BACKGROUND Approximately 85% of hereditary angioedema (HAE) attacks are associated with prodromal symptoms. OBJECTIVE We investigated the clinical effect of treating HAE C1-esterase inhibitor (HAE-C1-INH) type 1 patients with recombinant human C1-INH (rhC1-INH) during their prodrome versus an active swelling episode and associated changes in blood transcriptomic genes and pathways before and after treatment. METHODS A 2-center, unblinded, case-crossover study randomly assigned 5 HAE-C1-INH type 1 patients to prodrome or attack treatment groups; after a patient was treated for either 2 prodromes or 2 HAE attacks, they were crossed over to be treated for 2 HAE attacks or 2 prodromes. All patients were treated during the prodrome or acute attack with rhC1-INH; (conestat alfa, 50 IU/kg body weight, maximum 4200 IU for body weight ≥85 kg). Blood samples for analysis by RNA sequencing were obtained (1) at baseline, (2) during the prodrome before and after treatment, and (3) during an attack before and after treatment. Differentially expressed genes and pathways were elucidated by Ingenuity Pathway Analysis (IPA; Qiagen). RESULTS Treatment during the HAE prodrome with rhC1-INH was as effective at preventing progression to a swelling episode as treatment of an acute attack. HAE prodromes were associated with upregulation of multiple inflammatory extracellular matrix genes, neuropeptide, and inflammasome member genes (eg, SPARCL1, AGRP, NLRP9; log2 fold change = 4.1, 3.9, and 3.0, respectively). TNF-α and IL-10 were 2 major hub genes in prodrome-associated enriched gene networks. rhC1-INH treatment resulted in reversal of the disease signature in HAE-associated dysregulated pathways. Approximately 42% of prodrome-associated differentially expressed genes were also associated with HAE attacks. The enriched gene networks with hub genes for prodrome (ERK and VEGF) and for acute attack (insulin and SERPINA1) stages of HAE were identified. The major enriched pathways shared between HAE prodrome and attack were associated with neutrophil function and prostaglandin metabolism. CONCLUSION Treatment of HAE-C1-INH type 1 patients who have a well-defined prodrome that historically results in an acute attack may be justified clinically and mechanistically. This approach would represent a paradigm shift for management of HAE on-demand treatment.

中文翻译：

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与活动性肿胀发作相比，遗传性血管性水肿前驱症状治疗前后的临床反应和相应的血液转录组途径。


背景 大约 85% 的遗传性血管性水肿 （HAE） 发作与前驱症状有关。目的 我们研究了重组人 C1-INH （rhC1-INH） 治疗 HAE C1-酯酶抑制剂 （HAE-C1-INH） 1 型患者前驱症状与活动性肿胀发作的临床效果，以及治疗前后血液转录组基因和通路的相关变化。方法 一项 2 中心、非盲、病例交叉研究 将 5 例 HAE-C1-INH 1 型患者随机分配到前驱或发作治疗组;在患者接受 2 次前驱症状或 2 次 HAE 发作治疗后，他们被交叉接受 2 次 HAE 发作或 2 次前驱症状的治疗。所有患者在前驱或急性发作期间均接受 rhC1-INH 治疗;（conestat alfa，50 IU/kg 体重，体重 ≥4200 kg） 最大 85 IU）。（1） 在基线时，（2） 在治疗前后的前驱期间，以及 （3） 在治疗前后的发作期间获得用于 RNA 测序分析的血样。通过 Ingenuity Pathway Analysis （IPA;Qiagen）。结果 在 HAE 前驱期用 rhC1-INH 治疗在预防进展为肿胀发作方面与治疗急性发作一样有效。HAE 前驱症状与多个炎症细胞外基质基因、神经肽和炎性小体成员基因 （例如，SPARCL1、AGRP、NLRP9;log2 倍数变化 = 4.1、3.9 和 3.0 的上调有关。TNF-α 和 IL-10 是前驱相关富集基因网络中的 2 个主要枢纽基因。rhC1-INH 治疗导致 HAE 相关失调通路中的疾病特征逆转。 大约 42% 的前驱症状相关差异表达基因也与 HAE 发作有关。确定了具有 HAE 前驱期 （ERK 和 VEGF） 和急性发作 （胰岛素和 SERPINA1） 期枢纽基因的富集基因网络。HAE 前驱症状和发作之间共享的主要富集途径与中性粒细胞功能和前列腺素代谢有关。结论 对于具有明确前驱症状且历史上导致急性发作的 HAE-C1-INH 1 型患者的治疗可能在临床和机制上是合理的。这种方法将代表 HAE 按需治疗管理的范式转变。