Budesonide treatment for microscopic colitis from immune checkpoint inhibitors
Budesonide treatment for microscopic colitis from immune checkpoint inhibitors
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DOI：
10.1186/s40425-019-0756-0
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发表时间：
2019-11-07
影响因子：
10.9
通讯作者：
Dougan, Michael
中科院分区：
文献类型：
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作者：
Hughes, Michael S.;Molina, Gabriel E.;Dougan, Michael
免疫检查点抑制剂（CPI）对多种恶性肿瘤有效，但可能受到炎症毒性（如小肠结肠炎）的限制。小肠结肠炎通常用全身活性糖皮质激素治疗。内镜检查可以根据粘膜炎症的严重程度对患者进行分层，包括在没有可见粘膜变化的情况下识别结肠炎患者：显微镜下结肠炎。CPI显微镜下结肠炎患者是否可以与更严重的粘膜受累的结肠炎患者进行不同的治疗尚不清楚。本研究的目的是描述CPI显微镜下结肠炎的结局，重点关注布地奈德一线治疗的反应。方法我们评估了来自一家单中心大型学术医院的回顾性队列数据。参与者均为2017年3月至2019年3月期间通过内镜检查评估疑似CPI小肠结肠炎的成年患者。暴露为：马约内镜评分（范围0-3）。亚组为：口服布地奈德，最大剂量12 mg/天，至少给药5周。主要结局和指标为：主要：首次CPI暴露至首次使用糖皮质激素的时间;全身性糖皮质激素的使用;症状发作至消退的时间; CPI治疗的持续时间;接受额外CPI输注的次数。次要：为症状控制而入院;新发irAE;需要二线免疫抑制;肿瘤学结局。结果我们确定了38例活检证实CPI小肠结肠炎的患者，13例在显微镜下结肠炎队列中，25例在非显微镜下结肠炎队列中。显微镜下结肠炎队列中布地奈德使用率较高（12/13 vs 3/25，p < 0.001），非显微镜下结肠炎队列中全身糖皮质激素使用率较高（22/25 vs 3/13，p < 0.001）。从症状发作到消退的时间没有差异。显微镜下结肠炎患者在发生（肠）结肠炎后更频繁地保持CPI（76.9% vs 16.0%，p < 0.001）。耐受进一步CPI的显微镜下结肠炎患者比耐受CPI的非显微镜下结肠炎患者平均多接受4.2次CPI输注（5.8 vs 1.6，p = 0.03）。显微镜下结肠炎与至治疗失败时间（HR 0.30，95% CI 0.14-0.66）和无进展生存期（HR 0.22，95% CI 0.07-0.70）延长相关。结论无可见粘膜损伤的胃肠粘膜炎症是一种独特的、流行的CPI小肠结肠炎亚型，可通过内镜诊断。一线布地奈德在控制“显微镜下结肠炎”症状和延长免疫治疗持续时间方面似乎有效。这些发现为常规内镜评价疑似CPI小肠结肠炎提供了令人信服的依据，并为此类患者的一个子集提出了替代糖皮质激素保留治疗策略。
Background Immune checkpoint inhibitors (CPIs) are effective against a variety of malignancies but can be limited by inflammatory toxicities such as enterocolitis. Enterocolitis is typically treated with systemically active glucocorticoids. Endoscopy can stratify patients by the severity of mucosal inflammation, including identifying patients with colitis in the absence of visible mucosal changes: microscopic colitis. Whether patients with CPI microscopic colitis could be managed differently from colitis with more severe mucosal involvement is unclear. The objective of this study was to describe outcomes in CPI microscopic colitis focusing on the response to first line treatment with budesonide. Methods We evaluated data from a retrospective cohort from a single-center large academic hospital. The participants were all adult patients evaluated by endoscopy for suspected CPI enterocolitis between 3/2017 and 3/2019. The exposures were: Mayo Endoscopic Score (range 0-3). The subset was: oral budesonide, maximum dose 12 mg daily, administered minimum of 5 weeks. The main outcomes and measures were: Primary: time from first CPI exposure to first glucocorticoid use; use of systemic glucocorticoids; time from symptom onset to resolution; continuation of CPI therapy; number of additional CPI infusions received. Secondary: admissions for symptom control; novel irAE development; need for second-line immunosuppression; oncologic outcomes. Results We identified 38 patients with biopsy confirmed CPI enterocolitis, 13 in the microscopic colitis cohort, and 25 in the non-microscopic colitis cohort. Budesonide use was higher in the microscopic colitis cohort (12/13 vs 3/25, p < 0.001), and systemic glucocorticoid use was higher in non-microscopic colitis (22/25 vs. 3/13, p < 0.001). Time from symptom onset to resolution did not differ. Microscopic colitis patients more frequently remained on CPI after developing (entero)colitis (76.9% vs 16.0%, p < 0.001). Microscopic colitis patients tolerating further CPI received, on average, 4.2 CPI infusions more than non-microscopic colitis patients tolerating CPI (5.8 vs 1.6, p = 0.03). Microscopic colitis was associated with increased time-to-treatment-failure (HR 0.30, 95% CI 0.14-0.66) and progression-free survival (HR 0.22, 95% CI 0.07-0.70). Conclusions Gastrointestinal mucosal inflammation without visible mucosal injury is a distinct, prevalent CPI enterocolitis subset that can be diagnosed by endoscopy. First-line budesonide appears effective in controlling "microscopic colitis" symptoms and prolonging immunotherapy duration. These findings present a compelling rationale for routine endoscopic evaluation of suspected CPI enterocolitis and suggest an alternative glucocorticoid-sparing treatment strategy for a subset of such patients.