Division of Cardiovascular Medicine, Department of Medicine, University of Cambridge, Cambridge, UK.
Department of Cardiology, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK.
Cardiovasc Res. 2022 Feb 21;118(3):872-882. doi: 10.1093/cvr/cvab113.
In pre-clinical models of acute myocardial infarction (MI), mature B cells mobilize inflammatory monocytes into the heart, leading to increased infarct size and deterioration of cardiac function, whilst anti-CD20 antibody-mediated depletion of B cells limits myocardial injury and improves cardiac function. Rituximab is a monoclonal anti-CD20 antibody targeted against human B cells. However, its use in cardiovascular disease is untested and is currently contraindicated. Therefore, we assessed the safety, feasibility, and pharmacodynamic effect of rituximab given to patients with acute ST-elevation MI (STEMI).
Rituximab in patients with acute ST-elevation myocardial infarction (RITA-MI) was a prospective, open-label, dose-escalation, single-arm, phase 1/2a clinical trial, which tested rituximab administered as a single intravenous dose in patients with STEMI within 48 h of symptom onset. Four escalating doses (200, 500, 700, and 1000 mg) were used. The primary endpoint was safety, whilst secondary endpoints were changes in circulating immune cell subsets including B cells, and cardiac and inflammatory biomarkers. A total of 24 patients were dosed. Rituximab appeared well tolerated. Seven serious adverse events were reported, none of which were assessed as being related to the rituximab infusion. Rituximab caused a mean 96.3% (95% confidence interval 93.8-98.8%) depletion of circulating B cells within 30 min of starting the infusion. Maximal B-cell depletion was seen at Day 6, which was significantly lower than baseline for all doses (P < 0.001). B-cell repopulation at 6 months was dose-dependent, with modulation of returning B-cell subsets. Immunoglobulin (IgG, IgM, and IgA) levels were not affected during the 6 months of follow-up.
A single infusion of rituximab appears safe when given in the acute STEMI setting and substantially alters circulating B-cell subsets. We provide important new insight into the feasibility and pharmacodynamics of rituximab in acute STEMI, which will inform further clinical translation of this potential therapy.
NCT03072199 at https://www.clinicaltrials.gov/.
在急性心肌梗死（MI）的临床前模型中，成熟 B 细胞将炎症性单核细胞募集到心脏，导致梗死面积增加和心功能恶化，而抗 CD20 抗体介导的 B 细胞耗竭则限制心肌损伤并改善心功能。利妥昔单抗是一种针对人类 B 细胞的单克隆抗 CD20 抗体。然而，其在心血管疾病中的应用尚未得到验证，目前被禁用。因此，我们评估了利妥昔单抗在急性 ST 段抬高型心肌梗死（STEMI）患者中的安全性、可行性和药效学效应。
急性 ST 段抬高型心肌梗死患者中的利妥昔单抗（RITA-MI）是一项前瞻性、开放标签、剂量递增、单臂、1/2a 期临床试验，该试验在症状发作后 48 小时内对 STEMI 患者单次静脉给予利妥昔单抗。使用了 4 个递增剂量（200、500、700 和 1000mg）。主要终点是安全性，次要终点是循环免疫细胞亚群（包括 B 细胞）和心脏及炎症生物标志物的变化。共对 24 名患者进行了给药。利妥昔单抗耐受性良好。报告了 7 例严重不良事件，均未评估与利妥昔单抗输注相关。利妥昔单抗在开始输注后 30 分钟内使循环 B 细胞平均减少 96.3%（95%置信区间 93.8-98.8%）。所有剂量在第 6 天达到最大 B 细胞耗竭，均显著低于基线（P<0.001）。6 个月时 B 细胞再增殖呈剂量依赖性，且返回的 B 细胞亚群也受到调节。在 6 个月的随访期间，免疫球蛋白（IgG、IgM 和 IgA）水平不受影响。
在急性 STEMI 环境中单次输注利妥昔单抗似乎是安全的，并且可显著改变循环 B 细胞亚群。我们为利妥昔单抗在急性 STEMI 中的可行性和药效学提供了重要的新见解，这将为该潜在疗法的进一步临床转化提供信息。
NCT03072199 于 https://www.clinicaltrials.gov/ 注册。
