Diagnosis And Treatment Of Ocular Inflammatory Disease (uveitis)

该项目的目标是开发用于诊断和治疗所有年龄段的人类患者的眼部炎性疾病的改进方法，包括葡萄膜炎、巩膜炎、眼表炎性疾病和眼内恶性肿瘤。在过去的一年里，临床研究继续集中在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安全性更温和。我们完成了一系列研究，以评估人源化抗IL-2受体单克隆抗体（Daclizumab）治疗严重、威胁视力、中间和后部非感染性葡萄膜炎患者的长期安全性和潜在治疗活性。这是基于我们在人类葡萄膜炎动物模型中的初步观察。我们在患者中进行的初步研究是一项非随机、开放标签研究，旨在评估达克珠单抗的长期安全性和潜在治疗活性。在该研究中，患有慢性、非感染性、双侧、威胁视力的葡萄膜炎的患者根据标准化时间表停用免疫抑制剂，最终每4周接受一次Daclizumab输注。许多患者现在已经接受抗IL 2受体治疗数年。在这些患者中未观察到感染率明显增加。在治疗过程中，一些患者改为每月皮下给药，而不是输注。患者可以耐受这种过渡，没有任何问题。根据这些发现，我们开始了第二项研究。：在3个研究中心招募了15名在免疫抑制治疗中静止的威胁视力的葡萄膜炎的研究参与者，并接受皮下达克珠单抗治疗，2 mg/kg，每2周一次x2，然后维持1 mg/kg，每2周一次，同时逐渐减少标准免疫抑制治疗。治疗耐受性良好，11/15的患者在12周内消除了50%的标准免疫抑制药物，达到了预设的结果，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，而没有明显的视力丧失或疾病活动增加。一项研究是在少数患者中进行的，这些患者尽管接受了标准的免疫抑制治疗，但仍患有活动性葡萄膜炎。大剂量（8 mg/kg后4 mg/kg）治疗后，所有患者的病情均得到改善。一项使用高剂量daclizumab治疗幼年型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，尽管似乎是一个良好的安全性。 我们继续使用英夫利西单抗（类克）治疗巩膜炎和后段葡萄膜炎（包括视网膜血管炎）的经验，英夫利西单抗是一种嵌合的人/鼠单克隆抗体，可中和TNF-α的生物活性。 虽然英夫利西单抗似乎是治疗眼部炎症性疾病的有效替代疗法，但眼部并发症的可能性可能限制该药物的使用。 依法利珠单抗（Raptiva），一种人源化抗CD 11 a单克隆抗体，显示可逆性抑制白细胞粘附和运输。我们在一项非随机前瞻性研究中评价了开放标签依法利珠单抗治疗继发于非感染性中间和后葡萄膜炎的黄斑水肿的安全性和有效性。共有6名患有CME的中间和/或后/全葡萄膜炎的受试者入选本研究，受试者平均年龄为42岁，3名受试者为女性，3名为男性。 所有患者均显示CME减少（这是研究的主要结局）和视力改善。已提交3份IND安全性报告，涉及1例妊娠受试者和2例伴侣在接受研究药物期间妊娠的受试者。患者未报告可归因于研究药物的严重不良事件，并且他们对药物耐受良好。 然而，由于老年银屑病患者的PML病例，这种药物被从市场上撤下。目前没有设想进一步的研究。我们评估了人类中T调节细胞的存在并确定了它们的特征.我们已经看到，对类固醇治疗有抗性的葡萄膜炎患者在CD 4 + CD 25+亚群中具有一组IL-17产生细胞。 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IL-10与IL-6比值大于1.0的PIOL疾病诊断临界点。此外，MUST（多中心葡萄膜炎类固醇治疗研究）已完成招募，研究结果将很快公布。 我们参与的SITE研究表明，葡萄膜炎的长期免疫抑制治疗不会增加死亡率。SITE 2将在不久的将来启动。一项治疗继发于葡萄膜炎的黄斑囊样水肿的局部药物研究也已开始。

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. Efalizumab (Raptiva), a humanized anti-CD11a monoclonal antibody shown to reversibly inhibit leukocyte adhesion and trafficking. We evaluated the safety and efficacy of treating macular edema, secondary to non-infectious intermediate and posterior uveitis, with open label efalizumab in a nonrandomized, prospective study. A total of 6 participants with intermediate and/or posterior/panuveitis with CME were enrolled in the study.The average age of participants was 42, 3 participants were female and 3 were male. All patients showed a reduction in CME which was the primary outcome of the study, and improvement in vision. Three IND safety reports have been submitted regarding 1 participant who became pregnant and 2 participants whose partners became pregnantwhile receiving study medication. No serious adverse events attributable to the study medication were reported by the patients and they tolerated the medication well. However, this medication was removed from the market because of cases of PML in older psoriasis patients. No further studies are envisaged at this time. 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 has completed recruitment and results of the study should be available soon. 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. A topical interfeon study for the tretment of cystoid macular edema secondary to uveitis has also begun.