Ocular involvement in adult and paediatric patients with monogenic autoinflammatory diseases: a Spanish multicentre retrospective study.

OBJECTIVES: Ophthalmologic involvement in monogenic autoinflammatory diseases has been explored mainly in paediatric patients. The aim of this study is to characterise ophthalmologic manifestations, therapeutic management and visual outcomes in a Spanish (UVESAI) cohort of adult/paediatric patients with monogenic autoinflammatory diseases. METHODS: Multicentre and retrospective study of patients with monogenic autoinflammatory diseases and ocular involvement. Eye manifestations, structural complications, treatments used and visual outcomes were analysed, and compared with previous studies. RESULTS: Forty-six patients (44/2 adults/children; 21/25 adult/paediatric-onset) with monogenic autoinflammatory diseases [cryopyrin associated periodic syndromes (n=13/28.3%), mainly Muckle-Wells syndrome (MWS) (n=11/24%); familial Mediterranean fever (FMF) (n=12/26%); TNF receptor-associated periodic syndrome (TRAPS); (n=9/20%); Blau syndrome (n=8/17%); hyperimmunoglobulin D syndrome (HIDS) (n=2/4.3%), deficiency of adenosine deaminase-2 and NLRC4-Autoinflammatory disease] (one each) were included. Conjunctivitis (n=26/56.5%) and uveitis (n=23/50%) were the most frequent ocular manifestations. Twelve (26.1%) patients developed structural complications, being cataracts (n=11/24%) and posterior synechiae (n=10/22%) the most frequent. Conjunctivitis predominated in TRAPS, FMF, MWS and HIDS (mainly in adults), and uveitis, in Blau syndrome. Seven (8%) eyes (all with uveitis) presented with impaired visual acuity. Local and systemic treatment led to good visual outcomes in most patients. Compared with previous studies mainly including paediatric patients, less severe ocular involvement was observed in our adult/paediatric cohort. CONCLUSIONS: Conjunctivitis was the most common ocular manifestation in our TRAPS, FMF, MWS and HIDS patients, and uveitis predominated in Blau syndrome. Severe eye complications and poor visual prognosis were associated with uveitis. Adults with monogenic autoinflammatory diseases seem to exhibit a less severe ophthalmologic presentation than paediatric patients.

Intravitreal fluocinolone acetonide 0.19 mg (ILUVIEN®) in patients with non-infectious uveitis: real-world effectiveness and safety outcomes at 12 months.

PURPOSE: This study assessed the effectiveness of the 0.19-mg fluocinolone acetonide (FAc) implant by multimodal measurements in patients with non-infectious uveitis (NIU) in a real-world setting in Spain. METHODS: A prospective study of patients who had NIU including uveitic macular oedema (UME) with ≥ 12 months follow-up was done. Exclusion criteria include infectious uveitis and uncontrolled glaucoma or ocular hypertension requiring more than 2 medications. Effectiveness was assessed using a multicomponent outcome measure that included nine outcomes. Effectiveness was defined as all components being met at every timepoint. Secondary outcome measures were onset or progression of glaucoma and investigator-reported adverse events. RESULTS: Twenty-six eyes from 22 patients were included, with 96.2% having an indication including UME. During the 12-month study, the FAc implant was effective in 15 (57.7%) eyes, reaching effectiveness as soon as 2 weeks post-implantation. Mean best-corrected visual acuity and mean central macular thickness (CMT) were significantly improved vs. baseline at all timepoints (all comparisons p < 0.01). During the 12-month study, inflammation markers (anterior chamber cells and vitreous haze) had also significantly declined. Factors predicting effectiveness at month 12 were systemic corticosteroid dose pre-FAc, higher immunomodulatory therapy (IMT) load at baseline and thicker retinal nerve fibre layer (RNFL) at baseline (all p < 0.05). Factors predicting failure were male gender, thinner RNFL at baseline and treatment ineffectiveness at 1 month (all p < 0.05). In parallel, corticosteroid and IMT use also declined significantly. No significant increase in IOP was detected. CONCLUSION: The FAc implant is safe and effective at treating NIU over 12 months in a real-world setting in Spain.

Microbiome in Immune-Mediated Uveitis.

In the last decades, personalized medicine has been increasing its presence in different fields of medicine, including ophthalmology. A new factor that can help us direct medicine towards the challenge of personalized treatments is the microbiome. The gut microbiome plays an important role in controlling immune response, and dysbiosis has been associated with immune-mediated diseases such as non-infectious uveitis (NIU). In this review, we gather the published evidence, both in the pre-clinical and clinical studies, that support the possible role of intestinal dysbiosis in the pathogenesis of NIU, as well as the modulation of the gut microbiota as a new possible therapeutic target. We describe the different mechanisms that have been proposed to involve dysbiosis in the causality of NIU, as well as the potential pharmacological tools that could be used to modify the microbiome (dietary supplementation, antibiotics, fecal microbiota transplantation, immunomodulators, or biologic drugs) and, consequently, in the control of the NIU. Furthermore, there is increasing scientific evidence suggesting that the treatment with anti-TNF not only restores the composition of the gut microbiota but also that the study of the composition of the gut microbiome will help predict the response of each patient to anti-TNF treatment.

A multidisciplinary registry of patients with autoimmune and immune-mediated diseases with symptomatic COVID-19 from a single center.

BACKGROUND AND AIM: There is increasing interest regarding SARS-CoV-2 infection in patients with autoimmune and immune-mediated inflammatory diseases (AI/IMID) with some discrepancies in different cohorts about their risk and outcomes. The aim was to describe a multidisciplinary cohort of patients with AI/IMID and symptomatic SARS-CoV-2 infection in a single tertiary center and analyze sociodemographic, clinical, and therapeutic factors associated with poor outcomes. METHODS: A retrospective observational study was conducted from the 1st of March until May 29th, 2020 in a University tertiary hospital in Barcelona, Spain. Patients with an underlying AI/IMID and symptomatic SARS-CoV-2 infection were identified in our local SARS-CoV-2 infection database. Controls (2:1) were selected from the same database and matched by age and gender. The primary outcome was severe SARS-CoV-2 infection, which was a composite endpoint including admission to the intensive care unit (ICU), need for mechanical ventilation (MV), and/or death. Several covariates including age, sex, and comorbidities among others were combined into a multivariate model having severe SARS-CoV-2 as the dependent variable. Also, a sensitivity analysis was performed evaluating AID and IMID separately. RESULTS: The prevalence of symptomatic SARS-CoV-2 infection in a cohort of AI/IMID patients was 1.3%. Eighty-five patients with AI/IMID and symptomatic SARS-CoV-2 were identified, requiring hospitalization in 58 (68%) cases. A total of 175 patients admitted for SARS-CoV-2 (58 with AI/IMID and 117 matched-controls) were analyzed. In logistic regression analysis, a significant inverse association between AI/IMID group and severe SARS-CoV-2 (OR 0.28; 95% CI 0.12-0.61; p = 0.001), need of MV (OR 0.20; IC 95% 0.05-0.71; p = 0.014), and ICU admission (OR 0.25; IC 95% 0.10-0.62; p = 0.003) was found. CONCLUSIONS: Patients with AI/IMID who require admission for SARS-CoV-2 infection have a lower risk of developing severe disease, including the need to stay in the ICU and MV.

Uveitic macular edema response to intravitreal dexamethasone implant is independent of optical coherence tomography findings.

PURPOSE: To identify predictive response optical coherence tomography (OCT) findings in uveitic macular edema (UME) treated with intravitreal dexamethasone implant (DEX). METHODS: Retrospective study of 66 eyes (53 patients) treated with DEX for UME. SD-OCT macular scans were collected prior to DEX treatment and 6 weeks and 3 months after the DEX implant. OCT images were evaluated for qualitative and quantitative characteristics (central retinal thickness, CRT and macular volume, MV). A multivariate analysis of covariance (ANCOVA) was carried out to study the predictive influence of OCT and clinical covariates on outcomes. The main outcome was a composite endpoint based on the simultaneous gain of 5 or more letters associated with a 20% or more reduction in CRT. RESULTS: A significant improvement in BCVA at 6 weeks (mean change from baseline -0.2, SD 0.3) and 3 months (mean -0.2, SD 0.4) was observed after the DEX implant. A significant decrease in CRT (change from baseline -187.7 µm at 3 months) and MV (change from baseline -1.7 mm3 at 3 months) were also observed. An association of ≥ 5-letter improvement in BCVA and a ≥ 20% CRT reduction was observed in 44.6% of cases at 6 weeks and 31.4% at 3 months. ANCOVA multivariate analyses found CRT at 3 months independent from baseline clinical variables but from CRT. CONCLUSION: DEX implant is an effective treatment for UME independently of basal characteristics, producing both a gain of visual acuity and improvement of macular anatomy by OCT measures at 3 months.

Drug Retention Rate and Causes of Discontinuation of Adalimumab in Uveitis: Real-World Data from the Biotherapies in Uveitis (BioÚvea) Study Group.

PURPOSE: To study the drug retention rate (DRR), causes, and predictors of discontinuation of adalimumab (ADA) in a real-world uveitis setting. DESIGN: Multicentric, nationwide, registry-based, ambispective, observational study. PARTICIPANTS: Patients treated with ADA for noninfectious uveitis (NIU) in the Biotherapies for Uveitis (BioÚvea) Spanish registry from November 2016 to November 2017. METHODS: Demographics, clinical data, timing, and reasons for discontinuation, if occurred, were recorded. The DRR and drug retention time (DRT) were estimated using the Kaplan-Meier method. Median follow-up was analyzed by reverse Kaplan-Meier. Log-rank test was used for comparisons. Cox proportional-hazards model (PHM) and propensity score matching were used to identify predictors for discontinuation due to inefficacy and adverse events. MAIN OUTCOME MEASURES: Drug retention rate and DRT. RESULTS: A total of 392 patients were analyzed, including 218 women. Median age was 39 (interquartile range, 25) years. Nonanterior uveitis was recorded in 242 patients. Median follow-up was 49.07 (0.97-131.67) months, median DRT (survival) was 69.3 months, and 14 patients were lost to follow-up. The DRR at 6, 12, 24, and 60 months was 92.97%, 87.68%, 76.31%, and 54.28%, respectively. Adalimumab was discontinued in 151 patients. Discontinuation was due to lack or loss of efficacy in 74 patients, adverse event in 34 patients, and sustained quiescence in 25 patients. Recorded adverse events included infections in 10 patients and malignant neoplasms in 3 patients. Concurrent classic immunomodulatory therapy (IMT) was given to 251 patients. We did not find DRT differences regarding the use of concurrent IMT. Adalimumab was prescribed as a second or greater biotherapy line in 76 patients who showed shorter DRT (P = 0.038). Starting ADA in nonbiotherapy-naive patients was a predictor for "discontinuation due to inefficacy," whereas undifferentiated uveitis was a predictor for "discontinuation due to adverse event." Drug retention time was significantly shorter when spared or intensified, mainly due to discontinuation after sustained quiescence. CONCLUSIONS: Drug retention rate of ADA in uveitis at 60 months was 54.28%, with a good safety profile. The use of concurrent IMT did not show a significant influence on DRT. The use of ADA as a second or further biotherapy could be predictive for discontinuation due to inefficacy. Undifferentiated uveitis may be prone to premature discontinuation of ADA due to adverse events.

Anti-VEGF treatment for choroidal neovascularization complicating pattern dystrophy-like deposit associated with pseudoxanthoma elasticum.

PURPOSE: To evaluate the efficacy of intravitreal anti-VEGF injections in choroidal neovascularization (CNV) related to pattern dystrophy-like deposit in pseudoxanthoma elasticum (PXE). METHODS: One-year prospective, interventional study. Nine eyes were recruited in the ophthalmology departments of San Raffaele University and University of Barcelona. Each patient underwent best corrected visual acuity (BCVA) measurement on ETDRS chart, slit-lamp biomicroscopy, fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT). The protocol included a first anti-VEGF injection, followed by monthly evaluations with re-treatments based on new funduscopic hemorrhages, fluid on OCT or leakage on FA and/or ICGA. Primary outcome measures were the mean BCVA changes. Secondary outcomes included central macular thickness (CMT) variations and the number of injections needed. RESULTS: At month 12, mean BCVA significantly improved from 20/45 to 20/35 Snellen equivalent, with 3 eyes gaining at least 3 ETDRS lines. Mean CMT decreased from 297 ± 22 to 262 ± 13 µm, after 5.5 ± 4.0 injections. No leakage was observed at the end of follow-up. CONCLUSIONS: Intravitreal anti-VEGF injections represent an effective treatment for CNV related to pattern dystrophy-like deposit in PXE, with an improvement of BCVA and CMT. Mean injection number is in line with other studies performed in CNV secondary to angioid streaks.

New insights into the genetic component of non-infectious uveitis through an Immunochip strategy.

BACKGROUND: Large-scale genetic studies have reported several loci associated with specific disorders involving uveitis. Our aim was to identify genetic risk factors that might predispose to uveitis per se, independent of the clinical diagnosis, by performing a dense genotyping of immune-related loci. METHODS: 613 cases and 3693 unaffected controls from three European case/control sets were genotyped using the Immunochip array. Only patients with non-infectious non-anterior uveitis and without systemic features were selected. To perform a more comprehensive analysis of the human leucocyte antigen (HLA) region, SNPs, classical alleles and polymorphic amino acid variants were obtained via imputation. A meta-analysis combining the three case/control sets was conducted by the inverse variance method. RESULTS: The highest peak belonged to the HLA region. A more detailed analysis of this signal evidenced a strong association between the classical allele HLA-A*2902 and birdshot chorioretinopathy (p=3.21E-35, OR=50.95). An omnibus test yielded HLA-A 62 and 63 as relevant amino acid positions for this disease. In patients with intermediate and posterior uveitis, the strongest associations belonged to the rs7197 polymorphism, within HLA-DRA (p=2.07E-11, OR=1.99), and the HLA-DR15 haplotype (DRB1*1501: p=1.16E-10, OR=2.08; DQA1*0102: p=4.37E-09, OR=1.77; DQB1*0602: p=7.26E-10, OR=2.02). Outside the HLA region, the MAP4K4/IL1R2 locus reached statistical significance (rs7608679: p=8.38E-07, OR=1.42). Suggestive associations were found at five other loci. CONCLUSIONS: We have further interrogated the association between the HLA region and non-infectious non-anterior uveitis. In addition, we have identified a new non-HLA susceptibility factor and proposed additional risk loci with putative roles in this complex condition.

TWENTY-FOUR MONTH FOLLOW-UP OF TOCILIZUMAB THERAPY FOR REFRACTORY UVEITIS-RELATED MACULAR EDEMA.

BACKGROUND: To report the 24-month efficacy and safety of the interleukin-6 receptor antagonist tocilizumab (TCZ) for refractory uveitis-related macular edema (ME). METHODS: Data were obtained by standardized chart review. Patients with quiescent uveitis seen at a single tertiary referral center, for whom ME was the principal cause of reduced visual acuity. OUTCOME MEASURES: Central foveal thickness measured by optical coherence tomography; degree of anterior and posterior chamber; inflammation (Standardization of Uveitis Nomenclature Working Group criteria); and visual acuity (Snellen and logarithm of the minimum angle of resolution) were recorded in all patients during TCZ therapy at months 1, 3, 6, 12, 18, and 24. RESULTS: Sixteen eyes from 12 patients (10 women) were included. Mean age was 34.6 years. Mean duration of ME was 13.2 years. All patients achieved 24 months of follow-up and that is the census date for data collection. Before TCZ was commenced, ME was present, and all patients had been previously treated with immunosuppressive therapy and biologic agents. Uveitis diagnoses were juvenile idiopathic arthritis associated, uveitis (n = 6), birdshot chorioretinopathy (n = 2), idiopathic panuveitis (n = 2), sympathetic ophthalmia (n = 1), and ankylosing spondylitis (n = 1). Mean central foveal thickness (95%; confidence interval) was 516 ± 55 µm at baseline, improving to 274 ± 13 at Month 12 (P = 0.0004), and sustained at 274 ± 14 at Month 24 of follow-up (P = 0.00039). Mean logarithm of the minimum angle of resolution best-corrected visual acuity improved from 0.78 ± 0.18 (Snellen 20/120 ± 20/30) at baseline to 0.42 ± 0.17 (20/52 ± 20/30) at Month 12 (P = 0.0001) and 0.40 ± 0.17 (20/50 ± 20/30) at Month 24 of follow-up (P = 0.0002). Tocilizumab therapy was withdrawn in 5 patients with sustained remission at Month 12 but in all, ME relapsed between 1 and 3 months after TCZ discontinuation. Rechallenge of TCZ infusions led to recovery of uveitis control and ME resolution. Two adverse events were reported during two 4-month follow-ups: one Grade 1 neutropenia and one community-acquired pneumonia. CONCLUSION: In this long-term study, TCZ was effective and had a comparable safety profile to published data for TCZ use in other indications, when used for the treatment of refractory uveitis-related ME.

Behavior of hyperreflective foci in non-infectious uveitic macular edema, a 12-month follow-up prospective study.

BACKGROUND: Hyperreflective foci have been described in OCT imaging of patients with retinal vascular diseases. It has been suggested that they may play a role as a prognostic factor of visual outcomes in these diseases. The purpose of this study is to describe the presence of hyperreflective foci in patients with non-infectious uveitic macular edema and evaluate their behavior after treatment. METHODS: We conducted a multicenter, prospective, observational, 12-month follow-up study. Inclusion criteria were age > 18 years and a diagnosis of non-infectious uveitic macular edema, defined as central macular thickness of > 300 µm as measured by OCT and fluid in the macula. Collected data included best corrected visual acuity, central macular thickness and the presence, number and distribution (inner or outer retinal layers) of hyperreflective foci. Evaluations were performed at baseline, and at 1, 3, 6, and 12 months after starting treatment. RESULTS: We included 24 eyes of 24 patients. The frequency of patients with ≥11 hyperreflective foci was 58.4% at baseline, falling to 20.8% at 12 months. Further, hyperreflective foci were observed in the outer retinal layers in 50% of patients at baseline and just 28.6% at 12 months. Mean LogMAR visual acuity improved from 0.55 (95% CI 0.4-0.71) at baseline to 0.22 (95% CI 0.08-0.35) at 12 months (p < 0.001). Mean central macular thickness decreased from 453.83 µm (95% CI 396.6-511) at baseline to 269.32 µm (95% CI 227.7-310.9) at 12 months (P < 0.001). Central macular thickness was associated with number (p = 0.017) and distribution (p = 0.004) of hyperreflective foci. CONCLUSIONS: We have observed hyperreflective foci in most of our patients with non-infectious uveitic macular edema. During follow-up and after treatment, the number of foci diminished and they tended to be located in the inner layers of the retina.

C-reactive protein isoforms differentially affect outer blood-retinal barrier integrity and function.

The retinal pigment epithelium (RPE) forms the outer blood-retinal barrier (oBRB) and is the prime target of early age-related macular degeneration (AMD). C-reactive protein (CRP), a serum biomarker for chronic inflammation and AMD, presents two different isoforms, monomeric (mCRP) and pentameric (pCRP), that may have a different effect on inflammation and barrier function in the RPE. The results reported in this study suggest that mCRP but not pCRP impairs RPE functionality by increasing paracellular permeability and disrupting the tight junction proteins ZO-1 and occludin in RPE cells. Additionally, we evaluated the effect of drugs commonly used in clinical settings on mCRP-induced barrier dysfunction. We found that a corticosteroid (methylprednisolone) and an anti-VEGF agent (bevacizumab) prevented mCRP-induced ARPE-19 barrier disruption and IL-8 production. Furthermore, bevacizumab was also able to revert mCRP-induced IL-8 increase after mCRP stimulation. In conclusion, the presence of mCRP within retinal tissue may lead to disruption of the oBRB, an effect that may be modified in the presence of corticosteroids or anti-VEGF drugs.

A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy.

Birdshot chorioretinopathy (BSCR) is a rare form of autoimmune uveitis that can lead to severe visual impairment. Intriguingly, >95% of cases carry the HLA-A29 allele, which defines the strongest documented HLA association for a human disease. We have conducted a genome-wide association study in 96 Dutch and 27 Spanish cases, and 398 unrelated Dutch and 380 Spanish controls. Fine-mapping the primary MHC association through high-resolution imputation at classical HLA loci, identified HLA-A*29:02 as the principal MHC association (odds ratio (OR) = 157.5, 95% CI 91.6-272.6, P = 6.6 × 10(-74)). We also identified two novel susceptibility loci at 5q15 near ERAP2 (rs7705093; OR = 2.3, 95% CI 1.7-3.1, for the T allele, P = 8.6 × 10(-8)) and at 14q32.31 in the TECPR2 gene (rs150571175; OR = 6.1, 95% CI 3.2-11.7, for the A allele, P = 3.2 × 10(-8)). The association near ERAP2 was confirmed in an independent British case-control samples (combined meta-analysis P = 1.7 × 10(-9)). Functional analyses revealed that the risk allele of the polymorphism near ERAP2 is strongly associated with high mRNA and protein expression of ERAP2 in B cells. This study further defined an extremely strong MHC risk component in BSCR, and detected evidence for a novel disease mechanism that affects peptide processing in the endoplasmic reticulum.

SAFETY AND EFFICACY OF INTRAVITREAL DEXAMETHASONE IMPLANTS IN THE MANAGEMENT OF MACULAR EDEMA SECONDARY TO INFECTIOUS UVEITIS.

PURPOSE: To assess the safety and efficacy of intravitreal dexamethasone implants in the treatment of macular edema secondary to infectious uveitis. METHODS: We retrospectively reviewed clinical records from three uveitis referral units in Spain. The main outcome measures were rate of reactivation of infection, improvements in visual acuity and resolution of macular edema, as measured by optical coherence tomography. RESULTS: We included eight eyes from seven patients with a median age of 64 years (30-75). Etiologies of the infections were Herpes simplex virus-type 1, Varicela-Zoster virus, Treponema pallidum, Brucella mellitensis, Borrelia burgdorferi, Toxoplasma gondii, and cytomegalovirus. Median visual acuity was 20/160 (20/30-20/400) at baseline and 20/70 (20/25-20/200) at the last follow-up visit. Mean macular thickness was 516 µm (115) at baseline and 266.3 µm (40) at the last follow-up visit. Visual acuity improved in 100% of the eyes and none of the eyes showed macular edema at the last follow-up visit. Five patients required reinjections of the implant. Only one patient required antiglaucoma drops for a temporary increase in ocular pressure. There were no cases of reactivation of the infectious ocular disease. Median follow-up time was 18 months. CONCLUSION: In this small case series of eyes with macular edema secondary to infectious uveitis, treatment with dexamethasone intravitreal implants was not associated with reactivation of the infectious ocular disease. Furthermore, significant improvements in visual acuity and macular thickness were observed in our patients.

Long-term effects of tocilizumab therapy for refractory uveitis-related macular edema.

OBJECTIVE: To report the long-term efficacy and safety of the interleukin-6 receptor antagonist tocilizumab for refractory uveitis-related macular edema (ME). DESIGN: Retrospective cohort study. PARTICIPANTS: Eyes with uveitis seen at a single tertiary referral center for which ME was the principal cause of reduced visual acuity. METHODS: Data were obtained by standardized chart review. MAIN OUTCOME MEASURES: Central foveal thickness (CFT) measured by optical coherence tomography, degree of anterior and posterior chamber inflammation (Standardization of Uveitis Nomenclature Working Group criteria), and visual acuity (logarithm of the minimum angle of resolution [logMAR]) were recorded during tocilizumab therapy at months 1, 3, 6, and 12. RESULTS: Eleven eyes from 7 patients (all women) were included. Mean age was 43.4 years. Mean duration of ME was 14.2 years. Mean follow-up with tocilizumab therapy was 15.2 months (range, 12-18 months). Before tocilizumab therapy, conventional immunosuppressive therapy and 1 or more biologic agents failed in all patients. Uveitis diagnoses were birdshot chorioretinopathy (n = 3), juvenile idiopathic arthritis-associated uveitis (n = 3), and idiopathic panuveitis (n = 1). Mean CFT was 550 ± 226 µm at baseline, 389 ± 112 µm at month 1 (P = 0.007), 317 ± 88 µm at month 3 (P = 0.01), 292 ± 79 µm at month 6 (P = 0.006), and 274 ± 56 µm at month 12 of follow-up (P = 0.002). Mean logMAR best-corrected visual acuity improved from 0.67 ± 0.53 at baseline to 0.4 ± 0.56 at month 12 (P = 0.008). Tocilizumab therapy was withdrawn in 2 patients because of sustained remission at month 12. In both patients, ME relapsed 3 months after tocilizumab withdrawal. Reinitiation of tocilizumab therapy led to good uveitis control and ME resolution. Tocilizumab generally was well tolerated and no serious adverse events were reported. CONCLUSIONS: In this study, tocilizumab was effective in the treatment of refractory inflammatory ME. No serious adverse events were observed.

Use of ultra-wide-field retinal imaging in the management of active Behçet retinal vasculitis.

BACKGROUND: Retinal vasculitis (RV) is an important component of Behçet disease. It may be difficult to detect either clinically or with conventional retinal imaging. The role of ultra-wide-field (UWF) retinal imaging was assessed in the diagnosis and management of RV associated with Behçet disease. METHODS: A total of 38 eyes of 20 patients with active RV associated to Behçet disease underwent UWF imaging with the Optos scanning laser ophthalmoscope, fundus autofluorescence, and/or fluorescein angiography. This study determined the UWF findings and percentage of patients in whom this imaging modality assisted in diagnosing the extent of vasculitis, planning treatment, and monitoring disease activity. RESULTS: Optos UWF imaging assisted in diagnosing and quantifying the extent of RV in 16 patients (80%), planning medical treatment or laser photocoagulation in 13 of 20 patients (65%), and enhanced disease monitoring in 11 of 20 patients (55%). UWF fluorescein angiography revealed vasculitis not clinically evident in 28 of 33 eyes (84.8%). Predominant angiographic findings were diffuse vascular leakage (75.7%), peripheral retinal nonperfusion (66.7%), optic disk leakage (63.6%), macular leakage (30.3%), and macular edema (27.3%). Eighteen patients (34 eyes) underwent UWF fundus autofluorescence, showing multiple hyperfluorescent spots in retinal periphery in 28 eyes (82.3%). CONCLUSION: Ultra-wide-field imaging is a valuable tool in the management of patients with RV associated to Behçet disease and can be used for the diagnosis, treatment, and follow-up. Additional studies, including longitudinal evaluations, are needed to elucidate whether these findings or the subsequent management alterations may improve patients' outcomes.

Proinflammatory cytokines and C-reactive protein in uveitis associated with Behçet's disease.

The aim of the present study was to determine the serum cytokine profile and levels of high sensitivity C-reactive protein (hsCRP) in patients with uveitis associated with Behçet's disease (BD) and to compare them with those obtained from healthy control subjects. We determined the serum concentration of interferon-γ (IFN-γ), interleukin-1ß (IL-1ß), IL-12p70, IL-17A, tumor necrosis factor-α (TNF-α), and hsCRP in 13 patients with active uveitis associated to BD, 24 inactive BD patients, and 20 controls. In a subgroup of 10 active patients, a second serum sample was obtained when the disease was inactive. Cytokine profiles and hsCRP levels were correlated with disease activity, severity, complications, and visual outcome. Levels of IFN-γ and TNF-α were significantly increased in patients with active uveitis associated to BD compared to controls (P < 0.05). IFN-γ, TNF-α, and hsCRP were significantly higher during active uveitis associated to BD compared to inactive disease (P < 0.05). Furthermore, IL-17A was significantly increased in patients with active BD without pharmacological treatment compared to controls (P < 0.05). No significant correlations were found with specific cytokine profiles and disease severity, visual outcome, or complications. In summary, increased serum levels of IFN-γ, TNF-α, IL-17A, and hsCRP were associated with active uveitis associated with BD and might serve as markers of disease activity.

Current and future treatments for Behçet's uveitis: road to remission.

Behçet's disease (BD) is a multisystem inflammatory disorder of uncertain origin, although it remains defined within the spectrum of systemic immune-mediated vasculitic disorders and also represents a spectrum of putative autoimmune disease. Major symptoms include oral aphthous ulcers, genital ulcerations, skin lesions, and ocular lesions. Despite afflicting many systems, ocular complications of BD are some of the more devastating for the patient and their quality of life. Eye involvement, which affects 60-80 % of BD patients, is characterized in its more severe form by posterior or panuveitis including occlusive retinal vasculitis. While pathogenesis of BD remains complex, association with Class I MHC (HLA-B*51) predisposing to inflammation with engagement of the innate-immune system (neutrophils, NK cells), and perpetuated by the adaptive T cell responses against infectious- and/or auto-antigens. Despite the choice of conventional immunosuppressive therapies available, only recently with the advent of biologic therapy has visual prognosis and outcomes been substantially and favorably altered. For example, both interferon-α (IFN-α) and tumour necrosis factor (TNF)-α antagonists deliver promising results and for the first time improve prognosis. With IFN-α therapy, durable remissions of uveitis can be achieved and lead to drug-free remission. Similarly, anti-TNF therapy with infliximab is reported to be rapidly effective in inducing and maintaining remission. Most recently, rising evidence reports on the use of adalimumab, etanercept, and golimumab, while use of anti-interleukin (IL)-1 agents (anakinra, canakinumab, gevokizumab), IL-6 blockers (tocilizumab), and rituximab (depleting anti-CD20 antibody) is also increasing. The aim of this review is to provide evidence for the role of conventional therapies combined with evidence for advantages and disadvantages of biologic therapies in the treatment of ocular BD. Although randomized controlled trials remain sparse, evidence remains strong and enticing that biologic agents are invaluable for the treatment of sight-threatening Behçet's uveitis and makes it an exciting time for Behçet's specialists worldwide.

Biomaterial engineering strategies for modeling the Bruch's membrane in age-related macular degeneration.

Age-related macular degeneration, a multifactorial inflammatory degenerative retinal disease, ranks as the leading cause of blindness in the elderly. Strikingly, there is a scarcity of curative therapies, especially for the atrophic advanced form of age-related macular degeneration, likely due to the lack of models able to fully recapitulate the native structure of the outer blood retinal barrier, the prime target tissue of age-related macular degeneration. Standard in vitro systems rely on 2D monocultures unable to adequately reproduce the structure and function of the outer blood retinal barrier, integrated by the dynamic interaction of the retinal pigment epithelium, the Bruch's membrane, and the underlying choriocapillaris. The Bruch's membrane provides structural and mechanical support and regulates the molecular trafficking in the outer blood retinal barrier, and therefore adequate Bruch's membrane-mimics are key for the development of physiologically relevant models of the outer blood retinal barrier. In the last years, advances in the field of biomaterial engineering have provided novel approaches to mimic the Bruch's membrane from a variety of materials. This review provides a discussion of the integrated properties and function of outer blood retinal barrier components in healthy and age-related macular degeneration status to understand the requirements to adequately fabricate Bruch's membrane biomimetic systems. Then, we discuss novel materials and techniques to fabricate Bruch's membrane-like scaffolds for age-related macular degeneration in vitro modeling, discussing their advantages and challenges with a special focus on the potential of Bruch's membrane-like mimics based on decellularized tissue.

Non-invasive biomarkers for close activity monitoring in birdshot chorioretinitis: Optical coherence tomography angiography and beyond.

PURPOSE: The purpose of the study was to identify non-invasive imaging biomarkers potentially useful for close activity monitoring in birdshot chorioretinitis (BSCR). METHODS: Cross-sectional study of BSCR eyes included as per Levinson's and/or SUN criteria. Eyes were blindly classified into active or inactive groups per clinical inflammatory parameters, ultra-widefield (UWF) pseudocolour images, UWF fluorescein angiography (FA) and macular optical coherence tomography (OCT) cube. Qualitative and quantitative OCT and OCT-angiography (OCT-A) parameters at the fundus, superonasal and inferonasal fields were compared between active and inactive eyes. RESULTS: Thirty consecutive BSCR patients (60 eyes) were analysed. 28 eyes (46.66%) were from women and the overall mean age was 59.7 ± 12.3 years. Active eyes showed an abnormal retinal thickening at inferonasal field (nasal retinal thickness) and a higher averaged thickened retinal index (ATRI) (72.36 active vs. 20.12 inactive, p < 0.0001). A significant moderate correlation was observed between ATRI and FA scores (r = 0.259, p = 0.022). Macular vascular loops were more frequent in the superficial vascular plexus of OCT-A in the active eyes (p = 0.028). The vascular perfusion index tended to be higher in all subfields of active eyes but did not reach statistical significance. CONCLUSION: Multimodal imaging could be key to discerning activity in BSCR eyes. Higher ATRI and the presence of vascular loops in the superficial plexus are potential non-invasive activity biomarkers for the close monitoring of BSCR.

Fluocinolone acetonide 0.2 µg/day intravitreal implant in non-infectious uveitis affecting the posterior segment: EU expert user panel consensus-based clinical recommendations.

BACKGROUND: Non-infectious uveitis affecting the posterior segment of the eye (NIU-PS) is an inflammatory disease, which can significantly impair visual acuity if not adequately treated. Fluocinolone-acetonide sustained-release-0.2 µg/day intravitreal (FAc) implants are indicated for prevention of relapse in recurrent NIU-PS. The aim here was to provide treating clinicians with some consensus-based-recommendations for the clinical management of patients with NIU-PS with 0.2 µg/day FAc implants. METHODS: A European-clinical-expert-group agreed to develop a consensus report on different issues related to the use of FAc implants in patients with NIU-PS. RESULTS: The Clinical-expert-panel provided specific recommendations focusing on clinical presentation (unilateral/bilateral) of the NIU-PS; systemic involvement of NIU-PS and the lens status. Treatment algorithms were developed; one that refers to the management of patients with NIU-PS in clinical practice and another that establishes the best clinical scenarios for the use of FAc implants, both as monotherapy and as adjuvant therapy. Additionally, the Clinical-expert-panel has provided recommendations about the use of the FAc implants in a clinical-setting. The Clinical-expert-panel also considered the safety profile of FAc implants and their possible implications in the daily practice. CONCLUSIONS: As more clinical experience has been gained using FAc implants, it was necessary to update the clinical recommendations that guide patient management in the clinic. The current consensus document addresses relevant issues related to the use of FAc implants on different types of patients with various etiologies of NIU-PS, and was conducted to standardize approaches to help specialists obtain better clinical outcomes.