CLINICAL, IMMUNOPATHOGENIC AND THERAPEUTIC STUDIES OF SYSTEMIC VASCULITIS AND ..

我们之前已经证明，环磷酰胺治疗韦格纳斯肉芽肿病（WG）是成功的；然而，药物毒性限制了它在某些患者中的使用。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。42名没有立即危及生命的疾病的患者被研究。每周给予甲氨蝶呤和强的松治疗导致33/42例患者（79%）疾病缓解。在34名获得缓解的患者中，有19人经历了疾病复发。所有获得缓解的患者到复发的估计中位时间为29个月。80%的复发发生在停用甲氨蝶呤或将其剂量减少到15毫克/周或更少的患者中。因此，甲氨蝶呤加强的松可能是一种可接受的替代形式治疗的选定的WG患者。我们也在研究MTX在环磷酰胺诱导疾病缓解的患者中作为维持治疗的潜力。在该方案中，患者接受糖皮质激素加环磷酰胺治疗，直到疾病缓解；环磷酰胺然后切换到MTX维持缓解。通过这种方法，我们希望将环磷酰胺的疗效与MTX更有利的毒性结合起来。前31例患者的初步数据表明，该方案是有效和安全的。所有31例患者均获得疾病缓解，中位缓解时间为3个月（范围1-10个月）。该组的中位随访时间为21个月，31例患者中只有5例（16%）出现疾病复发。两名患者因药物相关毒性退出研究（均发展为MTX-肺炎）。这些初步结果表明，环磷酰胺/MTX方案非常有效，对于严重疾病患者来说，可能是一种毒性较低的替代标准CP方案。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。将重组IL-10添加到细胞培养物中以剂量依赖性的方式抑制WG T细胞过量产生干扰素γ。基于这些发现，我们启动了一项抗炎细胞因子IL-10在韦格纳？肉芽肿病。我们还将启动一项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的Fc部分相关的p75 TNF受体的细胞外部分（TNFR:Fc）。具体而言，我们将研究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。-血管，韦格纳？肉芽肿病，自身免疫，免疫抑制治疗，甲氨蝶呤-人类受试者

We have previously demonstrated that therapy with cyclophosphamide was successful as a treatment for Wegeners granulomatosis (WG); however, drug toxicity has limited its use in certain patients. We have therefore evaluated the safety and efficacy of methotrexate (MTX) as an alternative therapy for WG. Forty-two patients who did not have immediately life-threatening disease were studied. Weekly administration of MTX and prednisone resulted in remission of disease in 33/42 patients (79%). Nineteen of the 34 patients achieving remission experienced a relapse of disease. The estimated median time to relapse for all patients achieving remission was 29 months. Eighty percent of these relapses occurred in patients who had discontinued MTX or had reduced their dose to 15 mg/week or less. Thus, MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. We are also investigating the potential for MTX to be used as maintenance therapy in patients in whom cyclophosphamide has induced a disease remission. In this protocol patients receive glucocorticoid plus cyclophosphamide therapy until remission of disease is achieved; cyclophosphamide is then switched to MTX for maintenance of remission. By using this approach, we hope to combine the efficacy of cyclophosphamide with the more favorable toxicity profile of MTX. Preliminary data on the first 31 patients entered into this study indicate that this regimen is effective and safe. Disease remission was achieved in all 31 patients with a median time to remission of 3 months (range 1-10 months). The median duration of follow up for this group is 21 months and only 5 (16%) of these 31 patients have experienced a disease relapse. Two patients were withdrawn from the study for drug-related toxicity (both developed MTX- pneumonitis). These preliminary results suggest that this cyclophosphamide /MTX regimen is highly effective and may represent a less toxic alternative to the standard CP regimen for patients with severe disease.In studies of disease pathogenesis we have found that peripheral blood lymphocytes from patients with active WG produce 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. The addition of recombinant IL-10 to cell cultures suppressed the overproduction of interferon-gamma by WG T cells in a dose-dependent manner. Based on these findings, we have initiated a therapeutic trial of the anti-inflammatory cytokine IL-10 in patients with active Wegener?s granulomatosis. We will also be initiating a phase I/II trial to assess the safety, efficacy, and immunologic effects of a recombinant fusion protein that contains the extracellular portion of the p75 TNF receptor linked to the Fc portion of human IgG1 (TNFR:Fc). Specifically, we will seek to examine whether TNFR:Fc is able to reduce the need for glucocorticoid treatment and lower relapse rates in patients with WG. - Vasculits, Wegener?s granulomatosis, Autoimmunity, Immunosuppressive therapy, Methotrexate - Human Subjects