Autoantibody-Targeted Therapy for Acute Exacerbations of Idiopathic Pulmonary Fibrosis

一些患者患有特发性肺纤维化(IPF)，这是一种进行性纤维增生性肺疾病 老年人突发急性加重(AE-IPF)，可导致呼吸衰竭和死亡 几天之内。类固醇是AE-IPF的标准治疗方法，尽管这些和所有其他药物治疗都尝试过 到目前为止，这些措施都是无效的。我们的研究小组以及其他研究小组的发现表明，许多 与传统的自身抗体介导综合征相同的免疫异常也很常见。 在IPF患者中，特别是在正在或即将发生急性加重的患者中。 自身免疫发病机制也可以解释AE-IPF对当前治疗的难治性，因为 许多传统的自身抗体介导的肺部疾病也对类固醇和 其他非特异性剂。然而，专门减少先前存在的自身抗体的方案会耗尽 产生自身抗体的B细胞和/或抑制B细胞自身抗体的产生更常有益于 这些症状。 我们已经进行了一项概念验证试点试验，在该试验中，重症AE-IPF患者接受了 治疗性血浆交换(TPE)非常迅速地减少循环自身抗体，加上利妥昔单抗 消耗产生自身抗体的B细胞，加上静脉注射免疫球蛋白(IVIG)，以进一步抑制自身 抗体的产生。与历史对照组相比，这些自身抗体减少疗法 在大多数AE-IPF患者中产生了前所未有的临床反应。 因此，我们假设：减少自身抗体对AE-IPF患者是有益的。 我们在这里建议进行一项随机的IIb期临床试验，通过比较以下两种药物的疗效来检验这一假设： TPE+利妥昔单抗+IVIG与常规治疗(TAU)治疗AE-IPF患者的比较。在提供了知情的 同意后，在五个参与医疗中心因AE-IPF住院的受试者将随机(2：1)到 要么是试验性的ARM，要么是TAU。这项试验的主要终点是六个月的存活期。 次要终点包括补充氧气和步行6分钟的需求的变化 距离以及不良事件发生率。我们期待这一创新的试验性治疗将会取得成果 在提高存活率、减少需氧量、增加功能容量和可接受的毒性方面 侧写。更多的翻译研究将检验自身抗体检测在AE- IPF患者。 这项调查的结果可能会极大地改变治疗方法，并拯救未来的生命 患有这种进展迅速且往往致命的肺部疾病的患者。

Some patients with idiopathic pulmonary fibrosis (IPF), a progressive fibroproliferative lung disease of older adults, develop sudden acute exacerbations (AE-IPF) that can result in respiratory failure and death within days. Steroids are standard treatment for AE-IPF, although these and all other medical therapies tried to date have been ineffectual. Findings of our research group, as well as others, show that numerous immune abnormalities that are identical to conventional autoantibody-mediated syndromes are also common in IPF patients, especially among those who are having or will soon have acute exacerbations. An autoimmune pathogenesis could also explain the refractoriness of AE-IPF to current therapy, since many conventional autoantibody-mediated lung diseases are also resistant to treatment with steroids and other nonspecific agents. However, regimens that specifically reduce preexisting autoantibodies, deplete autoantibody-producing B-cells, and/or inhibit B-cell autoantibody production are more often beneficial for these syndromes. We have conducted a proof-of-concept pilot trial in which seriously-ill AE-IPF patients were treated with therapeutic plasma exchange (TPE) to very rapidly reduce circulating autoantibodies, plus rituximab to deplete autoantibody-producing B-cells, plus intravenous immunoglobulin (IVIG) to further inhibit auto- antibody production. In comparisons to a historical control group, these autoantibody reduction therapies resulted in unprecedented clinical responses in most AE-IPF patients. Accordingly, we hypothesize: AUTOANTIBODY REDUCTION IS BENEFICIAL FOR AE-IPF PATIENTS. We propose here a randomized Phase IIb clinical trial to test this hypothesis by comparing efficacy of TPE plus rituximab plus IVIG vs. treatment as usual (TAU) for AE-IPF patients. After providing informed consent, subjects hospitalized for AE-IPF at five participating medical centers will be randomized (2:1) to either the experimental arm or TAU, respectively. The primary endpoint of this trial is six-month survival. Secondary endpoints include changes in requirements for supplemental oxygen and six-minute walk distances, as well as adverse events rates. We anticipate this innovative experimental treatment will result in improved survival, lesser oxygen requirements, greater functional capacities, and an acceptable toxicity profile. Additional translational studies will examine the potential clinical use of autoantibody assays in AE- IPF patients. Results of this investigation could substantially alter treatment approaches, and save the lives of future patients who have this rapidly progressive and too-often lethal lung disease.