RESUMEN
PURPOSE: To assess efficacy and safety of sarilumab, a human anti-interleukin-6 receptor antibody, for treatment of posterior segment noninfectious uveitis (NIU). DESIGN: Randomized, double-masked, placebo-controlled, phase 2 study. PARTICIPANTS: Fifty-eight patients (eyes) with noninfectious intermediate, posterior, or panuveitis. METHODS: Eyes received treatment every 2 weeks for 16 weeks with subcutaneous sarilumab 200 mg or placebo. MAIN OUTCOME MEASURES: The primary end point was the proportion of patients with ≥2-step reduction in vitreous haze (VH) on the Miami scale or with a reduction of systemic corticosteroids (prednisolone or equivalent) to a dose of <10 mg/day at week 16. Primary end point was based on VH evaluation by a central reading center. Investigator evaluation of VH was a prespecified, planned secondary analysis. RESULTS: At week 16, proportion of patients taking sarilumab or placebo with ≥2-step reduction in VH or corticosteroid dose <10 mg/day was 46.1% vs. 30.0% (P = 0.2354) based on central reading center assessment of VH and 64.0% vs. 35.0% (P = 0.0372) based on investigator assessment of VH, respectively. In the subgroup of eyes with VH grade ≥2 at baseline, the mean VH reduction from baseline to week 16 was significantly greater with sarilumab vs. placebo regardless of assessment by the central reading center (-2.1 [n = 11] vs. -1.7 [n = 3], respectively; P = 0.0255) or investigator (-2.5 [n = 19] vs. -1.2 [n = 11], respectively; P = 0.0170). The mean best-corrected visual acuity gain from baseline to week 16 was greater with sarilumab vs. placebo in the overall population (8.9 vs. 3.6 letters, respectively; P = 0.0333) and in the subgroup of eyes with central subfield thickness (CST) ≥300 µm at baseline (12.2 [n = 13] vs. 2.1 [n = 7] letters, respectively; P = 0.0517). Corresponding changes in CST were -46.8 vs. +2.6 µm (P = 0.0683) in the overall population and -112.5 [n = 13] vs. -1.8 [n = 6] µm (P = 0.1317) in the subgroup of eyes with CST ≥300 µm at baseline, respectively. The most common ocular adverse events were worsening of uveitis (0 [placebo] and 3 [sarilumab] patients) and retinal infiltrates (1 [placebo] and 2 [sarilumab] patients). CONCLUSIONS: Subcutaneous sarilumab may provide clinical benefits in the management of NIU of the posterior segment, especially in eyes with uveitic macular edema.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/uso terapéutico , Uveítis Posterior/tratamiento farmacológico , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Antirreumáticos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Inyecciones Intravítreas , Edema Macular/diagnóstico , Edema Macular/tratamiento farmacológico , Edema Macular/fisiopatología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Uveítis Posterior/diagnóstico , Uveítis Posterior/fisiopatología , Agudeza Visual/fisiologíaRESUMEN
BACKGROUND: Long-term intraocular injections of vascular endothelial growth factor (VEGF)-neutralising proteins can preserve central vision in many patients with neovascular age-related macular degeneration. We tested the safety and tolerability of a single intravitreous injection of an AAV2 vector expressing the VEGF-neutralising protein sFLT01 in patients with advanced neovascular age-related macular degeneration. METHODS: This was a phase 1, open-label, dose-escalating study done at four outpatient retina clinics in the USA. Patients were assigned to each cohort in order of enrolment, with the first three patients being assigned to and completing the first cohort before filling positions in the following treatment groups. Patients aged 50 years or older with neovascular age-related macular degeneration and a baseline best-corrected visual acuity score of 20/100 or less in the study eye were enrolled in four dose-ranging cohorts (cohort 1, 2â×â108 vector genomes (vg); cohort 2, 2â×â109 vg; cohort 3, 6â×â109 vg; and cohort 4, 2â×â1010 vg, n=3 per cohort) and one maximum tolerated dose cohort (cohort 5, 2â×â1010 vg, n=7) and followed up for 52 weeks. The primary objective of the study was to assess the safety and tolerability of a single intravitreous injection of AAV2-sFLT01, through the measurement of eye-related adverse events. This trial is registered with ClinicalTrials.gov, number NCT01024998. FINDINGS: 19 patients with advanced neovascular age-related macular degeneration were enrolled in the study between May 18, 2010, and July 14, 2014. All patients completed the 52-week trial period. Two patients in cohort 4 (2 ×â1010 vg) experienced adverse events that were possibly study-drug related: pyrexia and intraocular inflammation that resolved with a topical steroid. Five of ten patients who received 2â×â1010 vg had aqueous humour concentrations of sFLT01 that peaked at 32·7-112·0 ng/mL (mean 73·7 ng/mL, SD 30·5) by week 26 with a slight decrease to a mean of 53·2 ng/mL at week 52 (SD 17·1). At baseline, four of these five patients were negative for anti-AAV2 serum antibodies and the fifth had a very low titre (1:100) of anti-AAV2 antibodies, whereas four of the five non-expressers of sFLT01 had titres of 1:400 or greater. In 11 of 19 patients with intraretinal or subretinal fluid at baseline judged to be reversible, six showed substantial fluid reduction and improvement in vision, whereas five showed no fluid reduction. One patient in cohort 5 showed a large decrease in vision between weeks 26 and 52 that was not thought to be vector-related. INTERPRETATION: Intravitreous injection of AAV2-sFLT01 seemed to be safe and well tolerated at all doses. Additional studies are needed to identify sources of variability in expression and anti-permeability activity, including the potential effect of baseline anti-AAV2 serum antibodies. FUNDING: Sanofi Genzyme, Framingham, MA, USA.
Asunto(s)
Terapia Genética/métodos , Degeneración Macular/terapia , Parvovirinae/genética , Proteínas Recombinantes de Fusión/genética , Anciano , Anciano de 80 o más Años , Inhibidores de la Angiogénesis/biosíntesis , Inhibidores de la Angiogénesis/genética , Neovascularización Coroidal/diagnóstico por imagen , Neovascularización Coroidal/fisiopatología , Neovascularización Coroidal/terapia , Dependovirus , Femenino , Terapia Genética/efectos adversos , Vectores Genéticos/administración & dosificación , Humanos , Inyecciones Intravítreas , Degeneración Macular/diagnóstico por imagen , Degeneración Macular/fisiopatología , Masculino , Persona de Mediana Edad , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/biosíntesis , Tomografía de Coherencia Óptica , Agudeza VisualRESUMEN
Background: Stargardt disease (STGD), a rare, inherited macular degeneration most commonly affecting children and young adults, is a rapidly progressive disease leading to severe central vision loss. This research aimed to develop a conceptual disease model describing STGD symptoms and their impact on patients' lives.Material and Methods: Qualitative interviews were conducted with patients (juvenile and adult) and parents of children and adolescents with STGD. Interviewed subjects were enrolled through ophthalmologists from specialized eye centers in the USA and in France. Trained interviewers used semi-structured techniques to elicit concepts relevant to patients and their parents. Thematic analysis of interview transcripts led to the identification of concepts which were organized to generate a disease model.Results: A total of 21 patients (12 in the US; 9 in France) - 14 adults, 7 juveniles - and 7 parents were interviewed. The most cited ocular symptoms were photosensitivity and central vision decline. Interviewees reported limitations on Physical (e.g. difficulty with sports/physical activities), Mental (e.g. frustration and worry, reduced ability to concentrate), Social (e.g. issue with facial recognition and difficulty discussing disease) and Role (e.g. impact on driving and reading, difficulties at school/work) functioning. These impacts were, when possible, mitigated by coping strategies and support (e.g. using electronic devices, setting up routines or accepting the disease).Conclusions: This research provides an overview of symptoms experienced by patients with STGD and highlights the dramatic impact these have on patients' lives, allowing the identification of concepts of importance when evaluating new therapeutic options for STGD.
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Actividades Cotidianas/psicología , Adaptación Psicológica , Padres/psicología , Calidad de Vida , Enfermedad de Stargardt/psicología , Adolescente , Adulto , Anciano , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Stargardt/fisiopatología , Enfermedad de Stargardt/rehabilitación , Adulto JovenRESUMEN
Noninfectious uveitis is a predominantly T cell-mediated autoimmune, intraocular inflammatory disease. To characterize the gene expression profile from patients with noninfectious uveitis, PBMCs were isolated from 50 patients with clinically characterized noninfectious uveitis syndrome. A pathway-specific cDNA microarray was used for gene expression profiling and real-time PCR array for further confirmation. Sixty-seven inflammation- and autoimmune-associated genes were found differentially expressed in uveitis patients, with 28 of those genes being validated by real-time PCR. Several genes previously unknown for autoimmune uveitis, including IL-22, IL-19, IL-20, and IL-25/IL-17E, were found to be highly expressed among uveitis patients compared with the normal subjects with IL-22 expression highly variable among the patients. Furthermore, we show that IL-22 can affect primary human retinal pigment epithelial cells by decreasing total tissue resistance and inducing apoptosis possibly by decreasing phospho-Bad level. In addition, the microarray data identified a possible uveitis-associated gene expression pattern, showed distinct gene expression profiles in patients during periods of clinical activity and quiescence, and demonstrated similar expression patterns in related patients with similar clinical phenotypes. Our data provide the first evidence that a subset of IL-10 family genes are implicated in noninfectious uveitis and that IL-22 can affect human retinal pigment epithelial cells. The results may facilitate further understanding of the molecular mechanisms of autoimmune uveitis and other autoimmune originated inflammatory diseases.
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Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/inmunología , Uveítis/genética , Uveítis/inmunología , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes/metabolismo , Células Cultivadas , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Epitelio Pigmentado de la Retina/citología , Epitelio Pigmentado de la Retina/inmunología , Epitelio Pigmentado de la Retina/metabolismo , Transducción de Señal/genética , Transducción de Señal/inmunología , Uveítis/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Age-related macular degeneration (AMD) is the leading cause of blindness in Western countries. Numerous risk factors have been reported but the evidence and strength of association is variable. We aimed to identify those risk factors with strong levels of evidence which could be easily assessed by physicians or ophthalmologists to implement preventive interventions or address current behaviours. METHODS: A systematic review identified 18 prospective and cross-sectional studies and 6 case control studies involving 113,780 persons with 17,236 cases of late AMD that included an estimate of the association between late AMD and at least one of 16 pre-selected risk factors. Fixed-effects meta-analyses were conducted for each factor to combine odds ratio (OR) and/or relative risk (RR) outcomes across studies by study design. Overall raw point estimates of each risk factor and associated 95% confidence intervals (CI) were calculated. RESULTS: Increasing age, current cigarette smoking, previous cataract surgery, and a family history of AMD showed strong and consistent associations with late AMD. Risk factors with moderate and consistent associations were higher body mass index, history of cardiovascular disease, hypertension, and higher plasma fibrinogen. Risk factors with weaker and inconsistent associations were gender, ethnicity, diabetes, iris colour, history of cerebrovascular disease, and serum total and HDL cholesterol and triglyceride levels. CONCLUSIONS: Smoking, previous cataract surgery and a family history of AMD are consistent risk factors for AMD. Cardiovascular risk factors are also associated with AMD. Knowledge of these risk factors that may be easily assessed by physicians and general ophthalmologists may assist in identification and appropriate referral of persons at risk of AMD.
Asunto(s)
Degeneración Macular/etiología , Envejecimiento , Enfermedades Cardiovasculares/complicaciones , Extracción de Catarata/efectos adversos , Complicaciones de la Diabetes , Medicina Basada en la Evidencia/métodos , Color del Ojo , Fibrinógeno/metabolismo , Predisposición Genética a la Enfermedad , Humanos , Obesidad/complicaciones , Oportunidad Relativa , Grupos Raciales , Riesgo , Factores de Riesgo , Factores Sexuales , Fumar/efectos adversosRESUMEN
Non-infectious uveitis is a heterogenous group of potentially blinding ocular autoimmune diseases that may represent a manifestation of a systemic condition or may affect the eyes only. A systemically administered anti-TNF has recently been approved for the treatment of non-infectious uveitis, broadening the therapeutic arsenal available to control intraocular inflammation and reduce uveitis complications that can lead to vision loss. When uveitis affects only the eyes, a local anti-TNF-α administration strategy could optimize the ocular therapeutic effect and reduce undesirable systemic side-effects. A new ocular method of non-viral gene therapy, currently in development, may broaden the indications for ocular anti-TNF-α agents, not only for uveitis but also for other diseases in which TNF-α-mediated neuro-inflammation has been demonstrated.
TITLE: Les anti-TNF-α pour le traitement des uvéites non infectieuses. ABSTRACT: Les molécules anti-TNF-α administrés par voie générale ont été approuvés récemment pour le traitement des uvéites non inflammatoires, élargissant l'arsenal thérapeutique dans le traitement de ces pathologies responsables de cécité évitable si l'inflammation est contrôlée. Quand seul l'Åil est atteint, des stratégies d'administration locale permettraient d'optimiser les effets intraoculaires des molécules anti-TNF-α et d'en réduire les effets indésirables. Une nouvelle méthode de thérapie génique non virale, actuellement en développement, pourrait élargir les indications des molécules anti-TNF-α oculaires, non seulement pour les uvéites, mais également pour d'autres maladies dans lesquelles une neuro-inflammation impliquant le TNF-α a été démontrée.
Asunto(s)
Terapia Genética , Factor de Necrosis Tumoral alfa/inmunología , Uveítis/terapia , Trastornos de la Visión/prevención & control , Anticuerpos Neutralizantes/genética , Anticuerpos Neutralizantes/uso terapéutico , Enfermedades Autoinmunes/terapia , Terapia Genética/métodos , Terapia Genética/tendencias , Humanos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
BACKGROUND: Type 1 Usher syndrome (USH1) is a rare disease and major cause of genetic deaf-blindness. Deafness is present from birth while retinitis pigmentosa (RP) which typically presents during childhood is progressive leading to blindness. The aim of this research was to develop a disease model describing USH1 symptoms and their impact on patients' lives. MATERIALS AND METHODS: Qualitative interviews were conducted with patients (pediatric and adult) and parents of children and adolescents with USH1. Interviewed subjects were enrolled through ophthalmologists from specialized eye centers in the USA and in France. Trained interviewers used semi-structured techniques to elicit concepts relevant to patients and their parents. Thematic analysis of interview transcripts led to the identification of concepts which were organized to generate a disease model. RESULTS: A total of 18 patients (7 in the US; 11 in France)- 9 adults, 4 adolescents, and 5 children- and 9 mothers were interviewed. The most cited ocular symptoms were difficulty seeing at night and loss of peripheral vision. Interviewees reported limitations on Physical (e.g. difficulty moving), Mental (e.g. fear about falling), Social (e.g. difficulty discussing disease with others) and Role (e.g. difficulties at school/work) functioning. These impacts were, when possible, mitigated by coping strategies and support (e.g. using electronic devices, having a positive/proactive attitude). CONCLUSIONS: This research provides an overview of symptoms experienced by patients with USH1 and highlights the dramatic impact these have on patients' lives, allowing the identification of concepts of importance when evaluating therapeutic treatments in development for RP.
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Actividades Cotidianas/psicología , Adaptación Psicológica , Padres/psicología , Medición de Resultados Informados por el Paciente , Síndromes de Usher/psicología , Adolescente , Adulto , Anciano , Niño , Femenino , Estudios de Seguimiento , Humanos , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Pronóstico , Investigación Cualitativa , Síndromes de Usher/fisiopatología , Síndromes de Usher/rehabilitación , Adulto JovenRESUMEN
PURPOSE: To describe the natural history and progression of visual loss in eyes with untreated neovascular age-related macular degeneration (AMD). DESIGN: Systematic review and meta-analysis. PARTICIPANTS: Four thousand three hundred sixty-two untreated neovascular AMD patients from published interventional studies. METHODS: A systematic review of the literature from 1980 to August 2005 was performed. Studies reporting disease progression outcomes for untreated patients with neovascular AMD were included. Outcome measures were summarized using simple counts and means. Random effects meta-analyses were conducted and tests of heterogeneity were performed where appropriate. MAIN OUTCOME MEASURES: Changes in visual acuity (VA) loss, development of comorbidities, and fellow eye involvement. RESULTS: Fifty-three primary studies were included. Nearly half of the studies (28) were randomized clinical trials. The quality of the studies was high, with over 80% providing level I or II evidence. Mean baseline VA among study patients was 0.64 logarithm of the minimum angle of resolution (logMAR) (approximately 20/87 Snellen). The mean VA change in logMAR progressed from 0.1 (1 line lost) at 3 months to 0.3 (2.7 lines lost) after 12 months and 0.4 (4 lines lost) after 24 months. The proportion of patients who developed severe vision loss (>6 lines) from baseline increased from 21.3% at 6 months to 41.9% by 3 years. The proportion of patients with VA worse than logMAR 1.0 (20/200 Snellen) increased from 19.7% at baseline to 75.7% by 3 years. Neovascular AMD developed in the fellow eye in 12.2% of patients by 12 months and in 26.8% by 4 years. Meta-analyses of vision outcome by subtype of neovascular AMD were not possible. CONCLUSIONS: A doubling of the visual angle of presenting VA may be expected to occur in the year after initial presentation in eyes with untreated neovascular AMD. No conclusions can be drawn as to the differences in rates of disease progression by neovascular AMD subtype. The diversity of reporting formats, paucity of long-term natural history data, and heterogeneity among the reported clinical studies impose limits to the clear understanding of long-term prognosis for visual function in neovascular AMD.
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Neovascularización Coroidal/diagnóstico , Degeneración Macular/diagnóstico , Anciano , Anciano de 80 o más Años , Ceguera/fisiopatología , Neovascularización Coroidal/fisiopatología , Comorbilidad , Femenino , Humanos , Degeneración Macular/fisiopatología , Masculino , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Agudeza VisualRESUMEN
BACKGROUND: There is limited previous research examining the healthcare costs of neovascular age-related macular degeneration (NV-AMD), which constrains our understanding of the economic impact of this condition. With aging populations, this leading cause of rapid vision loss in Western countries is expected to become a pressing health predicament, requiring decision makers to evaluate alternative treatment strategies for AMD. OBJECTIVE: To document the economic burden of bilateral NV-AMD, the late stage of AMD, in elderly patients, from a societal perspective. STUDY DESIGN, SETTING AND PARTICIPANTS: A cross-sectional, observational study surveyed 401 patients with bilateral NV-AMD and 471 non-AMD subjects in Canada, France, Germany, Spain and the UK. Physicians' records and subjects' standardized telephone interviews were used to record medical resource utilization, assistance with daily living and social benefits. Annual bilateral NV-AMD-related socioeconomic costs were calculated in euro, year 2005 values. MAIN OUTCOME MEASURES: Societal costs including direct vision-related medical costs (e.g. treatment of AMD and vision-related equipment), direct non-vision-related medical costs (e.g. medications) and direct non-medical-related costs (e.g. home healthcare and social services) were the main outcome measures. RESULTS: The demographic profile of NV-AMD patients was similar across countries; however, co-morbid condition profiles varied. NV-AMD patients reported substantial health-related problems and associated health resource utilization (HRU). In the previous 12 months, 12-22% of patients fell, and half of these patients required medical treatments. More than 20% (range 21-59%) of patients were prescribed vision-enhancing equipment. More than half of the patients (54-81%) were living with a spouse or family member and 19-41% reported receiving assistance for activities of daily living. The average annual societal cost per bilateral NV-AMD patient treated was estimated to be euro 7879 in Canada, euro 7349 in France, euro 12 445 in Germany, euro 5732 in Spain and euro 5300 in the UK, and direct vision-related medical costs accounted for 23-63% of the total cost. Half of the patients were diagnosed with bilateral NV-AMD for <1 year, with an average length of 5 months; there were no statistically significant differences in total annual costs per patient between these patients and those who were diagnosed with bilateral disease for > or =1 year. Estimated annual societal costs of bilateral NV-AMD patients in these countries ranged from euro 268 to euro 1311 million. Estimated annual societal costs of all NV-AMD patients in these countries ranged from euro 671 to euro 3278 million. CONCLUSIONS: Bilateral NV-AMD imposes significant functional impairment on patients, leading to increased HRU and a high societal cost burden. Differences in national healthcare systems and NV-AMD treatment patterns were reflected in the wide variation of NV-AMD costs across the five surveyed countries. Even though the prevalence rates and per-patient costs varied by country, the societal costs of NV-AMD patients were substantial in each country. Earlier intervention with effective therapies is expected to reduce disease burden and disability associated with NV-AMD and, thus, decrease the overall societal cost.
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Neovascularización Coroidal/economía , Neovascularización Coroidal/epidemiología , Costo de Enfermedad , Degeneración Macular/economía , Degeneración Macular/epidemiología , Anciano , Anciano de 80 o más Años , Canadá/epidemiología , Estudios de Casos y Controles , Comorbilidad , Comparación Transcultural , Estudios Transversales , Europa (Continente)/epidemiología , Femenino , Costos de la Atención en Salud , Recursos en Salud/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Perfil de Impacto de Enfermedad , Encuestas y Cuestionarios , Agudeza VisualRESUMEN
Non-infectious uveitis (NIU) is the first cause of blindness that can be cured if optimal anti-inflammatory therapy can be achieved. Systemic anti-TNF (Tumor Necrosis Factor) agents have been recently approved for NIU but no local delivery of anti-TNF is available. For sustained production of secreted therapeutic proteins into the eye, non-viral gene therapy using plasmid electrotransfer in the ciliary muscle has been proposed. In this paper, we report the development steps of pEYS606, a clinical-grade plasmid DNA, devoid of antiobiotic selection gene, encoding a fusion protein consisting of the extracellular domain of the soluble p55 TNF-α receptor linked to the human IgG1 Fc domain (hTNFR-Is/hIgG1 or Protein 6), with high affinity for human TNF-α, for non-viral gene transfer into the ocular ciliary muscle. Electrotransfer of pEYS606 in the ciliary muscle significantly reduced ocular inflammation in two well-established rat models of uveitis, the endotoxin-induced uveitis (EIU) and the experimental autoimmune uveitis (EAU). In addition, in EAU, a significant protection of photoreceptors was demonstrated after pEYS606 treatment. The improved pharmacokinetic profile of intraocularly-secreted protein as compared to direct intravitreous injection of recombinant protein allowed to demonstrate Protein 6 efficacy at very low concentrations. Based on these results, a phase I/II clinical trial is conducted [ClinicalTrials.gov Identifier: NCT03308045].
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Terapia Genética/métodos , Plásmidos/uso terapéutico , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores Señuelo del Factor de Necrosis Tumoral/genética , Uveítis/terapia , Animales , Cuerpo Ciliar/metabolismo , Cuerpo Ciliar/patología , Femenino , Inmunoglobulina G/genética , Masculino , Plásmidos/genética , Conejos , Ratas Endogámicas Lew , Proteínas Recombinantes de Fusión/genética , Transfección/métodos , Uveítis/genética , Uveítis/patologíaRESUMEN
BACKGROUND: Progressive outer retinal necrosis (PORN) is an ocular disease in individuals with AIDS and is associated with substantial morbidity. The optimal management of PORN and its clinical course in the HAART era is unclear. OBJECTIVE: We report a case of successfully managed PORN that provides insight into the monitoring and treatment of this disease. STUDY DESIGN: Intravitreal injections and intravenous therapy targeted towards varicella zoster virus (VZV) were used to treat PORN. HAART was initiated for HIV-1 therapy. Serial PCR for VZV was performed on aqueous humor to monitor the clinical course. RESULTS: The presence of VZV DNA from aqueous humor correlated with clinical exacerbations of disease. Initiation of twice weekly intravitreal injections with dual antiviral drugs appeared to be an important therapeutic intervention that resulted in remission of PORN. Secondary prophylaxis against VZV was successfully withdrawn after HAART induced partial immune recovery. CONCLUSION: In addition to aggressive therapy with intravitreal injections, HAART and quantitative measurements of VZV DNA from aqueous humor have important roles in the management of PORN. A multidisciplinary approach involving specialists in infectious diseases, ophthalmology, and clinical microbiology will improve the chances for successful long-term outcomes.
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Terapia Antirretroviral Altamente Activa , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Herpesvirus Humano 3 , Síndrome de Necrosis Retiniana Aguda/tratamiento farmacológico , Síndrome de Necrosis Retiniana Aguda/virología , Adulto , Humor Acuoso/virología , Femenino , Infecciones por VIH/patología , Herpes Zóster/tratamiento farmacológico , Herpesvirus Humano 3/genética , Humanos , Reacción en Cadena de la Polimerasa/métodos , Cuerpo Vítreo/irrigación sanguínea , Cuerpo Vítreo/efectos de los fármacosRESUMEN
OBJECTIVE: To describe the burden of bilateral neovascular age-related macular degeneration (NV-AMD) on patient-reported functioning and health resource utilization. METHODS: A cross-sectional study of 401 patients with bilateral NV-AMD and 471 elderly control subjects without AMD was conducted in 5 countries. Subjects completed a telephone survey, including the National Eye Institute 25-Item Visual Function Questionnaire, the EuroQol instrument, the Hospital Anxiety and Depression Scale, and history of falls, fractures, and health care resource utilization. RESULTS: The mean age for patients with NV-AMD was 78.1 years, and 65% were women. The patients reported 45% worse vision-related functioning, 13% worse overall well-being, and 30% more anxiety and 42% more depression symptoms than controls after adjusting for covariates (all, P < .001). The effect of NV-AMD was also observed as a doubled fall rate (16% vs 8% [P < .001]) and a quadrupled need for assistance with daily activities (29% vs 7% [P < .001]) in the patients compared with controls. CONCLUSIONS: The evidence of extensive decline in quality of life and increased need of daily living assistance for patients with NV-AMD compared with a control population substantiates the need for new treatments that prevent vision loss and progression to blindness.
Asunto(s)
Neovascularización Coroidal/economía , Costo de Enfermedad , Recursos en Salud/estadística & datos numéricos , Degeneración Macular/economía , Anciano , Anciano de 80 o más Años , Canadá , Neovascularización Coroidal/fisiopatología , Comorbilidad , Estudios Transversales , Europa (Continente) , Femenino , Investigación sobre Servicios de Salud , Humanos , Degeneración Macular/fisiopatología , Masculino , Persona de Mediana Edad , Calidad de Vida , Perfil de Impacto de Enfermedad , Encuestas y Cuestionarios , Agudeza Visual/fisiologíaRESUMEN
PURPOSE: To investigate the safety and efficacy of daclizumab (Zenapax, humanized anti-Tac, HAT) in controlling the ocular manifestations of Behçet's disease. DESIGN: Randomized, placebo-controlled, double-masked clinical trial. PARTICIPANTS: Seventeen participants with Behçet's disease experiencing at least two prior ocular attacks and requiring treatment with immunosuppressive agents for the ocular complications of Behçet's disease. METHODS: Participants received either intravenous placebo or daclizumab (1 mg/kg) infusions every two weeks for six weeks, then every four weeks while continuing their standard immunosuppressive regimens. If clinically indicated, tapering of the standard immunosuppressive medications was allowed after six months of study enrollment. Complete ocular and physical examinations and an adverse event assessment were performed at baseline and prior to each study infusion. MAIN OUTCOME MEASURES: Primary safety endpoints were the development of a life-threatening complication or a severe opportunistic infection. Primary efficacy outcomes were the number of ocular attacks and an assessment of systemic immunosuppressive medications required during the study, including the ability to taper concomitant immunosuppressive therapy. RESULTS: Nine participants randomized to daclizumab and eight to placebo were followed monthly. Follow-up ranged from one to 34 months, with a median follow-up of 15 months. Two participants randomized to daclizumab discontinued study therapy prior to the end of the study for personal reasons. No participant experienced a safety endpoint, and visual acuity remained stable in all participants during the course of the study. Ten participants (six daclizumab, four placebo) experienced ocular attacks requiring therapy. The median ocular attack rate during the study was greater in the daclizumab arm than the placebo arm (median 1.27 vs. 0.17 attacks/year, respectively). Participants in the placebo arm also experienced a greater reduction in the immunosuppressive medication score compared to participants receiving daclizumab (median -4.0 vs. -1.0, respectively). CONCLUSIONS: The observed results in the placebo group demonstrate that careful follow-up and treatment with standard combination immunosuppressive therapy can be effective for the management of the ocular complications of Behçet's disease. In our small study, there was no suggestion that daclizumab was beneficial in comparison with placebo. However, the low observed attack rate limited our ability to make a definitive treatment group comparison.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Síndrome de Behçet/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Inmunosupresores/uso terapéutico , Uveítis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Síndrome de Behçet/diagnóstico , Niño , Daclizumab , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Angiografía con Fluoresceína , Estudios de Seguimiento , Fondo de Ojo , Humanos , Inmunoglobulina G/administración & dosificación , Inmunoglobulina G/efectos adversos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Uveítis/diagnósticoRESUMEN
PURPOSE: Primary intraocular lymphoma (PIOL) is a diffuse large B cell lymphoma that initially infiltrates the retina, vitreous, or optic nerve head, with or without central nervous system involvement. This study examined the expression of the bcl-2 t(14;18) translocation, the bcl-10 gene, and high expression of bcl-6 mRNA in PIOL cells. METHODS: Microdissection and PCR analysis were used to examine vitreous specimens in patients with PIOL for the presence of bcl-2 t(14;18) translocations, the bcl-10 gene, and expression of bcl-6 mRNA. A medical record review was also conducted to determine whether the bcl-2 t(14;18) translocation correlated with prognosis. RESULTS: Forty of 72 (55%) PIOL patients expressed the bcl-2 t(14;18) translocation at the major breakpoint region. Fifteen of 68 (22%) patients expressed the translocation at the minor cluster region. The bcl-10 gene was detected in 6 of 26 (23%) patients, whereas 4 of 4 (100%) PIOL patients expressed higher levels of bcl-6 mRNA compared with inflammatory lymphocytes. An analysis of clinical outcome in 23 PIOL patients revealed no significant association between bcl-2 t(14;18) translocations and survival or relapse. However, patients with the translocation were significantly younger. CONCLUSIONS: PIOL has unique molecular patterns of bcl-2, bcl-10, and bcl-6 when compared with other systemic lymphomas. This study lays the foundation for future studies aimed at exploring the genotypic classification of PIOL based on the quantitative molecular framework of gene expression profiling, with the goal of providing useful adjuncts to the pathologic diagnosis of this complex disease.
Asunto(s)
Cromosomas Humanos Par 14/genética , Cromosomas Humanos Par 18/genética , Neoplasias del Ojo/genética , Regulación Neoplásica de la Expresión Génica/fisiología , Genes bcl-2/genética , Linfoma de Células B/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Translocación Genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteína 10 de la LLC-Linfoma de Células B , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Neoplasias del Ojo/mortalidad , Neoplasias del Ojo/patología , Humanos , Linfoma de Células B/mortalidad , Linfoma de Células B/patología , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas c-bcl-6 , ARN Mensajero/metabolismo , Vitrectomía , Cuerpo Vítreo/patologíaRESUMEN
Testicular lymphoma is a rare neoplasm of the testis that is most commonly seen in older patients. It metastasizes preferentially to extranodal sites, including the skin, central nervous system, Waldeyer ring, contralateral testis, and lung. Two case reports of patients with a history of testicular lymphoma who developed involvement of the vitreous and retina are presented. These are interesting cases as the testis, central nervous system, and eye are all immune privileged organs, which may account for occurrence of disease in these sites. Histopathologic examination of diagnostic vitrectomy specimens from both cases showed atypical lymphoid cells with immunoglobulin heavy chain (IgH) gene rearrangements, consistent with the diagnosis of intraocular B-cell lymphoma. The results of a literature review of all reports of ocular involvement with testicular lymphoma are discussed. Patients with testicular lymphoma are at risk for relapse, particularly in the central nervous system. Clinicians should be suspicious for intraocular lymphoma in patients with a history of testicular lymphoma who present with vitritis or retinal lesions.
Asunto(s)
Neoplasias del Ojo/secundario , Linfoma de Células B/patología , Neoplasias de la Retina/secundario , Neoplasias Testiculares/patología , Cuerpo Vítreo/patología , Anciano , Antineoplásicos/uso terapéutico , Diagnóstico Diferencial , Neoplasias del Ojo/tratamiento farmacológico , Neoplasias del Ojo/cirugía , Angiografía con Fluoresceína , Fondo de Ojo , Humanos , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B/cirugía , Masculino , Persona de Mediana Edad , Neoplasias de la Retina/tratamiento farmacológico , Neoplasias de la Retina/cirugía , Neoplasias Testiculares/tratamiento farmacológico , VitrectomíaRESUMEN
PURPOSE: To investigate the relationship between serum immunoglobulin levels and corneal opacities in a cohort of patients with human T-cell lymphotrophic virus type-1 (HTLV-1). DESIGN: Retrospective case series. METHODS: Complete ophthalmologic examination was performed on 44 patients with HTLV-1 infection (25 patients with adult T-cell leukemia/lymphoma [ATL], 18 patients with HTLV-1 that was associated myelopathy/tropical spastic paraparesis [HAM/TSP], and one patient who was asymptomatic). Corneal opacities were described by shape, size, color, and location. Serum immunoglobulin (Ig) levels (IgG, IgM, and IgA) were measured by nephelometry. RESULTS: Corneal opacities were identified in 15 of 25 patients (60%) with ATL and five of 18 patients (28%) with HAM/TSP. The prevalence of corneal opacities was associated statistically with elevated IgG level (P = .023) in patients with ATL, but not in patients with HAM/TSP (P > .99). CONCLUSION: Although the mechanism remains unclear, hypergammaglobulinemia is associated with the development of the corneal opacities in patients of African descent with ATL.
Asunto(s)
Opacidad de la Córnea/etiología , Infecciones por HTLV-I/complicaciones , Hipergammaglobulinemia/etiología , Opacidad de la Córnea/sangre , Opacidad de la Córnea/diagnóstico , Infecciones por HTLV-I/sangre , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Humanos , Hipergammaglobulinemia/sangre , Hipergammaglobulinemia/diagnóstico , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Nefelometría y Turbidimetría , Prevalencia , Estudios RetrospectivosRESUMEN
PURPOSE: To investigate whether high-dose alpha-tocopherol (vitamin E) could reduce vision loss and retinal thickening associated with uveitis-associated cystoid macular edema. DESIGN: A double-masked, randomized study. METHODS: Uveitis patients with macular edema seen at the NIH were randomized and received either 1600 IU/day of vitamin E or placebo for 4 months. Visual acuity and retinal thickening were collected for the efficacy and the safety of the high dose of vitamin E. RESULTS: Changes in visual acuity and retinal thickening. CONCLUSIONS: Four-month oral supplementation with 1600 IU/d of vitamin E had no apparent effect on uveitis-associated macular edema or visual acuity in this small study.
Asunto(s)
Edema Macular/tratamiento farmacológico , Uveítis/tratamiento farmacológico , Vitamina E/uso terapéutico , Adulto , Anciano , Niño , Método Doble Ciego , Femenino , Humanos , Edema Macular/etiología , Masculino , Persona de Mediana Edad , Retina/efectos de los fármacos , Uveítis/complicaciones , Agudeza Visual/efectos de los fármacosRESUMEN
BACKGROUND: To evaluate the QuantiFERON-TB test (gamma interferon assay), approved by the Centers for Disease Control and Prevention for the detection of latent tuberculosis (LTB), in patients who potentially may require immunosuppressive therapy for ocular inflammatory disease. METHODS: Blood samples from 12 consecutive patients with granulomatous ocular inflammatory disease were evaluated first with the purified protein derivative (PPD) skin test and then with the QuantiFERON-TB test (11 of 12 patients, 1 declined). The results of the 2 tests in both U.S.- and non-U.S.-born patients were compared with their Bacillus Calmette-Guérin (BCG) vaccination status and chest x-rays. RESULTS: In our small series there was a high degree of concordance between the QuantiFERON-TB assay and the PPD skin test. INTERPRETATION: The QuantiFERON-TB test did not demonstrate intrinsic merit over PPD skin testing for screening for LTB in selected patients when immunosuppressive therapy is considered. The confounding effect of BCG vaccination renders interpretation of both tests difficult. Early reports suggest the second-generation tests that are now available may hold promise for use in the uveitis clinic and should be formally evaluated.
Asunto(s)
Bioensayo/métodos , Interferón gamma , Seudotumor Orbitario/diagnóstico , Tuberculosis Ocular/diagnóstico , Adulto , Biopsia , Niño , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Seudotumor Orbitario/sangre , Prueba de Tuberculina/métodosRESUMEN
PURPOSE: To assess the feasibility of a study design that may determine whether subcutaneous administration of the interleukin-2 receptor antibody daclizumab can safely reduce the dependence on standard systemic corticosteroids or other immunosuppressive regimens in patients with sight-threatening, noninfectious intermediate uveitis, posterior uveitis, or panuveitis. DESIGN: Prospective, multicenter, nonrandomized, noncomparative, open-label interventional trial. PARTICIPANTS: Fifteen patients, 5 each at 3 clinical centers, with noninfectious intermediate, posterior, or panuveitis, who require a currently stable immunosuppression regimen of systemic corticosteroids and/or other systemic treatments to control noninfectious intraocular inflammation. METHODS: After enrollment and baseline ophthalmic evaluations, 2 induction treatments were given 2 weeks apart using subcutaneous (SC) daclizumab at 2 mg/kg. Subcutaneous daclizumab maintenance treatments were then continued every 2 weeks at 1 mg/kg for 6 months. The initial immunosuppression load was tapered over 8 to 12 weeks in a staggered fashion beginning with the first induction treatment. Safety evaluations were performed at each treatment visit, with a primary efficacy evaluation at 12 weeks and a repeat efficacy evaluation at 26 weeks. MAIN OUTCOME MEASURES: Best-corrected visual acuity (Early Treatment of Diabetic Retinopathy Study [ETDRS] method) with a concurrent taper of concomitant systemic immunosuppression medication load (tabulated by use of a weighted scoring system) was assessed; target for success was defined as a 50% or greater reduction in concomitant immunosuppression load by 12 weeks while maintaining visual acuity within 5 ETDRS letters of baseline. Ocular inflammation was assessed at each visit with standardized grading scales. RESULTS: Ten of 15 patients (67%) receiving SC daclizumab treatments every other week successfully achieved the primary efficacy end point of reducing their concomitant immunosuppression load by at least 50% while maintaining their baseline visual acuity at 12 and 26 weeks. Subcutaneous daclizumab injections were well tolerated with no serious adverse events observed during the 6 months of treatments, although 3 patients experienced possibly related, nonserious adverse events. CONCLUSIONS: Subcutaneous daclizumab induction treatments at 2 mg/kg followed by 1 mg/kg maintenance treatments every other week seems safe and, in most cases, may reduce the concomitant immunosuppressive load required to treat noninfectious uveitis for 12 to 26 weeks.