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.
Front Immunol. 2024 Aug 7;15:1421684. doi: 10.3389/fimmu.2024.1421684. eCollection 2024.
Immune-related epidermal necrolysis (irEN), including Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), represents a potentially lethal reaction to immune checkpoint inhibitors. An optimal treatment strategy remains undefined. This study evaluates the effectiveness and safety of combination therapy with corticosteroids and tumor necrosis factor inhibitors (TNFi) in treating irEN patients.
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).
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.
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.
免疫相关的表皮坏死松解症（irEN），包括史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死松解症（TEN），是一种潜在的致命性免疫检查点抑制剂反应。目前仍未明确最佳的治疗策略。本研究评估了皮质类固醇和肿瘤坏死因子抑制剂（TNFi）联合治疗 irEN 患者的疗效和安全性。
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联合 TNFi 治疗（SJS 用依那西普，TEN 用英夫利昔单抗）。主要终点为再上皮化时间，次要终点包括皮质类固醇暴露、主要不良事件发生率、急性死亡率和反映疾病活动和预后的生物标志物。该研究在中国临床试验注册中心（ChiCTR2100051052）注册。
共纳入 32 例患者（21 例 SJS，11 例 TEN）；14 例接受联合治疗，18 例接受皮质类固醇单药治疗。irEN 通常在接受 ICI 治疗 1 个周期后发生，潜伏期中位数为 16 天。尽管联合组的 SCORTEN 评分更高（3 分 vs. 2 分，p = 0.008），但这些患者的再上皮化速度更快（14 天 vs. 21 天；p < 0.001），皮质类固醇治疗时间更短（22 天 vs. 32 天；p = 0.005），泼尼松累积剂量更低（1177 mg vs. 1594 mg；p = 0.073）。两组的主要不良事件发生率相似。3 例死亡归因于肺部感染或弥漫性血管内凝血，两组的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（CD4 T 细胞、CD8 T 细胞、自然杀伤细胞）计数持续减少和炎症标志物（血清铁蛋白、白细胞介素-6、TNF-α）持续升高。再上皮化时间与体重指数呈负相关，与表皮脱落面积和血清白细胞介素-6 和 TNF-α水平呈正相关。
皮质类固醇联合 TNFi 可显著促进 irEN 患者的再上皮化，减少皮质类固醇的使用，并降低急性死亡率，而不增加主要不良事件，是皮质类固醇单药治疗的更好选择。炎症标志物和淋巴细胞亚群可用于评估疾病活动和预后。
