Low health literacy levels in patients with chronic retinal disease.

BACKGROUND: A patient's health literacy is fundamental for navigating the health system and managing disease. This study aimed to compare the health literacy levels of patients with chronic retinal disease in Denmark. METHODS: This cross-sectional questionnaire study used the validated HLS-EU-Q16 questionnaire to determine the health literacy of 225 patients with age-related macular degeneration (AMD), diabetic macular edema (DME) or retinal vein occlusion (RVO), receiving intravitreal treatment at the retinal clinic, Zealand University Hospital, Denmark. Patients were consecutively included as participants for the study. All patients had the option of having the survey read aloud to them. RESULTS: Health literacy levels between the patient groups did not differ significantly, however, the proportion of patients with poor health literacy was high-65% of AMD patients, 73% of DME patients, and 63% of patients with RVO. CONCLUSIONS: Low health literacy of patients with retinal disease signify a need for more health literacy research in the field of retinal diseases, to secure that patients have the timely and appropriate knowledge and competencies to manage their condition.

Patients with a fast progression profile in geographic atrophy have increased CD200 expression on circulating monocytes.

IMPORTANCE: Geographic atrophy (GA) is a progressing atrophy of the neuroretina with no treatment option. BACKGROUND: Age-related malfunction of retinal microglia amplifies response towards age-related tissue stress in age-related macular degeneration. Here, we investigated monocyte CD200 expression - the circulating middleman negotiating retinal microglial activity - in a poorly understood subtype of age-related macular degeneration. DESIGN: Prospective case-control study. PARTICIPANTS: Forty-six patients with GA and 26 healthy controls were included. METHODS: All participants were subjected to a structured interview and detailed retinal examination. Controls were recruited from patient's spouses accompanying them in the clinic to match the groups best possibly. Participants had no history of immune disorders or cancer, and did not receive any immune-modulating medication. Patients did not have any history or sign of choroidal neovascularization in either eye. Fresh drawn blood was stained with monoclonal antibodies and prepared for flow cytometry to evaluate CD200 expression in monocytes and their functional subsets. MAIN OUTCOME MEASURES: The percentage of CD200+ monocytes in patients and controls. RESULTS: We found that monocytes were more CD200 positive in patients with GA compared to healthy age-matched controls. Then, we explored the potential relationship between CD200 expression and important fundus autofluorescence patterns that predict disease progression. Patients with a high risk of progression (patients with high degree of hyperautofluorescence) had distinctly increased CD200 expression compared to other patients with GA. CONCLUSIONS AND RELEVANCE: Our data reveals that abnormal monocytic CD200 expression is present in GA, and in particular among those identified as fast progressors.

Altered proportion of CCR2+ and CX3CR1+ circulating monocytes in neovascular age-related macular degeneration and polypoidal choroidal vasculopathy.

BACKGROUND: We investigated the expression of chemokine receptors CCR2 (C-C chemokine receptor) 2 and CX3CR1 (C-X3-C receptor 1) on circulating monocyte subsets in patients with neovascular age-related macular degeneration (AMD) and patients with polypoidal choroidal vasculopathy (PCV). METHODS: We recruited patients with neovascular AMD, patients with PCV and age-matched healthy controls for this prospective case-control study. All participants underwent comprehensive clinical examination and imaging. Freshly sampled venous blood was prepared for flow cytometry, where we determined the proportion of CCR2+ - and CX3CR1+ -positive cells in monocyte subsets identified using monocyte identification and subgrouping surface markers CD14, CD16 and HLA-DR. RESULTS: Patients with neovascular AMD had significantly increased proportion of CCR2+ and CX3CR1+ non-classical monocytes. PCV type 1 was associated with significantly increased CCR2+ and CX3CR1+ in all monocyte subsets when compared to PCV type 2. CONCLUSIONS: Neovascular AMD is associated with increased expression of angiogenesis-associated chemokine receptors in the pro-inflammatory non-classical monocytes. PCV differs from neovascular AMD immunologically and show immunological heterogeneity across angiographic subtypes.

Altered activation state of circulating neutrophils in patients with neovascular age-related macular degeneration.

BACKGROUND: Neutrophil dysfunction plays a key role in the development of diseases characterized by inflammation and angiogenesis. Here, we studied the systemic expression of neutrophil markers reflecting activation, adhesion, and resolution of inflammation in patients with neovascular age-related macular degeneration (AMD). RESULTS: This was a prospective case-control study of patients with neovascular AMD and age-matched healthy control individuals. Patients were recruited from an outpatient program, and control individuals were recruited amongst patients' relatives. Current smokers and individuals with either active immune-disease or ongoing cancer were not included, as these factors are known to affect neutrophil function. Fresh-drawn venous blood was processed for flow cytometric analysis of neutrophil markers. We determined percentages of positive cells and compared expression levels using fluorescence intensity measures. We found conditional differences on marker expression between patients with neovascular AMD (n = 29) and controls (n = 28): no differences were found when looking broadly, but several differences emerged when focusing on non-smokers. Here, patients with neovascular AMD had increased expression of the activity marker cluster of differentiation (CD) 66b (P = 0.003; Mann-Whitney U test), decreased expression of adhesion marker CD162 (P = 0.044; Mann-Whitney U test), and lower expression of the resolution of inflammation marker C-X-C chemokine receptor 2 (P = 0.044; Mann-Whitney U test). CONCLUSIONS: We present novel evidence suggesting that the activity of circulating neutrophils, sensitive to smoking, may differ in patients with neovascular AMD.

Interleukin-8 Promoter Polymorphism -251 A/T and Treatment Response in Neovascular Age-related Macular Degeneration.

Purpose: Interleukin-8 (IL-8) is a potent pro-angiogenic and pro-inflammatory chemokine, suggested to hold a role in neovascular age-related macular degeneration (nAMD). Our aim is to study the association of the single-nucleotide polymorphism -251 A/T (rs4073) in the IL-8 promoter region with the treatment response to intravitreal anti-vascular endothelial growth factor (VEGF) injections in nAMD. Patients and Methods: This is a prospective study of treatment-naïve patients with nAMD. Treatment response after a loading dose of three intravitreal anti-VEGF injections was defined as functional response based on change in visual acuity, and morphological response based on change in central retinal thickness (CRT) and intraretinal fluid on optical coherence tomography. Morphological response was categorized in good, partial, and poor responders. Blood DNA was analyzed for -251 A/T genotype. Results: The IL-8 promoter polymorphism -251 A/T was not significantly associated to functional treatment response (P=0.09). No significant association was found between genotype and morphological treatment response (P=0.799). Older age was significantly associated to good morphological responders compared to partial and poor responders (P=0.014). Conclusion: The IL-8 polymorphism -251 A/T is not associated to morphological nor functional treatment response to intravitreal anti-VEGF injections in patients with nAMD.

Chemokine Receptor Profile of T Cells and Progression Rate of Geographic Atrophy Secondary to Age-related Macular Degeneration.

Purpose: Geographic atrophy (GA) secondary to age-related macular degeneration is a progressive retinal degenerative disease. Systemic chemokine receptors and known risk-associated single-nucleotide polymorphisms have been associated with GA pathogenesis. Because halting progression is pivotal for patients, we investigated the association of candidate chemokine receptors and progression rate (PR) of atrophic lesions in patients with GA. Methods: This prospective observational study conducted at a single center included 85 patients with GA and 45 healthy controls. Patients were followed up after 13 months on average. Serial fundus autofluorescence images were used to determine the PR of atrophic lesions. The proportion of chemokine receptors on peripheral lymphocytes were determined by flow cytometric analysis. Results: Patients with GA had a lower proportion of CCR6 on CD8+T cells compared to healthy controls. Importantly, the proportion of CCR6 on CD4+T cells was lower in patients with fast GA progression compared to patients with slow progression of disease, suggesting that dysregulation of CCR6 could be involved in progression of GA. We also found that GA patients had a markedly higher percentage of CCR5 on CD4+ and CD8+T cells compared to healthy controls. After stratification according to ARMS2 polymorphism, we found a significantly lower level of CCR5 on CD8+T cells among patients with high-risk genotypes compared with patients with the low-risk genotype. Conclusions: Our study finds that chemokine receptors are dysregulated in patients with GA and that CCR6 might be involved in GA progression, making it a potential target for intervention.

Geographic atrophy - Signs, symptoms, and quality of life.

Geographic atrophy (GA) is a prevalent cause of vision loss among elderly and is associated with a significant loss of function. We reviewed the current literature to assess the effect of GA on patients' daily lives and well-being. We record and organize the signs, symptoms, and impacts that are important in life with GA. Further, we examined the impact of GA on vision-related quality of life. The main complaint among patients was difficulties regarding daily tasks, especially reading and other near activities. However, a large proportion of patients also reported fear, frustration, and anxiety as salient symptoms with large impact. Many patients do not have adequate information about their condition as well as the prognosis. The most commonly used measure of patient-reported outcome measure (PROM) is the National Eye Institute Visual Function Questionnaire (VFQ), that reflects the severity of impact on 12 subscales, from where near activities, general vision, mental health, and role difficulties had the lowest scores. Longitudinal studies of GA and the impact of low-vision rehabilitation efforts on health-related quality of life are sparse but suggest a significant improvement on several items. PROM is included in clinical trials, and so far, no drug has shown to improve the functional outcome in terms of PROM.

Association between structural and functional treatment outcomes in neovascular age-related macular degeneration.

PURPOSE: The administration frequency of intravitreal anti-vascular endothelial growth factor (anti-VEGF) in neovascular age-related macular degeneration (AMD) have been widely discussed. The primary objective of the study was to explore the association between anatomical outcomes and changes in functional outcome. METHODS: This was a retrospective cohort study of patients with newly diagnosed neovascular AMD with a minimum of 12 months of follow-up. Only one eye per patient was included. Patients were treated according to the observe-and-plan or the pro-re-nata regimen. All patients were regularly examined from the time of diagnosis up to 24 months. The effect of intraretinal fluid (IRF), subretinal fluid (SRF) and pigment epithelium detachment (PED) at any time point on visual acuity (VA) was tested, as well as the long-term effect and the risk of losing VA. Further, the variability of central retinal thickness (CRT) was calculated for each eyes' individual measures during the observation period, excluding the monthly loading phase. The prognostic effect of each factor on VA was estimated by regression analysis. The primary outcome measure was VA, which was correlated with the presence or absence of fluid, seen as IRF, SRF or PED. RESULTS: A total of 504 treatment naïve eyes from 504 patients was included. The presence of IRF was associated with lower VA at all visits (p < 0.001). However, the presence of SRF or PED was not significantly associated with worse VA at any time point during the observation period. Patients in the upper quartile of CRT variance had a greater loss in VA after 12 and 24 months (p < 0.001). CONCLUSIONS: In this retrospective cohort study, the presence of intraretinal fluid was associated with poorer visual outcome in neovascular AMD patients treated with anti-VEGF, but the presence of subretinal fluid and PEDs was not. This suggests that IRF is worse than subretinal fluid and PEDs for AMD outcomes and therefore requires the most intensive treatment. Further, we found that patients with the highest CRT variability during the study period had poorer visual outcomes after 12 and 24 months, indicating that stringent control of retinal fluid volume fluctuations is important to prevent visual acuity decline over time.

Prevalence of geographic atrophy in Nordic countries and number of patients potentially eligible for intravitreal complement inhibitor treatment: A systematic review with meta-analyses and forecasting study.

We systematically reviewed the literature on the prevalence of geographic atrophy (GA) in Nordic populations, conducted meta-analyses on age-stratified estimates, and calculated current and future number of patients and those potentially eligible for intravitreal complement inhibitor treatment. We followed the PRISMA guidelines, and our protocol was registered in PROSPERO. Ten databases were searched on 22 April 2023 for population-based studies of GA prevalence. Based on clinical descriptive analyses of GA and eligibility criteria of the phase III studies for intravitreal pegcetacoplan (complement C3 and C3b inhibitor), we were able to calculate the proportion of patients with GA potentially eligible for therapy. Finally, we extracted population data for Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) from Eurostat, applied prevalence statistics to the extracted census and forecasting data to estimate the number of patients with GA, and then applied the proportion eligible for intravitreal pegcetacoplan therapy. We identified six studies with a total of 10 159 individuals. Prevalence of GA was estimated to 0.4% (95% confidence intervals [CI]: 0.2%-0.8%), 1.5% (95% CI: 0.7%-2.6%), and 7.6% (95% CI: 4.6%-11.3%) for individuals aged 60-69, 70-79, and 80+ years, respectively. In Nordic countries, we estimate a total of 166 307 individuals with GA in 2023, increasing to 277 893 in 2050. Of these, 90 803 individuals in 2023, increasing to 151 730 in 2050, are potentially eligible for intravitreal complement inhibitor treatment. Considering these large numbers, our study highlights the importance of this topic in the coming years and its potential to significantly impact our clinical practice, organization, and staffing.

Systemic levels of C-reactive protein in patients with age-related macular degeneration: A systematic review with meta-analyses.

Ageing of the retina is associated with the gradual accumulation of basal deposits and the formation of drusen. However, in some individuals this process is exacerbated and causes development of age-related macular degeneration. Late features of age-related macular degeneration include geographic atrophy of the neuroretina or choroidal neovascularization. Such changes lead to blurred vision, metamorphopsia, and scotoma, and is the leading cause of vision loss in developed countries. Chronic low-grade inflammation has been investigated because of its relationship to ageing and its role in the gap between chronological and biological ageing. Here, we systematically reviewed studies investigating systemic C-reactive protein in patients with age-related macular degeneration. We identified 53 studies with 60,598 participants (10,392 patients and 38,901 controls). Our meta-analyses revealed that early age-related macular degeneration was not associated to systemic C-reactive protein (Cohen's d = 0.03 [-0.04 to 0.10]; OR = 1.06 [0.93-1.20]; P = 0.39) whereas late age-related macular degeneration (Cohen's d = 0.38 [0.24 to 0.51]; OR = 1.99 [1.55-2.52]; P < 0.0001), and neovascular age-related macular degeneration (Cohen's d = 0.40 [0.24 to 0.56]; OR = 2.07 [1.55-2.76]; P < 0.0001) was associated with a small-to-moderate increase in systemic C-reactive protein. Our review provides an overview of this extensively studied field, provide summary estimates that provide insight into when and to what extent systemic C-reactive protein is associated with age-related macular degeneration, and help in distinguishing the potentially reversible disease processes from that of irreversible retinal ageing.

Systemic levels of interleukin-6 in patients with age-related macular degeneration: a systematic review and meta-analysis.

Age-related macular degeneration (AMD) is the most prevalent cause of irreversible vision loss in industrialized countries. Several studies have investigated systemic interleukin-6 (IL-6) levels of patients with AMD. In this study, we systemically reviewed the literature to provide an overview of the field and used meta-analyses to provide a summary estimate of the standardized mean difference (SMD) of systemic IL-6 between patients with AMD and control individuals. We searched the literature databases PubMed/MEDLINE, Embase, Web of Science and the Cochrane Central on 1 June 2019 for relevant studies on humans. Two authors independently extracted data and evaluated risk of bias. We identified 19 studies for the qualitative review with a total of more than 3586 individuals (1865 controls and 1721 with AMD). We found an overall random-effects SMD in systemic IL-6 levels 0.63 (95% CI: 0.28 to 0.99, p = 0.0005) corresponding to a medium effect size. In a subgroup analysis, we found that early AMD was not strongly associated with elevated IL-6 levels (0.12, 95% CI: -0.01 to 0.24, p = 0.06), which was in contrast to the significantly elevated IL-6 levels in patients with geographic atrophy (1.21, 95% CI: 0.41 to 2.01, p = 0.003) and patients with neovascular AMD (0.99, 95% CI: 0.34 to 1.63, p = 0.003). Our results show that the evidence today suggests an increased systemic IL-6 in patients with AMD, but that this may be a phenomenon more closely related to the late subtypes of AMD.

Plasma Levels of Matrix Metalloprotease MMP-9 and Tissue Inhibitor TIMP-1 in Caucasian Patients with Polypoidal Choroidal Vasculopathy.

BACKGROUND: Matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases 1 (TIMP-1) are regulating enzymes of the extracellular matrix. A systemic imbalance of MMP-9 and TIMP-1, thought to reflect an imbalance of the extracellular matrix homeostasis, is previously associated with polypoidal choroidal vasculopathy (PCV) in Asian patients. Previous studies suggest inter-ethnical differences in the genetic background and etiology of PCV. To further explore this issue, we studied the plasma levels of MMP-9 and TIMP-1 in Caucasian patients with PCV and compared to healthy age-matched controls. METHODS: For this prospective case-control study, 60 participants were recruited who were either patients with PCV (n = 26) or healthy controls (n = 34). All participants underwent detailed clinical examination. We sampled fresh venous blood, isolated plasma, and quantified plasma concentrations of the extracellular matrix regulators MMP-9 and TIMP-1 using electrochemiluminescence immunoassays. RESULTS: Plasma levels of MMP-9 (p = 0.4), TIMP-1 (p = 0.9), and MMP-9/TIMP-1 ratio (p = 0.4) did not differ significantly between patients with PCV and healthy controls. No differences appeared after adjusting for influencing co-variates in multivariate analyses. CONCLUSION: We demonstrate that Caucasian patients with PCV do not have altered levels of plasma MMP-9 or plasma TIMP-1. These findings suggest no strong evidence of a systemic imbalance of the extracellular matrix homeostasis in Caucasian patients with PCV. Our findings are in line with studies of other aspects of PCV that are also subject to significant inter-ethnical differences.

Prevalence of Charles Bonnet syndrome in patients with age-related macular degeneration: systematic review and meta-analysis.

Age-related macular degeneration (AMD) is the most common cause of visual impairment in the developed world. A number of patients experience complex lifelike visual experiences-Charles Bonnet syndrome (CBS). In this systematic review, our aim was to provide an overview of the CBS literature in relation to AMD, to determine the prevalence of CBS in patients with AMD and to provide an overview of associated demographical and clinical aspects. We searched the literature databases PubMed/MEDLINE, EMBASE, Web of Science, the Cochrane Central, and PsycINFO on 22 March 2019 for studies evaluating the prevalence of CBS in patients with AMD. Two independent authors extracted the data and evaluated risk of bias. Studies were reviewed qualitatively in the text and quantitatively in a meta-analysis including subgroup analyses for differences between demographic and clinical factors. We identified 18 studies with data on >4303 patients with AMD. We found an overall prevalence of CBS of 15.8% (95% confidence interval: 11.0%-21.2%). When looking at consecutively recruited patients with neovascular AMD from the clinic, prevalence of CBS was 7.2% (95% confidence interval: 4.3%-10.6%). Among visitors to visual rehabilitation centres, prevalence of CBS was 31.6% (95% confidence interval: 21.7%-42.3%). Taken together, we find that CBS is rather common in patients with AMD.

Plasma levels of inflammatory chemokines in patients with polypoidal choroidal vasculopathy.

PURPOSE: Chemokines are a group of cytokines that guide immune cell migration. We studied plasma levels of inflammatory chemokines in patients with polypoidal choroidal vasculopathy (PCV) and compared with healthy age-matched control individuals. METHODS: This was a clinic-based prospective case-control study of participants (n = 60) with either PCV (n = 26) or age-matched healthy controls (n = 34). We sampled fresh venous blood and isolated plasma for analysis. We used U-PLEX Human Assays to quantify concentrations of the inflammatory chemokines MCP-1/CCL2, RANTES/CCL5, eotaxin/CCL11, IP-10/CXCL10 and fractalkine/CX3CL1. RESULTS: Plasma levels of fractalkine was significantly higher in patients with PCV when compared to healthy controls (mean ± SD: 7291 ± 2461 pg/ml versus 5879 ± 2001 pg/ml; p = 0.021). Plasma levels of MCP-1 (p = 0.846), RANTES (p = 0.288), eotaxin (p = 0.496) and IP-10 (p = 0.352) did not differ significantly between the groups. To evaluate possible biomarker quality of fractalkine, we used a ROC analysis and found a positive but weak discriminatory ability (AUC = 0.68). CONCLUSION: Patients with PCV have a higher plasma level of fractalkine. Although the differences do not possess strong biomarker qualities, they inform on disease processes of a poorly understood disease and suggest that the fractalkine-CX3CR1 axis may be involved. As this study did not investigate local chemokine concentrations, we are unable to confirm or disprove any local chorioretinal interaction, and our findings should be interpreted with such caution.

Chemokine Profile and the Alterations in CCR5-CCL5 Axis in Geographic Atrophy Secondary to Age-Related Macular Degeneration.

Purpose: Geographic atrophy (GA) secondary to age-related macular degeneration (AMD) is a progressive disease with no treatment option. Previous studies show chemokine-mediated recruitment of immune cells in the retina, and therefore we investigated systemic levels of chemokines and chemokine receptors in patients with GA. Methods: This observational prospective study was conducted at a single center. We included 122 participants with no immune disease: 41 participants with GA and no choroidal neovascularization, 51 patients with neovascular AMD, and 30 healthy control individuals. Flow cytometric analysis was used to detect expression level of C-C chemokine receptor (CCR)1, CCR2, CCR3, CCR5, and C-X-C motif chemokine receptor (CXCR)3 on peripheral blood mononuclear cells (CD14+ monocytes, CD4+ T cells, CD8+ T cells). Plasma levels of C-C motif ligand (CCL)11, C-X-C motif chemokine (CXCL)10, and CCL5 were measured by specific immunoassays. Enlargement rate of GA lesion was measured from autofluorescence images. Results: Participants with GA have a specific chemokine profile with a higher expression of CCR5 than healthy controls in peripheral blood mononuclear cells, and a higher plasma levels of CCL-5. Further, GA was associated with higher monocytic expression of CCR2 than in neovascular AMD. We found that a high expression level of CCR5 on CD8+ T cells was associated with slower enlargement rate of atrophic lesion. Conclusions: The study showed an association between systemic chemokine profile and GA formation. Further studies are needed to fully elucidate the possible role of systemic chemokine regulation in mediating pathogenesis of GA.

Age-related macular degeneration: A two-level model hypothesis.

Age-related diseases, including age-related macular degeneration (AMD), are of growing importance in a world where population ageing has become a dominant global trend. Although a wide variety of risk factors for AMD have been identified, age itself remains by far the most important risk factor, making it an urgent priority to understand the connections between underlying ageing mechanisms and pathophysiology of AMD. Ageing is both multicausal and variable, so that differences between individuals in biological ageing processes are the focus of a growing number of pathophysiological studies seeking to explain how ageing contributes to chronic, age-related conditions. The aim of this review is to integrate the available knowledge on the pathophysiology of AMD within the framework of the biology of ageing. One highly significant feature of biological ageing is systemic inflammation, which arises as a second-level response to a first level of molecular damage involving oxidative stress, mutations etc. Combining these insights, the various co-existing pathophysiological explanations in AMD arrange themselves according to a two-level hypothesis. Accordingly, we describe how AMD can be considered the consequence of age-related random accumulation of molecular damage at the ocular level and the subsequent systemic inflammatory host response thereof. We summarize evidence and provide original data to enlighten where evidence is lacking. Finally, we discuss how this two-level hypothesis provides a foundation for thoughts and future studies in prevention, prognosis, and intervention.

Neutrophil-to-lymphocyte ratio in age-related macular degeneration: a systematic review and meta-analysis.

Age-related macular degeneration (AMD) is aetiologically linked to immunological ageing and dysfunction. One aspect of this is the altered neutrophil-to-lymphocyte ratio (NLR), which in other domains have been associated with inflammation and angiogenesis, and therefore investigated in patients with AMD in several papers. In this systematic review and meta-analysis, we summarize findings in patients with AMD in relation to NLR, both qualitatively and quantitatively. We searched PubMed/MEDLINE, EMBASE, Web of Science, and the Cochrane Central and identified six studies from where we extracted data on 1178 individuals (777 patients with AMD and 401 healthy controls). Patients with AMD had a higher NLR (weighted mean difference: 0.37, CI 95% 0.08 to 0.66, p = 0.013) when compared to healthy controls. In subgroup analyses, we did not find a significant difference between patients with dry AMD and healthy controls (weighted mean difference: 0.34, CI 95% -0.03 to 0.69, p = 0.068), but did find a strong significant difference between patients with neovascular AMD and healthy controls (weighted mean difference: 0.54, CI 95% 0.23 to 0.86, p = 0.00068). Hence, we find that the association between AMD and elevated NLR may have stronger relevance to the neovascular subtype of AMD. However, the clinical value of measuring the NLR remains unclear.

Treatment failure in neovascular age-related macular degeneration is associated with a complex chemokine receptor profile.

OBJECTIVE: To investigate if chemokine expression patterns on leucocyte subsets influence the short-term anatomical treatment response of intravitreal antivascular endothelial growth factor therapy against neovascular age-related macular degeneration (AMD). METHODS AND ANALYSIS: This study was conducted as a prospective observational cohort study of 79 patients with neovascular AMD. We used optical coherence tomography to quantify central retinal thickness (CRT) and to evaluate the presence of intraretinal and subretinal fluids in treatment-naive patients at baseline and after loading dose. Anatomical response was categorised into either good responders (complete regression of fluid or a reduction of >75% in CRT), partial responders (reduction of 0%-75% in CRT) or non-responders (increase of CRT). Expression levels of chemokine receptors (CCR1, CCR2, CCR3, CCR5, CXCR3 and CX3CR1) were measured on leucocyte subsets (monocytes, CD4 +T cells, and CD8 +T cells) using flow cytometry. Finally, we explored potential correlation patterns of chemokine expression between the leucocyte subsets using group-specific correlation networks. RESULTS: Non-responders had higher CCR1 expression on monocytes (p=0.016) and lower CCR3 expression on CD8+ T cells (p=0.037). Correlation network analyses of chemokine receptor expression patterns on leucocyte subsets revealed intergroup differences. CONCLUSION: Short-term anatomical treatment response in neovascular AMD varies according to the leucocyte subset chemokine expression pattern, which confirms that immune dysfunction is a complex issue in AMD. Our results suggest that focusing on chemokines may be a relevant approach towards personalised treatment in neovascular AMD.

Plasma markers of chronic low-grade inflammation in polypoidal choroidal vasculopathy and neovascular age-related macular degeneration.

PURPOSE: Ageing is the strongest predictor of neovascular age-related macular degeneration (AMD), where neuroinflammation is known to play a major role. Less is known about polypoidal choroidal vasculopathy (PCV), which is an important differential diagnosis to neovascular AMD. Here, we report plasma markers of inflammation with age (inflammaging) in patients with PCV, patients with neovascular AMD and a healthy age-matched control group. METHODS: We isolated plasma from fresh venous blood obtained from participants (n = 90) with either PCV, neovascular AMD, or healthy maculae. Interleukin(IL)-1ß, IL-6, IL-8, IL-10 and tumour necrosis factor receptor 2 (TNF-R2) were measured using U-PLEX Human Assays. Routine plasma C-reactive protein (CRP) was measured using Dimension Vista 1500. RESULTS: Patients with PCV had plasma levels of IL-1ß, IL-6, IL-8, IL-10 and TNF-R2 similar to that in healthy controls. Patients with neovascular AMD had significantly higher plasma IL-1ß, IL-6 and IL-10 than healthy controls, whereas no significant differences were observed for plasma IL-8 and TNF-R2. Differences between plasma IL-1ß, IL-6 and IL-10 possessed a positive but weak ability in discriminating neovascular AMD from PCV. Both patients with PCV and patients with neovascular AMD had significantly higher levels of routine plasma CRP. CONCLUSION: Patients with PCV differ from patients with neovascular AMD in terms of plasma inflammaging profile. Apart from increased CRP, no signs of inflammaging were observed in patients with PCV. In patients with neovascular AMD, we find a specific angiogenesis-twisted inflammaging profile.

Imbalances in tissue inhibitors of metalloproteinases differentiate choroidal neovascularization from geographic atrophy.

PURPOSE: Tissue inhibitor of metalloproteinase (TIMP) is known to play a role in age-related macular degeneration (AMD). We wished to investigate alterations in different late stages of AMD: neovascular AMD and geographic atrophy (GA). METHODS: This was a prospective case-control study. A total of 125 participants were included consecutively during a period of 18 months. We included 46 patients with neovascular AMD, 46 patients with GA without any sign of choroidal neovascularization in either eye, and 33 healthy aged controls. Patients with immune-affecting disorders were not included. Commercial immunoassay kits were used to quantify levels of TIMP-1, TIMP-3, MMP-2 and MMP-9 in blood plasma. RESULTS: We found that patients with neovascular AMD had lower plasma concentration of TIMP-3 (p = 0.028) than healthy controls. Patients with GA had higher plasma levels of TIMP-1 (p < 0.001) and MMP-9 (p = 0.022) compared to healthy controls. Also, we found that TIMP-1 levels in patients with GA increased with age (Spearman's rho = 0.04, p = 0.006). CONCLUSION: Matrix metalloproteinases (MMPs) and TIMPs, which are known to be involved in age-related changes in Bruch's membrane, are significantly altered systemically, suggesting the presence of an imbalance in the homeostasis of the extracellular matrix. These imbalances may explain differences in the clinical manifestation of late AMD.