussed, including anti-amyloid therapies. In addition, the role of autophagy in AMD and prevention of oxidative stress through modulation of the antioxidant system will be explored. Finally, the success of these new therapies in clinical trials and beyond relies on early detection, disease typing, and predicting disease progression, areas that are currently being rapidly transformed by improving imaging modalities and functional assays.
Topics: Angiogenesis Inhibitors; Antioxidants; Diagnostic Techniques, Ophthalmological; Disease Management; Disease Progression; Dry Eye Syndromes; Humans; Macular Degeneration; Oxidative Stress
PubMed: 24335072
DOI: 10.1167/iovs.13-12757