Ghosh Debajyoti, Anderson John, Singh Umesh, Bernstein Cheryl K, Bernstein Jonathan A
Department of Internal Medicine, Division of Rheumatology, Allergy and Immunology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
AllerVie Health, Birmingham, Ala.
J Allergy Clin Immunol. 2025 Mar;155(3):947-955. doi: 10.1016/j.jaci.2024.11.035. Epub 2024 Dec 13.
Approximately 85% of hereditary angioedema (HAE) attacks are associated with prodromal symptoms.
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.
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).
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; log 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.
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.
约85%的遗传性血管性水肿（HAE）发作与前驱症状相关。
我们研究了在前驱期而非肿胀发作期用重组人C1酯酶抑制剂（rhC1-INH）治疗1型HAE-C1-INH患者的临床效果，以及治疗前后血液转录组基因和通路的相关变化。
一项2中心、非盲、病例交叉研究将5例1型HAE-C1-INH患者随机分为前驱期治疗组或发作期治疗组；在一名患者接受2次前驱期或2次HAE发作治疗后，他们交叉接受2次HAE发作或2次前驱期治疗。所有患者在前驱期或急性发作期用rhC1-INH治疗；（重组抗C1酯酶抑制剂，50 IU/kg体重，体重≥85 kg者最大剂量为4200 IU）。通过RNA测序进行分析的血样在以下时间点采集：（1）基线时，（2）前驱期治疗前后，（3）发作期治疗前后。通过Ingenuity Pathway Analysis（IPA；Qiagen公司）阐明差异表达基因和通路。
在前驱期用rhC1-INH治疗在预防进展为肿胀发作方面与急性发作期治疗同样有效。HAE前驱期与多种炎症性细胞外基质基因、神经肽和炎性小体成员基因（如SPARCL1、AGRP、NLRP9；对数变化倍数分别为4.1、3.9和3.0）的上调相关。TNF-α和IL-10是前驱期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。约42%的前驱期相关差异表达基因也与HAE发作相关。确定了HAE前驱期和发作期以枢纽基因为特征的富集基因网络（前驱期为ERK和VEGF，发作期为胰岛素和SERPINA1）。HAE前驱期和发作期共有的主要富集通路与中性粒细胞功能和前列腺素代谢相关。
对于有明确前驱期且既往会导致急性发作的1型HAE-C1-INH患者进行治疗，在临床和机制上可能是合理的。这种方法将代表HAE按需治疗管理的范式转变。
