Clinical, Immunopathogenic and Therapeutic Studies of Systemic Vasculitis

系统性血管炎的临床、免疫致病性和治疗研究

• 批准号: 6431525
• 负责人: MICHAEL C SNELLER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431525
• 关键词: Wegener's granulomatosis; antiinflammatory agents; blister; cardiovascular disorder chemotherapy; clinical research; clinical trials; combination chemotherapy; connective tissue disorder chemotherapy; cytokine; drug screening /evaluation; epiglottis; glucocorticoids; hormone therapy; human subject; human therapy evaluation; immunotherapy; larynx disorder; longitudinal human study; medical complication; methotrexate; prednisone; tissue /cell culture; tracheotomy; vasculitis; xanthine analog

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.

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；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)作为湿性胃炎替代疗法的安全性和有效性。对42名没有立即患上危及生命的疾病的患者进行了研究。每周服用甲氨蝶呤和泼尼松可使33/42名患者病情缓解(79%)。在获得缓解的34名患者中，有19名患者病情复发。所有患者获得缓解的中位复发时间估计为29个月。其中80%的复发发生在停用MTX或将剂量减少到每周15毫克或更少的患者中。对该患者队列的长期随访显示，在20例肾小球肾炎患者中，只有2例在接受MTX治疗后肾功能有任何恶化。因此，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。基于这些结果，我们启动了一项II期试验，以评估MTX与霉酚酸酯在维持环磷酰胺和糖皮质激素诱导的WG和相关血管炎患者缓解方面的比较疗效。我们还在研究MTX在环磷酰胺导致疾病缓解的患者中用作维持治疗的可能性。在这个方案中，患者接受糖皮质激素加环磷酰胺治疗，直到病情缓解；然后环磷酰胺改用甲氨蝶呤维持缓解。通过使用这种方法，我们希望将环磷酰胺的疗效与MTX更有利的毒性相结合。进入这项研究的第一批31名患者的初步数据表明，该方案是有效和安全的。31例患者均获得疾病缓解，中位缓解时间为3个月(1-10个月)。这组患者的平均随访时间为21个月，在这31名患者中只有5名(16%)经历了疾病复发。两名患者因药物相关毒性(均发展为甲氨蝶呤肺炎)而退出研究。这些初步结果表明，这种环磷酰胺/MTX方案是高效的，可能是一种毒性较低的标准CP方案，适用于重症患者。在疾病发病机制的研究中，我们发现，活动期WG患者的外周血淋巴细胞产生的干扰素-γ水平是正常对照外周血淋巴细胞的10-20倍。CD4T淋巴细胞产生肿瘤坏死因子(TNF)，纯化的单核细胞产生IL-12，但不增加IL-4、IL-5和IL-10的产生。在细胞培养中加入重组IL-10以剂量依赖的方式抑制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在活动期WG患者中的治疗试验。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、有效性和免疫学效果，该融合蛋白包含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。