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

系统性血管炎的临床、免疫致病性和治疗研究......

• 批准号: 6288806
• 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/6288806
• 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 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

我们之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 替代疗法的安全性和有效性。对四十二名没有立即危及生命的疾病的患者进行了研究。每周服用 MTX 和泼尼松可使 33/42 名患者 (79%) 的疾病得到缓解。 34 名获得缓解的患者中有 19 名出现了疾病复发。所有达到缓解的患者的预计中位复发时间为 29 个月。 80% 的复发发生在已停用 MTX 或已将剂量减少至每周 15 毫克或更少的患者中。因此，对于选定的 WG 患者，MTX 加泼尼松可能是可接受的替代治疗形式。我们还在研究 MTX 作为环磷酰胺已诱导疾病缓解的患者维持治疗的潜力。在该方案中，患者接受糖皮质激素加环磷酰胺治疗，直至疾病缓解；然后环磷酰胺改用 MTX 以维持缓解。通过使用这种方法，我们希望将环磷酰胺的功效与 MTX 更有利的毒性特征结合起来。参与本研究的首批 31 名患者的初步数据表明，该方案有效且安全。所有 31 名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，这 31 名患者中只有 5 名 (16%) 出现疾病复发。两名患者因药物相关毒性退出研究（两人均出现 MTX 肺炎）。这些初步结果表明，这种环磷酰胺/MTX方案非常有效，并且可能是重症患者标准CP方案毒性较小的替代方案。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。还注意到 CD4 T 淋巴细胞产生的肿瘤坏死因子 (TNF) 和纯化的单核细胞产生的 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，我们启动了一项抗炎细胞因子 IL-10 对活动性韦格纳肉芽肿患者的治疗试验。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，该重组融合蛋白含有与人 IgG1 (TNFR:Fc) 的 Fc 部分连接的 p75 TNF 受体的胞外部分。具体来说，我们将寻求检查 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。 - 血管炎、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