Influence of inflammatory plasma biomarkers on choroidal thickness in type 2 diabetes mellitus.

PURPOSE: To assess the influence of inflammatory plasma biomarkers on choroidal thickness (CT) in patients with type 2 diabetes (T2D). METHODS: Cross-sectional study enrolling T2D patients and age-matched healthy controls (>55 years of age, Caucasian, axial length <26 mm, no macular edema, and naïve). Patients were examined with swept-source OCT Triton, obtaining automatic measurements. CT was analyzed using the ETDRS grid and the recently proposed choroidal division. A blood analysis was commanded: general biochemical profile, liver status, T2D status, thyroid and parathyroid activity, coagulation, general immunological profile, and inflammatory biomarkers. RESULTS: 124 eyes of 124 patients with a mean age between 66 and 68 years were examined. The new choroidal division showed differences between groups (p < 0.05) in more sectors than the ETDRS grid, and more biomarkers influenced these new sectors. T2D patients had higher levels of IL-8, TNF-α, MCP1, adiponectin and L-selectin. CT was influenced by TNF-α, IL-17, leukocytes and erythrocyte sedimentation rate, as well as by HDL cholesterol, albumin, liver function biomarkers, and TSH. HbA1c showed little influence on CT. CONCLUSIONS: T2D patients present increased plasma inflammatory biomarkers, exhibiting an influence on CT. IL-17 is related to a thicker choroid but TNF-α is related to a thinner choroid. HbA1c has little influence on CT. The recently proposed choroidal division is more sensitive to CT changes than the ETDRS grid. Some sectors are more sensitive to plasma biomarkers.

Anti-TNF vs tocilizumab in refractory uveitic cystoid macular edema due to Behcet's disease. Multicenter study of 49 patients.

OBJECTIVE: To compare the efficacy of TNF inhibitors (adalimumab (ADA) and infliximab (IFX)) vs tocilizumab (TCZ) in patients with refractory cystoid macular edema (CME) due to Behçet's disease (BD). METHODS: Multicenter study of patients with BD-associated CME refractory to conventional and/or biological immunosuppressive drugs. From a cohort of 177 patients treated with anti-TNF and 14 patients treated with TCZ, we selected those with CME at baseline. We analyzed the evolution of macular thickness (main outcome), best-corrected visual acuity (BCVA) and intraocular inflammation (Tyndall and vitritis) from baseline up to 4 years in the 3 groups mentioned. RESULTS: 49 patients and 72 eyes with CME were included. ADA was used in 25 patients (40 eyes), IFX in 15 (21 eyes) and TCZ in 9 (11 eyes). No statistically significant baseline differences were observed between the 3 groups except for a lower basal BCVA in TCZ group and a higher basal degree of intraocular inflammation in ADA group. Most patients from all groups had received several conventional immunosuppressive drugs. In addition, most patients in the group of TCZ had also received anti-TNF agents. Biological therapy was used in monotherapy (n=8) or combined with conventional immunosuppressive drugs (n=41). Macular thickness progressively decreased in the 3 groups, with no signs of CME after 1 year of treatment. Similarly, BCVA improvement and inflammatory intraocular remission was achieved in all groups. CONCLUSION: Refractory CME associated with BD uveitis can be effectively treated either with ADA, IFX or TCZ. Furthermore, TCZ is effective in patients resistant to anti-TNF therapy.

The role of retinal fluid location in atrophy and fibrosis evolution of patients with neovascular age-related macular degeneration long-term treated in real world.

PURPOSE: To assess the effect of clinical factors on the development and progression of atrophy and fibrosis in patients with neovascular age-related macular degeneration (nAMD) receiving long-term treatment in the real world. METHODS: An ambispective 36-month multicentre study, involving 359 nAMD patients from 17 Spanish hospitals treated according to the Spanish Vitreoretinal Society guidelines, was designed. The influence of demographic and clinical factors, including the presence and location of retinal fluid, on best-corrected visual acuity (BCVA) and progression to atrophy and/or fibrosis were analysed. RESULTS: After 36 months of follow-up and an average of 13.8 anti-VEGF intravitreal injections, the average BCVA gain was +1.5 letters, and atrophy and/or fibrosis were present in 54.8% of nAMD patients (OR = 8.54, 95% CI = 5.85-12.47, compared to baseline). Atrophy was associated with basal intraretinal fluid (IRF) (OR = 1.87, 95% CI = 1.09-3.20), whereas basal subretinal fluid (SRF) was associated with a lower rate of atrophy (OR = 0.40, 95% CI = 0.23-0.71) and its progression (OR = 0.44, 95% CI = 0.26-0.75), leading to a slow progression rate (OR = 0.34, 95% CI = 0.14-0.83). Fibrosis development and progression were related to IRF at any visit (p < 0.001). In contrast, 36-month SRF was related to a lower rate of fibrosis (OR = 0.49, 95% CI = 0.29-0.81) and its progression (OR = 0.50, 95% CI = 0.31-0.81). CONCLUSION: Atrophy and/or fibrosis were present in 1 of 2 nAMD patients treated for 3 years. Both, especially fibrosis, lead to vision loss. Subretinal fluid (SRF) was associated with good visual outcomes and lower rates of atrophy and fibrosis, whereas IRF yields worse visual results and a higher risk of atrophy and especially fibrosis in routine clinical practice.

Macro and microangiopathy related to retinopathy and choroidopathy in type 2 diabetes.

PURPOSE: To describe the relationship between diabetic retinopathy (DR) and choroidal thickness (CT), and systemic macro and microangiopathy in patients with type 2 diabetes (T2D). METHODS: Cross-sectional study enrolling 200 eyes (100 T2D naïve patients) without macular edema. DR was graded and swept-source optical coherence tomography Triton DRI (Topcon) was used to measure CT, which gave automatic measurements in ETDRS grid. An endocrinologist examined all the patients and searched in their medical records for data about macro and microangiopathy: ischemic cardiopathy (IC), cerebrovascular accident (CVA), peripheral artery disease (PAD), nephropathy, and peripheral polyneuropathy (PPN). RESULTS: Mean age was 67.38 ± 8.15 years, mean axial length was 23.26 ± 0.09 mm, and mean IOP was 16.75 ± 3.06 mmHg. Sixty eyes had no DR, 46 had mild, 64 had moderate, 20 had severe, and 10 had proliferative DR. IC was correlated with horizontal choroidal zones (p < 0.05 and η between 0.16 and 0.21) but not with DR (p = 0.16). CVA was neither correlated with CT (p > 0.05) nor with DR (p = 0.39). PAD was not correlated with CT (p > 0.05) but it was with DR (p = 0.03). The type of nephropathy was correlated both with CT in vertical sectors (p < 0.05 and η between 0.15 and 0.27) and DR (p = 0.01, τ = 0.24). PPN was not correlated with CT (p > 0.05) but it was with DR (p = 0.03). CONCLUSIONS: DR is correlated with microangiopathy (nephropathy and PPN) but not with macroangiopathy (IC, CVA, and PAD). CT is mildly correlated with nephropathy and IC. Some choroidal regions are more sensitive than others to each diabetic macro and microvascular manifestation.

OCULAR ADVERSE EVENTS ASSOCIATED WITH MEK INHIBITORS.

PURPOSE: Mitogen-activates protein kinase (MAPK) inhibitors, particularly MEK inhibitors, have shifted the treatment paradigm for metastatic BRAF-mutant cutaneous melanoma; however, oncologists, ophthalmologists, and patients have noticed different toxicities of variable importance. This review aims to provide an update of the ocular adverse events (OAEs), especially retinal toxicity, associated with the use of MEK inhibitors. METHODS: We conducted a scientific literature search using the PubMed database up to July 2018 with the terms "MEK inhibitors" with a "review" filter and "MEK inhibitors" with a "clinical trials" filter. Phase I-III experimental studies and reviews were selected. Current principles and techniques for diagnosing and managing MEK inhibitor retinopathy and other OAEs are discussed. RESULTS: In patients treated with MEK inhibitors, including asymptomatic patients, OAEs occur with an incidence of up to 90%. Mild to severe ophthalmic toxicities are described, including visual disturbances, a 2-line decrease in Snellen visual acuity, dry eye symptoms, ocular adnexal abnormalities, visual field defects, panuveitis, and retinal toxicities, such as different degrees of MEK-associated retinopathy, vascular injury, and retinal vein occlusion. CONCLUSION: MEK inhibitors can lead to different degrees of retinal, uveal, and adnexal OAE, causing visual disturbances or discomfort. One of the most relevant OAE of MEK therapy is MEK inhibitor-associated retinopathy (MEKAR), which is usually mild, self-limited, and may subside after continuous use of the drug for weeks or months, or discontinuation, thereby restoring the normal visual function of the retina, with some exceptions. Ocular adverse events are often associated with other systemic adverse effects that can modify the dosage of treatment, so the communication with the oncologist is fundamental.

Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease.

PURPOSE: To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behçet disease (BD) who achieved remission after the use of this biologic agent. DESIGN: Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants. SUBJECTS: Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients. METHODS: After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed. MAIN OUTCOME MEASURES: Efficacy, safety, and cost-effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed. RESULTS: No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean ± standard deviation follow-up of 34.7±13.3 and 26±21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01). CONCLUSION: ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.

Golimumab in refractory uveitis associated to juvenile idiopathic arthritis: multicentre study of 7 cases and literature review.

OBJECTIVES: To assess the efficacy of golimumab (GLM), a fully humanised anti-TNF-α monoclonal antibody, in refractory juvenile idiopathic arthritis (JIA)-associated uveitis. METHODS: This was a multicentre study of JIA-associated uveitis refractory to standard synthetic immunosuppressive drugs and in most cases to other anti-TNF-α agents. Results were expressed as mean±standard deviation or as median (range or interquartile range). The Wilcoxon signed-rank test was used to compare continuous variables. A literature review of the efficacy of GLM in uveitis related to JIA was also conducted. RESULTS: We studied 7 patients (5 females; mean age 21.7±7.5 years; 13 affected eyes). Uveitis was bilateral in 6. Cystoid macular oedema (CME) occurred in 3 patients (5 eyes). Besides corticosteroids and synthetic immunosuppressive drugs, patients had received before GLM a median of 2 biologic agents (range 0-3) including adalimumab (n=6), etanercept (n=2), infliximab (n=3) and abatacept (n=2). GLM dose was 50 mg/sc every 4 weeks. After 6 months of therapy the number of anterior chamber cells decreased from 1 [0.25-1.5] to 0 [0-0.5] (p=0.02) and optical coherence tomography (in patients with CME) from 313.6±77.05 to 261.4±75.1 µm (p=0.03). The best-corrected visual acuity increased from 0.5 to 0.62 (p=0.018). Complete remission of uveitis was achieved in 4 of 7 patients after 16.8±11.4 months of follow-up. However, 2 of the seven patients had to be switched to tocilizumab due to inefficacy. Local erythema at the injection site was observed in 2. CONCLUSIONS: GLM may be considered in the management of refractory JIA-related uveitis.

Diabetic Macular Edema: Options for Adjunct Therapy.

Diabetes mellitus (DM) is a chronic disease that affects 387 million people worldwide. Diabetic retinopathy (DR), a common complication of DM, is the main cause of blindness in the active population. Diabetic macular edema (DME) may occur at any stage of DR, and is characterized by vascular hyperpermeability accompanied by hard exudates within the macula. Medical and surgical therapies have dramatically reduced the progression of DR, and timely intervention can reduce the risk of severe vision loss by more than 90 %. In 2012, intravitreal ranibizumab became the first antivascular endothelial growth factor (anti-VEGF) agent approved for DME and, since then, many reports of the use of ranibizumab for DME have been promising. Randomized, prospective, multicenter clinical trials-most notably, RESOLVE, READ-2, RISE/RIDE, RESTORE, DRCR.net protocol I, and RETAIN-reported improvements in best-corrected visual acuity and decreased central retinal thickness as measured with optical coherence tomography in patients with DME. Similar treatment benefits have also been noted in clinical trials evaluating intravitreal aflibercept and bevacizumab (DAVINCI, VISTA/VIVID, and BOLT) and more recently DRCR.net protocol T. Intravitreal steroids (dexamethasone intravitreal implant and fluocinolone acetonide), particularly in refractory cases, also play a significant role in the management of DME (MEAD/CHAMPLAIN and FAMOUS/FAME studies). In summary, over the last 5 years, blocking VEGF and inflammation has been shown to improve visual outcomes in patients with macular edema due to DM, revolutionizing the treatment of center-involved DME and establishing a new standard of care.

Anti-TNF-α therapy in patients with refractory uveitis due to Behçet's disease: a 1-year follow-up study of 124 patients.

OBJECTIVE: The aim of this study was to assess the efficacy of anti-TNF-α therapy in refractory uveitis due to Behçet's disease (BD). METHODS: We performed a multicentre study of 124 patients with BD uveitis refractory to conventional treatment including high-dose corticosteroids and at least one standard immunosuppressive agent. Patients were treated for at least 12 months with infliximab (IFX) (3-5 mg/kg at 0, 2 and 6 weeks and then every 4-8 weeks) or adalimumab (ADA) (usually 40 mg every 2 weeks). The main outcome measures were degree of anterior and posterior chamber inflammation, visual acuity, macular thickness and immunosuppression load. RESULTS: Sixty-eight men and 56 women (221 affected eyes) were studied. The mean age was 38.6 years (s.d. 10.4). HLA-B51 was positive in 66.1% of patients and uveitis was bilateral in 78.2%. IFX was the first biologic agent in 77 cases (62%) and ADA was first in 47 (38%). In most cases anti-TNF-α drugs were used in combination with conventional immunosuppressive drugs. At the onset of anti-TNF-α therapy, anterior chamber and vitreous inflammation was observed in 57% and 64.4% of patients, respectively. In both conditions the damage decreased significantly after 1 year. At baseline, 50 patients (80 eyes) had macular thickening [optical coherence tomography (OCT) >250 µm] and 35 (49 eyes) had cystoid macular oedema (OCT>300 µm) that improved from 420 µm (s.d. 119.5) at baseline to 271 µm (s.d. 45.6) at month 12 (P < 0.01). The best-corrected visual acuity and the suppression load also showed significant improvement. After 1 year of follow-up, 67.7% of patients were inactive. Biologic therapy was well tolerated in most cases. CONCLUSION: Anti-TNF-α therapy is effective and relatively safe in refractory BD uveitis.

Interface corneal edema secondary to steroid-induced elevation of intraocular pressure simulating diffuse lamellar keratitis.

PURPOSE: To describe interface corneal edema secondary to steroid-induced elevation of intraocular pressure (IOP) following LASIK. METHODS: Retrospective observational case series. Diffuse interface edema secondary to steroid-induced elevation of IOP was observed after LASIK simulating diffuse lamellar keratitis (DLK) in 13 eyes. Mean patient age was 31.4 +/- 5.3 years. Patients were divided into two groups according to provisional misdiagnosis: DLK group (group 1) comprised 11 eyes and infection group (group 2) comprised 2 eyes (microbial keratitis). Mean follow-up was 8.1 +/- 0.5 weeks. RESULTS: In the DLK group, typical diffuse haze was confined to the interface and extended to the visual axis, impairing vision in all eyes. Provisional diagnosis was late-onset DLK and topical steroids were started. Repeat examination showed elevated IOP as measured at the corneal center and periphery using applanation tonometry (mean 19.1 mmHg and 39.5 mmHg, respectively), causing interface edema with evident interface fluid pockets. Steroids were stopped and topical anti-glaucoma therapy was started. The interface edema decreased and at the end of follow-up the corneal transparency was restored and IOP dropped to normal values. The infection group demonstrated a microbial keratitis-like reaction and underwent flap lifting and interface wound debridement and biopsy with administration of fortified antibiotics and steroids. After elevated IOP was detected, steroids and antibiotics were stopped and topical anti-glaucoma therapy was started, resulting in the resolution of the interface edema. CONCLUSIONS: Interface fluid syndrome secondary to steroid-induced elevation of IOP might develop in steroid responders after LASIK with a misleading clinical picture simulating DLK or infectious keratitis. Management includes stopping topical steroids and starting topical antiglaucoma therapy.

Choroidal neovascularization in phakic eyes with anterior chamber intraocular lenses to correct high myopia.

PURPOSE: To analyze the appearance, incidence, and characteristics of choroidal neovascularization (CNV) in patients with high myopia corrected by implantation of a phakic anterior chamber intraocular lens (PACL). SETTING: University Miguel Hernández, Instituto Oftalmológico de Alicante, Alicante, Spain. METHODS: The CNV observed in 294 consecutive eyes (181 patients) implanted with a PACL for the correction of high myopia (-7.0 to -38.0 diopters) was studied. The mean follow-up was 50.6 months +/- 32.8 (SD) (range 6 to 120 months). RESULTS: Choroidal neovascularization occurred in 5 eyes (1.70%); 3 eyes were in women, and 2 were in men. The interval between PACL implantation and CNV was 63.2 +/- 27.3 months (range 18 to 87 months). The CNV was subfoveal in 4 eyes and juxtafoveal in 1 case. The mean best spectacle-corrected visual acuity (BSCVA) after PACL implantation and before the appearance of CNV was 0.53 +/- 0.18 (range 0.4 [20/50] to 0.8 [20/25]); after CNV appeared, it was 0.26 +/- 0.18 (range 0.05 [20/400] to 0.5 [20/40]), a statistically significant difference (P =.001, paired Student t test). In 2 cases, the CNV was treated with photodynamic therapy (PDT); in the other 3 cases, PDT was rejected. The cumulative risk for CNV (Kaplan-Meier survival analysis) in highly myopic patients corrected by PACL implantation was 0.43% at 18 months and 5.4% at 87 months. CONCLUSIONS: Implantation of a PACL to correct high myopia was followed by a small incidence of CNV (cumulative risk of 5.4% at 87 months). The appearance of CNV was followed by a significant decrease in BSCVA.