Clinical/Immunopathogenic/Therapeutic Studies:Vasculitis

我们之前已经证明，环磷酰胺（CP）治疗韦格纳肉芽肿病（WG）是成功的；然而，药物毒性限制了它在许多患者中的应用。因此，我们评估了甲氨蝶呤（MTX）作为WG替代疗法的安全性和有效性。这些已发表的研究结果表明，甲氨蝶呤加强的松可能是一种可接受的替代治疗形式的选定的WG患者。我们还研究了MTX在CP引起疾病缓解的患者中用作维持治疗的潜力。在该方案中，患者接受泼尼松加CP治疗，直到疾病缓解；然后将CP切换到MTX以维持缓解。这种CP/MTX方案非常有效，对于严重疾病的患者来说，可能是一种毒性较小的标准CP方案的替代方案。此外，在一项小型开放标签试验中，我们研究了免疫抑制剂霉酚酸酯是否可以代替MTX用于维持cp诱导的WG患者缓解。本研究的初步结果表明霉酚酸酯似乎对维持CP治疗后的缓解有效。基于这些结果，我们启动了一项II期随机试验，以评估使用MTX与霉酚酸酯对维持CP和强的松诱导的WG和相关血管病变患者缓解的比较疗效。在疾病发病机制的研究中，我们发现活动性WG患者的外周血淋巴细胞产生的干扰素γ水平比正常对照的外周血淋巴细胞高10至20倍。CD4 T淋巴细胞的肿瘤坏死因子（TNF）和纯化单核细胞的IL-12的产生也增加，但IL-4、IL- 5和IL-10的产生没有增加。基于这些发现，我们启动了一项I/II期试验，以评估一种重组融合蛋白的安全性、有效性和免疫效应，该蛋白含有与人IgG1 Fc部分相关的p75 TNF受体的细胞外部分（TNFR:Fc）。我们正在研究TNFR:Fc是否能够减少对糖皮质激素治疗的需求并降低WG患者的复发率。

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. In addition, 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. Based on these results, we have initiated a phase II randomized trial to assess the comparative efficacy of using MTX versus mycophenolate mofetil for maintaining remission that has been induced by CP and prednisone in patients with WG and related vasculitides. In studies of disease pathogenesis we have found that peripheral blood lymphocytes from patients with active WG produced 10 to 20- fold higher levels of interferon-gamma compared with peripheral blood lymphocytes from normal controls. Increased production of tumor necrosis factor (TNF) by CD4 T lymphocytes and IL-12 by purified monocytes were also noted, but production of IL-4, IL- 5, and IL-10 was not increased. Based on these findings, we have initiated a phase I/II trial 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.