Inflammatory cytokines as mediators of retinal endothelial barrier dysfunction in non-infectious uveitis.

Characterised by intraocular inflammation, non-infectious uveitis includes a large group of autoimmune and autoinflammatory diseases that either involve the eye alone or have both ocular and systemic manifestations. When non-infectious uveitis involves the posterior segment of the eye, specifically the retina, there is substantial risk of vision loss, often linked to breakdown of the inner blood-retinal barrier. This barrier is formed by non-fenestrated retinal vascular endothelial cells, reinforced by supporting cells that include pericytes, Müller cells and astrocytes. Across the published literature, a group of inflammatory cytokines stand out as prominent mediators of intraocular inflammation, with effects on the retinal endothelium that may contribute to breakdown of the inner blood-retinal barrier, namely tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, IL-8, IL-17 and chemokine C-C motif ligand (CCL)2. This article reviews the function of each cytokine and discusses the evidence for their involvement in retinal endothelial barrier dysfunction in non-infectious uveitis, including basic laboratory investigations, studies of ocular fluids collected from patients with non-infectious uveitis, and results of clinical treatment trials. The review also outlines gaps in knowledge in this area. Understanding the disease processes at a molecular level can suggest treatment alternatives that are directed against appropriate biological targets to protect the posterior segment of eye and preserve vision in non-infectious uveitis.

Human retinal endothelial cells express functional interleukin-6 receptor.

BACKGROUND: Interleukin (IL)-6 is an inflammatory cytokine present in the eye during non-infectious uveitis, where it contributes to the progression of inflammation. There are two major IL-6 signaling pathways: classic signaling and trans-signaling. Classic signaling requires cellular expression of the IL-6 receptor (IL-6R), which exists in membrane-bound (mIL-6R) and soluble (sIL-6R) forms. Prevailing dogma is that vascular endothelial cells do not produce IL-6R, relying on trans-signaling during inflammation. However, the literature is inconsistent, including with respect to human retinal endothelial cells. FINDINGS: We examined IL-6R transcript and protein expression in multiple primary human retinal endothelial cell isolates, and assessed the effect of IL-6 on the transcellular electrical resistance of monolayers. Using reverse transcription-polymerase chain reaction, IL-6R, mIL-6R and sIL-6R transcripts were amplified in 6  primary human retinal endothelial isolates. Flow cytometry on 5 primary human retinal endothelial cell isolates under non-permeabilizing conditions and following permeabilization demonstrated intracellular stores of IL-6R and the presence of mIL-6R. When measured in real-time, transcellular electrical resistance of an expanded human retinal endothelial cell isolate, also shown to express IL-6R, decreased significantly on treatment with recombinant IL-6 in comparison to non-treated cells across 5 independent experiments. CONCLUSIONS: Our findings indicate that human retinal endothelial cells produce IL-6R transcript and functional IL-6R protein. The potential for classic signaling in human retinal endothelial cells has implications for the development of therapeutics targeted against IL-6-mediated pathology in non-infectious uveitis.

Mechanisms of macular edema.

Macular edema is the pathological accumulation of fluid in the central retina. It is a complication of many retinal diseases, including diabetic retinopathy, retinal vascular occlusions and uveitis, among others. Macular edema causes decreased visual acuity and, when chronic or refractory, can cause severe and permanent visual impairment and blindness. In most instances, it develops due to dysregulation of the blood-retinal barrier which permits infiltration of the retinal tissue by proteins and other solutes that are normally retained in the blood. The increase in osmotic pressure in the tissue drives fluid accumulation. Current treatments include vascular endothelial growth factor blockers, corticosteroids, and non-steroidal anti-inflammatory drugs. These treatments target vasoactive and inflammatory mediators that cause disruption to the blood-retinal barrier. In this review, a clinical overview of macular edema is provided, mechanisms of disease are discussed, highlighting processes targeted by current treatments, and areas of opportunity for future research are identified.

Posterior segment findings by spectral-domain optical coherence tomography and clinical associations in active toxoplasmic retinochoroiditis.

Toxoplasmic retinochoroiditis is a common, potentially blinding parasitic infection. We sought to define the spectrum and frequency of signs of active toxoplasmic retinochoroiditis by spectral domain optical coherence tomography (SD-OCT), and to identify clinical associations. Ninety eyes of 90 individuals presenting consecutively to a tertiary referral uveitis service with active toxoplasmic retinochoroiditis and gradable SD-OCT scans were evaluated prospectively. SD-OCT features were collated, and associations with lesion location, primary versus recurrent episode, serological status, human immunodeficiency virus infection and best-corrected Snellen visual acuity were explored. Active toxoplasmic retinochoroiditis presented with thickened (65%) and hyperreflective (61%) retina, choroidal thickening (55%) and hyporeflectivity (61%), hyperreflective vitreous dots (80%) and deposits (36%), and posterior hyaloid thickening (35%) on SD-OCT. Most signs occurred with similar frequency across clinical groups. Retinal hyporeflectivity (17%) was significantly associated with a visual acuity of 20/200 or worse at resolution. Our observations demonstrate that active toxoplasmic retinochoroiditis has diverse SD-OCT signs and that none are universally present. Retinal hyporeflectivity-suggesting liquefactive necrosis-predicts poor visual outcome.

Treatment of noninfectious uveitis / Tratamento das uveítes não-infecciosas

ABSTRACT Uveitis is a broad term that refers to a large group of eye disorders categorized by intraocular inflammation, a leading cause of visual impairment. Historically, treatment of noninfectious uveitis has depended on corticosteroid drugs. Owing to the myriad of side effects caused by corticosteroids, immunomodulatory therapy has become the preferred treatment for chronic noninfectious intraocular inflammation. Recently, biological response modifiers have established a new era in uveitis therapy, with the range of targets continuing to expand. In this review, we aimed to convey up-to-date information on the treatment of noninfectious uveitis to the general ophthalmologist.

RESUMO Uveíte é um termo amplo utilizado para denominar várias desordens categorizadas como inflamação intraocular, uma causa importante de deficiência visual. Historicamente, o tratamento das uveítes não infecciosas baseou-se no uso de corticosteróides. Devido aos diversos efeitos colaterais do uso de corticosteróides a longo prazo, a terapia imunomoduladora é indicada no tratamento das uveítes não infecciosas crônicas. A introdução dos medicamentos biológicos estabeleceu uma nova era no tratamento das uveítes, com constante desenvolvimento de novas drogas. O objetivo desta revisão é trazer informações atuais sobre tratamento das uveítes não infecciosas para a prática clínica do oftalmologista geral.

Treatment of noninfectious uveitis.

Uveitis is a broad term that refers to a large group of eye disorders categorized by intraocular inflammation, a leading cause of visual impairment. Historically, treatment of noninfectious uveitis has depended on corticosteroid drugs. Owing to the myriad of side effects caused by corticosteroids, immunomodulatory therapy has become the preferred treatment for chronic noninfectious intraocular inflammation. Recently, biological response modifiers have established a new era in uveitis therapy, with the range of targets continuing to expand. In this review, we aimed to convey up-to-date information on the treatment of noninfectious uveitis to the general ophthalmologist.

Biologic Drugs for the Treatment of Noninfectious Uveitis.

ABSTRACT: The management of noninfectious uveitis is constantly evolving. A new "biologic era" in treatment began after the effectiveness of tumor necrosis factor-alpha blocking drugs was demonstrated in rheumatologic inflammatory diseases. The goal of specific immunomodulation with a biologic drug is to target inflammation at the molecular level with a low rate of serious adverse events. The purpose of this review is to summarize current knowledge of biologic drugs in the treatment of noninfectious uveitis by describing clinical studies and recent pharmacological developments.

Clinical features of multiple sclerosis in the south of Brazil: a partial analysis / Características clínicas da esclerose múltipla no sul do Brasil: uma análise parcial

There are no published studies on the characteristics of multiple sclerosis (MS) patients from the south of Brazil. OBJECTIVE: To identify the clinical features of a series of MS patients and to compare to other Brazilian series. METHOD: Retrospective study with 67 patients followed in The MS Reference Center - RS, Brazil during the year of 2008. We analyzed demographic and clinical data. RESULTS: Most were women (74.6 percent), the general average age was 43.5 years old, and the general average EDSS score was 4.1. Of those patients, 81.8 percent had relapsing-remitting MS. Sexual dysfunction prevalence was 31.1 percent in men and 68.9 percent in women (p<0.01). We found a positive correlation (Spearman=0.444, p<0.05) between EDSS and depressive symptoms. CONCLUSION: This study showed a very similar sample compared to other states of Brazil. Moreover, there was found a high prevalence of sexual dysfunction and a straight relation between EDSS and depressive symptoms.

Não há dados publicados sobre as características clínicas da esclerose múltipla (EM) no estado do Rio Grande do Sul (RS). OBJETIVO: Identificar e comparar as características clínicas de uma série de pacientes com EM no RS com as de outras séries nacionais. MÉTODO: Foram coletados e avaliados dados demográficos e clínicos de 67 pacientes atendidos em nosso centro. RESULTADOS: Houve predomínio de mulheres (74,6 por cento), idade média geral foi de 43,5 anos e EDSS médio de 4,1. O tipo surto-remissão correpondeu a 81,8 por cento. A prevalência de disfunção sexual foi de 31,1 por cento nos homens e 68,9 por cento nas mulheres (p<0,01). Encontrou-se correlação de 0,444 (p<0,05) entre depressão e EDSS. CONCLUSÃO: Este estudo demonstrou uma amostra semelhante às demais amostras brasileiras, apresentando, adicionalmente, elevada prevalência de sintomas sexuais e a estreita associação entre depressão e o grau de incapacidade.

Clinical features of multiple sclerosis in the south of Brazil: a partial analysis.

UNLABELLED: There are no published studies on the characteristics of multiple sclerosis (MS) patients from the south of Brazil. OBJECTIVE: To identify the clinical features of a series of MS patients and to compare to other Brazilian series. METHOD: Retrospective study with 67 patients followed in The MS Reference Center - RS, Brazil during the year of 2008. We analyzed demographic and clinical data. RESULTS: Most were women (74.6%), the general average age was 43.5 years old, and the general average EDSS score was 4.1. Of those patients, 81.8% had relapsing-remitting MS. Sexual dysfunction prevalence was 31.1% in men and 68.9% in women (p<0.01). We found a positive correlation (Spearman=0.444, p<0.05) between EDSS and depressive symptoms. CONCLUSION: This study showed a very similar sample compared to other states of Brazil. Moreover, there was found a high prevalence of sexual dysfunction and a straight relation between EDSS and depressive symptoms.