Farag Ahmed, Visvanathan Sudha, Bachelez Hervé, Morita Akimichi, Lebwohl Mark G, Barker Jonathan N, Choon Siew Eng, Burden A David, Tsai Tsen-Fang, Leparc Germán, Delic Denis, Lang Benjamin, Thoma Christian, Krueger James G
Boehringer Ingelheim Pharma, Biberach, Germany.
Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA.
J Invest Dermatol. 2025 Mar;145(3):573-582.e8. doi: 10.1016/j.jid.2024.05.034. Epub 2024 Jul 14.
EFFISAYIL 1 was a randomized, placebo-controlled study of spesolimab, an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare. Treatment with spesolimab led to more rapid pustular and skin clearance versus treatment with placebo in approximately half of the patients. In this study, we present histologic, transcriptomic, and proteomic analyses of lesional and nonlesional skin and whole-blood samples collected from EFFISAYIL 1. Treatment with spesolimab led to a transition toward a nonlesional profile, with a downregulation of gene expressions in the skin of IL-36 transcripts (IL36α, IL36β, IL36γ) and those associated with neutrophil recruitment (CXCL1, CXCL6, CXCL8), proinflammatory cytokines (IL6, IL19, IL20), and skin inflammation (DEFB4A, S100A7, S100A8). Changes were manifest at week 1 and sustained to week 8. At the systemic level, reductions in serum biomarkers of inflammation (IL-17, IL-8, IL-6) were sustained until 12 weeks after spesolimab treatment. Considerable overlap was observed in the spesolimab-induced changes in gene and protein expressions from skin and blood samples, demonstrating the molecular basis of the effects of spesolimab on controlling local and systemic inflammation. Data are consistent with the mode of action of spesolimab, whereby inhibition of the IL-36 pathway leads to subsequent reductions in the key local and systemic pathologic events associated with generalized pustular psoriasis flares.
EFFISAYIL 1是一项关于抗IL-36受体抗体斯佩索利单抗的随机、安慰剂对照研究，研究对象为出现泛发性脓疱型银屑病发作的患者。在大约一半的患者中，与安慰剂治疗相比，斯佩索利单抗治疗使脓疱和皮肤清除速度更快。在本研究中，我们展示了对从EFFISAYIL 1收集的皮损和非皮损皮肤以及全血样本进行的组织学、转录组学和蛋白质组学分析。斯佩索利单抗治疗导致向非皮损状态转变，皮肤中IL-36转录本（IL36α、IL36β、IL36γ）以及与中性粒细胞募集相关的基因（CXCL1、CXCL6、CXCL8）、促炎细胞因子（IL6、IL19、IL20）和皮肤炎症相关基因（DEFB4A、S100A7、S100A8）的表达下调。这些变化在第1周就很明显，并持续到第8周。在全身水平上，炎症血清生物标志物（IL-17、IL-8、IL-6）的降低在斯佩索利单抗治疗后12周内持续存在。在斯佩索利单抗诱导的皮肤和血液样本基因和蛋白质表达变化中观察到相当大的重叠，这证明了斯佩索利单抗控制局部和全身炎症作用的分子基础。数据与斯佩索利单抗的作用模式一致，即抑制IL-36途径会导致随后与泛发性脓疱型银屑病发作相关的关键局部和全身病理事件减少。
