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State of Art of Idiosyncratic Drug-Induced Neutropenia or Agranulocytosis, with a Focus on Biotherapies.
J Clin Med 2019; 8(9)JC

Abstract

INTRODUCTION

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.

MATERIALS AND 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).

CONCLUSION

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.

Authors+Show Affiliations

Department of Internal Medicine, Medical Clinic B, University Hospital of Strasbourg, 67084 Strasbourg, France. emmanuel.andres@chru-strasbourg.fr.Department of Internal Medicine, Medical Clinic B, University Hospital of Strasbourg, 67084 Strasbourg, France.Department of Internal Medicine, Medical Clinic B, University Hospital of Strasbourg, 67084 Strasbourg, France.Departments of Internal Medicine, University Hospital of Oujda, 59000 Oujda, Morocco.Department of Internal Medicine, Medical Clinic B, University Hospital of Strasbourg, 67084 Strasbourg, France.Department of Rheumatology, University Hospital of Strasbourg, 67084 Strasbourg, France. Referral Center of Immune Cytopenias, University Hospital of Strasbourg, 67084 Strasbourg, France.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

31480527

Citation

Andrès, Emmanuel, et al. "State of Art of Idiosyncratic Drug-Induced Neutropenia or Agranulocytosis, With a Focus On Biotherapies." Journal of Clinical Medicine, vol. 8, no. 9, 2019.
Andrès E, Villalba NL, Zulfiqar AA, et al. State of Art of Idiosyncratic Drug-Induced Neutropenia or Agranulocytosis, with a Focus on Biotherapies. J Clin Med. 2019;8(9).
Andrès, E., Villalba, N. L., Zulfiqar, A. A., Serraj, K., Mourot-Cottet, R., & Gottenberg, A. J. (2019). State of Art of Idiosyncratic Drug-Induced Neutropenia or Agranulocytosis, with a Focus on Biotherapies. Journal of Clinical Medicine, 8(9), doi:10.3390/jcm8091351.
Andrès E, et al. State of Art of Idiosyncratic Drug-Induced Neutropenia or Agranulocytosis, With a Focus On Biotherapies. J Clin Med. 2019 Sep 1;8(9) PubMed PMID: 31480527.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - State of Art of Idiosyncratic Drug-Induced Neutropenia or Agranulocytosis, with a Focus on Biotherapies. AU - Andrès,Emmanuel, AU - Villalba,Noel Lorenzo, AU - Zulfiqar,Abrar-Ahmad, AU - Serraj,Khalid, AU - Mourot-Cottet,Rachel, AU - Gottenberg,And Jacques-Eric, Y1 - 2019/09/01/ PY - 2019/08/15/received PY - 2019/08/29/revised PY - 2019/08/29/accepted PY - 2019/9/5/entrez KW - B-cell activating factor (BAFF) inhibitor KW - IL1-inhibitor KW - IL6 inhibitor KW - agranulocytosis KW - anti-CD20 agent KW - anti-TNF-alpha agent KW - antibiotics as trimethoprim-sulfamethoxazole (cotrimoxazole), and deferiprone KW - antithyroid medications KW - auto-inflammatory disorder KW - autoimmune disease KW - biotherapy KW - clozapine KW - drug KW - idiosyncratic KW - infections KW - neutropenia KW - orphan disease KW - sulfasalazine KW - systemic vasculitis KW - ticlopidine JF - Journal of clinical medicine JO - J Clin Med VL - 8 IS - 9 N2 - INTRODUCTION: 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. MATERIALS AND 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). CONCLUSION: 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. SN - 2077-0383 UR - https://www.unboundmedicine.com/medline/citation/31480527/State_of_Art_of_Idiosyncratic_Drug-Induced_Neutropenia_or_Agranulocytosis,_with_a_Focus_on_Biotherapies DB - PRIME DP - Unbound Medicine ER -