Clinical, Immunopathogenic And Therapeutic Studies Of Sy

我们以前已经证明，环磷酰胺(CP)治疗韦格纳肉芽肿(WG)是成功的；然而，药物毒性限制了它在许多患者中的使用。因此，我们评估了甲氨蝶呤(MTX)作为湿性胃炎替代疗法的安全性和有效性。这些已发表的研究结果表明，甲氨蝶呤联合泼尼松可能是WG患者可接受的替代治疗形式。我们还研究了甲氨蝶呤作为维持疗法用于CP导致疾病缓解的患者的可能性。在这个方案中，患者接受泼尼松加CP治疗，直到病情得到缓解；然后将CP切换到MTX以维持缓解。这种CP/MTX方案非常有效，对于重症患者来说可能是一种毒性较低的标准CP方案的替代方案。我们还探索了其他免疫抑制药物作为缓解维持剂的用途。在一项小型开放试验中，我们调查了免疫抑制剂霉酚酸酯是否可以用来替代MTX来维持CP诱导的WG患者的缓解。这项研究的初步结果表明，霉酚酸酯似乎在维持CP治疗后的缓解方面有疗效。除了这些使用标准免疫抑制药物的研究外，我们还在WG患者中进行了两项试验，这些试验使用了针对参与炎症反应的特定细胞因子的生物制剂。这些试验中的第一项旨在评估重组融合蛋白的安全性、有效性和免疫学效果，该融合蛋白含有p75肿瘤坏死因子受体的胞外部分，与人IgG1的Fc部分相连(TNFR：Fc)。我们正在研究TNFR：FC是否能够减少糖皮质激素治疗的需要，并降低WG患者的复发率。第二个试验研究了达利珠单抗(一种人源化的单抗，阻断T细胞上高亲和力的白细胞介素2受体)治疗湿性胃炎的安全性和有效性。这项试验将寻求确定Daclizumab在预防疾病复发方面的疗效。除了我们在WG的研究外，我们最近还启动了一项I/I期试验，评估利妥昔单抗(一种B细胞耗竭单抗)治疗丙型肝炎相关性冷球蛋白血症血管炎(HCV-CV)的安全性和有效性。

We have previously demonstrated that therapy with cyclophosphamide (CP) was successful as a treatment for Wegener's granulomatosis (WG); however, drug toxicity has limited its use in many patients. Therefore, we evaluated the safety and efficacy of methotrexate (MTX) as an alternative therapy for WG. Results of these published studies demonstrated that MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. We have also investigated the potential for MTX to be used as maintenance therapy in patients in whom CP has induced a disease remission. In this protocol, patients receive prednisone plus CP therapy until remission of disease is achieved; CP is then switched to MTX for maintenance of remission. This CP/MTX regimen was highly effective and may represent a less toxic alternative to the standard CP regimen for patients with severe disease. We have also explored the use of other immunosuppressive drugs as remission maintenance agents. In a small open-label trial we investigated whether the immunosuppressive agent mycophenolate mofetil could be used in place of MTX for maintenance of CP-induced remission in patients with WG. Preliminary results of this study indicated that mycophenolate mofetil appeared to have efficacy in maintaining remission following CP therapy. In addition to these studies that utilize standard immunosuppressive drugs, we are also conducting 2 trials in patients with WG that utilized biologic agents that target specific cytokines involved in the inflammatory response. The first of these trials is designed to assess the safety, efficacy, and immunologic effects of a recombinant fusion protein that contains the extra cellular portion of the p75 TNF receptor linked to the Fc portion of human IgG1 (TNFR:Fc). We are seeking to examine whether TNFR:Fc is able to reduce the need for glucocorticoid treatment and lower relapse rates in patients with WG. The second trial investigates the safety and efficacy of daclizumab (a humanized monoclonal antibody that blocks the high-affinity interleukin-2 receptor on T cells) in the treatment of WG. This trial will seek to determine the efficacy of daclizumab in preventing disease relapses. In addition to our studies in WG we have recently initiated a phase I/I trial that will assess the safety and efficacy of Rituximab (a B cell depleting monoclonal antibody) in the treatment of patients with hepatitis C associated cryoglobulinemic vasculitis (HCV-CV).