Autoantibody-Targeted Therapy for Acute Exacerbations of Idiopathic Pulmonary Fibrosis

一些患有特发性肺纤维化（IPF）的患者，IPF是一种进行性纤维增生性肺病， 老年人发生可导致呼吸衰竭和死亡的突发急性加重（AE-IPF） 几天之内。类固醇是AE-IPF的标准治疗，尽管尝试了这些和所有其他药物治疗 迄今为止都是无效的。我们的研究小组以及其他人的研究结果表明， 与常规自身抗体介导的综合征相同的免疫异常也很常见 在IPF患者中，尤其是正在发生或即将发生急性加重的患者。 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 许多常规的自身抗体介导的肺病也对类固醇治疗有抗性， 其他非特异性药物。然而，专门减少预先存在的自身抗体的方案， 产生自身抗体的B细胞和/或抑制B细胞自身抗体的产生通常更有益于 这些症状。 我们进行了一项概念验证试点试验，其中重症AE-IPF患者接受以下治疗 治疗性血浆置换（TPE），以非常迅速地减少循环自身抗体，加上利妥昔单抗， 消耗自身抗体产生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产生。 抗体生产。与历史对照组相比，这些自身抗体减少疗法 导致大多数AE-IPF患者出现前所未有的临床缓解。 因此，我们假设：自身抗体减少对AE-IPF患者有益。 我们在此提出一项随机化IIb期临床试验，通过比较 TPE+利妥昔单抗+IVIG vs.常规治疗（TAU）治疗AE-IPF患者。在提供知情的 同意后，在5家参与的医学中心因AE-IPF住院的受试者将被随机（2：1）分配至 无论是实验组还是TAU。这项试验的主要终点是6个月生存率。 次要终点包括补充氧气和6分钟步行要求的变化 距离以及不良事件发生率。我们预计这种创新的实验性治疗将导致 提高生存率，减少对氧气的需求，提高功能能力，以及可接受的毒性 profile.其他转化研究将检查自身抗体检测在AE中的潜在临床用途- IPF患者。 这项研究的结果可能会大大改变治疗方法，并挽救未来的生命。 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.