Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials.
Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials.
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DOI：
10.1093/rheumatology/kew370
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发表时间：
2017-04-01
期刊：
影响因子：
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通讯作者：
Genovese MC
中科院分区：
文献类型：
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作者：
Moots RJ;Sebba A;Rigby W;Ostor A;Porter-Brown B;Donaldson F;Dimonaco S;Rubbert-Roth A;van Vollenhoven R;Genovese MC
目标。旨在调查接受 IL-6 受体-α 抑制剂托珠单抗 (TCZ) 治疗的 RA 患者中性粒细胞计数的变化和感染发生情况。 方法。数据来自接受静脉注射的患者。 3/4 期临床试验、长期扩展或药理学研究中的 TCZ（4 mg/kg + MTX、8 mg/kg ± DMARD、10 mg/kg）或安慰剂 + DMARD。根据不良事件通用毒性标准等级常规测量中性粒细胞计数；必要时调整 TCZ 剂量。通过多变量回归分析评估与中性粒细胞计数减少相关的协变量。中性粒细胞计数变化后 30 天内的感染率按每 100 患者年 TCZ 暴露计算。 结果。在试验的安慰剂对照部分中，接受 TCZ 治疗的患者多于接受安慰剂治疗的患者，其中性粒细胞计数为 1/2 或 3/4 级（TCZ：28.2%/3.1%；安慰剂：8.9%/0.2%）。在安慰剂对照试验+长期扩展中，4171 名患者提供了 16204.8 患者年的 TCZ 暴露。中性粒细胞计数在第 6 周从基线开始下降 [平均 (s.d.) 变化，–2.17 (2.16) × 109/l]，此后保持稳定。 30 天内严重感染率 (95% CI) 与正常 [4.66 (4.31, 5.03)]、1/2 级 [2.48 (1.79, 3.34)] 和 3/4 [2.77 (0.34, 10.01)] 中性粒细胞计数相似。基线中性粒细胞计数 <2 × 109/l 和女性与 3/4 级中性粒细胞计数相关 [比值比 (OR) (95% CI)：19.02 (6.76, 53.52)、2.55 (1.40, 4.66)]。因中性粒细胞计数减少而停止 TCZ 的患者比减少或继续服用剂量的患者更快恢复到正常水平。 结论。服用 TCZ 的患者中性粒细胞计数的减少似乎与严重感染无关，并且根据当前的风险缓解指南已正常化。
Objectives. To investigate changes in neutrophil count and occurrences of infection in RA patients treated with the IL-6 receptor-α inhibitor tocilizumab (TCZ). Methods. Data were pooled from patients who received i.v. TCZ (4 mg/kg + MTX, 8 mg/kg ± DMARDs, 10 mg/kg) or placebo + DMARDs in phase 3/4 clinical trials, long-term extensions or a pharmacology study. Neutrophil counts were measured routinely according to the Common Toxicity Criteria for Adverse Events grades; TCZ dosing was adjusted if necessary. Covariates associated with decreased neutrophil counts were assessed with multivariate regression analysis. Infection rates within 30 days of neutrophil count changes were calculated per 100 patient-years of TCZ exposure. Results. In placebo-controlled parts of trials, more TCZ-treated than placebo-treated patients had grade 1/2 or 3/4 neutrophil counts (TCZ: 28.2%/3.1%; placebo: 8.9%/0.2%). In placebo-controlled trials + long-term extensions, 4171 patients provided 16204.8 patient-years of TCZ exposure. Neutrophil counts decreased through week 6 from baseline [mean (s.d.) change, –2.17 (2.16) × 109/l) and remained stable thereafter. Rates (95% CI) of serious infections within 30 days of normal [4.66 (4.31, 5.03)], grade 1/2 [2.48 (1.79, 3.34)] and 3/4 [2.77 (0.34, 10.01)] neutrophil counts were similar. Baseline neutrophil count <2 × 109/l and female gender were associated with grade 3/4 neutrophil counts [odds ratio (OR) (95% CI): 19.02 (6.76, 53.52), 2.55 (1.40, 4.66)]. Patients who stopped TCZ in response to decreased neutrophil count returned more quickly to normal levels than patients who reduced or continued their dose. Conclusion. Decreases in neutrophil counts in patients taking TCZ do not appear to be associated with serious infections and are normalized by current risk mitigation guidelines.