Diagnosis And Treatment Of Ocular Inflammatory Disease (uveitis)

这个项目的目标是开发改进的方法来诊断和治疗所有年龄段的人类患者的眼部炎症性疾病，包括葡萄膜炎、巩膜炎、眼表炎症性疾病和眼内恶性肿瘤。在过去的一年里，临床研究继续集中于检查新的治疗药物的有效性，这些药物的安全性比目前可用的标准免疫抑制药物提供的更温和。我们完成了一系列研究，以评估人源化抗IL-2受体单抗(Daclizumab)治疗严重、威胁视力、中度和后部非感染性葡萄膜炎患者的长期安全性和潜在的治疗活性。这是基于我们在人类葡萄膜炎动物模型中的初步观察。我们最初在患者中进行的研究是一项非随机、开放标签的研究，以评估Daclizumab的长期安全性和潜在的治疗活性。在这项研究中，患有慢性、非传染性双眼、威胁视力的葡萄膜炎的患者根据标准化的时间表停用免疫抑制剂，同时最终接受每4周一次的Daclizumab输液。许多患者现在已经接受了数年的抗IL2受体治疗。这些患者的感染率没有明显增加。在他们的治疗过程中，一些患者被转换为每月皮下给药而不是输液。患者已经毫无问题地忍受了这种过渡。基于这些发现，我们启动了第二项研究。：15名患有视力威胁的葡萄膜炎患者在3个地点接受免疫抑制治疗，皮下注射Daclizumab，每2周x2次，2 mg/kg，然后每2周维持1 mg/kg，同时逐渐减少标准免疫抑制治疗。治疗耐受性良好，15名患者中有11名在12周内取消了50%的标准免疫抑制药物，达到了预定的结果，而他们的眼部炎症性疾病没有复发或视力下降。在完成6个月随访的10名参与者中，9名能够减少或维持50%的基线药物负荷，而不会显著丧失视力或增加疾病活动性。一项研究是在少数尽管接受标准免疫抑制治疗但仍有活动期葡萄膜炎的患者中进行的。所有患者均对大剂量(8 mg/kg后4 mg/kg)治疗有效。一项使用大剂量Daclizumab方案治疗幼年类风湿性关节炎的初步研究已经完成，初步结果表明这种方法可能具有有益的临床效果。该公司已决定不生产这种药物，尽管似乎有良好的安全状况。我们继续使用英夫利昔单抗(Remicade)，这是一种人/鼠嵌合单抗，中和了肿瘤坏死因子-α的生物活性，用于治疗巩膜炎和包括视网膜血管炎在内的后段葡萄膜炎。虽然英夫利昔单抗似乎是治疗眼炎性疾病的一种有效的替代疗法，但潜在的眼部并发症可能会限制该药的使用。我们评估了T调节细胞在人类中的存在，并确定了它们的特征。我们已经看到，对类固醇治疗耐药的葡萄膜炎患者在CD4+CD25+亚群中有一组产生IL-17的细胞。我们继续分析原发性眼内淋巴瘤(PIOL)和葡萄膜炎患者的玻璃体细胞因子水平，并继续使用PIOL中IL-10/IL-6比率大于1.0的疾病诊断截断点。同时，这项研究的多中心葡萄膜炎类固醇治疗研究结果也已公布。我们参与的现场研究表明，长期免疫抑制治疗葡萄膜炎不会增加死亡率。第二站将在不久的将来开工。计划使用抗IL-12和其他生物制品

The goal of this project is to develop improved methods for the diagnosis and treatment of ocular inflammatory diseases in human patients of all ages including uveitis, scleritis, inflammatory diseases of the ocular surface, and intraocular malignancies. Over the past year clinical studies have continued to focus on examining the effectiveness of new therapeutic agents with a milder safety profile than that offered by currently available standard immunosuppressive medications. We completed a series of studies to evaluate the long term safety and potential therapeutic activity of humanized anti-IL-2 receptor monoclonal antibody (Daclizumab) therapy in the treatment of patients with severe, sight-threatening, intermediate and posterior non-infectious uveitis. This was based on our initial observations in an animal model for human uveitis. Our initial study in patients was a non-randomized, open-label study to evaluate the long term safety and potential therapeutic activity of daclizumab. In that study, patients with chronic, non-infectious bilateral, sight-threatening uveitiswere weaned off their immunosuppressive agents according to a standardized schedule, while ultimately receiving Daclizumab infusions every 4 weeks. Many patients have now received anti-IL2 receptor therapy for several years. No apparent increase in the infection rate has been seen in these patients. In the course of their therapy some patients were converted to monthly subcutaneous administration of the medication instead of infusions. Patients have tolerated this transition with no problems. Based on these findings we have initiated a second study. : Fifteen study participants with sight-threatening uveitis quiescent on immunosuppressive therapy were enrolled at 3 sites and treated with subcutaneous daclizumab, 2 mg/kg every 2 weeks x2, then maintenance at 1 mg/kg every 2 weeks, with simultaneous tapering of the standard immunosuppressive therapy. Treatments were well tolerated and 11/15 patients reached the preset outcome by eliminating 50% of their standard immunosuppressive medications by 12 weeks without recurrence of their ocular inflammatory disease or reduction in visual acuity. Of the 10 participants that have completed 6 months of followup, 9 were able to reduce or maintain 50% of their baseline medication load without significant loss of vision or increase in disease activity. A study was performed in a small number of patients who had active uveitis in spite of standard immunosuppressive therapy. All the patients' disease responded to the administration of high dose (8mg/kg followed by 4mg/kg) therapy with good results. A pilot study using the high dose regimen of daclizumab in the treatment of juvenile rheumatoid arthritis has been completed with the initial findings suggesting that this approach may have beneficial clinical effects. The company has decided not to produce the medication in spite of what seems to be a good safety profile. We continue our experience with infliximab (Remicade), a chimeric human/murine monoclonal antibody that neutralizes the biologic activity of TNF-alpha for the treatment of scleritis, and posterior segment uveitis including retinal vasculitis. Although infliximab seems to be an effective alternate therapy for the treatment of ocular inflammatory disease the potential for ocular complications may limit the usage of the agent. We evaluated the presence of T -regulatory cells in humans and defined their characteristics. We have seen that uveitis patients resistant to steroid therapy have a group of IL-17 producing cells in the CD4+CD25+ subpopulation. We continue to analyze vitreal cytokine levels from primary intraocular lymphoma (PIOL) and uveitic patients and continue to use the cutoff point in disease diagnosis with an IL-10 to IL-6 ratio greater than 1.0 for PIOL. As well, the MUST (multicenter uveitis steroid treatment study results of the study were made available. The SITE study,in which we participated demonstrated that there was no increased mortality due to long term immunosuppressive therapy for uveitis. SITE 2 will start in the near future. The use of anti-IL-12 and other biologics are planned