Risk of age-related macular degeneration in men receiving 5α-reductase inhibitors: a population-based cohort study.

BACKGROUND: Recent studies suggest that 5α-reductase inhibitors (5ARIs) for benign prostate hyperplasia (BPH) result in abnormal retinal anatomical alteration. OBJECTIVE: To compare age-related macular degeneration (AMD) incidence in BPH patients receiving 5ARIs or tamsulosin. DESIGN: Retrospective, population-based cohort study using new-user and active-comparator design. SETTING: General population. SUBJECTS: Males with BPH, newly receiving 5ARIs or tamsulosin from 2010 to 2018. METHODS: Data were extracted from Taiwan's National Health Insurance Research Database. We used Cox proportional hazards model with 1:4 propensity score (PS) matching, based on intention-to-treat analysis to determine the risk of incident AMD. Sensitivity analyses included an as-treated approach and weighting-based PS methods. We also separately reported the risks of incident AMD in patients receiving finasteride and dutasteride to determine risk differences among different 5ARIs. RESULTS: We included 13 586 5ARIs users (mean age: 69 years) and 54 344 tamsulosin users (mean age: 68.37 years). After a mean follow-up of 3.7 years, no differences were observed in the risk of incident AMD between 5ARIs and tamsulosin users [hazard ratio (HR): 1.06; 95% confidence intervals (95% CI): 0.98-1.15], with similar results from sensitivity analyses. However, increased risk of incident age-related macular degeneration was observed in patients receiving dutasteride [HR: 1.13; 95% CI: 1.02-1.25], but not in those receiving finasteride [HR: 0.99; 95% CI: 0.87-1.12], in the subgroup analyses. CONCLUSIONS: We found no difference between 5ARIs and tamsulosin regarding the incidence of AMD in BPH patients. However, the risk profiles for AMD differed slightly between dutasteride and finasteride, suggesting that the potency of androgen inhibition is a factor related to AMD incidence.

The matricellular protein CCN5 prevents anti-VEGF drug-induced epithelial-mesenchymal transition of retinal pigment epithelium.

Age-related macular degeneration (AMD) is one of the major causes of blindness in the elderly worldwide. Anti-vascular endothelial growth factor (VEGF) drugs have been widely used to treat the neovascular type of AMD (nAMD). However, VEGF acts not only as a pro-angiogenic factor but also as an anti-apoptotic factor in the eyes. In this study, we found that anti-VEGF drugs, including bevacizumab (Bev), ranibizumab (Ran), and aflibercept (Afl), induced epithelial-mesenchymal transition (EMT) in ARPE-19 cells in vitro, accompanied by the induction of CCN2, a potent pro-fibrotic factor. Similarly, intravitreal injection of Afl into mouse eyes resulted in EMT in the retinal pigmented epithelium (RPE). Co-treatment with CCN5, an anti-fibrotic factor that down-regulates CCN2 expression, significantly attenuated the adverse effects of the anti-VEGF drugs both in vitro and in vivo. Inhibition of the VEGF signaling pathway with antagonists of VEGF receptors, SU5416 and ZM323881, induced EMT and up-regulated CCN2 in ARPE-19 cells. Additionally, knock-down of CCN2 with siRNA abolished the adverse effects of the anti-VEGF drugs in ARPE-19 cells. Collectively, these results suggest that anti-VEGF drugs induce EMT in RPE through the induction of CCN2 and that co-treatment with CCN5 attenuates the adverse effects of anti-VEGF drugs in mouse eyes.

Leading edge of the a-wave of the electroretinogram and sodium iodate-induced age-related macular degeneration: A model.

BACKGROUND: Iron-induced oxidative stress was thought to be the reason why the a-wave amplitude of the electroretinogram (ERG) dropped when iron ions were present. It is assumed that reactive oxygen species (ROS) are generated in the presence of iron ions, and this leads to a decrease in hyperpolarization of the photoreceptor. It is known that in age-related macular degeneration (AMD), sodium iodate can induce oxidative stress, apoptosis, and retinal damage, which mimic the effects of clinical AMD. Here, the reduction of the a-wave amplitude in mice with sodium iodate-induced age-related macular degeneration is explained. METHODS: The leading edge of the a-wave is divided into voltages developed by cones and rods. The same oxidative stress model is applied here since sodium iodate causes the creation of ROS in a manner similar to that caused by iron ions, with the exception that the retina is treated as a circuit of various resistances when computing the photoresponse. Moreover, sodium iodate also leads to apoptosis and, hence, may cause misalignment in cones (not in rods) during the initial stage of apoptosis in AMD. To include the effects of apoptosis and shortening in cones and rods, we have used a factor representing the fraction of total cones and rods that are alive. To include the effect of misalignment of cones on the reduction of the a-wave amplitude, we have used the Stiles-Crawford function to calculate the number of photoisomerizations occurring in a photoreceptor misaligned at an angle θ. The results are compared with experimental data. RESULTS: In sodium iodate-treated eyes, the ROS produced can attract calcium ions in the photoreceptor, which increases the calcium influx. In the case of the cones, the inclusion of the misalignment angle in the phototransduction process helps in determining the voltage and slope of the voltage vs. time graph.The smaller the fraction of active photoreceptors, the smaller the amplitude of the a-wave. The calcium influx, misaligned photoreceptors, and total photoreceptor loss all cause the amplitude of the a-wave to decrease, and at any time from the beginning of phototransduction cascade, the calcium influx causes the slope of the a-wave to increase. CONCLUSION: The reduction in the a-wave amplitude in the eyes of sodium iodate-treated mice is attributed to oxidative stress in both cones and rods and cone misalignment, which ultimately lead to apoptosis and vision loss in AMD.

Screening practices and risk assessment for maculopathy in pentosan polysulfate users across different exposure levels.

In this population-based cohort study, we investigated screening practices for maculopathy and incidences of specific macular/retinal conditions in pentosan polysulfate (PPS) users and assessed the relationship between these outcomes and drug exposure levels. Using a health claims database that covers approximately 50 million Koreans, we identified 138,593 individuals who were prescribed PPS between 2010 and 2021. For the 133,762 PPS users who initiated therapy between 2012 and 2021, the cumulative PPS dose for each participant was evaluated, and based on their cumulative PPS dose, patients were categorized into the high-risk (≥ 500 g), low-risk (50-500 g), and minimal exposure (< 50 g) groups. We analyzed the performance and methods of these examination methods used between 2018 and 2021 and compared them among cumulative dose groups to determine whether high-risk users underwent maculopathy screening more frequently or appropriately. We assessed the cumulative incidence of overall macular degeneration and maculopathy excluding common macular diseases following PPS therapy initiation. Most PPS users (99.7%) received a cumulative PPS dose < 500 g and the high- and low-risk groups comprised 445 (0.3%) and 22,185 (16.6%) patients, respectively. During the study period, monitoring examinations were conducted in 52.6% and 49.4% of high- and low-risk patients, respectively, revealing no significant difference between the two groups (P = 0.156). No significant differences were observed in the annual percentages of patients receiving ophthalmic examinations between the high- and low-risk groups (all P > 0.05). The cumulative incidences of overall macular degeneration and maculopathy excluding common macular diseases in high-risk users were 19.3% and 9.0%, respectively, which were significantly different from those of low-risk users (both P < 0.001). Multivariate Cox regression analysis revealed significantly higher risks of maculopathy excluding common macular diseases in the low- (Hazard ratio [HR] of 1.55 [95% CI 1.13-2.12]) and high-risk groups (HR of 1.66 [95% CI 1.22-2.27]) compared to the minimal exposure group. Our findings suggest a need for increased emphasis on PPS maculopathy screening in high-risk patients, highlighting raising awareness regarding exposure-dependent risks and the establishment of screening guidelines.

Retinal toxicity of heavy metals and its involvement in retinal pathology.

The objective of the present review is to discuss epidemiological evidence demonstrating the association between toxic metal (Cd, Pb, Hg, As, Sn, Ti, Tl) exposure and retinal pathology, along with the potential underlying molecular mechanisms. Epidemiological studies demonstrate that Cd, and to a lesser extent Pb exposure, are associated with age-related macular degeneration (AMD), while the existing evidence on the levels of these metals in patients with diabetic retinopathy is scarce. Epidemiological data on the association between other toxic metals and metalloids including mercury (Hg) and arsenic (As), are limited. Clinical reports and laboratory in vivo studies have shown structural alterations in different layers of retina following metal exposure. Examination of retina samples demonstrate that toxic metals can accumulate in the retina, and the rate of accumulation appears to increase with age. Experimental studies in vivo and in vitro studies in APRE-19 and D407 cells demonstrate that toxic metal exposure may cause retinal damage through oxidative stress, apoptosis, DNA damage, mitochondrial dysfunction, endoplasmic reticulum stress, impaired retinogenesis, and retinal inflammation. However, further epidemiological as well as laboratory studies are required for understanding the underlying molecular mechanisms and identifying of the potential therapeutic targets and estimation of the dose-response effects.

Association of sildenafil use with age-related macular degeneration: a retrospective cohort study.

OBJECTIVE: Despite significant advances in clinical care and understanding of the underlying pathophysiology, age-related macular degeneration (AMD)-a major cause of global blindness-lacks effective treatment to prevent the irreversible degeneration of photoreceptors leading to central vision loss. Limited studies suggest phosphodiesterase type 5 (PDE5) inhibitors, such as sildenafil, may prevent AMD by increasing retinal blood flow. This study explores the potential association between sildenafil use and AMD risk in men with erectile dysfunction using UK data. METHODS AND ANALYSIS: Using the UK's IQVIA Medical Research Data, the study analysed 31 575 men prescribed sildenafil for erectile dysfunction and no AMD history from 2007 to 2015, matched with a comparator group of 62 155 non-sildenafil users in a 1:2 ratio, over a median follow-up of approximately three years. RESULTS: The primary outcome was the incidence of AMD in the two groups. The study found no significant difference in AMD incidence between the sildenafil users and the non-users, with an adjusted hazard ratio (HR) of 0.99 (95% CI 0.84 to 1.16), after accounting for confounders such as age, ethnicity, Townsend deprivation quintile, body mass index category, and diagnosis of hypertension and type 2 diabetes. CONCLUSION: The study results indicated no significant association between sildenafil use and AMD prevention in UK men with erectile dysfunction, suggesting sildenafil's protective effect on AMD is likely insignificant.

Pentosan polysulfate and a pigmentary maculopathy: causation versus correlation?

INTRODUCTION: Interstitial cystitis (IC) is a chronic disease with urinary tract symptoms and pain. Pentosan polysulfate (PPS) is the only U.S. Food and Drug Administration approved oral medication for the treatment of IC pain and symptoms. Recently, articles described a pigmentary maculopathy in IC patients on long term PPS therapy. Currently, there is no definitive study directly linking PPS as the cause of the pigmentary maculopathy. The aim of this review is to evaluate if PPS is the causative factor of the pigmentary maculopathy or if PPS use is only associated with the pigmentary maculopathy. MATERIALS AND METHODS: A comprehensive review of peer reviewed journals using the search terms IC, maculopathy, mast cells, immune inflammatory components, Tamm-Horsfall protein, cations and tight junctions was performed to examine the pathophysiology and role of chronic inflammation in IC and known retinal maculopathies. RESULTS: Chronic inflammatory cells have been reported in age-related macular degeneration choroid blood vessels and in bladder submucosal and detrusor layers in IC patients. Studies in IC and maculopathies demonstrate a significant milieu of activated chronic inflammatory and immunologic responses that cause a more "leaky" epithelium and a subsequent cascade of inflammatory events that results in the pathological changes seen in these two conditions. CONCLUSIONS: After an analysis of the literature describing a pigmentary maculopathy in IC patients on long term PPS, a causal relationship does not appear to be present. An alternate model is proposed postulating that the causative factor for the pigmentary maculopathy is the underlying inflammatory state associated with IC and not PPS use.

Ultra-high resolution optical coherence tomography analysis of bull's eye maculopathy in chloroquine users / Análise da maculopatia em bull's eye pela tomografia de coerência óptica de alta resolução em usuários de cloroquina

Purpose: Register and compare anatomical changes, structural and quantitative found in optical coherence tomography Stratus and Topcon 3D in chronic users of chloroquine. Methods: Five patients were diagnosed with toxic "bull's eye" maculopathy was submitted to macular optical coherence tomography examination (Stratus and Topcon 3D). Results: Both tools demonstrated an increase reflectivity of choriocapillaris unit just foveal retinal pigment epithelium atrophy. However, Topcon 3D provided to all patients better description of the line corresponding to the transition between inner and outer segments of photoreceptors. Using the possibility of assembling threedimensional images and subtraction selective retinal layers, we found a lesion with a target that reflects the greater thickness of retinal pigment epithelium in central and parafoveal region that is matched to preserve macular photoreceptors. Conclusion: it was observed better resolution and faster image capture by Topcon 3D than Stratus OCT, that provided more detailed analysis of the line corresponding to transition between outer and inner segment of photoreceptors in macular region. With Topcon 3D, it was possible to evaluate soundly the thickness of retinal pigment epithelium in central and parafoveal region that caused an increase reflectivity of choriocapillaris creating a image with a target unpublished before. .

Objetivo: Comparar e registrar as alterações quantitativas e qualitavivas na tomografia de coerência óptica nos pacientes com uso prolongado de cloroquina. Métodos: Avaliaram-se cinco pacientes com diagnóstico de bull’s eye no exame de tomografia de coerência óptica macular com dois modelos de aparelhos: Stratus e Topcon 3D. Resultados: Ambos aparelhos registraram aumento da refletividade coriocapilar foveal provocada pela atrofia do epitélio pigmentar da retina. Somente o Topcon 3D permitiu melhor visibilização da linha de transição entre o segmento interno e externo dos fotorreceptores. Este aparelho também permitiu a formação de imagens tridimensionais e subtração das camadas retinianas, com registro da diminuição da espessura do epitélio pigmentado da retina na região central e parafoveal macular. Conclusão: Foi possível observar a captação mais rápida e com melhor resolução das imagens geradas pelo Topcon 3D. A diminuição da espessura do epitélio pigmentado da retina, provocando o aumento da refletividade coriocapilar, com a formação de uma imagem linear circular cincundando a fóvea, foi mais detalhado pelos cortes realizados no Topcon 3D. .

SIRT1 negatively regulates amyloid-beta-induced inflammation via the NF-B pathway

Chronic inflammation induced by amyloid-beta (Aβ) plays a key role in the development of age-related macular degeneration (AMD), and matrix metalloproteinase-9 (MMP-9), interleukin (IL)-6, and IL-8 may be associated with chronic inflammation in AMD. Sirtuin 1 (SIRT1) regulates inflammation via inhibition of nuclear factor-kappa B (NF-κB) signaling, and resveratrol has been reported to prevent Aβ-induced retinal degeneration; therefore, we investigated whether this action was mediated via activation of SIRT1 signaling. Human adult retinal pigment epithelial (RPE) cells were exposed to Aβ, and overactivation and knockdown of SIRT1 were performed to investigate whether SIRT1 is required for abrogating Aβ-induced inflammation. We found that Aβ-induced RPE barrier disruption and expression of IL-6, IL-8, and MMP-9 were abrogated by the SIRT1 activator SRT1720, whereas alterations induced by Aβ in SIRT1-silenced RPE cells were not attenuated by SRT1720. In addition, SRT1720 inhibited Aβ-mediated NF-κB activation and decrease of the NF-κB inhibitor, IκBα. Our findings suggest a protective role for SIRT1 signaling in Aβ-dependent retinal degeneration and inflammation in AMD.

Tela de Amsler e campo visual no rastreamento da retinopatia por cloroquina / Amsler grid and visual field on screening for chloroquine retinopathy

OBJETIVOS: Comparar a tela de Amsler modificada com o campo visual Humphrey® 10-2 vermelho nos usuários de cloroquina, na detecção da maculopatia precoce, e correlacionar com as variáveis de risco. MÉTODOS: Foram analisados 116 olhos de 58 pacientes, acompanhados no Serviço de Oftalmologia do Hospital do Servidor Público Estadual de São Paulo, entre abril de 2006 e abril de 2008. Todos os usuários tinham fundo de olho normal e mais de dois anos de terapia com cloroquina. Os participantes tiveram seus dados clínicos avaliados e foram submetidos ao exame da acuidade visual corrigida, biomicroscopia de fundo, campimetria macular automatizada e tela de Amsler. RESULTADOS: A incidência da maculopatia precoce foi de 7 a 10%, dependendo do exame considerado. A concordância entre a tela de Amsler e o campo visual foi baixa. Para o grupo de olhos que apresentaram ambos os exames alterados, houve significância estatística com a alta dose diária, dose cumulativa elevada e baixa acuidade visual; a idade do paciente e a duração do tratamento não mostraram boa correlação nestes casos, mas suas médias (67,4 anos e 8,4 anos, respectivamente) situaram-se dentro da faixa dos fatores de alto risco. CONCLUSÕES: O estudo sugere que a tela de Amsler pode ser útil na complementação das informações do campo visual no rastreamento periódico da retinopatia por cloroquina, sobretudo naqueles com fatores de alto risco bem estabelecidos, selecionando melhor os candidatos à realização de testes objetivos, como o OCT de alta resolução e o ERG multifocal.

PURPOSE: To compare the modified Amsler grid to the Humphrey® 10-2 red visual field in chloroquine users for the detection of early maculopathy, and to correlate with the risk variables. METHODS: The study included 116 eyes of 58 patients followed at the Department of Ophthalmology of Hospital do Servidor Público Estadual de São Paulo, from April, 2006 to April, 2008. All users had normal fundus and more than 2 years of chloroquine therapy. Their clinical data were evaluated and they underwent visual acuity examination, fundus biomicroscopy, visual field and Amsler grid. RESULTS: The incidence of early maculopathy was 7 to 10%, depending on the examination considered. The agreement between the Amsler grid and visual field was low. There was statistical significance with the use of high daily dose, elevated cumulative dose and low visual acuity in patients whose eyes had both abnormal tests; patient age and duration of treatment did not show good correlation in these cases, but their averages (67.4 years and 8.4 years, respectively) were within the range of high risk factors. CONCLUSIONS: The study suggests that Amsler can be useful in complementing the information on the visual field for chloroquine retinopathy periodic screening, especially for those patients who present high risk factors well established, selecting better candidates for objective tests, such as HD OCT and mfERG.

Toxicidade ocular por tamoxifeno / Ocular toxicity by tamoxifen use

O tamoxifeno é um modulador seletivo dos receptores de estrogênio, sendo considerado uma das principais drogas utilizadas no tratamento do câncer de mama. A despeito do comprovado benefício de sua utilização, diversos efeitos adversos têm sido relacionados a ele, como o câncer de endométrio, fenômenos tromboembólicos, sarcomas uterinos e toxicidade ocular. Neste artigo de revisão, descrevemos as principais alterações oculares relacionadas ao uso do tamoxifeno, suas características e o diagnóstico diferencial. Em decorrência da freqüência com que ocorre a toxicidade ocular, chamamos atenção para a avaliação quanto ao acompanhamento periódico das pacientes sob uso desta medicação, sendo por vezes necessária à interrupção da medicação e sua substituição por drogas de outros grupos terapêuticos visando à preservação visual dessas pacientes.

Toxicidade ocular causada pelo tamoxifeno: relato de caso / Ocular toxicity caused by tamoxifen: case report

O objetivo desse trabalho é relatar um caso de toxicidade ocular pelo tamoxifeno. Para isso, aferiu-se a melhor acuidade visual corrigida de ambos os olhos em tabela de Snellen. Foram realizados biomicroscopia do segmento anterior, refração, oftalmoscopia, angiofluoresceinografia e retinografia numa paciente de 63 anos, sexo feminino, cor branca, em uso de tamoxifeno 20 mg/dia há 4 anos, com acuidade visual corrigida de 20/70 e 20/40. A biomicroscopia do segmento anterior apresentava ceratopatia verticilata e catarata nuclear e cortical posterior de 1+/4 em ambos os olhos. A oftalmoscopia, foi verificado alteração do brilho macular de ambos os olhos. E a angiofluoresceinografia mostrou hiperfluorescência na área macular em fase precoce (defeito em janela). Relata-se um caso de ceratopatia e maculopatia causadas pelo tamoxifeno.