RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
肿瘤坏死因子抑制剂增强皮质类固醇治疗与免疫检查点抑制剂相关的 Stevens-Johnson 综合征和中毒性表皮坏死松解症：一项前瞻性研究
英文原题：Tumor necrosis factor inhibitors enhance corticosteroid therapy for Stevens-Johnson syndrome and toxic epidermal necrolysis linked to immune checkpoint inhibitors: a prospective study.
查看英文原题
Tumor necrosis factor inhibitors enhance corticosteroid therapy for Stevens-Johnson syndrome and toxic epidermal necrolysis linked to immune checkpoint inhibitors: a prospective study.
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研究概要
糖皮质激素联合 TNFi 可显著促进 irEN 患者再上皮化，减少糖皮质激素用量，并降低急性死亡率，且不增加重大不良事件，为糖皮质激素单药治疗提供了一种更优的替代方案。炎症标志物和淋巴细胞亚群对于评估疾病活动度和预后具有重要价值。
研究思路结论见上方概要
背景
免疫相关表皮坏死松解症（irEN），包括Stevens-Johnson综合征（SJS）和中毒性表皮坏死松解症（TEN），是免疫检查点抑制剂的一种潜在致死性反应。最佳治疗策略仍未明确。本研究评估了皮质类固醇联合肿瘤坏死因子抑制剂（TNFi）治疗irEN患者的有效性和安全性。
方法
在这项单中心、前瞻性、观察性研究中，irEN患者接受皮质类固醇单药治疗或皮质类固醇与TNFi联合治疗（SJS使用依那西普，TEN使用英夫利西单抗）。主要终点为再上皮化时间，次要终点包括皮质类固醇暴露量、主要不良事件发生率、急性死亡率以及指示疾病活动度和预后的生物标志物。该研究已在中国临床试验注册中心注册（ChiCTR2100051052）。
结果
共纳入32例患者（21例SJS，11例TEN）；14例接受联合治疗，18例接受单用糖皮质激素治疗。IrEN通常在接受ICI给药1个周期后发生，中位潜伏期为16天。尽管联合治疗组的SCORTEN评分更高（3 vs. 2，p = 0.008），但这些患者的上皮再形成更快（14 vs. 21天；p < 0.001），糖皮质激素治疗持续时间更短（22 vs. 32天；p = 0.005），泼尼松累积剂量更低（1177 mg vs. 1594 mg；p = 0.073）。两组主要不良事件发生率相似。3例死亡由肺部感染或弥散性血管内凝血导致，两组死亡率均低于预测值。死亡率增加的潜在危险因素包括淋巴细胞亚群计数（CD4 + T细胞、CD8 + T细胞、NK 细胞）持续下降以及炎症标志物（血清铁蛋白、白细胞介素-6、TNF-α）持续升高。上皮再形成时间与体重指数呈负相关，与表皮剥脱面积及血清白细胞介素-6和TNF-α水平呈正相关。
展开英文摘要原文
METHODS
In this single-center, prospective, observational study, patients with irEN received either corticosteroid monotherapy or a combination therapy of corticosteroids and TNFi (etanercept for SJS, infliximab for TEN). The primary endpoint was re-epithelization time, with secondary endpoints including corticosteroid exposure, major adverse event incidence, acute mortality rates, and biomarkers indicating disease activity and prognosis. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2100051052).
RESULTS
Thirty-two patients were enrolled (21 SJS, 11 TEN); 14 received combination therapy and 18 received corticosteroid monotherapy. IrEN typically occurred after 1 cycle of ICI administration, with a median latency of 16 days. Despite higher SCORTEN scores in the combination group (3 vs. 2, p = 0.008), these patients experienced faster re-epithelization (14 vs. 21 days; p < 0.001), shorter corticosteroid treatment duration (22 vs. 32 days; p = 0.005), and lower prednisone cumulative dose (1177 mg vs. 1594 mg; p = 0.073). Major adverse event rates were similar between groups. Three deaths occurred due to lung infection or disseminated intravascular coagulation, with mortality rates for both groups lower than predicted. Potential risk factors for increased mortality included continuous reduction in lymphocyte subset counts (CD4 + T cells, CD8 + T cells, natural killer cells) and consistent rises in inflammatory markers (serum ferritin, interleukin-6, TNF-α). Re-epithelization time negatively correlated with body mass index and positively correlated with epidermal detachment area and serum levels of interleukin-6 and TNF-α.
CONCLUSIONS
Corticosteroids combined with TNFi markedly promote re-epithelization, reduce corticosteroid use, and decrease acute mortality in irEN patients without increasing major adverse events, offering a superior alternative to corticosteroid monotherapy. Inflammatory markers and lymphocyte subsets are valuable for assessing disease activity and prognosis.
论文信息
- 作者
- He CX、Guo L、Qu T、Jin HZ
- 单位
- Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China.China
- 文献类型
- 观察性研究 · 非美国政府资助研究
- 期刊
- Frontiers in immunology2024
- 原文标识
- PubMed 39170619 · DOI 10.3389/fimmu.2024.1421684
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