Neutrophil CD64 as a marker of infection in patients treated with tocilizumab
Neutrophil CD64 as a marker of infection in patients treated with tocilizumab
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DOI：
10.1007/s10165-009-0223-8
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发表时间：
2009-12-01
影响因子：
2.2
通讯作者：
Tohma, Shigeto
中科院分区：
文献类型：
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作者：
Matsui, Toshihiro;Komiya, Akiko;Tohma, Shigeto
Tocilizumab是一种人源化抗人白细胞介素-6受体抗体，已被证明对类风湿性关节炎（RA）[1]、全身性特发性幼年关节炎[2]、克罗恩病[3]和Castleman病[4]具有治疗效果。然而，感染是托珠单抗治疗的主要不良反应。托珠单抗对感染反应中白细胞介素-6信号的抑制也可能防止发热诱导和急性期反应物如CRP的升高。我们之前报道了外周中性粒细胞表达的CD64 （FccR I）的定量是RA患者感染的有用标志物。中性粒细胞CD64的表达可因血管炎或间质性肺炎引起的并发症而上调，但不受RA疾病活动性的影响。CD64在中性粒细胞上的上调可以在任何病原体引起的感染中观察到，如细菌、病毒、真菌和分枝杆菌[5]。基于这一背景信息，我们监测了一位接受tocilizumab治疗4年的RA患者的中性粒细胞CD64，该患者反复遭受不同感染，但几乎没有发烧或CRP升高（图1）。一名53岁的RA女性患者从2003年7月开始接受tocilizumab （8mg /kg，每4周）的临床试验。患者的临床疾病活动性指数（CDAI，从2003年7月的148降至9月的93，再降至12月的35）有所下降，CRP保持在0.02 mg/dl以下。2004年1月，患者出现胃肠炎伴发热（38.4℃），CRP升高（4.16 mg/dl）。2004年2月，她主诉轻微喉咙痛和轻微发烧（37.2摄氏度）。我们怀疑是普通感冒，但经免疫检测咽拭子中A型流感抗原呈阳性。虽然CRP没有升高（0.05 mg/dl），但中性粒细胞CD64升高至5500分子/细胞（正常范围\2000[5]）。此后，患者出现支气管炎和上呼吸道感染，无发热或CRP升高，但再次出现CD64上调（约2800分子/细胞）。之后，尽管反复遭受不同的感染（上呼吸道感染、支气管炎、肠胃炎），但除了在临床试验之间中断tocilizumab治疗（CDAI爆发至133）和鼻窦炎手术期间外，她仍无CRP升高的发热症状。这两种情况都伴有短暂的RA耀斑。在未感染期间，CD64水平保持在400-1000分子/细胞，但每次感染发作都会导致比基线升高50%，尽管不一定超过正常上限。
Tocilizumab, a humanized antihuman interleukin-6 receptor antibody, has proven therapeutically effective for rheumatoid arthritis (RA)[1], systemic-onset juvenile idiopathic arthritis [2], Crohn’s disease [3] and Castleman’s disease [4]. However, infection is a major adverse effect of tocilizumab treatment. Inhibition by tocilizumab of interleukin-6 signaling in response to infection may also prevent fever induction and the elevation of acutephase reactants such as CRP. We previously reported that quantification of CD64 (FccR I) expressed on peripheral neutrophils is a useful marker for infection in patients with RA [5]. Neutrophil CD64 expression can be upregulated by complications due to vasculitis or interstitial pneumonia, but it is not affected by the disease activity of RA. Upregulation of CD64 on neutrophils can be observed in infections caused by any kind of pathogen, such as bacteria, viruses, fungi, and mycobacteria [5]. Based on this background information, we monitored neutrophil CD64 in an RA patient undergoing treatment with tocilizumab for 4 years who had repeatedly suffered from different infections but had little fever or elevated CRP (Fig. 1).A 53-year-old female patient with RA received tocilizumab (8 mg/kg, every 4 weeks) starting July 2003 in a clinical trial. She responded with a decrease in her clinical disease activity index (CDAI; from 148 in July to 93 in September to 35 in December of 2003), and her CRP remained less than 0.02 mg/dl. In January 2004, she had gastroenteritis with fever (38.4 C) and increased CRP (4.16 mg/dl). In February 2004, she complained of mild sore throat and slight fever (37.2 C). We suspected the common cold, but influenza A antigen in a pharyngeal swab tested positive by immunological detection. Although CRP was not elevated (0.05 mg/dl), neutrophil CD64 was increased to 5500molecules/cell (normal range\2000 [5]). Thereafter, she suffered bronchitis and upper respiratory tract infection without fever or increased CRP, but again with upregulated CD64 (approximately 2800 molecules/cell). Afterwards, despite repeatedly suffering different infections (upper respiratory tract infection, bronchitis, gastroenteritis), she remained afebrile without CRP elevation except for the periods when the tocilizumab treatment was interrupted between clinical trials (CDAI flared up to 133) and for sinusitis surgery. Both of these occasions were accompanied by transient RA flares. CD64 levels remained at 400–1000 molecules/cell during periods without infection, but each infectious episode led to [50% elevation from the baseline, although it did not necessarily exceed the normal upper limit.