New York University School of Medicine, New York, New York.
Albert Einstein College of Medicine, Bronx, New York.
J Am Coll Cardiol. 2020 Jul 21;76(3):292-302. doi: 10.1016/j.jacc.2020.05.045.
Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB).
Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB.
This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon's optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash.
By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4).
These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).
实验和临床证据支持巨噬细胞 Toll 样受体信号在母体抗 SSA/Ro 介导的先天性心脏传导阻滞（CHB）中的作用。
羟氯喹（HCQ）是一种口服的 Toll 样受体拮抗剂，广泛用于狼疮治疗，包括在怀孕期间使用，本研究评估其疗效以降低 CHB 的历史复发率 18%。
本多中心、开放性、单臂、2 期临床试验采用 Simon 的最优方法设计。招募了抗 SSA/Ro 阳性且既往妊娠并发 CHB 的母亲（第 1 阶段 n=19；第 2 阶段 n=35）。患者在妊娠 10 周前每天接受 400mg HCQ，直至妊娠结束。主要结局为整个孕期任何时间发生 2°或 3°CHB，次要结局包括孤立性心内膜弹力纤维增生症、出生时 1°CHB 和皮疹。
按意向治疗（ITT）分析，54 例可评估妊娠中有 4 例（7.4%；90%置信区间：3.4%至 15.9%）发生主要结局。因为 9 位母亲在入组后但在主要结局发生前使用了潜在的混杂药物（氟化糖皮质激素和/或静脉注射免疫球蛋白），为了单独评估 HCQ，又招募了 9 位母亲并遵循相同的方案。在仅暴露于 HCQ 的妊娠中进行的符合方案分析中，54 例妊娠中有 4 例（7.4%）胎儿发生主要结局。次要结局包括轻度心内膜弹力纤维增生症（n=1）和新生儿狼疮皮疹（n=4）。
这些前瞻性数据支持 HCQ 显著降低 CHB 的复发率至历史水平以下 50%以上，提示该药物应在抗 SSA/Ro 暴露的妊娠中用于胎儿心脏疾病的二级预防。（预防性羟氯喹治疗先天性心脏阻滞 [PATCH]；NCT01379573）。
