Association between C-reactive protein and polypoidal choroidal vasculopathy: a systematic review and meta-analysis.

Aetiological processes of polypoidal choroidal vasculopathy (PCV) remains poorly understood, but several studies indicate that immunity may play a role and report elevated levels of systemic C-reactive protein (CRP). In this systematic review and meta-analysis, we summarize available evidence in the field. We searched the databases PubMed/MEDLINE, EMBASE, Web of Science and the Cochrane Central on 19 March 2020. Two independent authors reviewed the studies and extracted data. Two independent authors reviewed the studies, extracted data and evaluated risk of bias within individual studies. Studies were reviewed in the text qualitatively and measures of association were included for quantitative analyses. Results from univariate analyses and multivariate-adjusted analyses were included for separate meta-analyses to evaluate whether the association was only due to factors associated with PCV. Four studies (246 patients with PCV and 2861 control individuals) were identified and included for a qualitative and quantitative analysis. Increased CRP was associated with PCV when pooling both univariate measures (OR 3.54, 95% CI: 2.13-5.89, p < 0.0001) and multivariate-adjusted measures (OR 3.05, 95% CI: 1.56-5.98, p = 0.0011). Sensitivity analyses confirmed robustness of the results. Increased CRP is associated to PCV, even after adjusting for demographics, lifestyle factors and co-morbidities. Clinical value of CRP in relation to PCV remains unclear, but the association gives much needed insight into the aetiology of a poorly understood disease.

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.

Cytokine Profiling in Patients With Exudative Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy.

Purpose: The purpose of this study was to investigate the cytokine profiles in plasma and aqueous humor of patients with choroidal neovascularization (CNV) due to exudative AMD and polypoidal choroidal vasculopathy (PCV). Methods: In this cross-sectional study, 16 patients clinically diagnosed with AMD, 18 patients with PCV, and 50 age- and sex-matched cataract patients without AMD/PCV (controls) were enrolled. Study subjects were treatment naïve, and 200 µL undiluted aqueous humor and 5 mL peripheral venous blood were collected from the study subjects. Clinical samples were analyzed for 41 different cytokines by Luminex bead-based multiplex assay. Cytokines concentrations with detection rates of 50% or more were included for the analysis, and the differences in plasma and aqueous humor cytokines levels between each group were analyzed. Results: The age of the patients with AMD and PCV was 70.62 ± 10.15 (mean ± SD) and 71.48 ± 9.08 years, respectively, and that in the control group was 62.8 ± 10.67 years. Aqueous humor cytokines growth-regulated oncogene (GRO), macrophage-derived chemokine (MDC), and macrophage inflammatory protein (MIP)-1α were significantly higher in AMD patients than controls (all P < 0.04), and GRO, MDC, MIP-1α, IL-8, IFN-γ-inducible protein 10, and monocyte chemotactic protein levels were significantly higher in PCV patients than controls (all P < 0.03). Soluble CD40 ligand and platelet-derived growth factor-AA levels were higher in plasma of healthy controls compared with AMD subjects. No significant differences in cytokine levels were observed between AMD and PCV patients for both plasma and aqueous humor. Conclusions: In AMD and PCV patients, our data suggest that the pathologic changes are primarily driven by dysregulation of local immune factors in the eye, whereas the plasma cytokine levels are not elevated.

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.

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.

Changes in subfoveal choroidal thickness and reduction of serum levels of vascular endothelial growth factor in patients with POEMS syndrome.

AIMS: To determine the changes in the subfoveal choroidal thickness (CT), the foveal thickness (FT) and the serum level of vascular endothelial growth factor (VEGF) after thalidomide treatment in patients with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes (POEMS) syndrome. METHODS: We studied 13 left eyes of 13 treatment-naïve patients with POEMS syndrome. The subfoveal CT and FT were determined by enhanced depth imaging optical coherence tomography, and the serum level of VEGF was determined by ELISA at the baseline and at 6 months after thalidomide treatment. The correlations in the serum level of VEGF and the subfoveal CT or the FT at the baseline and at 6 months after treatment were determined. RESULTS: Together with the reduction in the serum level of VEGF, the subfoveal CT was also reduced significantly from 439.1±66.5 µm at the baseline to 307.2±75.4 µm at 6 months (p=0.001). The mean FT at the baseline was 236.4±30.7 µm which did not change significantly at 6 months at 228.1±33.1 µm (p>0.05). The change in the subfoveal CT was significantly and linearly correlated with the change in the serum level of VEGF at 6 months after treatment (r=0.67, p=0.011). CONCLUSIONS: The significant correlation between the CT and the serum level of VEGF may offer clues on the pathogenesis of ocular diseases of POEMS syndrome and on the role of serum VEGF on the choroid.

Interleukin-1ß Level Is Increased in Vitreous of Patients with Neovascular Age-Related Macular Degeneration (nAMD) and Polypoidal Choroidal Vasculopathy (PCV).

PURPOSE: To examine the expression of pro-interleukin-1ß (pro-IL-1ß) and interleukin-1ß (IL-1ß) in the vitreous body of patients with neovascular age-related macular degeneration(nAMD), polypoidal choroidal vasculopathy (PCV), proliferative diabetic retinopathy (PDR), retinal vein occlusion (RVO) or Eales' disease to further elucidate the role of IL-1ß and inflammation in the pathogenesis of neovascular retinal disease. DESIGN: Prospective clinical laboratory investigation study. METHODS: All patients enrolled had vitreous hemorrhage due to nAMD, PCV, PDR, RVO or Eales' disease that required vitrectomy. Patients were excluded for any history of active intraocular inflammation, or other ophthalmic surgery besides vitrectomy. Control samples were obtained from patients with idiopathic macular epiretinal membrane. A total of fifty vitreous samples were collected from patient during vitrectomy. Pro-IL-1ß and IL-1ß expression were measured by enzyme-linked immunosorbent assay (ELISA). Results were analyzed statistically using nonparametric tests. RESULTS: Expression of pro-IL-1ß protein was increased by 2.83-fold and 9.19-fold in PCV and nAMD vitreous samples relative to control, respectively. Expression of IL-ß protein was increased by 10-fold and 4.83-fold in PCV and nAMD vitreous samples relative to control, respectively. CONCLUSIONS: Our results demonstrate that expression of pro-IL-1ß and IL-1ß proteins is higher in PCV and nAMD. The roles of pro-IL-1ß and IL-1ß as inflammatory mediators in the development of PCV and nAMD may be associated with photoreceptor degeneration and neovascularization which necessitates further study.

Hyperhomocysteinemia in patients with polypoidal choroidal vasculopathy: a case control study.

PURPOSE: To determine whether elevated plasma homocysteine and serum high sensitivity C-reactive protein (hsCRP) levels, two established risk factors of vascular diseases, are associated with polypoidal choroidal vasculopathy (PCV). DESIGN: Retrospective case-control study. METHODS: One hundred and nineteen consecutive patients with PCV and 119 matched controls were enrolled in a tertiary hospital from September 2008 to June 2013. Plasma homocysteine and serum hsCRP levels were measured. Associations among plasma homocysteine, serum hsCRP levels and PCV were further evaluated using multivariable logistic regression analysis. RESULTS: The median plasma homocysteine level was significantly higher in patients with PCV than in the controls (12.20 µmol/L vs. 9.80 µmol/L, p<0.001). The median serum hsCRP level was slightly higher in the PCV group (0.16 mg/dl vs. 0.11 mg/dl in control group, p = 0.07). After multivariable logistic regression analysis, each 1 µmol/L increase of plasma homocysteine was associated with a 1.5-fold increase in likelihood of having PCV (OR, 1.54; 95% confidence interval (CI), 1.33-1.79, p<0.001). CONCLUSIONS: Hyperhomocysteinemia was associated with PCV and might play a role in the pathogenesis of PCV.

Optical coherence tomography findings in ocular argyrosis.

A 68-year-old Caucasian man with a remote history of daily colloidal silver ingestion presented for ophthalmic examination in which he was noted to have a distinct slate gray skin discoloration. Funduscopy revealed confluent perimacular drusenoid deposits bilaterally, most of which localized at the level of or anterior to the inner segment ellipsoid band by optical coherence tomography (OCT) imaging. Enhanced depth imaging OCT demonstrated marked choroidal thinning. Fluorescein angiogram displayed a dark or silent choroid. Confirmatory serum silver levels were found to be markedly elevated. This report describes a unique geographic maculopathy with large drusenoid deposits anterior to the ellipsoid layer and severe choroidal thinning in association with ocular argyrosis.

Serum levels of matrix metalloproteinase 2 and matrix metalloproteinase 9 elevated in polypoidal choroidal vasculopathy but not in age-related macular degeneration.

PURPOSE: Age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV) are the leading causes of vision loss in the elderly Asian population. Previous studies have confirmed that abnormal extracellular matrix (ECM) metabolism plays an important role in the pathogenesis of AMD and PCV. However, the dynamic metabolism of the ECM is closely regulated by matrix metalloproteinases (MMPs) and tissue metalloproteinase inhibitors (TIMPs). Whether MMPs and TIMPs participate in the pathogenesis of AMD and PCV remains unclear. The aim of this study was to investigate the correlation between circulating MMP and TIMP levels and AMD and PCV. METHODS: The serum levels of MMPs (MMP1, MMP2, MMP3, and MMP9) and TIMPs (TIMP1 and TIMP3) were quantified using enzyme-linked immunosorbent assays in four groups of subjects (n=342): early AMD (group 1, n=75), neovascular AMD (group 2, n=89), PCV (group 3, n=98), and age- and gender-matched controls (group 4, n=80). RESULTS: The mean concentrations of the two gelatinases, MMP2 and MMP9, in the PCV group were significantly higher than that of the control (p=0.001, p<0.001, respectively), early AMD (both p<0.001), and neovascular AMD (p=0.005, p=0.001, respectively) groups. Moreover, the serum MMP2 concentration was positively correlated with the serum MMP9 concentration in the PCV group (r=0.822, p<0.001). However, the mean concentrations of MMP2 and MMP9 in the early AMD and neovascular AMD groups were not significantly different from that of the control group (p>0.05). The mean serum levels of MMP1, MMP3, TIMP1, and TIMP3 were not significantly different among the four groups. CONCLUSIONS: This pilot study first reveals a link between increased levels of circulating gelatinases (MMP2 and MMP9) and PCV but not AMD, which may provide a biologically relevant marker of ECM metabolism in patients with PCV. This finding suggests that the two disorders may have different molecular mechanisms.

[Circulating bone marrow-derived stem cells in patients with polypoidal choroidal vasculopathy].

PURPOSE: The current study was designed to investigate the role of circulating bone marrow (BM)-derived stem cells in the pathogenesis of polypoidal choroidal vasculopathy (PCV), a distinct type of neovascular age-related macular degeneration (AMD). METHODS: Thirty one clinically documented PCV patients were enrolled. Circulating BM-derived stem cells were collected from the patients' peripheral blood and cultured. Colony forming capacity (Hill assay) and migration activity (Boyden chamber system) were examined and analyzed. RESULTS: Colony forming units (CFU-Hill) were significantly fewer in bilateral PCV patients than in unilateral PCV patients. CFU-Hill was impaired in patients with larger (> 5000 microm) PCV lesions compared with patients with smaller PCV lesions. Migration activity of BM-derived stem cells was also reduced significantly in the bilateral PCV patients than in the unilateral PCV patients. CONCLUSIONS: Similar to CNV associated with AMD, impaired functional activity of circulating BM-derived stem cells was observed in PCV patients with bilateral or larger lesions. Circulating BM-derived stem cells may have a role in the pathogenesis of PCV.

Elevated C-reactive protein levels in patients with polypoidal choroidal vasculopathy and patients with neovascular age-related macular degeneration.

PURPOSE: To determine the relationship between systemic C-reactive protein (CRP) levels and polypoidal choroidal vasculopathy (PCV) and advanced neovascular age-related macular degeneration (AMD) in Japanese patients. DESIGN: Case-control study. PARTICIPANTS: Ninety-seven patients with PCV, 176 with advanced neovascular AMD, and 262 control subjects without any macular abnormality were studied. METHODS: Color fundus photographs of the macular area were taken from both eyes in all subjects. Indocyanine green angiography and fluorescein angiography were performed for diagnosis. The CRP level was measured by a high-sensitivity assay using a latex aggregation immunoassay, and the levels in patients with PCV and neovascular AMD were compared with that in the control group using the Kruskal-Wallis test. Associations between CRP and PCV or neovascular AMD were compared using logistic regression analysis by computing the odds ratios (ORs) and 95% confidence intervals (CIs) after the study populations were divided into quartiles. MAIN OUTCOME MEASURES: The CRP levels in patients with PCV, patients with neovascular AMD, and control subjects. Standard univariate and multivariate analyses between groups. RESULTS: Median CRP levels were significantly higher in cases with PCV (0.94 mg/l) or with advanced neovascular AMD (0.95 mg/l) than in control subjects (0.43 mg/l) (P<0.001 for Kruskal-Wallis test). After adjusting for baseline characteristics such as age, gender, smoking status, alcohol use, body mass index, history, and use of antiinflammatory drugs, the increase in risk was significant for the highest quartile of CRP for both PCV (OR, 3.53; 95% CI, 1.49-8.40) and neovascular AMD (OR, 4.08; 95% CI, 1.94-8.56), and for the third quartile of CRP for neovascular AMD (OR, 2.29; 95% CI, 1.07-4.91). The trends for an increase in risk of disease with increase in CRP were statistically significant for both PCV (P = 0.001) and neovascular AMD (P<0.001). CONCLUSIONS: The significant associations between elevated serum CRP levels and PCV or neovascular AMD in the Japanese strongly suggest that inflammatory processes are involved in the pathogenesis of PCV and neovascular AMD.

Sclerochoroidal calcification: clinical manifestations and systemic associations.

BACKGROUND: Sclerochoroidal calcification is an unusual ocular condition that is believed to be idiopathic in most cases. OBJECTIVES: To describe the clinical manifestations of sclerochoroidal calcification and to investigate its possible systemic associations. METHODS: This noncomparative consecutive case series included patients diagnosed as having sclerochoroidal calcification based on clinical characteristics and diagnostic test findings. We analyzed the demographic, systemic, and ocular features of 27 such patients. Systemic evaluation included tests for calcium-phosphorus metabolism in 19 patients and renal tubular hypokalemic metabolic alkalosis syndromes (Bartter or Gitelman syndrome) in 13. RESULTS: All the patients were asymptomatic older (mean age, 70 years) white individuals, incidentally noted as having a choroidal lesion on routine examination. Among 38 eyes, the main referral diagnoses were choroidal metastasis in 10 eyes (26%), choroidal melanoma in 8 (21%), and choroidal nevus in 4 (11%). Sixteen patients (59%) had unilateral clinical findings, while 11 (41%) had bilateral. The Snellen visual acuity was 20/50 or better in 37 eyes (97%). Cogan scleral plaque was visible anterior to the insertion of horizontal rectus muscles in 10 eyes (26%). Among 77 foci, there were a mean of 2 foci of sclerochoroidal calcification in each eye, 41 yellow (53%), 32 yellow-white (42%), 2 white (3%), and 2 orange (3%), measuring a mean 2.6 mm in diameter and 1.1 mm in thickness. The most common locations were postequatorial in 45 (58%), along the temporal vascular arcades in 30 (39%), and in the superotemporal quadrant in 43 (56%). A-scan and B-scan ultrasonography revealed dense echoes compatible with calcium, with orbital shadowing. All the lesions remained stable in size and configuration during a mean follow-up of 38 months. One patient developed a choroidal neovascular membrane over the area of sclerochoroidal calcification. Investigations for abnormal calcium-phosphorus metabolism in 19 patients revealed primary hyperparathyroidism in 1 patient (5%). Clinical and biochemical evaluation of 13 patients demonstrated hypomagnesemia in 6 (46%). Four patients (31%) met the criteria for the diagnosis of Gitelman syndrome. CONCLUSIONS: Sclerochoroidal calcification usually manifests as multiple discrete yellow placoid lesions in the midperipheral fundus of asymptomatic older white individuals. Although most cases may be idiopathic in nature, some patients may have underlying systemic disorders involving abnormal calcium-phosphorus metabolism or renal tubular hypokalemic metabolic alkalosis syndromes. All patients with sclerochoroidal calcification should be tested for these treatable systemic associations.

[Effect of therapy with blood component (activated autoplasma) on blood glutathione level in patients with vascular abnormalities on the fundus oculi]. / Vliianie gemokomponentnoi terapii (aktivirovannoi autoplazmy) na uroven' glutationa v krovi u bol'nykh s sosudistoi patologiei glaznogo dna.

Thirty-three patients with central chorioretinal dystrophy, 18 with proliferative diabetic retinopathy, and 15 controls without ocular diseases were examined. All patients were treated by blood components. The treatment started with activation of blood plasma platelets. Glutathione was measured in two portions of plasma: intact and containing platelet activation products. The content of glutathione was higher in activated autoplasma of 21 patients with central chorioretinal dystrophy and 6 patients with diabetic retinopathy than in intact plasma by 107 and 72%, respectively. A decrease in glutathione level in activated autoplasma was observed in 1 patient with central chorioretinal dystrophy and in 9 with diabetic retinopathy. Hence, antioxidant defense is decreased in diabetic retinopathy, since glutathione is involved in reduction of organic hydroperoxides.

Choroidal calcification in Bartter syndrome.

PURPOSE: Bartter syndrome is characterized by hyperplasia of the renal juxtaglomerular apparatus, hyperaldosteronism, and hypokalemic alkalosis. We report a case of Bartter syndrome associated with normal serum calcium levels and posterior choroidal calcification. METHODS: Case report. A 59-year-old man with bilateral cataract and Bartter syndrome underwent a complete ophthalmic examination, including standardized echography before and after cataract surgery. RESULTS: Before cataract surgery, echography identified small, hyperreflective, multifocal, bilateral choroidal lesions with posterior shadowing. After surgery, these lesions appeared as yellow-white, barely elevated plaques with smooth edges and were diagnosed as choroidal calcification. CONCLUSIONS: Choroidal calcification may occur in patients with Bartter syndrome. This condition should be added to the differential diagnosis of posterior segment calcification.

Taches de bougie.

BACKGROUND: Posterior segment lesions, including taches de bougie, may be the presenting sign of sarcoidosis. In patients with unrecognized sarcoidosis, taches de bougie may be misinterpreted as the lesions of birdshot chorioretinopathy (BCR) or multifocal choroiditis (MFC). METHODS: In a retrospective study, the authors identified 22 patients with taches de bougie and sarcoidosis. A tissue biopsy showed noncaseating granulomas in 17 patients. All available ophthalmic and medical records of these patients were reviewed. RESULTS: Two patterns of taches de bougie were observed. Sixteen patients (73%) had small, discrete white spots in the inferior or nasal periphery, indistinguishable from the lesions of MFC. In six patients (27%), larger, posterior, pale yellow-orange streaks developed that were identical to the lesions of BCR. Visual prognosis was better with posterior streaks. The chest x-ray was normal in 5 of 16 patients with peripheral spots and in 3 of 6 patients with posterior streaks. Serum angiotensin-converting enzyme was negative in 5 of 14 patients. Gallium scan showed increased hilar uptake in five patients, three of whom had a normal chest x-ray. Human lymphocyte antigen A29 was positive in one of nine patients. CONCLUSIONS: Sarcoidosis should be considered in patients with fundus findings that resemble BCR or MFC. Initial evaluation should include chest x-ray and testing the angiotensin-converting enzyme level. These test results may be negative in patients outside the 20- to 40-year age group for typical sarcoid. Further evaluation with nondirected conjunctival biopsy and whole-body gallium scan may be indicated in certain patients, including (1) those with BCR or MFC with normal chest x-ray and elevated angiotensin-converting enzyme level; (2) patients older than 50 years with MFC; or (3) human lymphocyte antigen A29-negative BCR.