免疫检查点抑制剂相关类天疱疮文献病例分析

Literature and case analysis of pemphigoid caused by immune checkpoint inhibitors

目的了解免疫检查点抑制剂(ICI)相关类天疱疮的临床特点。方法检索国内外相关数据库(截至2021年10月15日),收集ICI致类天疱疮的病例报告类文献,提取患者相关信息(性别、年龄、肿瘤类型、使用的ICI药物、类天疱疮潜伏期、主要症状、分布部位、活检及免疫检查情况、治疗及转归等)进行描述性分析。结果共纳入相关文献82篇,涉及患者103例,男性72例,女性31例,年龄30~90岁,其中≥60岁者82例(79.6%);原发疾病为黑色素瘤者45例(43.7%),肺癌29例(28.2%)。103例患者共涉及6个品种的ICI,包括PD-1抑制剂帕博利珠单抗(47例,45.6%)、纳武利尤单抗(44例,42.7%)和特瑞普利单抗(4例,3.9%);PD-L1抑制剂阿特珠单抗(3例,2.9%)、度伐利尤单抗(2例,1.9%)和CTLA-4抑制剂伊匹木单抗(3例,2.9%)。84例患者有开始应用ICI至发生类天疱疮的时间记录,帕博利珠单抗为3~850 d,纳武利尤单抗为21~790 d,特瑞普利单抗为70~728 d。103例患者中,类天疱疮类型为大疱性类天疱疮者88例(85.4%),黏膜类天疱疮8例(7.8%),非大疱性类天疱疮4例(3.9%),汗疱疹样型类天疱疮1例(1.0%);临床表现为大疱、水疱样皮损98例(95.1%),皮疹51例(49.5%)和瘙痒48例(45.6%)等。94例患者有皮肤活检结果记录,78例(83.0%)病变部位可见嗜酸粒细胞浸润;92例(97.8%)进行了免疫学检查,其中63例(68.5%)为IgG沉积和C3沉积。53例患者有类天疱疮相关抗原抗体检测结果记录,检测抗原共35例,其中检测BP180者25例,24例阳性;同时检测BP180和BP230者8例,其中6例2项均阳性,2例BP180阳性而BP230阴性;检测BP-Ag2者2例,均阳性。经糖皮质激素或免疫抑制剂治疗和/或停用ICI等措施,103例患者中86例(83.5%)好转,6例未见好转;8例死亡,其中7例类天疱疮好转但死于其他病因,1例死因未报道;9例未报道结局。结论使用ICI类药物可致类天疱疮,老年人发生率高,潜伏期不一,最短3 d,最长可达2年以上;经糖皮质激素或免疫抑制剂治疗和/或停用ICI等措施,多数预后良好。

Objective To investigate the clinical characteristics of pemphigoid caused by immune checkpoint inhibitors(ICIs).Methods The relevant databases at home and abroad(up to October 15,2021)were searched and the case reports on pemphigoid caused by ICIs were collected.The relevant information of patients(gender,age,tumor type,drug varieties of ICIs,incubation period of pemphigoid,main symptoms,distribution site of lesions,biopsy and immunological examination,treatment and outcome,etc.)were collected and analyzed descriptively.Results A total of 82 relevant literature were included,involving 103 patients,72 males and 31 females,aged 30-90 years,of which 82(79.6%)were≥60 years old.The primary diseases were melanoma in 45 cases(43.7%)and lung cancer in 29 cases(28.2%).The 103 patients involved 6 varieties of ICI,including programmed cell death 1 receptors[pablizumab(47 cases,45.6%),navulizumab(44 cases,42.7%),and terepril(4 cases,3.9%)],and programmed cell death ligand 1 inhibitors[atezumab(3 cases,2.9%),duvalizumab(2 cases,1.9%)],and CTLA-4 inhibitor ipimamab(3 cases,2.9%).Eighty-four patients had a record of the time from the beginning of ICI to the occurrence(incubation period)of pemphigoid.The incubation period of pabolizumab was 3-850 days,of navulizumab was 21-790 days,and of terepril was 70-728 days.Among 103 patients,88(85.4%)were bullous pemphigoid,8(7.8%)were mucous pemphigoid,4(3.9%)were non bullous pemphigoid,and 1(1.0%)was dyshidrosiform pemphigoid;the clinical manifestations were bullous and vesicular lesions in 98 cases(95.1%),rash in 51 cases(49.5%),and pruritus in 48 cases(45.6%).Nine four patients had skin biopsy results,78 patients(83.0%)had eosinophil infiltration in the lesion site;immunological examination was performed in 92 cases(97.8%),of which 63 cases(68.5%)were IgG and C3 deposits.Thirty-five patients had pemphigoid associated antigen test records,BP180 was detected in 25 patients,and 24 patients(96%)were positive;BP180 and BP 230 were detected simultaneously in 8 cases,both were positive in 6 cases,and BP180 was positive and BP 230 was negative in the other 2 cases;BP-Ag2 was detected in 2 cases,all of them were positive.After treatment with glucocorticoid or immunosuppressant and/or withdrawal of ICIs,86(83.5%)of 103 patients were improved,and 6 were not;8 cases died,of which 7 cases of pemphigoid were improved but died of other causes,and 1 case died of unreported causes;9 cases did not report the outcome.Conclusions ICIs can cause pemphigoid,and the incidence in the elderly is higher.The incubation period of pemphigoid varies from 3 days to more than 2 years.After glucocorticoid or immunosuppressant treatment and/or withdrawal of ICIs,most patients had good prognosis.