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INTRODUCCIÓN: El tratamiento de la tuberculosis (TB) ocular es un tema que genera controversia en el mundo. Para el correcto manejo de estos pacientes, es necesario el desarrollo de guías que consideren la epidemiología de la TB ocular en cada nación. El objetivo de este consenso fue discutir de forma interdisciplinaria la epidemiología, fisiopatología, clínica, diagnóstico, estudio y tratamiento de los pacientes con TB ocular, para establecer un algoritmo de tratamiento y proponer qué pacientes deben ser tratados en Chile y con qué tratamiento. Además, se establecieron acuerdos para efectuar quimioprofilaxis de los pacientes con TB latente que tienen indicación de tratamiento inmunosupresor por enfermedades inflamatorias oculares.

The treatment of ocular tuberculosis (TB) remains controversial worldwide. The development of guidelines for ocular TB can facilitate the approach and management of these patients. These guidelines should be developed regionally, considering the local TB epidemiology. The objectives of this consensus are: to initiate an interdisciplinary discussion about the epidemiology, pathophysiology, clinical presentation, diagnosis, workup and treatment of patients with ocular TB, to establish a treatment algorithm and define which patients should be treated in Chile and how and, to analyze and discuss the published data regarding chemoprophylaxis for patients with latent TB who need to start immunosuppressive treatment due to inflammatory ocular conditions.

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BACKGROUND: Appraisals of Vogt-Koyanagi-Harada disease (VKH) have become progressively more complete, since its first description in 1906. The availability of new investigational methods has improved our knowledge of the immunopathology, clinicopathology, diagnosis, and management of VKH disease. This review aimed to describe some of the steps that led to better characterization of VKH as a clinical entity. METHODS: We searched on PubMed for articles that described the history of VKH disease and analyzed the progress in disease appraisal with new investigational and imaging methods. In particular, we searched for articles that investigated the clinicopathology, diagnosis, and management of VKH. FINDINGS: The following developments were considered essential for improving the appraisal and understanding of VKH: (1) the history of the disease, (2) immunopathological mechanisms, (3) clinicopathology, (4) the importance of distinguishing initial-onset from chronic disease, (5) relevant imaging modalities, among which indocyanine green angiography is crucial, (6) diagnostic criteria that facilitate early diagnosis, and (7) the need for early, prolonged, aggressive treatment that combines steroidal and non-steroidal immunosuppression. CONCLUSION: Based on these findings, the definition of VKH has improved. VKH disease starts in the choroidal stroma and later involves other structures when it is not diagnosed and treated early. Indocyanine green angiography and enhanced depth imaging optical coherence tomography facilitate early diagnosis and precise monitoring of choroidal inflammation. ICGA is clearly the gold standard for appraisals and follow-ups in VKH disease, however EDI-OCT should be especially considered in those areas where ICGA is not fully available. These modalities have contributed substantially to a "cure" for VKH, when treatment is introduced within the therapeutic window of opportunity.

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PURPOSE: To evaluate the different definition of refractoriness in uveitis in the literature. METHODS: We systematically searched the literature in order to identify definitions of refractory noninfectious uveitis in adult patients. A search strategy in the databases of MEDLINE and Scopus was used to find articles published between January 2005 and October 2018. RESULTS: Definitions of corticosteroids-refractoriness were related to two main concepts: persistence of inflammation despite the use of corticosteroid and recurrences above a dosage threshold. In terms of immunomodulatory therapy and biologic agents, we observed a great variety of definitions: persistence of inflammation, number of attacks, side effects or complications, symptoms, and best-corrected visual acuity. CONCLUSIONS: The results of this systematic review demonstrate the current lack of consensus on the definition for refractory uveitis, regardless of the treatment being used and revealed a new terminology based on a comprehensive and operational definition for each specific category of refractoriness.

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miRNAs, one of the members of the noncoding RNA family, are regulators of gene expression in inflammatory and autoimmune diseases. Changes in miRNA pool expression have been associated with differentiation of CD4+ T cells toward an inflammatory phenotype and with loss of self-tolerance in autoimmune diseases. Vogt-Koyanagi-Harada (VKH) disease is a chronic multisystemic pathology, affecting the uvea, inner ear, central nervous system, and skin. Several lines of evidence support an autoimmune etiology for VKH, with loss of tolerance against retinal pigmented epithelium-related self-antigens. This deleterious reaction is characterized by exacerbated inflammation, due to an aberrant T H 1 and T H 17 polarization and secretion of their proinflammatory hallmark cytokines interleukin 6 (IL-6), IL-17, interferon γ, and tumor necrosis factor α, and an impaired CD4+ CD25 high FoxP3+ regulatory T cell function. To restrain inflammation, VKH is pharmacologically treated with corticosteroids and immunosuppressive drugs as first and second line of therapy, respectively. Changes in the expression of miRNAs related to immunoregulatory pathways have been associated with VKH development, whereas some genetic variants of miRNAs have been found to be risk modifiers of VKH. Furthermore, the drugs commonly used in VKH treatment have great influence on miRNA expression, including those miRNAs associated to VKH disease. This relationship between response to therapy and miRNA regulation suggests that these small noncoding molecules might be therapeutic targets for the development of more effective and specific pharmacological therapy for VKH. In this review, we discuss the latest evidence regarding regulation and alteration of miRNA associated with VKH disease and its treatment.

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BACKGROUND: Due to the guarded prognosis of acute retinal necrosis (ARN), it is relevant to develop a strategy to early categorize those patients in a higher risk of worse outcomes. The purpose of this study is to describe clinical features and predictive factors for retinal detachment (RD) in patients with ARN. METHODS: Retrospective observational case series of 34 adult patients (38 eyes) with ARN examined between January 2005 and July 2015 in the National Eye Institute (Bethesda, USA), the Department of Ophthalmology, University of Chile (Santiago, Chile), and APEC (CDMX, Mexico). RESULTS: A total of 16 males and 18 females with a mean age at presentation of 44.5 ± 16.8 years were included. Twenty-seven patients (79.4%) received intravenous acyclovir as first-line treatment, and 7 patients received either oral antiviral (4 patients) or oral plus intravitreal antiviral (3 patients). All subjects were treated with prednisone, with a mean initial dose of 57.7 ± 16.3 mg per day. Seventeen patients (50.0%) developed retinal detachment. An association of retinal detachment with age at onset was observed (p = 0.04), with patients younger than 50 years presenting a higher risk (OR = 14.86, p = 0.0009). Additionally, patients in this higher risk group had more inflammation in both anterior chamber and vitreous (p = 0.04 and 0.03, respectively). No other predictive factor for retinal detachment was found in the present study. CONCLUSIONS: RD represents an important complication in patients with ARN. Younger patients may be at higher risk of this complication, possibly secondary to the presence of a higher level of inflammation.

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PURPOSE: To describe distinctive stages of Vogt-Koyanagi-Harada (VKH) disease: initial-onset acute versus chronic recurrent disease. METHODS: A comprehensive literature review regarding stages and clinical presentations of VKH disease was conducted. RESULTS: Despite a list of signs that has been described as characteristic features of early or late phases of VKH disease, the current classification -developed by an international committee and published in 2001- does not consider a distinction regarding the time from onset of disease symptoms, and specific findings observed at certain time point from the symptoms presentation and outcomes related to the stage of VKH disease. In that sense, chronic recurrent VKH disease is more refractory to treatment and is associated with a higher rate of complications. Accordingly, this subset of VKH patients has poorer functional and anatomical outcomes than patients with an initial-onset acute disease. CONCLUSIONS: An early clear distinction of VKH phenotype [Initial-onset acute versus chronic recurrent disease] should be considered in each clinical scenario, evaluating the delay in diagnosis and the clinical presentation, since it may help clinicians to perform a correct disease prognosis categorization and thus to make treatment decisions in terms of potential refractoriness or expected clinical outcomes.

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Non-infectious uveitis (NIU) is a group of disorders characterized by intraocular inflammation at different levels of the eye. NIU is a leading cause of irreversible blindness in working-age population in the developed world. The goal of uveitis treatment is to control inflammation, prevent recurrences, and preserve vision, as well as minimize the adverse effects of medications. Currently, the standard of care for NIU includes the administration of corticosteroids (CS) as first-line agents, but in some cases a more aggressive therapy is required. This includes synthetic immunosuppressants, such as antimetabolites (methotrexate, mycophenolate mofetil, and azathioprine), calcineurinic inhibitors (cyclosporine, tacrolimus), and alkylating agents (cyclophosphamide, chlorambucil). In those patients who become intolerant or refractory to CS and conventional immunosuppressive treatment, biologic agents have arisen as an effective therapy. Among the most evaluated treatments, TNF-α inhibitors, IL blockers, and anti-CD20 therapy have emerged. In this regard, anti-TNF agents (infliximab and adalimumab) have shown the strongest results in terms of favorable outcomes. In this review, we discuss latest evidence concerning to the effectiveness of biologic therapy, and present new therapeutic approaches directed against immune components as potential novel therapies for NIU.

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PURPOSE: To describe clinical features of patients with diabetes mellitus-associated uveitis (DMAU). METHODS: Retrospective analysis of clinical records of patients with uveitis and diabetes mellitus (DM) presented in an uveitis referral centre in Chile. Demographic data, comorbidities, complete ophthalmic examination, and treatments were analyzed. RESULTS: We found 72 patients with uveitis and DM: 16 with DMAU and poorly regulated DM (22%), 15 with DMAU and well-controlled DM (21%), and 41 with uveitis due to established other causes than DM (57%). Patients with DMAU in poorly regulated diabetes, presented inflammation of 3-4+ cells in 33%, a fibrinous reaction in 28%, hypopyon in 17% and posterior synechiae in 83%, compared with 5%, 0%, 0%, and 50% in the group with well-controlled DM, respectively (p < 0.05). Most DMAU patients responded well to topical or periocular steroids. CONCLUSION: Patients with DMAU with poorly regulated DM present a more severe inflammation compared with patients with DMAU with well-controlled DM.

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Purpose: This study is aimed to investigate the role of glucocorticoid receptor (GR) isoforms in peripheral blood mononuclear cells (PBMC) as biomarkers of glucocorticoid (GC) resistance and to validate a set of clinical predictive factors in patients with Vogt-Koyanagi-Harada (VKH) disease. Methods: This was a prospective cohort study that included a total of 21 patients with VKH. A complete ophthalmologic evaluation was carried out at baseline that recorded the presence of any clinical predictive factors (visual acuity ≤ 20/200, tinnitus, chronic disease, and fundus depigmentation). Real-time quantitative PCR was performed to measure the mRNA levels of GR alpha (GRα) and beta (GRß) isoforms at baseline and at 2 weeks after prednisone therapy initiation. Results: There were no differences between GRα and GRß levels in GC-sensitive and GC-resistant patients at baseline before treatment initiation. After 2 weeks of prednisone treatment, GC-sensitive patients had a median 5.5-fold increase in levels of GRα, whereas GC-resistant patients had a median 0.7-fold decrease in levels of this isoform (P = 0.003). Similarly, GRß increased in GC-sensitive patients, in comparison with GR-resistant patients (6.49-fold versus 1.01 fold, respectively, I = 0.04). The mRNA levels of GR isoforms were independent of disease activity. Fundus depigmentation and chronic disease at diagnosis were associated with GC resistance (P = 0.03, odds ratio = 21.0; and P = 0.008, odds ratio = 37.8, respectively). However, associations with visual acuity or tinnitus were not confirmed in this study. Conclusions: The evaluation of clinical predictive factors and determination of the change in expression of GR isoforms as potential biomarkers can contribute to the early identification of GC-resistant patients with VKH.

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PURPOSE: To characterize the clinical features in patients with presumed ocular tuberculosis (TB) and determine prognostic factors of visual outcomes and complications in this disease. MATERIAL AND METHODS: Retrospective case series of 35 patients (29 females, 6 males) with presumed ocular TB from referral centers in Chile and Spain between 2002 and 2012. Medical records were reviewed, and data regarding clinical features, complications, best-corrected visual acuity (BCVA), duration of disease, extraocular manifestations, and therapy were retrieved. Prognostic factors for low vision (BCVA 20/50 or less), legal blindness (BCVA 20/200 or less), and complications (cataract, glaucoma, and macular lesion) were evaluated. To calculate correlations, we used Spearman's rank correlation test. To determine clinical predictors, we used the binary logistic regression test. RESULTS: Anterior and non-granulomatous uveitis was the most common types of inflammation. Only 2 (5.7%) patients had respiratory symptoms, and 6 (17.1%) patients had an abnormal chest X-ray at diagnosis. All patients received combined antitubercular therapy with a mean duration of 6.9 ± 2.3 months. A longer duration of symptoms at diagnosis was associated with both low vision and legal blindness. Older patients had a higher risk of legal blindness. A longer duration of symptoms as well as anterior inflammation demonstrated an increased risk for cataract formation. The duration of the symptoms and baseline BCVA had a positive correlation with the final BCVA. Prognostic factors of macular lesions were not found. CONCLUSIONS: The diagnosis of ocular TB can be difficult due to the lack of extraocular manifestations and the broad spectrum of ocular features. A longer duration of symptoms at diagnosis was associated with poorer visual outcomes and cataracts. Therefore, efforts should be made to avoid a delay in the diagnosis of ocular TB and to identify prognostic factors for visual outcomes and complications.

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PURPOSE: To determine the performance of T-SPOT.TB, an interferon gamma release assay test, in patients with ocular tuberculosis (TB) in a BCG-vaccinated, non-endemic population. METHODS: We employed a nested case-control design. In total, 45 subjects were enrolled (23 patients with ocular tuberculosis and 22 patients with other causes of uveitis). A blood sample was collected from each subject, and T-SPOT.TB was executed. Laboratory professionals were blinded to the disease status of each subject. RESULTS: Five patients were excluded because of indeterminate results. The calculated sensitivity and specificity were 0.80 and 0.85, respectively. The positive likelihood ratio was 5.33 and the negative likelihood ratio was 0.23. The overall accuracy of the test was 0.83. CONCLUSIONS: T-SPOT.TB adequately diagnosed ocular TB. This technique is particularly useful in populations where BCG vaccinations are still mandatory.

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BACKGROUND: Diabetic retinopathy is a common complication of diabetes and the leading cause of irreversible vision loss in the Western world. The reduction in color/contrast sensitivity due to the loss of neural cells in the ganglion cell layer of the retina is an early event in the onset of diabetic retinopathy. Multipotent mesenchymal stromal cells (MSCs) are an attractive tool for the treatment of neurodegenerative diseases, since they could differentiate into neuronal cells, produce high levels of neurotrophic factors and reduce oxidative stress. Our aim was to determine whether the intravitreal administration of adipose-derived MSCs was able to prevent the loss of retinal ganglion cells in diabetic mice. METHODS: Diabetes was induced in C57BL6 mice by the administration of streptozotocin. When retinal pro-damage mechanisms were present, animals received a single intravitreal dose of 2 × 10(5) adipose-derived MSCs or the vehicle. Four and 12 weeks later we evaluated: (a) retinal ganglion cell number (immunofluorescence); (b) neurotrophic factor levels (real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA)); (c) retinal apoptotic rate (TUNEL); (d) retinal levels of reactive oxygen species and oxidative damage (ELISA); (e) electrical response of the retina (electroretinography); (f) pro-angiogenic and anti-angiogenic factor levels (RT-qPCR and ELISA); and (g) retinal blood vessels (angiography). Furthermore, 1, 4, 8 and 12 weeks post-MSC administration, the presence of donor cells in the retina and their differentiation into neural and perivascular-like cells were assessed (immunofluorescence and flow cytometry). RESULTS: MSC administration completely prevented retinal ganglion cell loss. Donor cells remained in the vitreous cavity and did not differentiate into neural or perivascular-like cells. Nevertheless, they increased the intraocular levels of several potent neurotrophic factors (nerve growth factor, basic fibroblast growth factor and glial cell line-derived neurotrophic factor) and reduced the oxidative damage in the retina. Additionally, MSC administration has a neutral effect on the electrical response of the retina and did not result in a pathological neovascularization. CONCLUSIONS: Intravitreal administration of adipose-derived MSCs triggers an effective cytoprotective microenvironment in the retina of diabetic mice. Thus, MSCs represent an interesting tool in order to prevent diabetic retinopathy.

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PURPOSE: To evaluate clinical outcomes of first-line immunomodulatory therapy (IMT) and prednisone alone or late IMT in Vogt-Koyanagi-Harada disease. METHODS: Retrospective cohort study of 152 patients with Vogt-Koyanagi-Harada disease evaluated in a referral uveitis clinic in Chile from 1985 to 2011. Medical records of these patients were reviewed. Demographic data, clinical evaluation, type of treatment, functional outcomes, glucocorticoid (GC) dose and complications were recorded. Multivariate logistic regression was used to identify prognostic factors of poor response to GC. RESULTS: There were no significant differences between first-line IMT group and prednisone alone/late IMT group in terms of visual acuity (VA) improvement, complications and GC sparing effect. There was a trend for a higher frequency of systemic adverse effects leading to discontinuation of treatment in patients receiving IMT than in those receiving prednisone (14.6% and 6.5%, respectively). The subgroup of patients with poor response to GC who showed functional improvement had a significantly earlier time to IMT initiation than the patients who had no improvement. We identified following prognostic factors of poor response to GC: VA ≤ 20/200, fundus depigmentation, chronic disease and tinnitus at diagnosis. Patients with a prognostic factor (excluding tinnitus) and VA improvement had an earlier IMT initiation than those who had worse functional outcome. CONCLUSION: There were no differences in outcomes between first-line IMT and prednisone alone/late IMT in the entire VKH group. However, in a subset of patients, there was a significant better functional outcome with earlier IMT initiation.

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PURPOSE: To describe the pattern of uveitis in a tertiary center in Santiago, Chile. METHODS: We reviewed all of the case records with a presumptive diagnosis of uveitis from patients referred to the Uveitis Department of Hospital del Salvador between 2002 and 2012. Initial assessment was standardized. We tested for association among causes, gender, and age groups. RESULTS: Anterior uveitis was the leading anatomical location of the inflammation (40.4%). A specific etiology was demonstrated in 59% of cases (28.7% infectious). Vogt-Koyanagi-Harada syndrome (VKH) was the most frequent cause of uveitis (17.2%). We found association between idiopathic intermediate uveitis, toxocariasis, juvenile idiopathic arthritis, VKH, toxoplasmosis, diabetes mellitus (DM)-associated uveitis, tuberculosis, and idiopathic anterior uveitis and age groups. VKH, DM-associated uveitis, and syphilis-associated uveitis were associated with gender. CONCLUSIONS: Our sample shows a distribution of causes of uveitis similar to those in developed countries. The prevalence of VKH is higher than expected.

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PURPOSE: To determine symptoms improvement in dry eye patients with short-term autologous serum (AS) eyedrops treatment using the standardized Ocular Surface Disease Index (OSDI) survey. MATERIALS AND METHODS: A double-blind randomized crossover clinical trial was conducted, comparing short-term (2 weeks) topical treatment with AS eyedrops diluted at 20% versus conventional artificial tears treatment in adult severe dry eye syndrome (DES) patients. The main outcome measure was assessment of symptoms with OSDI survey. Secondary outcomes were corneal and conjunctival fluorescein staining score of OXFORD and tear break up time (TBUT). The protocol was registered in www.clinicaltrials.gov , ID number: NCT00779987. RESULTS: Twelve severe DES patients were included. Autologous serum treatment showed a statistically significant (p = 0.002) higher OSDI decrease (50%) versus conventional treatment (22%). There were no significant changes in objectives parameters (OXFORD and TBUT). CONCLUSIONS: Severe DES patients treated with AS achieve better symptoms improvement compared to artificial tears in a short-term treatment.

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