Bulk Gene Expression Deconvolution Reveals Infiltration of M2 Macrophages in Retinal Neovascularization.

Purpose: This study interrogated the transcriptional features and immune cellular landscape of the retinae of rats subjected to oxygen-induced retinopathy (OIR). Methods: Bulk RNA sequencing was performed with retinal RNA isolated from control and OIR rats. Gene set enrichment analysis (GSEA) was undertaken to identify gene sets associated with immune responses in retinal neovascularization. Bulk gene expression deconvolution analysis by CIBERSORTx was performed to identify immune cell types involved in retinal neovascularization, followed by functional enrichment analysis of differentially expressed genes (DEGs). Protein-protein interaction analysis was performed to predict the hub genes relevant to identified immune cell types. CIBERSORTx was applied to profile immune cell types in the macula of patients with both proliferative diabetic retinopathy (PDR) and diabetic macular edema using a public RNA-seq dataset. Results: Transcriptome analysis by GSEA revealed that the retina of OIR rats and patients with PDR is characterized by increased immunoregulatory interactions and complement cascade. Deconvolution analysis demonstrated that M2 macrophages infiltrate the retinae of OIR rats and patients with PDR. Functional enrichment analysis of DEGs in OIR rats showed that the dysregulated genes are related to leukocyte-mediated immunity and myeloid leukocyte activation. Downstream protein-protein interaction analysis revealed that several potential hub genes, including Ccl2, Itgam, and Tlr2, contribute to M2 macrophage infiltration in the ischemic retina. Conclusions: This study highlights application of the gene expression deconvolution tool to identify immune cell types in inflammatory ocular diseases with transcriptomes, providing a new approach to assess changes in immune cell types in diseased ocular tissues.

Association between Inflammatory Factors in the Aqueous Humor and Hyperreflective Foci in Patients with Intractable Macular Edema Treated with Antivascular Endothelial Growth Factor.

BACKGROUND: To evaluate the correlations between the inflammatory factors in the aqueous humor and hyperreflective foci (HRF) in patients with intractable macular edema treated with antivascular endothelial growth factor (anti-VEGF). METHODS: This study included 17 patients with intractable macular edema (ME) treated with anti-VEGF agents. Inflammatory factors in the aqueous humor were measured by the Cytometric Beads Array before injection, and the numbers of HRF pre- and post-anti-VEGF treatment were counted from four different directions (90 degrees, 45 degrees, 180 degrees, and 135 degrees) in the SD-OCT images, respectively, before treatment and one month after treatment. The correlations between inflammatory factors and the numbers of HRF were assessed. RESULTS: The numbers of HRF were reduced significantly after anti-VEGF treatment. The change in the HRFs at the 90-degree location was significantly positively correlated with IL-8 and VCAM-1. The change of all HRFs was significantly positively correlated with IL-8. The HRFs before the treatment also had a positive correlation with IL-8 and VCAM-1. CONCLUSION: After anti-VEGF treatment, the numbers of HRF in intractable ME declined greatly. The higher the levels of IL-8 and VCAM-1 before treatment, the more significant the reduction of HRF after anti-VEGF treatment, which indicated that HRF could be an effective noninvasive imaging indicator for evaluating the effect of anti-VEGF on intractable macular edema. The OCT images at the 90-degree location could better show the inflammatory reaction of patients and also had better clinical significance for the prognosis evaluation of ME associated with inflammation.

Systemic Regulatory T Cells and IL-6 as Prognostic Factors for Anatomical Improvement of Uveitic Macular Edema.

Purpose: To investigate whether systemic immune mediators and circulating regulatory T cells (Tregs) could be prognostic factors for anatomic outcomes in macular edema secondary to non-infectious uveitis (UME). Methods: Multicenter, prospective, observational, 12-month follow-up study of 60 patients with UME. Macular edema was defined as central subfield thickness (CST) > 300 µm measured with spectral domain optical coherence tomography (SD-OCT). Serum samples and peripheral blood mononuclear cells (PBMC) were obtained from venous blood extraction at baseline. Serum levels of IL-1ß, IL-6, IL-8, IL-17, MCP-1, TNF-α, IL-10, and VEGF were determined by Luminex. Tregs population, defined as CD3+CD4+FoxP3+ in PBMC, was determined by flow cytometry. Main outcome measure was the predictive association between searched mediators and CST sustained improvement, defined as CST < 300 microns or a 20% CST decrease, at 6 months maintained until 12-months compared to baseline levels. Results: Multivariate logistic regression analysis showed an association between CST sustained improvement at 12 months follow-up and IL-6 and Tregs baseline levels. Higher IL-6 levels were associated with less events of UME improvement (OR: 0.67, 95% CI (0.45-1.00), P = 0.042), whereas higher levels of Tregs favored such improvement (OR: 1.25, 95% CI: 1.12-2.56, P = 0.049). Conclusions: Increased levels of Tregs and reduced levels of IL-6 in serum may be prognostic factors of sustained anatomical improvement in UME. These findings could enforce the opportunity to develop more efficient and personalized therapeutic approaches to improve long-term visual prognosis in patients with UME.

Comparison of two techniques used in routine care for the treatment of inflammatory macular oedema, subconjunctival triamcinolone injection and intravitreal dexamethasone implant: medical and economic importance of this randomized controlled trial.

BACKGROUND: Whether they are injected peri- or intraocularly, corticosteroids are still essential tools in the therapeutic arsenal for treating inflammatory macular oedema. A few years ago, however, only triamcinolone acetonide was available to ophthalmologists. While this compound was initially developed for rheumatological or dermatological use, it has been increasingly deployed in ophthalmology, despite still being off-label. In 2011, the system for delivery of dexamethasone from a biodegradable, injectable implant into the vitreous cavity obtained approval for use in inflammatory macular oedema. While the efficacy and safety of triamcinolone in macular oedema, including inflammatory oedema, have already been studied, there are currently no publications on subconjunctival triamcinolone injections, which are simple, effective and well tolerated. To date, the dexamethasone 700 µg implant has been authorized for the treatment of noninfectious intermediate and posterior uveitis, but there have been no studies to evaluate the efficacy and safety of the different peri- and intraocular strategies, including the treatment of inflammatory macular oedema. METHODS: This protocol is therefore designed to compare the efficacy and safety of peri- and intraocular corticosteroid injections in the treatment of inflammatory macular oedema. In this ongoing study, 142 patients will be included, and the oedematous eye will be randomised to treatment with either subconjunctival triamcinolone injection or an intravitreal implant containing 700 µg dexamethasone. Follow-up is planned for 6 months with monthly visits. Each visit will include visual acuity measurement, a slit lamp examination, fundoscopy, intraocular pressure measurement, laser flare measurement (if available) and spectral domain optical coherence tomography. DISCUSSION: The results of this trial will have a real impact on public health if it is shown that a Kenacort retard® (i.e. triamcinolone) injection costing just €2.84 and performed in the physician's office (with no additional overhead costs) is at least as effective as the dexamethasone 700 µg implant (Ozurdex®; costing approximately €960 with the injection performed in a dedicated room), with no increased side effects. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02556424. Registered on 22 September 2015.

NOD-like Receptors in the Eye: Uncovering Its Role in Diabetic Retinopathy.

Diabetic retinopathy (DR) is an ocular complication of diabetes mellitus (DM). International Diabetic Federations (IDF) estimates up to 629 million people with DM by the year 2045 worldwide. Nearly 50% of DM patients will show evidence of diabetic-related eye problems. Therapeutic interventions for DR are limited and mostly involve surgical intervention at the late-stages of the disease. The lack of early-stage diagnostic tools and therapies, especially in DR, demands a better understanding of the biological processes involved in the etiology of disease progression. The recent surge in literature associated with NOD-like receptors (NLRs) has gained massive attraction due to their involvement in mediating the innate immune response and perpetuating inflammatory pathways, a central phenomenon found in the pathogenesis of ocular diseases including DR. The NLR family of receptors are expressed in different eye tissues during pathological conditions suggesting their potential roles in dry eye, ocular infection, retinal ischemia, cataract, glaucoma, age-related macular degeneration (AMD), diabetic macular edema (DME) and DR. Our group is interested in studying the critical early components involved in the immune cell infiltration and inflammatory pathways involved in the progression of DR. Recently, we reported that NLRP3 inflammasome might play a pivotal role in the pathogenesis of DR. This comprehensive review summarizes the findings of NLRs expression in the ocular tissues with special emphasis on its presence in the retinal microglia and DR pathogenesis.

Aqueous Humor Mediator and Cytokine Aberrations in Diabetic Retinopathy and Diabetic Macular Edema: A Systematic Review and Meta-Analysis.

PURPOSE: To evaluate the relationship between the aqueous humor levels of VEGF, TNF-α, IL-10, IL-6, IL-12, MCP-1, and IP-10 with DR/DME. METHODS: PubMed, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang databases were searched up to October 2018. Systematic review and meta-analysis were conducted. RESULTS: 18 studies comprising 362 cases with DR (100 with DME) and 620 controls without DR were included in this meta-analysis. There was a significant association between VEGF levels in the aqueous humor and DR (standardized mean difference (SMD) 1.94 (95% CI 1.05-2.83)) and DME (1.07 (0.71, 1.42)). Furthermore, a significant correlation was observed between levels of IL-6 and DR (3.53 (0.37, 6.69)), and similarly correlation with DME (1.26 (0.30, 2.21)). The relationship between MCP-1 and DR and DME was significant, in which the SMD was (0.49 (0.09, 0.89)) and (1.49 (0.78, 2.20)), respectively. However, IL-12, IP-10, and TNF-α had no correlation with DR and DME, whereas there was a significant relationship between IL-8 and DME (1.68 (0.97, 2.40)). CONCLUSION: Elevated levels of VEGF, IL-6, and MCP-1 in the aqueous humor were associated with the risk for the presence of DR, and levels of VEGF, IL-6, IL-8, and MCP-1 were associated with the risk of DME. Furthermore, these biomarkers may be used as potential predictors or therapeutic targets for DR/DME.

Dexamethasone intravitreal implant (OZURDEX®) for macular edema secondary to noninfectious uveitis: a review of the literature.

Macular edema (ME) is the leading cause of visual loss in uveitis and may persist long after ocular inflammation has been resolved. Local steroids are the first line treatment for uveitis and uveitic ME. Dexamethasone intravitreal implant (OZURDEX®; Allergan, Inc., CA, USA) has been used to treat diabetic ME and ME secondary to retinal vein occlusion. Recent studies have also demonstrated that Ozurdex may be effective treatment for patients with persistent uveitic ME. In this review, we present the results of the real word studies concerning the efficacy and safety of Ozurdex for the treatment of uveitic ME.

Aqueous Humor Cytokine Levels in Diabetic Macular Edema Patients with Cotton-Wool Spots.

PURPOSE: To determine the characteristics of diabetic macular edema (DME) patients with cotton-wool spots (CWS). METHODS: We classified 80 treatment-naïve DME patients according to whether or not they had CWS involving macula and then compared the concentrations of interleukin- (IL-) 1ß, IL-6, IL-8, IL-10, IL-17, placental growth factor, vascular endothelial growth factor (VEGF), and intercellular adhesion molecule (ICAM)-1 in the aqueous humor between the groups, as well as optical coherence tomography (OCT) findings, baseline characteristics, and intravitreal bevacizumab responsiveness. RESULTS: Aqueous levels of ICAM-1 and VEGF in the group with CWS were significantly higher than those in the non-CWS (control) group (p < 0.001 and p = 0.006, respectively). In multiple logistic regression analysis to identify factors associated with CWS, the aqueous ICAM-1 (≥0.36 ng/mL) was significantly associated with CWS (odds ratio = 13.26, p < 0.001). Based on OCT, ellipsoid zone (EZ) disruption distribution was significantly different between the two groups (p = 0.038). Regarding responsiveness to treatment, although there was no significant difference in central subfield thickness between the two groups after treatments, the best-corrected visual acuity was worse in the group with CWS. CONCLUSIONS: The presence of CWS was accompanied by higher levels of aqueous ICAM-1. Based on OCT, EZ disruption was greater in DME patients with CWS, and their short-term visual prognosis was poorer.

Anti-fumarase antibody promotes the dropout of photoreceptor inner and outer segments in diabetic macular oedema.

AIMS/HYPOTHESIS: In diabetic macular oedema (DMO), blood components passing through the disrupted blood-retinal barrier cause neuroinflammation, but the mechanism by which autoantibodies induce neuroglial dysfunction is unknown. The aim of this study was to identify a novel autoantibody and to evaluate its pathological effects on clinically relevant photoreceptor injuries. METHODS: Biochemical purification and subsequent peptide fingerprinting were applied to identify autoantigens. The titres of autoantibodies in DMO sera were quantified and their associations with clinical variables were evaluated. Two animal models (i.e. passive transfer of autoantibodies and active immunisation) were characterised with respect to autoimmune mechanisms underlying photoreceptor injuries. RESULTS: After screening serum IgG from individuals with DMO, fumarase, a Krebs cycle enzyme expressed in inner segments, was identified as an autoantigen. Serum levels of anti-fumarase IgG in participants with DMO were higher than those in diabetic participants without DMO (p < 0.001) and were related to photoreceptor damage and visual dysfunction. Passively transferred fumarase IgG from DMO sera in concert with complement impaired the function and structure of rodent photoreceptors. This was consistent with complement activation in the damaged photoreceptors of mice immunised with fumarase. Fumarase was recruited to the cell surface by complement and reacted to this autoantibody. Subsequently, combined administration of anti-fumarase antibody and complement elicited mitochondrial disruption and caspase-3 activation. CONCLUSIONS/INTERPRETATION: This study has identified anti-fumarase antibody as a serum biomarker and demonstrates that the generation of this autoantibody might be a pathological mechanism of autoimmune photoreceptor injuries in DMO.

Relationship between aqueous humor cytokine level changes and retinal vascular changes after intravitreal aflibercept for diabetic macular edema.

The aim of this work was to investigate the changes in aqueous humor cytokine levels after intravitreal injection of aflibercept in diabetic macular edema (DME) and to evaluate the relationship between cytokines modifications and central macular thickness (CMT) and retinal/choroidal vascular changes using structural and functional optical coherence tomography (OCT). Aqueous concentrations of 38 cytokines were measured via multiplex bead assay. In addition, spectral domain OCT and OCT angiography with SSADA software (XR Avanti® AngioVue) were performed at baseline and after intravitreal injections. VEGF, IL-6, IL-5, IL-1ß, Eotaxin, GRO, IL-12p40, IL-12p70, IL-1RA, Flt-3L and IP-10 showed a statistically significant decrease through the follow-up (p < 0.05; p < 0.001), while Fraktalkine and GM-CSF significantly increased (p < 0.05). Best corrected visual acuity significantly increased and CMT significantly decreased during follow-up (p < 0.001 and p = 0.013). Superficial capillary plexus and deep capillary plexus density significantly increased (p < 0.001 and p = 0.014). A positive relation was found between GRO, VEGF, Fraktalkine, IP-10, IL-12p70 aqueous humor levels and CMT (p < 0.05; p < 0.001). Aflibercept is a primary anti-VEGF treatment producing a decrease of DME due to the reduction of vascular permeability, nevertheless other inflammatory cytokines showed modification after aflibercept intravitreal injections probably related to edema modification or to an interaction of aflibercept with other inflammatory cytokines.

The role of cystoid macular edema as a marker in the progression of non-paraneoplastic autoimmune retinopathy.

PURPOSE: To determine the relationship between cystoid macular edema (CME) and disease severity and progression in non-paraneoplastic autoimmune retinopathy (npAIR). METHODS: A retrospective study was conducted on patients seen between 2008 and 2016 with npAIR as defined by electroretinogram (ERG) dysfunction, visual field changes, presence of antiretinal antibodies, a negative malignancy workup, and no other apparent cause for visual dysfunction. Optical coherence tomography (OCT) scans were reviewed for each patient. A minimum follow-up of 1 year was necessary for study inclusion. The presence or absence of CME and the length of the preserved EZ on the centermost line scan of the SD-OCT images was recorded at each visit. The main outcome measure assessed was the rate of EZ loss (EZ final - EZ initial / days follow-up) over time, a marker for disease progression. RESULTS: Thirty-two eyes (16 patients) were included with an average follow-up of 42 months. Twenty-one eyes (66%) had CME on initial presentation and final follow-up (group 1), eight eyes (25%) did not have CME on presentation or final follow-up (group 2), and three eyes (9%) did not have CME on presentation but developed CME during follow-up (group 3). Group 1 eyes had a lower maximal a-wave amplitude (59.0 vs. 220.9 mV, p = 0.012) and lower maximal b-wave amplitude (88.1 vs 256.9 mV, p = 0.017) on baseline ERG compared to Group 2 eyes. The rate of EZ loss over time was significantly greater for group 1 with CME compared to group 2 without CME both at 12 months (- 1.26 µm/day vs. - 0.26 µm/day, p = 0.022) and at final follow-up (- 1.03 µm/day vs. - 0.08 µm/day, p = 0.012). CONCLUSIONS: CME was associated with decreased ERG amplitudes and greater velocity of EZ loss, suggesting that CME is a useful biomarker of more severe and more progressive disease in npAIR.

Is leukostasis a crucial step or epiphenomenon in the pathogenesis of diabetic retinopathy?

Leukostasis in the retinal microvasculature in animal model studies of diabetes is associated with the development of diabetes-like retinopathy. Therefore, it is generally assumed that adhesion of leukocytes is a central event inciting a chronic, low-grade form of inflammation that causes the vascular abnormalities that are specific for the early stages of diabetic retinopathy (DR), which culminate in diabetic macular edema, proliferative DR, and vision loss in humans. Here, we review the literature critically with respect to leukostasis and assess its pathologic consequences in the human diabetic retina. First, we review the pathologic processes that are known to be involved in the development of human DR. Then, we summarize experimental evidence for the role of leukostasis in the development of DR and the mechanisms involved in leukostasis in the retina. Based on our critical review, we conclude that leukostasis may be an epiphenomenon of the diabetic retinal milieu, rather than a crucial, specific step in the development of human DR.

Insights into the Physiopathology of Inflammatory Macular Edema.

Macular edema is one of the most common causes of permanent vision loss in patients with uveitis. The current understanding of water balance and metabolism within the retina has given us better insight into the mechanisms underlying macular edema arising from both acute and chronic inflammation. Uveitic macular edema (UME) occurs when the equilibrium between water influx and efflux is lost, and more importantly when compensatory mechanisms are overwhelmed. While in the acute setting, control of inflammation can reestablish homeostasis, chronic inflammation can lead to alternate pathways to establish a water balance. To understand UME, one must understand the regulation and consequences of inflammation at the tissular level. A fine interplay exists between inflammation and the retina replete with compensatory mechanisms, bystander effects, and structural sequelae once inflammation subsides. This understanding may allow us to develop new therapeutic strategies for the treatment of inflammatory macular edema.

Aqueous cytokine levels are associated with reduced macular thickness after intravitreal ranibizumab for diabetic macular edema.

PURPOSE: It is controversial whether the administration of anti-vascular endothelial growth factor drugs for diabetic macular edema (DME) affects intraocular inflammatory cytokines. In this study, we measured cytokine concentration in aqueous humor before and after intravitreal injection of ranibizumab (IVR). The aim was to determine changes in cytokine concentration and their effects on DME reduction. METHODS: Twelve patients (13 eyes) with DME received two IVR (0.5 mg) with a 1 month interval, and a total of 26 aqueous humor samples were obtained. Macular thickness was measured with an optical coherence tomography (OCT) using thickness-map mode with an Early Treatment Diabetic Retinopathy Study (ETDRS) 9-zone grid that was divided into two zones: a central circle with a diameter of 1 mm (zone1); and an outer circle with a diameter of 6 mm (zone2). RESULTS: The concentration of eotaxin-1 in aqueous humor samples decreased significantly after IVR. Baseline cytokine concentration was associated with IVR-induced DME reduction. In zone1, higher baseline concentration of interferon-induced protein (IP)-10, and in zone 2, higher baseline concentration of granulocyte-macrophage colony-stimulating factor, IP-10, and tumor necrosis factor (TNF) α; and lower baseline concentration of eotaxin-1, interleukin (IL)-5, and IL-8 were associated with improved DME. Cytokine changes were associated with IVR-induced DME reduction. In zone1, lower concentration of IP-10 compared to baseline or higher concentration of macrophage inflammatory protein (MIP) -α, and in zone 2, lower concentration of IL-5 compared to baseline, IL-8, and IP-10 or higher concentration of eotaxin-1 and MIP-1ß were associated with improved DME. CONCLUSIONS: These findings suggest that ranibizumab affects the concentration of cytokines in aqueous humor. Various cytokines contribute to a decrease in retinal thickness, both in the center of the macula and in a larger area of the retina.

Myelin-oligodendrocyte-glycoprotein (MOG) autoantibodies as potential markers of severe optic neuritis and subclinical retinal axonal degeneration.

Antibodies against conformation-dependent epitopes of myelin-oligodendrocyte-glycoprotein (MOG-abs) are present in subgroups of neuromyelitis optica spectrum disorder (NMOSD), recurrent optic neuritis (rON), multiple sclerosis (MS), and anti-NMDAR encephalitis. Using optical coherence tomography (OCT) we assessed whether MOG-abs might serve as potential marker of retinal axonal degeneration. We investigated a clinically heterogeneous cohort of 13 MOG-abs-positive patients (4 MOG-abs-positive rON, 4 MOG-abs-positive adult MS, 3 MOG-abs-positive relapsing encephalomyelitis, 2 MOG-abs-positive aquaporin-4-abs-negative NMOSD). As controls, we studied 13 age, sex and ON episode(s)-matched MOG-abs and aquaporin-4-abs-negative (AQP4-abs-negative) MS patients and 13 healthy controls (HC). In addition, we investigated 19 unmatched AQP4-abs-positive MOG-abs-negative NMOSD subjects. Considering all eyes, global pRNFL [in µm, mean (SD)] was significantly reduced in MOG-abs-positive patients [72.56 (22.71)] compared to MOG-abs-negative MS [80.81 (13.55), p = 0.0128], HCs [103.54 (8.529), p = 0.0014] and NMOSD [88.32 (18.43), p = 0.0353]. Non ON eyes from MOG-abs-positive subjects showed significant subclinical atrophy of temporal pRNFL quadrants. Microcystic macular edema (MME) was observed only in eyes of MOG-abs-positive (24%) and AQP4-abs-positive NMOSD (5.6%), but not in MOG-abs-negative MS or HC (p < 0.01). MOG-abs may serve as potential marker of retinal degeneration. Specifically, MOG-abs-related OCT features predominate in temporal pRNFL quadrants (resembling the MS retinal pattern), might be more severe than AQP4-abs-positive NMOSD, indicate subclinical pathology, and may be associated with MME.

A Case of Diabetic Macular Edema with Improvement in Severity of Diabetic Retinopathy following Frequent Anti-Vascular Endothelial Growth Factor Treatment.

Background: Intravitreal anti-vascular endothelial growth factor (VEGF) drug injections are the gold standard for the treatment of diabetic macular edema (DME). We report a case of DME in which frequent anti-VEGF treatment resulted in improvement of diabetic retinopathy. Case: A 73-year old woman with DME who had previously undergone bilateral posterior subtenon injections of triamcinolone acetonide and vitrectomy OD presented at Kyushu University Hospital. Best corrected visual acuity was 0.1 OD and 0.15 OS. The central macular thickness was 1570 µm OD and 578 µm OS. We performed focal macular laser photocoagulation OU but the DME was not resolved. Subsequent intravitreal anti-VEGF drug injections(approximately 20 times/2 years)resulted in an improvement of the best corrected visual acuity (0.3 OD, 0.6 OS) and CMT (1570 µm OD, 578 µm OS). There was an improvement of 2 steps in the Diabetic Retinopathy Severity Scale (DRSS) score OU. Conclusion: Frequent anti-VEGF treatment can improve the severity of diabetic retinopathy.

Th17 cell frequency and IL-17A concentrations in peripheral blood mononuclear cells and vitreous fluid from patients with diabetic retinopathy.

Objective To quantify T helper (Th)17 cells and determine interleukin (IL)-17A levels in peripheral blood mononuclear cell (PBMC) culture and vitreous fluid from patients with type 2 diabetes mellitus (T2DM) with diabetic retinopathy (DR). Methods Th17 cell frequency and IL-17A concentrations in PBMCs from 60 patients with T2DM with DR, 30 without DR and 30 sex- and age-matched healthy individuals were measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. IL-17A levels in vitreous fluid from 31 eyes with proliferative DR and diabetic macular oedema (DR group) and 32 eyes with an epiretinal membrane and macular hole (control group) that underwent vitrectomy were also examined by ELISA. Results Compared with the control group, the proportion of Th17 cells and IL-17A concentrations in PBMCs were significantly increased in patients without DR but decreased in those with DR. IL-17A concentrations and Th17 cell frequency in PBMCs tended to decrease with DR severity and were negatively correlated with body mass index, T2DM duration and glycated haemoglobin. Additionally, vitreous fluid IL-17A levels were significantly elevated in patients with DR compared with those of the control group. Conclusions We conclude that disturbances in Th17 cells and IL-17A levels are possibly associated with DR.

Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory.

Diabetic macular edema (DME) can cause blindness in diabetic patients suffering from diabetic retinopathy (DR). DM parameters controls (glycemia, arterial tension, and lipids) are the gold standard for preventing DR and DME. Although the vascular endothelial growth factor (VEGF) is known to play a role in the development of DME, the pathological processes leading to the onset of this disease are highly complex and the exact sequence in which they occur is still not completely understood. Angiogenesis and inflammation have been shown to be involved in the pathogenesis of this disease. However, it still remains to be clarified whether angiogenesis following VEGF overexpression is a cause or a consequence of inflammation. This paper provides a review of the data currently available, focusing on VEGF, angiogenesis, and inflammation. Our analysis suggests that angiogenesis and inflammation act interdependently during the development of DME. Knowledge of DME etiology seems to be important in treatments with anti-VEGF or anti-inflammatory drugs. Current diagnostic techniques do not permit us to differentiate between both etiologies. In the future, diagnosing the physiopathology of each patient with DME will help us to select the most effective drug.

Nonbiological pharmacotherapies for the treatment of diabetic macular edema.

INTRODUCTION: During the past decade, there have been significant advances in the pharmacotherapies for the treatment of diabetic macular edema (DME). Among the presently available treatment options, anti-vascular endothelial growth factors (anti-VEGF) agents are the most favored agents due to their efficacy and safety. The index review focuses on nonbiological therapies that have entered in phase 3 clinical trials for DME. AREAS COVERED: An extensive review of the literature was performed to identify various nonbiological immunotherapies i.e., drugs other than '-mAbs' (monoclonal antibodies including anti-VEGF agents), '-mibs' (proteasome inhibitors), '-NAbs' (nanoparticle albumin-bound), and '-nibs' (small molecule inhibitor/tyrosine kinase inhibitors), among others. Extended-release low-dose corticosteroid devices have been recently approved for the treatment of DME. Other compounds such as non-steroidal anti-inflammatory drugs, antibody mimetic proteins, nonbiological growth factor inhibitors, and inhibitors of protein kinase C have been described. EXPERT OPINION: A number of therapies are under development for the pharmacological management of DME. Due to the rising healthcare costs associated with anti-VEGF agents, a number of alternate treatment options have been explored recently. Some of these agents have reached phase 3 in clinical trials and appear to have a promising role in the management of DME. As further research is conducted, the role of each individual agent will become more defined, alone or in combination therapy.