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Investigación en Uveítis y Retina
El desarrollo científico se basa en la constante búsqueda de respuestas y soluciones frente a los problemas que nos vemos enfrentados día a día. La investigación es la herramienta para este fin. La investigación crea y modela el conocimiento.
En Uveitis Network buscamos respuesta basadas en el método científico para poder ofrecer lo mejor de la medicina a nuestros pacientes. Esto nos permite perfeccionar nuestro diagnóstico, tratamiento y así mejorar el pronóstico de estas enfermedades.
En esta sección encontrarán algunos de los estudios que hemos realizado o participado.
New Pharmacological Strategies for the Treatment of Non-Infectious Uveitis. A Minireview
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.
Publicado en Frontiers in Pharmacology, mayo 2020.
Glucocorticoid Receptor-α and MKP-1 as Candidate Biomarkers for Treatment Response and Disease Activity in Vogt-Koyanagi-Harada Disease
Purpose: To investigate the potential of utilizing the expression of genes for glucocorticoid receptor (GR) and mitogen-activated protein kinase phosphatase-1 (MKP-1) as biomarkers of corticosteroid (CS) refractoriness and disease activity in patients with Vogt-Koyanagi-Harada (VKH) disease.
Design: Prospective cohort study.
Methods: Twenty VKH patients receiving their first cycle of CS treatment in the absence of additional systemic immunosuppressive therapy and a control group of fifteen healthy volunteers were recruited from the University of Chile (Santiago, Chile) and US National Institutes of Health (Bethesda, United States). Intraocular inflammation was clinically quantified at enrolment and all follow-up visits. CS refractoriness was defined as an ocular reactivation of VKH upon CS withdrawal at a daily oral prednisone dose of 10 mg or more. Quantitative Reverse transcription polymerase chain reaction (qRT-PCR) was performed to measure the mRNA levels of the alpha (α) and beta (β) isoforms of GR and MKP-1 in peripheral blood mononuclear cells (PBMC) after in vitro stimulation with either anti-CD3/anti-CD28 antibodies, lipopolysaccharide (LPS), or phytohemagglutinin (PHA), in the presence or absence of dexamethasone (Dex).
Results: After 6 hours of stimulation in the presence of Dex, PBMC from CS-refractory VKH patients had an impaired elevation in GRα expression (P = .03). Furthermore, inactive patients showed a significant Dex-induced upregulation of MKP-1 (P = .005).
Conclusions: In this pilot study, the expression of GR isoforms and MKP-1 corresponded with patients’ clinical response to systemic CS treatment and disease activity, respectively. Hence, these candidate biomarkers have potential clinical utility in the early identification of CS refractoriness and subclinical inflammation in patients with VKH disease.
Publicado en American Journal of Ophthalmology. Am J Ophthalmol. 2019 Nov;207:319-325.
Isolated conjunctival granuloma as a first manifestation of Parinaud's oculoglandular syndrome: A case report
Purpose: Parinaud’s oculo-glandular syndrome (POGS) is the most frequent manifestation of ocular bartonellosis, and usually presents with local lymphadenopathies and systemic symptoms. We present a case of isolated conjunctival granuloma as the sole manifestation of ocular bartonellosis.
Observations: A 67-year-old female presented to the authors’ eye clinic with complaints of a 2-week history of unilateral red eye and chemosis. Slit lamp examination revealed an isolated bulbar conjunctival granuloma. The remainder of the eye examination was unremarkable. Topical treatment with gatifloxacin and prednisolone acetate was started. Etiological work-up was performed. General laboratory tests revealed only a mild leukocytosis, and interferon gamma-release assay and chest computed tomography were normal. Serological testing for Bartonella henselae was positive at titers of 1:1024. Three weeks after initial symptoms, lymphadenopathies, malaise, and fever appeared. Systemic azithromycin was added, which resulted in complete regression of the disease.
Conclusion and importance: Conjunctival granulomas present a wide range of differential diagnoses to the practitioner. Ocular bartonellosis is a relevant cause of conjunctival granuloma. POGS should be suspected in cases of conjunctival granulomata non-responsive to local therapy. It is important to consider that other agents to treat POGS have been described and are available, and that appropriate serological tests should be performed.
Publicado en American Journal of Ophthalmology Case Reports. Am J Ophthalmol Case Rep. 2019 Feb 23;14:58-60.
Uveítis asociada a terapia contra melanoma de piel
Propósito: Describir el cuadro clínico y evolución de uveítis secundarias drogas para el tratamiento de melanoma cutáneo metastásico (MCM)
Método: Descripción de 5 casos, evaluados en 2 centros.
Resultados: Primer caso, paciente varón de 45 años que consulta por dolor y baja visión bilateral. Usuario de Vemurafenib durante los últimos 16 meses. Al examen destaca una agudeza visual (AV) de 1.0 OU, celularidad moderada en cámara anterior, snowballs y envainamiento vascular retina periférico. El estudio etiológico fue negativo.
Segundo caso: Mujer de 34 años que consulta por cuadro de inflamación intensa en cámara anterior, asociado a lesiones redondas e hipopigmentadas retinales. Su AV era de OD:0,3 y OI: 0,5. Además con vitíligo en tronco y abdomen. En tratamiento actual de Vemurafenib y previo de Ipilimumab y Nivolumab por melanoma de piel.
Tercer caso: Varón de 52 años que consulta por baja de visión bilateral y ojo rojo, en tratamiento con Dabrafenib y Trametinib desde hace 5 meses por un MCM. Al examen físico destacaba una AV de 1.0 bilateral y solo celularidad anterior, con un fondo de ojos normal.
Cuarto caso: Mujer de 61 años con MCM en tratamiento con Trametinib y Dabrafenib, derivada por pérdida visual bilateral. Su examen arroja una paunuveitis bilateral, papilitis, desprendimientos serosos extensos de retina y AV de cuenta dedos OU. Un completo estudio etiológico fue también negativo.
Quinto caso: Varón de 52 años con diagnóstico de MCM que consultó por baja abrupta de visión bilateral. Tratado con Vemurafenib por 4 meses y posteriormente con Dabrafenib y Trametinib por 3 meses hasta el momento de la consulta. Al examen, su AV era de OD: 0,9 y OI 1,0. El segmento anterior estaba sano, pero al fondo de ojos presentaba un desprendimiento de retina bilateral, con líquido intraretinal, asociado a lesiones hipopigmentadas en forma de gusanos a nivel retinal.
Los 3 primeros casos, recibieron corticoides tópicos con buena respuesta, sin suspender su tratamiento de base. El 4º caso requirió metilprednisolona y Micofenolato para el control de la inflamación. El último paciente, no continuó en seguimiento por el pésimo pronóstico vital.
Conclusiones: Las uveítis asociadas al tratamiento del MCM son una nueva entidad reconocida recientemente. El oftalmólogo debe tenerlas presentes al momento del diagnóstico diferencial.
Presentado en el XXVI Congreso Chileno de Oftalmología. Viña del Mar, Chile. 2018.
Biologic therapy in non-infectious inflammatory eye diseases: Experience in a group of Chilean patients
Purpose: To describe the use of biologic therapy in a group of Chilean patients with non-infectious uveitis or scleritis, focusing on inflammation, visual acuity, adverse effects and associated therapies.
Methods: Retrospective, cross sectional, observational study. Medical records of patients with non-infectious uveitis and/or scleritis and biologic therapy were reviewed at 2 medical centres. Demographic data, degree of inflammation during follow-up, drugs used and complications were recorded in an Excel database and analysed using Stata®12 software.
Results: We found 41 patients with uveitis or scleritis and biologic treatment. The average age was 15 years at diagnosis (1.5-64). The most frequent aetiology of the inflammation was JIA-associated anterior uveitis. Adalimumab was the main drug used. In the subgroup of patients with ophthalmic indication of biologic therapy and a minimum follow-up of 1 year (1 to 5.6 years, 25 patients), we found a complete control of the inflammation in 72%, 84% and 92% at 3, 6 and 12 months, respectively. 44% had flares-up during follow-up (average 2.8 reactivations per-patient). In 6 patients the treatment was discontinued after 25 months (14-34) of quiescence, occurring reactivations in all but one.
Severe complications seen during treatment were one Varicella Zoster infection, one patient with Leukoencephalopathy, one with pustular psoriasis and one with a non-Hodgkin lymphoma.
Conclusions: Biologic treatment is effective in treating uveitis and scleritis in patients where conventional immunosuppressive drugs have failed. However, despite this high effectiveness, the withdrawal of treatment usually entails a reactivation of the disease and it is not exempted from complications.
Presentado en el 14th Congress of the International Ocular Inflammation Society (IOIS) and the 4th International Assembly of Ocular Inflammation Societies . Laussane, Switzerland. 18-21 october, 2017
Diabetes Mellitus-Associated Uveitis: Clinical Features in a Chilean Series
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.
Publicado en Ocular Immunology and Inflammation. Ocul Immunol Inflamm. 2019 Feb 27;1-4
Clinical Features and Prognostic Factors in Presumed Ocular Tuberculosis
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.
Publicado en Current Eye Research. Curr Eye Res. 2017 Jul;42(7):1029-1034.
Evaluation of the Accuracy of T-SPOT.TB for the Diagnosis of Ocular Tuberculosis in a BCG-vaccinated, Non-endemic Population
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.
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.
Publicado en Ocular Immunology and Inflammation. Ocul Immunol Inflamm. 2017 Aug;25(4):455-459.
Earlier immunomodulatory treatment is associated with better visual outcomes in a subset of patients with Vogt-Koyanagi-Harada disease
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.
Publicado en Acta Ophthalmologica. Acta Ophthalmol. 2015: 93: e475–e480.