Department of Pediatric Hematology, Amsterdam UMC, Emma Children's Hospital, University of Amsterdam, Amsterdam, Netherlands.
Hematology Research Center, Nemazee Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.
Front Immunol. 2020 May 7;11:563. doi: 10.3389/fimmu.2020.00563. eCollection 2020.
In hemophilia A the presence of non-neutralizing antibodies (NNAs) against Factor VIII (FVIII) may predict the development of neutralizing antibodies (inhibitors) and accelerate the clearance of administrated FVIII concentrates. This systematic review aimed to assess: (1) the prevalence and incidence of NNAs in patients with congenital hemophilia without inhibitors and (2) the association between NNAs and patient and treatment characteristics. We conducted a search in MEDLINE, Embase, Web of Science and the Cochrane database. We included cross-sectional and longitudinal studies reporting on NNAs in patients with hemophilia A and B, who were inhibitor-negative at the start of the observation period. Data were extracted on: hemophilia type and severity, patient and treatment characteristics, NNA prevalence and incidence, NNA assays and inhibitor development. Two independent reviewers performed study selection, data extraction and risk of bias assessment, using adapted criteria of the Joanna Briggs Institute. Studies were classified as high-quality when ≥5/9 criteria were met. NNA assays were classified as high-quality when both quality criteria were met: (1) use of positive controls and (2) competition with FVIII to establish FVIII-specificity. We reported NNA prevalence and incidence for each study. The pooled NNA prevalence was assessed for well-designed studies in previously treated patients, employing high-quality NNA assays. We included data from 2,723 inhibitor-negative patients with hemophilia A, derived from 28 studies. Most studies were cross-sectional (19/28) and none reported on NNAs in hemophilia B. Study design was of high quality in 16/28 studies and the NNA assay quality was high in 9/28 studies. Various NNA assays were used, predominantly ELISA (18/28) with different cut-off values. We found a large variety in NNA prevalence (Range, 0-100%). The pooled NNA prevalence in high-quality studies was 25% (95% CI, 16-38%). The incidence of new NNA development was reported in one study (0.01 NNA per person-exposure day). This systematic review identified studies that were heterogeneous in study design, patient population and NNA assay type, with NNA prevalence ranging from 0 to 100% in inhibitor-negative patients with hemophilia A. The pooled NNA prevalence was 25% in high-quality studies including only previously treated patients and performing high-quality NNA assays.
在血友病 A 中，针对因子 VIII（FVIII）的非中和抗体（NNAs）的存在可能预测中和抗体（抑制剂）的发展，并加速给予的 FVIII 浓缩物的清除。本系统评价旨在评估：（1）无抑制剂的先天性血友病患者中 NNAs 的患病率和发生率；（2）NNAs 与患者和治疗特征之间的关系。我们在 MEDLINE、Embase、Web of Science 和 Cochrane 数据库中进行了检索。我们纳入了报告血友病 A 和 B 患者 NNAs 的横断面和纵向研究，这些患者在观察期开始时均为抑制剂阴性。提取的数据包括：血友病类型和严重程度、患者和治疗特征、NNAs 的患病率和发生率、NNAs 检测和抑制剂的发展。两名独立的审查员使用 Joanna Briggs 研究所的改编标准进行了研究选择、数据提取和偏倚风险评估。当满足≥5/9 项标准时，研究被归类为高质量。当满足以下两个质量标准时，NNAs 检测被归类为高质量：（1）使用阳性对照；（2）与 FVIII 竞争以建立 FVIII 特异性。我们报告了每项研究的 NNA 患病率和发生率。对于使用高质量 NNA 检测的先前治疗过的患者，评估了精心设计的研究中的 NNA 总患病率。我们纳入了 28 项研究中 2723 名无抑制剂的血友病 A 患者的数据。大多数研究为横断面研究（19/28），无一项研究报告血友病 B 中的 NNAs。28 项研究中有 16 项研究的设计质量较高，9 项研究的 NNA 检测质量较高。使用了各种 NNA 检测，主要是 ELISA（18/28），具有不同的截止值。我们发现 NNA 患病率存在很大差异（范围 0-100%）。高质量研究中 NNA 的总患病率为 25%（95%CI，16-38%）。一项研究报告了新的 NNA 发展的发生率（0.01 个 NNA 人暴露日）。本系统评价确定了研究设计、患者人群和 NNA 检测类型在异质性方面存在差异的研究，在无抑制剂的血友病 A 患者中，NNAs 的患病率范围为 0-100%。在包括仅接受过治疗的患者和进行高质量 NNA 检测的高质量研究中，NNAs 的总患病率为 25%。
