Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis

BackgroundSevere acute exacerbations (AE) of idiopathic pulmonary fibrosis (IPF) are medically untreatable and often fatal within days. Recent evidence suggests autoantibodies may be involved in IPF progression. Autoantibody-mediated lung diseases are typically refractory to glucocorticoids and nonspecific medications, but frequently respond to focused autoantibody reduction treatments. We conducted a pilot trial to test the hypothesis that autoantibody-targeted therapies may also benefit AE-IPF patients.MethodsEleven (11) critically-ill AE-IPF patients with no evidence of conventional autoimmune diseases were treated with therapeutic plasma exchanges (TPE) and rituximab, supplemented in later cases with intravenous immunoglobulin (IVIG). Plasma anti-epithelial (HEp-2) autoantibodies and matrix metalloproteinase-7 (MMP7) were evaluated by indirect immunofluorescence and ELISA, respectively. Outcomes among the trial subjects were compared to those of 20 historical control AE-IPF patients treated with conventional glucocorticoid therapy prior to this experimental trial.ResultsNine (9) trial subjects (82%) had improvements of pulmonary gas exchange after treatment, compared to one (5%) historical control. Two of the three trial subjects who relapsed after only five TPE responded again with additional TPE. The three latest subjects who responded to an augmented regimen of nine TPE plus rituximab plus IVIG have had sustained responses without relapses after 96-to-237 days. Anti-HEp-2 autoantibodies were present in trial subjects prior to therapy, and were reduced by TPE among those who responded to treatment. Conversely, plasma MMP7 levels were not systematically affected by therapy nor correlated with clinical responses. One-year survival of trial subjects was 46+15% vs. 0% among historical controls. No serious adverse events were attributable to the experimental medications.ConclusionThis pilot trial indicates specific treatments that reduce autoantibodies might benefit some severely-ill AE-IPF patients. These findings have potential implications regarding mechanisms of IPF progression, and justify considerations for incremental trials of autoantibody-targeted therapies in AE-IPF patients.Trial RegistrationClinicalTrials.gov NCT01266317背景 特发性肺纤维化（idiopathic pulmonary fibrosis, IPF）的严重急性加重期（acute exacerbations, AE）目前尚无有效治疗手段，患者常在数日内死亡。近年研究表明自身抗体可能参与IPF的疾病进展。自身抗体介导的肺部疾病通常对糖皮质激素及非特异性药物治疗应答不佳，但常可通过针对性的自身抗体清除治疗获得缓解。本研究开展一项先导临床试验，旨在验证靶向自身抗体的治疗或许可使AE-IPF患者获益这一假说。 方法 本研究纳入11例无常规自身免疫性疾病证据的重症AE-IPF患者，予以治疗性血浆置换（therapeutic plasma exchanges, TPE）联合利妥昔单抗治疗，后续入组患者额外加用静脉注射免疫球蛋白（intravenous immunoglobulin, IVIG）。分别采用间接免疫荧光法与酶联免疫吸附试验（ELISA）检测血浆抗上皮细胞（HEp-2）自身抗体及基质金属蛋白酶7（matrix metalloproteinase-7, MMP7）水平。将本试验受试者的结局与20例在本试验开展前接受常规糖皮质激素治疗的历史对照AE-IPF患者进行对比。 结果 治疗后，9例试验受试者（占比82%）的肺气体交换功能得到改善，而历史对照组仅1例（占比5%）出现改善。3例仅接受5次TPE后复发的试验受试者，经追加TPE治疗后再次获得应答。3例接受强化治疗方案（9次TPE联合利妥昔单抗及IVIG）的最新入组受试者，在随访96至237天后仍维持应答且未出现复发。试验受试者治疗前即可检测到抗HEp-2自身抗体，治疗应答者的该抗体水平经TPE治疗后有所降低。与之相反，血浆MMP7水平未受治疗的系统性影响，亦与临床应答无相关性。试验受试者的1年生存率为46%±15%，而历史对照组为0%。本试验未出现与实验性治疗药物相关的严重不良事件。 结论 本项先导临床试验表明，降低自身抗体水平的特异性治疗或许可使部分重症AE-IPF患者获益。上述发现可为IPF进展的相关机制提供新的研究思路，同时支持开展针对AE-IPF患者的靶向自身抗体治疗的后续增量临床试验。 试验注册 ClinicalTrials.gov NCT01266317