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Abstract：
BACKGROUND: Idiosyncratic drug-induced neutropenia and agranulocytosis is seldom discussed in the literature, especially for new drugs such as biotherapies outside the context of oncology. In the present paper, we report and discuss the clinical data and management of this relatively rare disorder, with a focus on biotherapies used in autoimmune and auto-inflammatory diseases.
METHODS: A review of the literature was carried out using the PubMed database of the US National Library of Medicine. We searched for articles published between January 2010 and May 2019 using the following key words or associations: \"drug-induced neutropenia\", \"drug-induced agranulocytosis\", and \"idiosyncratic agranulocytosis\". We included specific searches on several biotherapies used outside the context of oncology, including: tumor necrosis factor (TNF)-alpha inhibitors, anti-CD20 agents, anti-C52 agents, interleukin (IL) 6 inhibitors, IL 1 inhibitors, and B-cell activating factor inhibitor.
RESULTS: Idiosyncratic neutropenia remains a potentially serious adverse event due to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia, and septic shock in approximately two-thirds of all hospitalized patients with grade 3 or 4 neutropenia (neutrophil count (NC) ≤ 0.5 × 109/L and ≤ 0.1 × 109/L, respectively). Over the last 20 years, several drugs have been strongly associated with the occurrence of idiosyncratic neutropenia, including antithyroid drugs, ticlopidine, clozapine, sulfasalazine, antibiotics such as trimethoprim-sulfamethoxazole, and deferiprone. Transient grade 1-2 neutropenia (absolute blood NC between 1.5 and 0.5 × 109/L) related to biotherapy is relatively common with these drugs. An approximate 10% prevalence of such neutropenia has been reported with several of these biotherapies (e.g., TNF-alpha inhibitors, IL6 inhibitors, and anti-CD52 agents). Grade 3-4 neutropenia or agranulocytosis and clinical manifestations related to sepsis are less common, with only a few case reports to date for most biotherapies. Special mention should be made of late onset and potentially severe neutropenia, especially following anti-CD52 agent therapy. During drug therapy, several prognostic factors have been identified that may be helpful when identifying \'susceptible\' patients. Older age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 109/L have been identified as poor prognostic factors. Idiosyncratic neutropenia should be managed depending on clinical severity, with permanent/transient discontinuation or a lower dose of the drug, switching from one drug to another of the same or another class, broad-spectrum antibiotics in cases of sepsis, and hematopoietic growth factors (particularly G-CSF).
CONCLUSIONS: Significant progress has been made in recent years in the field of idiosyncratic drug-induced neutropenia, leading to an improvement in their prognosis (currently, mortality rate between 5 and 10%). Clinicians must continue their efforts to improve their knowledge of these adverse events with new drugs as biotherapies.
METHODS: A review of the literature was carried out using the PubMed database of the US National Library of Medicine. We searched for articles published between January 2010 and May 2019 using the following key words or associations: \"drug-induced neutropenia\", \"drug-induced agranulocytosis\", and \"idiosyncratic agranulocytosis\". We included specific searches on several biotherapies used outside the context of oncology, including: tumor necrosis factor (TNF)-alpha inhibitors, anti-CD20 agents, anti-C52 agents, interleukin (IL) 6 inhibitors, IL 1 inhibitors, and B-cell activating factor inhibitor.
RESULTS: Idiosyncratic neutropenia remains a potentially serious adverse event due to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia, and septic shock in approximately two-thirds of all hospitalized patients with grade 3 or 4 neutropenia (neutrophil count (NC) ≤ 0.5 × 109/L and ≤ 0.1 × 109/L, respectively). Over the last 20 years, several drugs have been strongly associated with the occurrence of idiosyncratic neutropenia, including antithyroid drugs, ticlopidine, clozapine, sulfasalazine, antibiotics such as trimethoprim-sulfamethoxazole, and deferiprone. Transient grade 1-2 neutropenia (absolute blood NC between 1.5 and 0.5 × 109/L) related to biotherapy is relatively common with these drugs. An approximate 10% prevalence of such neutropenia has been reported with several of these biotherapies (e.g., TNF-alpha inhibitors, IL6 inhibitors, and anti-CD52 agents). Grade 3-4 neutropenia or agranulocytosis and clinical manifestations related to sepsis are less common, with only a few case reports to date for most biotherapies. Special mention should be made of late onset and potentially severe neutropenia, especially following anti-CD52 agent therapy. During drug therapy, several prognostic factors have been identified that may be helpful when identifying \'susceptible\' patients. Older age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 109/L have been identified as poor prognostic factors. Idiosyncratic neutropenia should be managed depending on clinical severity, with permanent/transient discontinuation or a lower dose of the drug, switching from one drug to another of the same or another class, broad-spectrum antibiotics in cases of sepsis, and hematopoietic growth factors (particularly G-CSF).
CONCLUSIONS: Significant progress has been made in recent years in the field of idiosyncratic drug-induced neutropenia, leading to an improvement in their prognosis (currently, mortality rate between 5 and 10%). Clinicians must continue their efforts to improve their knowledge of these adverse events with new drugs as biotherapies.
摘要：
背景：特异性药物诱导的中性粒细胞减少和粒细胞缺乏症在文献中很少讨论，特别是对于肿瘤学以外的新药，如生物疗法。在本论文中，我们报告并讨论了这种相对罕见的疾病的临床数据和管理，专注于自身免疫性和自身炎性疾病中使用的生物疗法。
方法：使用美国国家医学图书馆的PubMed数据库进行了文献综述。我们搜索了2010年1月至2019年5月之间发表的文章，使用以下关键词或关联：“药物诱导的中性粒细胞减少症”，“药物诱导的粒细胞缺乏症”，和“特殊粒细胞缺乏症”。我们包括对肿瘤学以外使用的几种生物疗法的特定搜索，包括:肿瘤坏死因子(TNF)-α抑制剂,抗CD20药物，抗C52药物,白细胞介素（IL）6抑制剂，IL1抑制剂，和B细胞活化因子抑制剂。
结果：特异性中性粒细胞减少症仍然是一种潜在的严重不良事件，原因是严重脓毒症合并严重的深部组织感染（例如，肺炎)，败血症,3级或4级中性粒细胞减少（中性粒细胞计数（NC）≤0.5×109/L和≤0.1×109/L，分别)。在过去的20年里,几种药物与特异性中性粒细胞减少症的发生密切相关，包括抗甲状腺药物,噻氯匹定,氯氮平,柳氮磺胺吡啶,抗生素如甲氧苄啶-磺胺甲恶唑，和延迟。与生物治疗相关的暂时性1-2级中性粒细胞减少症（绝对血液NC在1.5和0.5×109/L之间）在这些药物中相对常见。据报道，在这些生物疗法中，此类中性粒细胞减少症的患病率约为10％（例如，TNF-α抑制剂，IL6抑制剂，和抗CD52剂)。3-4级中性粒细胞减少或粒细胞缺乏症和与脓毒症相关的临床表现较少见，迄今为止，大多数生物疗法只有少数病例报告。应该特别提到迟发性和潜在的严重中性粒细胞减少症，特别是在抗CD52药物治疗之后。在药物治疗期间,已经确定了一些预后因素，这些因素在确定“易感”患者时可能是有帮助的。年龄较大（>65岁），败血症或休克，肾功能衰竭,中性粒细胞计数≤0.1×109/L已被确定为不良预后因素。特异性中性粒细胞减少症应根据临床严重程度进行管理，永久/短暂停药或较低剂量的药物，从一种药物切换到另一种相同或另一种药物，在脓毒症病例中使用广谱抗生素，和造血生长因子（特别是G-CSF）。
结论：近年来在特异性药物诱导的中性粒细胞减少症领域取得了重大进展，导致他们预后的改善(目前，死亡率在5%到10%之间)。临床医生必须继续努力，用新药作为生物疗法来提高他们对这些不良事件的认识。
方法：使用美国国家医学图书馆的PubMed数据库进行了文献综述。我们搜索了2010年1月至2019年5月之间发表的文章，使用以下关键词或关联：“药物诱导的中性粒细胞减少症”，“药物诱导的粒细胞缺乏症”，和“特殊粒细胞缺乏症”。我们包括对肿瘤学以外使用的几种生物疗法的特定搜索，包括:肿瘤坏死因子(TNF)-α抑制剂,抗CD20药物，抗C52药物,白细胞介素（IL）6抑制剂，IL1抑制剂，和B细胞活化因子抑制剂。
结果：特异性中性粒细胞减少症仍然是一种潜在的严重不良事件，原因是严重脓毒症合并严重的深部组织感染（例如，肺炎)，败血症,3级或4级中性粒细胞减少（中性粒细胞计数（NC）≤0.5×109/L和≤0.1×109/L，分别)。在过去的20年里,几种药物与特异性中性粒细胞减少症的发生密切相关，包括抗甲状腺药物,噻氯匹定,氯氮平,柳氮磺胺吡啶,抗生素如甲氧苄啶-磺胺甲恶唑，和延迟。与生物治疗相关的暂时性1-2级中性粒细胞减少症（绝对血液NC在1.5和0.5×109/L之间）在这些药物中相对常见。据报道，在这些生物疗法中，此类中性粒细胞减少症的患病率约为10％（例如，TNF-α抑制剂，IL6抑制剂，和抗CD52剂)。3-4级中性粒细胞减少或粒细胞缺乏症和与脓毒症相关的临床表现较少见，迄今为止，大多数生物疗法只有少数病例报告。应该特别提到迟发性和潜在的严重中性粒细胞减少症，特别是在抗CD52药物治疗之后。在药物治疗期间,已经确定了一些预后因素，这些因素在确定“易感”患者时可能是有帮助的。年龄较大（>65岁），败血症或休克，肾功能衰竭,中性粒细胞计数≤0.1×109/L已被确定为不良预后因素。特异性中性粒细胞减少症应根据临床严重程度进行管理，永久/短暂停药或较低剂量的药物，从一种药物切换到另一种相同或另一种药物，在脓毒症病例中使用广谱抗生素，和造血生长因子（特别是G-CSF）。
结论：近年来在特异性药物诱导的中性粒细胞减少症领域取得了重大进展，导致他们预后的改善(目前，死亡率在5%到10%之间)。临床医生必须继续努力，用新药作为生物疗法来提高他们对这些不良事件的认识。
