Clinical, Immunopathogenic and Therapeutic Studies of Systemic Vasculitis

我们以前已经证明，环磷酰胺治疗韦格纳肉芽肿（WG）是成功的，但药物毒性限制了其在某些患者中的使用。 因此，我们评估了甲氨蝶呤（MTX）作为WG的替代疗法的安全性和有效性。 研究了42名没有立即危及生命的疾病的患者。 MTX和泼尼松每周给药导致33/42例患者（79%）的疾病缓解。在34例达到缓解的患者中，有19例出现疾病复发。 所有患者达到缓解的估计中位复发时间为29个月。 这些复发的百分之八十发生在患者谁已停止MTX或已减少其剂量为15毫克/week或less. Long长期随访的患者队列显示，20例肾小球肾炎，只有2个有任何恶化后，MTX治疗肾功能。 因此，甲氨蝶呤加泼尼松可能是一个可接受的替代形式的治疗与WG选定的患者。基于这些结果，我们启动了一项II期临床试验，以评估MTX与霉酚酸酯在WG和相关血管炎患者中维持环磷酰胺和糖皮质激素诱导的缓解方面的比较疗效。 我们也在研究MTX作为环磷酰胺诱导疾病缓解患者的维持治疗的可能性。 在该方案中，患者接受糖皮质激素加环磷酰胺治疗，直至达到疾病缓解;然后将环磷酰胺转换为MTX以维持缓解。通过使用这种方法，我们希望联合收割机将环磷酰胺的功效与MTX更有利的毒性特征结合起来。 最初31名患者进入本研究的初步数据表明，该方案是有效和安全的。 所有31例患者均实现了疾病缓解，至缓解的中位时间为3个月（范围1-10个月）。 该组的中位随访时间为21个月，这31例患者中仅5例（16%）出现疾病复发。 2例患者因药物相关毒性退出研究（均发生MTX-肺炎）。 这些初步结果表明，这种环磷酰胺/MTX方案是非常有效的，并可能代表一个毒性较小的替代标准CP方案的患者严重diseases.In疾病发病机制的研究，我们发现，活跃WG患者的外周血淋巴细胞产生10至20倍的干扰素-γ水平高于正常对照组的外周血淋巴细胞。 还观察到CD 4 T淋巴细胞产生的肿瘤坏死因子（TNF）和纯化单核细胞产生的IL-12增加，但IL-4、IL-5和IL-10的产生没有增加。向细胞培养物中添加重组IL-10以剂量依赖性方式抑制WG T细胞过度产生干扰素-γ。 基于这些发现，我们开始了一项抗炎细胞因子IL-10治疗活动性WG患者的试验。我们还将启动一项I/II期试验，以评估重组融合蛋白的安全性、疗效和免疫学效应，该融合蛋白含有与人IgG 1 Fc部分连接的p75 TNF受体的胞外部分（TNFR：Fc）。 我们正在研究TNFR：Fc是否能够减少WG患者对糖皮质激素治疗的需求并降低复发率。

We have previously demonstrated that therapy with cyclophosphamide was successful as a treatment for Wegener's 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. Long term follow-up of this patient cohort showed that of the 20 patients with glomerulonephritis, only 2 had any deterioration in renal function after treatment with MTX. Thus, MTX plus prednisone may be an acceptable alternative form of therapy for selected patients with WG. Based on these results, we have initiated a phase II trial to assess the comparative efficacy of using MTX versus mycophenolate mofetil for maintaining remission that has been induced by cyclophosphamide and glucocorticoids in patients with WG and related vasculitides. 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 thesefindings, we have initiated a therapeutic trial of the anti-inflammatory cytokine IL-10 in patients with active WG. We will also initiated 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). 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.