PDF(Pubmed)
Abstract：
Neurological immune-related adverse events (irAE-n) are severe and potentially fatal toxicities of immune checkpoint inhibitors (ICI). To date, the clinical significance of neuronal autoantibodies in irAE-n is poorly understood. Here, we characterize neuronal autoantibody profiles in patients with irAE-n and compare these with ICI-treated cancer patients without irAE-n.
In this cohort study (DRKS00012668), we consecutively collected clinical data and serum samples of 29 cancer patients with irAE-n (n = 2 pre-ICI, n = 29 post-ICI) and 44 cancer control patients without irAE-n (n = 44 pre- and post-ICI). Using indirect immunofluorescence and immunoblot assays, serum samples were tested for a large panel of neuromuscular and brain-reactive autoantibodies.
IrAE-n patients and controls received ICI treatment targeting programmed death protein (PD-)1 (61% and 62%), programmed death ligand (PD-L)1 (18% and 33%) or PD-1 and cytotoxic T-lymphocyte-associated protein (CTLA-)4 (21% and 5%). Most common malignancies were melanoma (both 55%) and lung cancer (11% and 14%). IrAE-n affected the peripheral nervous system (59%), the central nervous system (21%), or both (21%). Prevalence of neuromuscular autoantibodies was 63% in irAE-n patients, which was higher compared to ICI-treated cancer patients without irAE-n (7%, p <.0001). Brain-reactive autoantibodies targeting surface (anti-GABABR, -NMDAR, -myelin), intracellular (anti-GFAP, -Zic4, -septin complex), or unknown antigens were detected in 13 irAE-n patients (45%). In contrast, only 9 of 44 controls (20%) presented brain-reactive autoantibodies before ICI administration. However, seven controls developed de novo brain-reactive autoantibodies after ICI initiation, therefore, prevalence of brain-reactive autoantibodies was comparable between ICI-treated patients with and without irAE-n (p = .36). While there was no clear association between specific brain-reactive autoantibodies and clinical presentation, presence of at least one of six selected neuromuscular autoantibodies (anti-titin, anti-skeletal muscle, anti-heart muscle, anti-LRP4, anti-RyR, anti-AchR) had a sensitivity of 80% (95% CI 0.52-0.96) and a specificity of 88% (95% CI 0.76-0.95) for the diagnosis of myositis, myocarditis, or myasthenia gravis.
Neuromuscular autoantibodies may serve as a feasible marker to diagnose and potentially predict life-threatening ICI-induced neuromuscular disease. However, brain-reactive autoantibodies are common in both ICI-treated patients with and without irAE-n, hence, their pathogenic significance remains unclear.
In this cohort study (DRKS00012668), we consecutively collected clinical data and serum samples of 29 cancer patients with irAE-n (n = 2 pre-ICI, n = 29 post-ICI) and 44 cancer control patients without irAE-n (n = 44 pre- and post-ICI). Using indirect immunofluorescence and immunoblot assays, serum samples were tested for a large panel of neuromuscular and brain-reactive autoantibodies.
IrAE-n patients and controls received ICI treatment targeting programmed death protein (PD-)1 (61% and 62%), programmed death ligand (PD-L)1 (18% and 33%) or PD-1 and cytotoxic T-lymphocyte-associated protein (CTLA-)4 (21% and 5%). Most common malignancies were melanoma (both 55%) and lung cancer (11% and 14%). IrAE-n affected the peripheral nervous system (59%), the central nervous system (21%), or both (21%). Prevalence of neuromuscular autoantibodies was 63% in irAE-n patients, which was higher compared to ICI-treated cancer patients without irAE-n (7%, p <.0001). Brain-reactive autoantibodies targeting surface (anti-GABABR, -NMDAR, -myelin), intracellular (anti-GFAP, -Zic4, -septin complex), or unknown antigens were detected in 13 irAE-n patients (45%). In contrast, only 9 of 44 controls (20%) presented brain-reactive autoantibodies before ICI administration. However, seven controls developed de novo brain-reactive autoantibodies after ICI initiation, therefore, prevalence of brain-reactive autoantibodies was comparable between ICI-treated patients with and without irAE-n (p = .36). While there was no clear association between specific brain-reactive autoantibodies and clinical presentation, presence of at least one of six selected neuromuscular autoantibodies (anti-titin, anti-skeletal muscle, anti-heart muscle, anti-LRP4, anti-RyR, anti-AchR) had a sensitivity of 80% (95% CI 0.52-0.96) and a specificity of 88% (95% CI 0.76-0.95) for the diagnosis of myositis, myocarditis, or myasthenia gravis.
Neuromuscular autoantibodies may serve as a feasible marker to diagnose and potentially predict life-threatening ICI-induced neuromuscular disease. However, brain-reactive autoantibodies are common in both ICI-treated patients with and without irAE-n, hence, their pathogenic significance remains unclear.
摘要：
未经证实：神经免疫相关不良事件（irAE-n）是免疫检查点抑制剂（ICI）的严重和潜在致命毒性。迄今为止,神经元自身抗体在irAE-n中的临床意义尚不清楚.这里,我们表征了irAE-n患者的神经元自身抗体谱,并将其与ICI治疗的无irAE-n的癌症患者进行了比较.
未经证实：在本队列研究（DRKS00012668）中，我们连续收集了29例患有irAE-n的癌症患者(n=2pre-ICI,n=29post-ICI)和44例未患有irAE-n的癌症对照患者(n=44在ICI前后)的临床数据和血清样本.使用间接免疫荧光和免疫印迹分析，对血清样本进行了大量神经肌肉和脑反应性自身抗体的检测.
未经批准：IrAE-n患者和对照组接受了针对程序性死亡蛋白（PD-）1（61％和62％）的ICI治疗，程序性死亡配体（PD-L）1（18％和33％）或PD-1和细胞毒性T淋巴细胞相关蛋白（CTLA-）4（21％和5％）。最常见的恶性肿瘤是黑色素瘤（55％）和肺癌（11％和14％）。IrAE-n影响周围神经系统（59％），中枢神经系统（21%），或两者（21％）。在irAE-n患者中，神经肌肉自身抗体的患病率为63%，与ICI治疗的没有irAE-n的癌症患者相比更高(7%，p<.0001)。靶向表面的脑反应性自身抗体（抗GABABR，-NMDAR,-髓鞘)，细胞内（抗GFAP，-Zic4，-隔膜复合物），在13例irAE-n患者(45%)中检测到未知抗原。相比之下,44例对照中只有9例(20%)在ICI给药前出现脑反应性自身抗体.然而,七个对照在ICI启动后发展了从头脑反应性自身抗体，因此,有和没有irAE-n的ICI治疗患者的脑反应性自身抗体患病率相当(p=.36).虽然特异性脑反应性自身抗体与临床表现之间没有明确的关联，存在至少一种选择的神经肌肉自身抗体（抗滴度，抗骨骼肌，抗心肌，抗LRP4，抗RyR，抗AchR）对诊断肌炎的敏感性为80％（95％CI0.52-0.96），特异性为88％（95％CI0.76-0.95），心肌炎,或者重症肌无力.
未经证实：神经肌肉自身抗体可作为诊断和潜在预测危及生命的ICI诱导的神经肌肉疾病的可行标志物。然而,脑反应性自身抗体在ICI治疗的有和没有irAE-n的患者中都很常见，因此，其致病意义仍不清楚。
未经证实：在本队列研究（DRKS00012668）中，
未经批准：IrAE-n患者和对照组接受了针对程序性死亡蛋白（PD-）1（61％和62％）的ICI治疗，
未经证实：神经肌肉自身抗体可作为诊断和潜在预测危及生命的ICI诱导的神经肌肉疾病的可行标志物。
