目的:以皮肤 K5(Keratin 5)条件性敲除 Ncstn( Ncstnflox/ flox; K5- Cre)反常性痤疮(acne inversa，AI)小鼠模型为研究对象，采用白介素-36受体抑制剂Spesolimab进行治疗，为AI寻找新的治疗方法。 方法:对出生15d和30 d的( Ncstnflox/ flox; K5- Cre)小鼠及其同窝对照K5-Cre鼠进行单细胞测序并分析(每组3只，共12只)；将出生10d的( Ncstnflox/ flox; K5- Cre)小鼠随机分成两组，实验组皮下注射Spesolimab(10 μL/g/2 d)，对照组注射PBS，小鼠年龄为50 d时取材。使用苏木精－伊红染色法观察小鼠皮肤组织学改变，利用实时荧光定量PCR和蛋白免疫印迹法检测细胞因子以及炎症因子的相对表达量以评估疗效。 结果:与PBS组相比，治疗组小鼠脱毛减少，皮肤组织角化现象减轻，同时炎症细胞的浸润也有所减少。利用单细胞测序所检测出在AI小鼠中升高的细胞因子，在治疗组小鼠中的表达明显降低，如炎症细胞因子肿瘤坏死因子受体超家族成员9(tumor necrosis factor receptor superfamily member 9， Tnfrs9)( P＝0.002)。治疗组各炎症因子蛋白表达水平低于PBS对照组(均 P<0.05)。 结论:Spesolimab对AI小鼠模型有一定的治疗效果，可能为AI提供新的治疗思路。

Generalized pustular psoriasis (GPP) is a rare and life-threatening autoinflammatory skin disease characterized by recurrent and sudden episodes of widespread rashes with scattered sterile pustules. Clinical and genetic evidence indicates that the pathogenesis of GPP both overlaps and is separate from psoriasis vulgaris (PV). Interleukin (IL)-23/IL-17 immune pathway is well known to play a critical role in the immunopathogenesis of PV, while the inflammation of GPP is more inclined to involve the innate immune response via the IL-1/IL-36–chemokine pathway. Mutations in IL36RN, CARD13, AP1S3, MPO, TNIP1, SERPINA3, and SERPINA1 have been shown to be associated with GPP, among which loss-of-function mutation in IL36RN is the dominant mutation with the highest prevalence. Recent studies have shown that interaction of the IL-36 pathway and the IL-23/IL-17 axis underlies the immunological disturbances of GPP, indicating that innate and adaptive immune responses intertwine in the pathogenesis of GPP. With this deeper understanding of the pathogenesis of GPP, treatment by biologics targeting the IL-1/IL-36 pathway appears to be promising. IL-1 inhibitors, anakinra, canakinumab, and gevokizumab have reportedly been effective in some cases. Spesolimab and imsidolimab, which are antibodies to the IL-36 receptor, are undergoing investigation in a phase II trial and showing promising results. In the present review, we illustrate the current understanding of the pathogenesis of GPP based on recent updates on the molecular genetics and immunopathology of GPP and review recent clinical trials and case reports of novel biologics in the treatment of GPP.

目的 为佩索利单抗注射液应用于泛发性脓疱型银屑病(GPP)的治疗提供参考.方法 采用计算机检索PubMed、万方外文数据库、美国临床试验数据库等数据库自建库起至 2023 年 5 月 6 日的佩索利单抗注射液相关文献,总结其药代动力学、有效性研究、安全性研究、特殊人群与适用人群.结果 佩索利单抗可特异性地结合白细胞介素 36 受体,抑制其信号传导,已在美国、欧盟、日本、中国等多个国家/地区上市.向GPP患者单次静脉输注佩索利单抗注射液 900 mg后,抗药物抗体阴性患者的血药浓度-时间曲线下面积为 4 750[95%CI(4 510,4 970)](μg·d)/mL,达峰浓度为 238[95%CI(218,256)]μg/mL,表观分布容积为 6.4L,终末半衰期为25.5 d.给药 1 周后,佩索利单抗注射液组GPP医师总体评估量表(GPPGA)脓疱单项评分为 0 分和GPPGA总分为 0～1 分的患者占比均显著高于安慰剂组(54.29%比 5.56%,42.86%比 11.11%,P<0.05);给药 12 周后,多数接受佩索利单抗注射液治疗的患者的GPPGA脓疱单项评分为 0 分(60.0%),GPPGA总分为 0～1 分(60.0%).无严重不良事件发生,多为轻度或中度.佩索利单抗适用于成年GPP患者急性发作时的症状改善,慎用于妊娠期、哺乳期、婴幼儿及老人.结论 佩索利单抗注射液治疗GPP起效迅速,疗效明确,患者耐受性良好.