Department of Dermatology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
Department of Dermatology.
Br J Dermatol. 2022 Nov;187(5):650-658. doi: 10.1111/bjd.21708. Epub 2022 Jul 15.
The pathogenesis of pityriasis rubra pilaris (PRP) is not completely understood, but interleukin (IL)-17 has been shown to play a critical role. There are no reliable immunomodulatory agents to treat PRP. We conducted an open-label, single-arm clinical trial of secukinumab, a monoclonal antibody that inhibits IL-17A, for the treatment of PRP.
To evaluate the clinical efficacy of secukinumab and define the transcriptomic landscape of PRP and its response to IL-17A blockade.
Twelve patients with PRP were recruited for an open-label trial of secukinumab. Patients received a 24-week course of secukinumab. The primary endpoint was a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) from baseline to week 28. Secondary endpoints included PASI 90, change in Physician's Global Assessment (PGA), and change in Dermatology Life Quality Index (DLQI). RNA sequencing was performed on lesional and nonlesional skin biopsies obtained at baseline and week 2. Sample groups were compared to identify differential gene expression and pathway enrichment. This trial was registered with ClinicalTrials.gov: 'Cosentyx (secukinumab) for the treatment of adult onset pityriasis rubra pilaris' - NCT03342573.
At week 28, six of 11 patients (55%) achieved PASI 75, and three patients (27%) achieved PASI 90. PGA (P = 0.008) and DLQI scores (P = 0.010) showed significant improvement with treatment. No serious treatment-related adverse events were encountered. Treatment with secukinumab normalized transcriptional differences between lesional and nonlesional skin. Transcriptomic data from nonresponsive patients suggest that overactivity of innate immune pathways may be driving resistance to secukinumab.
Secukinumab appears to be an effective treatment for PRP and warrants further investigation. PRP is a transcriptionally heterogeneous disease, reflecting its variable response to therapy. Agents targeting other IL-17 isoforms and innate immune mediators should be considered for future clinical trials. What is already known about this topic? The pathogenesis of pityriasis rubra pilaris is incompletely understood. Successful treatment has been reported with a variety of immunomodulatory agents, but disease is often refractory to therapy. Interleukin (IL)-17 is thought to drive keratinocyte proliferation and vascular dysfunction in this disease. A previous trial demonstrated efficacy of the anti-IL-17A drug ixekizumab for pityriasis rubra pilaris. What does this study add? Herein we describe the findings of a clinical trial of secukinumab, an anti-IL-17A monoclonal antibody, for the treatment of pityriasis rubra pilaris. Secukinumab was effective in treating pityriasis rubra pilaris. Our transcriptomic data give new insight into the expressional changes that occur in response to secukinumab and suggest mechanisms of treatment resistance.
红斑性毛囊角化病（PRP）的发病机制尚不完全清楚，但白细胞介素（IL）-17 已被证明在其中发挥关键作用。目前尚无可靠的免疫调节剂可用于治疗 PRP。我们对白细胞介素-17A 抑制剂司库奇尤单抗治疗 PRP 进行了一项开放标签、单臂临床试验。
评估司库奇尤单抗的临床疗效，并确定 PRP 的转录组图谱及其对 IL-17A 阻断的反应。
招募了 12 名 PRP 患者参加司库奇尤单抗的开放标签试验。患者接受了 24 周的司库奇尤单抗治疗。主要终点是从基线到第 28 周时，银屑病面积和严重程度指数（PASI）减少≥75%。次要终点包括 PASI90、医师总体评估（PGA）变化和皮肤病生活质量指数（DLQI）变化。在基线和第 2 周时采集病变和非病变皮肤活检标本进行 RNA 测序。将样本组进行比较，以确定差异表达基因和通路富集。该试验在 ClinicalTrials.gov 注册：“Cosentyx（司库奇尤单抗）治疗成人发病性红斑性毛囊角化病”-NCT03342573。
在第 28 周时，11 名患者中有 6 名（55%）达到 PASI75，3 名患者（27%）达到 PASI90。PGA（P=0.008）和 DLQI 评分（P=0.010）在治疗后显著改善。未发生与治疗相关的严重不良事件。司库奇尤单抗治疗使病变和非病变皮肤之间的转录差异正常化。非应答患者的转录组数据表明，固有免疫途径的过度活跃可能是导致对司库奇尤单抗耐药的原因。
司库奇尤单抗似乎是治疗 PRP 的有效药物，值得进一步研究。PRP 是一种转录异质性疾病，反映了其对治疗的不同反应。未来的临床试验应考虑针对其他 IL-17 同工型和固有免疫介质的药物。
关于这个话题已经知道些什么？红斑性毛囊角化病的发病机制尚不完全清楚。已报道多种免疫调节剂成功治疗，但疾病常对治疗有抗性。白细胞介素（IL）-17 被认为在这种疾病中驱动角质形成细胞增殖和血管功能障碍。先前的一项试验表明抗 IL-17A 药物依奇珠单抗治疗红斑性毛囊角化病有效。
本研究有哪些新发现？本文描述了白细胞介素-17A 单克隆抗体司库奇尤单抗治疗红斑性毛囊角化病的临床试验结果。司库奇尤单抗治疗红斑性毛囊角化病有效。我们的转录组数据为司库奇尤单抗治疗后发生的表达变化提供了新的见解，并提示了治疗耐药的机制。
