Melanoma Institute Australia, North Sydney, New South Wales, Australia.
Central Clinical School, The University of Sydney, Sydney, New South Wales, Australia.
J Immunother Cancer. 2020 Nov;8(2). doi: 10.1136/jitc-2020-001488.
Colitis is one of the common immune-related adverse events that leads to morbidity and treatment discontinuation of immunotherapy. The clinical presentation, endoscopic and histopathological features and best management of this toxicity are not well defined.
Patients with metastatic melanoma who received immunotherapy (programmed cell death protein 1 (PD1) antibodies, alone or in combination with a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody (PD1 +CTLA-4)) and who developed clinically significant colitis (requiring systemic corticosteroids) were identified retrospectively from two academic centers. Clinical data were collected for all patients; endoscopic and histopathological data were examined in a subset.
From May 2013 to May 2019, 118/1507 (7.8%) patients developed significant colitis; 80/553 (14.5%) after PD1+CTLA-4, 35/1000 (3.5%) PD1 alone, and three patients after Ipilimumab (IPI) alone. Combination therapy-induced colitis was more frequent (14.5% vs 3.5% in PD1 alone, p=<0.0001), had an earlier onset (6.3 weeks vs 25.7 weeks, p=<0.001), was more severe (grade 3/4 69% vs 31%, p=<0.001), and are more likely to require higher doses of steroids (91% vs 74%, p=0.01) than PD1 colitis. Among all patients treated with steroids (N=114), 54 (47%) responded and required no further therapy (steroid sensitive), 47 patients (41%) responded to infliximab (infliximab sensitive), and 13 (11%) were infliximab refractory and needed further immunosuppressive drugs. Infliximab-refractory patients all had onset within 4 weeks of immunotherapy commencement and were more likely to have an underlying autoimmune disease, have higher grade colitis, and require longer immunosuppression, yet had similar response and survival than other patients with colitis. Of 43 (37%) patients re-resumed treatment with PD1 monotherapy after colitis resolution, 16 (37%) of whom developed recurrent colitis. Endoscopic and histopathologic data were available for 64 patients. Most had left-sided colitis, with an increase in chronic inflammatory cells and neutrophils within the lamina propria, an increase in neutrophils in the surface epithelium, without increased lymphocytes or increased eosinophils. Infliximab-refractory colitis had a trend towards more confluent pancolitis with edema, erythema, ulceration, and absent vascularity with neutrophilic infiltration and erosion.
Clinically significant colitis varies in presentation, response to immunosuppression, and endoscopic/histologic features depending on the immunotherapy type. Infliximab-refractory colitis occurs early, is often high grade, and has adverse endoscopic and histopathologic features.
结肠炎是一种常见的免疫相关不良事件，可导致免疫治疗的发病率和治疗中断。这种毒性的临床表现、内镜和组织病理学特征以及最佳治疗方法尚未得到很好的定义。
我们回顾性地从两个学术中心确定了接受免疫治疗（程序性细胞死亡蛋白 1（PD1）抗体，单独或联合细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）抗体（PD1+CTLA-4））且出现临床显著结肠炎（需要全身皮质类固醇治疗）的转移性黑色素瘤患者。所有患者均收集临床数据；在亚组中检查内镜和组织病理学数据。
2013 年 5 月至 2019 年 5 月，118/1507（7.8%）名患者发生明显结肠炎；553/80（14.5%）例接受 PD1+CTLA-4 治疗，510/35（14.5%）例接受 PD1 治疗，3 例接受 Ipilimumab（IPI）单药治疗。联合治疗诱导的结肠炎更为常见（PD1+CTLA-4 组 14.5% vs PD1 单药组 3.5%，p<0.0001），发病更早（6.3 周 vs 25.7 周，p<0.001），更为严重（3/4 级 69% vs 31%，p<0.001），更需要更高剂量的类固醇（91% vs 74%，p=0.01）。在所有接受类固醇治疗的患者（N=114）中，54 名（47%）患者对治疗有反应且无需进一步治疗（类固醇敏感），47 名患者（41%）对英夫利昔单抗有反应（英夫利昔单抗敏感），13 名患者（11%）对英夫利昔单抗无反应，需要进一步免疫抑制治疗（英夫利昔单抗难治性）。英夫利昔单抗难治性患者均在免疫治疗开始后 4 周内发病，且更可能患有自身免疫性疾病，结肠炎分级更高，需要更长时间的免疫抑制治疗，但与其他结肠炎患者的反应和生存情况相似。在结肠炎缓解后重新开始 PD1 单药治疗的 43 名（37%）患者中，16 名（37%）患者出现复发性结肠炎。64 名患者可获得内镜和组织病理学数据。大多数为左半结肠炎，固有层慢性炎症细胞和中性粒细胞增多，表面上皮中性粒细胞增多，淋巴细胞和嗜酸性粒细胞无增多。英夫利昔单抗难治性结肠炎有融合性全结肠炎的趋势，伴有水肿、红斑、溃疡、血管缺失和中性粒细胞浸润和侵蚀。
根据免疫治疗类型，临床显著结肠炎的表现、对免疫抑制治疗的反应和内镜/组织病理学特征各不相同。英夫利昔单抗难治性结肠炎发病早，常为重度，且具有不良的内镜和组织病理学特征。
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