Diagnosis And Treatment Of Ocular Inflammatory Disease (uveitis)

该项目的目标是开发改进的方法，用于诊断和治疗所有年龄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，临床研究继续关注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更温和。我们已经开展了一系列研究，以评估人源化抗il -2受体单克隆抗体（Daclizumab）治疗严重、视力威胁、中期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。这是基于我们对人类葡萄膜炎动物模型的初步观察。我们在患者中的初始研究是一项非随机、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的时间表停用免疫抑制剂，同时最终每4周接受一次Daclizumab输注。许多患者已经接受抗il - 2受体治疗多年。这些患者的感染率未见明显增加。在治疗过程中，一些患者改为每月皮下给药，而不是输液。患者能够忍受这种转变，没有任何问题。基于这些发现，我们开始了第二项研究。： 15名接受免疫抑制治疗的视力威胁性葡萄膜炎的研究参与者在3个部位入组，使用皮下daclizumab治疗，每2周2 mg/kg x2，然后维持每2周1 mg/kg的剂量，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，达到了预定的结果，没有眼炎复发或视力下降。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性增加。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。所有患者对高剂量（8mg/kg后4mg/kg）治疗均有反应，效果良好。一项使用大剂量daclizumab治疗幼年类风湿性关节炎的初步研究已经完成，初步结果表明该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，尽管它的安全性似乎很好。目前，我们正在向公司申请继续治疗少数长期服药病情得到良好控制的患者。我们继续使用英夫利昔单抗（Remicade），这是一种嵌合人/鼠单克隆抗体，可中和tnf - α的生物活性，用于治疗白塞病、巩膜炎和后段葡萄膜炎（包括视网膜血管炎）。虽然英夫利昔单抗似乎是治疗眼部炎症性疾病的有效替代疗法，但潜在的眼部并发症可能限制了该药物的使用。Efalizumab （Raptiva）是一种人源抗cd11a单克隆抗体，可可逆地抑制白细胞粘附和运输。在一项非随机、前瞻性研究中，我们评估了开放标签efalizumab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名伴有CME的中度和/或后膜炎/全膜炎患者被纳入研究。参与者的平均年龄为42岁，女性3人，男性3人。所有患者都显示CME减少（这是研究的主要结果）和视力改善。已经提交了3份IND安全性报告，涉及1名怀孕的受试者和2名其伴侣在接受研究药物期间怀孕的受试者。患者未报告与研究药物相关的严重不良事件，且耐受性良好。这项试验的结果尚未公布。然而，由于老年牛皮癣患者的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。我们也报道了一例有后极炎症病史的患者用雷帕霉素治疗脉络膜新生血管的有效疗效。除了使用皮质类固醇进行全身治疗外，眼部炎症性疾病还可使用皮质类固醇进行局部或眼内或眼周注射治疗。我们还证明，选择性T淋巴细胞和B淋巴细胞抑制剂霉酚酸酯可作为活动性硬膜炎患者有效的类固醇保留剂。我们已经看到对类固醇治疗有耐药性的葡萄膜炎患者在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IL-10与IL-6比值大于1.0的疾病诊断临界值。我们已经使用免疫病理学技术来证明视网膜变性患者的推定原因。此外，我们也是多中心葡萄膜炎类固醇治疗研究的一个地点，该研究将评估类固醇眼内植入物在标准治疗中的使用（这将单独报道）。这项研究继续积极招募。我们参与的SITE研究表明，长期免疫抑制治疗葡萄膜炎不会增加死亡率。

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 have engaged in 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 are presently requesting from the company persmission to continue treating a small number of patients whose disease has been well controlled long term on the medication. 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 Behcet's disease, 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. Publication of the results of this trial are pending. 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 also reported the effective treatment of choroidal neovascularization with rapamycin in a patient with a history of posterior pole inflammatory disease. In addition to systemic therapy with corticosteroids, ocular inflammatory disease can be treated with corticosteroids given topically or by injection in or around the eye. We also demonstrated that mycophenolate mofetil, a selective inhibitor of T and B lymphocytes can be used as an effective steroid sparing agent in patients with active scleritis. 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. We have used immunopathologic techniques to demonstrate the putative cause of retinal degeneration in patients. As well, we are are a site for the MUST (multicenter uveitis steroid treatment study which will evaluate the use of the steroid intraocular implant to standard therapy (this will be reported separately). This study continues with active recruitment. The SITE study,in which we participated demonstrated that there was no increased mortality due to long term immunosuppressive therapy for uveitis.