Department of Dermatology, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
Department of Dermatology, The Royal Marsden Hospital NHS Foundation Trust, London, UK.
Br J Dermatol. 2022 Dec;187(6):981-987. doi: 10.1111/bjd.21836. Epub 2022 Sep 6.
Checkpoint inhibitor (CPI) therapy has significantly improved overall survival in several cancers including metastatic melanoma (MM) and in the adjuvant setting. Cutaneous immune-related adverse events (irAEs) secondary to CPIs are commonly observed; however, autoimmune blistering disorders such as bullous pemphigoid (BP) are rare.
To review the prevalence, incidence risk, clinicopathological features and management of toxicity in bullous cutaneous irAEs associated with CPI therapy.
A multicentre, retrospective, observational study of CPI-associated bullous irAEs in adults with all cancers across four UK specialist centres between 2006 and 2019.
In total, 7391 patients were identified. CPI-associated bullous irAEs including BP (n = 16) occurred in 0·3% (n = 22). The median age of onset was 76 years, and there was a male predominance. Most patients had cutaneous melanoma (73%, n = 16), of which 81% (13 of 16) were BRAF wildtype. Grade 1, 2, 3 and 4 skin toxicity occurred in 9%, 45%, 41% and 5%, respectively. The mucosae were involved in 27%, and 25% of confirmed cases of BP did not present with bullae. The median time to onset of bullous irAEs was 12 months, with a median total symptom duration of 6 months. Single PD-1/PD-L1 agents had a longer time to onset of symptoms than combination therapy (median 12 vs. 7 months, respectively). Overall, 91%, 64% and 9% of patients required one, two or three lines of treatment, respectively. Two cases occurred after completion of CPIs (1 and 3 months). Of the 20 cases that presented while on CPIs this was permanently discontinued in 55% (11 of 20) and temporarily held in 20% (four of 20). In the four held cases of CPI, bullous eruption reflared in 50%.
CPI-associated bullous skin toxicity is a rare cutaneous irAE occurring in approximately 0·3% of cases over 13 years of treated patients in this series. Not all cases are diagnostic of BP, but management remains the same. There is a prolonged latency of onset compared with other cutaneous irAEs, with a median time of 12 months, and they can occur after cessation of therapy. Discontinuation of CPIs may be required. Recognizing bullous irAEs promptly and referral to dermatology are essential to optimize management and improve patient outcomes and tumour responses. What is already known about this topic? Checkpoint inhibitor (CPI)-associated bullous pemphigoid is a rare dermatological immune-related adverse event (irAE) that has been reported in small case series and reports. What does this study add? This is the largest multicentre, observational study conducted in the UK over the longest period of 13 years, which demonstrates an overall incidence of bullous cutaneous irAEs secondary to CPIs of 0·3%. Clinical presentation is variable, with one-quarter of patients with bullous pemphigoid presenting without bullae, and mucosal involvement was noted in 27%. Prolonged pruritus is frequently a prodromal symptom. The median time to diagnosis is 12 months and irAEs rarely present after cessation of treatment. Time to onset of symptoms is longer with a single CPI, but with a shorter duration of symptoms compared with combination CPI therapy. Most patients had cutaneous melanoma, of which 81% were BRAF wildtype.
检查点抑制剂（CPI）治疗显著改善了包括转移性黑色素瘤（MM）在内的多种癌症的总生存率，并且在辅助治疗中也有应用。CPI 治疗后常发生皮肤免疫相关不良事件（irAE），但自身免疫性大疱性疾病如大疱性类天疱疮（BP）较为罕见。
综述与 CPI 治疗相关的免疫相关大疱性皮肤毒性的发生率、发病风险、临床病理特征和治疗管理。
在四家英国专业中心，对 2006 年至 2019 年间所有癌症成人患者接受 CPI 治疗后发生的与 CPI 相关的免疫相关大疱性皮肤毒性进行了一项多中心、回顾性、观察性研究。
共确定了 7391 例患者。包括 BP（n=16）在内的 CPI 相关免疫相关大疱性皮肤毒性的发生率为 0.3%（n=22）。发病中位年龄为 76 岁，男性居多。大多数患者患有皮肤黑色素瘤（73%，n=16），其中 81%（13/16）为 BRAF 野生型。1 级、2 级、3 级和 4 级皮肤毒性分别占 9%、45%、41%和 5%。黏膜受累占 27%，确诊的 BP 病例中有 25%无大疱。免疫相关大疱性皮肤毒性的中位发病时间为 12 个月，中位总症状持续时间为 6 个月。单药 PD-1/PD-L1 治疗的症状发病时间长于联合治疗（分别为 12 个月和 7 个月）。总体而言，分别有 91%、64%和 9%的患者需要一线、二线或三线治疗。2 例在完成 CPI 治疗后（分别为 1 个月和 3 个月）出现。在 20 例接受 CPI 治疗期间出现的病例中，55%（11/20）永久性停用 CPI，20%（4/20）暂时停用。在 4 例暂时停用 CPI 的病例中，50%的大疱性皮疹再次发作。
与 CPI 治疗相关的大疱性皮肤毒性是一种罕见的皮肤免疫相关不良事件，在本研究中，13 年间接受治疗的患者中，大约 0.3%的患者出现该毒性。并非所有病例均诊断为 BP，但治疗方法相同。与其他皮肤免疫相关不良事件相比，发病潜伏期较长，中位时间为 12 个月，且可能在治疗停止后出现。可能需要停用 CPI。及时识别大疱性免疫相关不良事件并转至皮肤科就诊对于优化管理、改善患者结局和肿瘤应答至关重要。
CPI 相关大疱性类天疱疮是一种罕见的皮肤科免疫相关不良事件（irAE），已在小病例系列和报告中报道过。本研究增加了哪些新信息：这是英国最长时间（13 年）进行的最大规模多中心观察性研究，表明 CPI 继发免疫相关大疱性皮肤毒性的总发生率为 0.3%。临床表现多样，四分之一的大疱性类天疱疮患者无大疱，27%有黏膜受累。瘙痒常为前驱症状。中位诊断时间为 12 个月，irAE 很少在治疗停止后出现。症状发病时间更长，但与联合 CPI 治疗相比，症状持续时间更短。大多数患者患有皮肤黑色素瘤，其中 81%为 BRAF 野生型。
