Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
Department of Pediatrics, St. Marianna University School of Medicine, Kawasaki, Kanagawa, Japan.
Haemophilia. 2022 Sep;28(5):745-759. doi: 10.1111/hae.14602. Epub 2022 Jun 11.
Inhibitor-development is a serious complication in patients with haemophilia (PwH). Previous studies reported that therapeutic and genetic factors could be associated with these alloantibodies. Relevant clinical features such as genetic-background and different treatment regimens in Japan remain unclear, however.
To analyse a nation-wide Japanese registry for PwH, and to examine risk factors for inhibitor-development.
Newly diagnosed patients with haemophilia A (PwHA) or haemophilia B (PwHB) without inhibitors after 2007, and with treatment records traceable from 0 to 75 exposure days (ED), were enrolled in the Japan Hemophilia Inhibitor Study 2 (J-HIS2) initiated in 2008. Of 417 patients (340 PwHA, 77 PwHB) from 46 facilities, 83 (76 PwHA, 7 PwHB) were recorded with inhibitors by July 2020. Inhibitors were observed in 31.0% of severe PwHA, 8.0% moderate and 1.6% mild and in 17.1% of severe PwHB. The majority of inhibitors (89.7% in severe PwHA and 71.4% in severe PwHB) were detected on or before 25ED (median 12ED in PwHA and 19ED in PwHB). Genotyping in these severe patients identified an association between inhibitor-development and null variants of F8 (P < .01) or F9 (P < .05). A lower incidence of inhibitors was recorded in severe PwHA treated with prophylaxis than in those treated on-demand (P < .01). A past-history of intracranial-haemorrhage appeared to be associated with inhibitor-development, while FVIII-concentrates infusion and routine vaccination on the same day was not related to inhibitor-development.
The J-HIS2 study has identified significant clinical variables associated with inhibitor-development in Japanese PwH, consistent with other global studies.
抑制剂的产生是血友病患者（PwH）的严重并发症。既往研究报道治疗和遗传因素可能与这些同种抗体相关。然而，在日本，相关的临床特征，如遗传背景和不同的治疗方案，尚不清楚。
分析日本全国性血友病登记处的数据，以检查抑制剂产生的危险因素。
2007 年后新诊断的无抑制剂的血友病 A（PwHA）或血友病 B（PwHB）患者，且从 0 至 75 暴露日（ED）的治疗记录可追踪，于 2008 年纳入日本血友病抑制剂研究 2（J-HIS2）。在 46 家机构的 417 名患者（340 名 PwHA，77 名 PwHB）中，截至 2020 年 7 月有 83 名（76 名 PwHA，7 名 PwHB）记录有抑制剂。抑制剂在重度 PwHA 中观察到 31.0%，中度为 8.0%，轻度为 1.6%，重度 PwHB 中为 17.1%。大多数抑制剂（重度 PwHA 中为 89.7%，重度 PwHB 中为 71.4%）在 25ED 或之前检测到（PwHA 中为 12ED 中位数，PwHB 中为 19ED）。对这些重度患者的基因分型发现，抑制剂的产生与 F8 的无义突变（P<0.01）或 F9 的无义突变（P<0.05）相关。预防性治疗的重度 PwHA 记录的抑制剂发生率低于按需治疗的患者（P<0.01）。既往颅内出血史似乎与抑制剂的产生相关，而 FVIII 浓缩物输注和同一天常规接种与抑制剂的产生无关。
J-HIS2 研究确定了与日本 PwH 抑制剂产生相关的显著临床变量，与其他全球研究一致。
