Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.
UOC Reumatologia Clinica, ASST Pini-CTO, Dipartimento di Scienze Cliniche e di Comunità, Università degli Studi di Milano, Milan, Italy.
Adv Ther. 2019 Dec;36(12):3494-3502. doi: 10.1007/s12325-019-01118-x. Epub 2019 Oct 25.
Rheumatoid arthritis (RA) is a chronic systemic auto-immune disease associated with a prothrombotic state. Tocilizumab, an interleukin-6 receptor inhibitor, is highly effective in controlling disease activity and thrombotic risk. Factor XIII (FXIII), involved in thrombotic complications, has been reported to be reduced in RA patients during maintenance treatment with tocilizumab, but no data are available before and after the drug administration. Thus, we investigated the effects of tocilizumab on FXIII, thrombin generation and inflammation in patients with RA naïve for the drug.
We studied 15 consecutive adult patients with RA at baseline and 4 weeks after the onset of parenteral administration of tocilizumab, measuring disease activity and plasma levels of C-reactive protein (CRP), FXIII, and prothrombin fragments F1+2 by immunoenzymatic methods. Fifteen healthy subjects, sex-and age-matched with patients, served as normal controls for laboratory measurements.
At baseline, patients with established RA had a median DAS28 of 4.8 (3.2-8.3) and, compared to healthy controls, had higher plasma levels of CRP (p < 0.0001), FXIII (p = 0.017) and F1+2 (p < 0.0001). Four weeks after starting treatment with tocilizumab, based on the EULAR response criteria, eight patients were classifiable as responders and seven as non-responders. In responders, we observed a statistically significant reduction not only of the values of DAS28 and CRP (p = 0.012 for both), ut also of plasma levels of FXIII (p = 0.05) and F1+2 (p = 0.025). In non-responders, all the studied parameters were unchanged.
The decrease of FXIII and F1+2 levels after tocilizumab treatment observed only in those patients who responded to the drug indicates that the effect of tocilizumab on the prothrombotic state is linked to the control of inflammation and disease activity and not to a direct effect of the drug, thus contributing to the reduction of the cardiovascular risk.
类风湿关节炎（RA）是一种与血栓前状态相关的慢性系统性自身免疫性疾病。托珠单抗是一种白细胞介素-6 受体抑制剂，在控制疾病活动和血栓风险方面非常有效。FXIII（因子 XIII）参与血栓并发症，据报道，在接受托珠单抗维持治疗的 RA 患者中，FXIII 会降低，但在药物给药前后尚无数据。因此，我们研究了托珠单抗对初治 RA 患者 FXIII、凝血酶生成和炎症的影响。
我们研究了 15 例连续的成年 RA 患者，在开始接受托珠单抗静脉注射治疗后 4 周时测量疾病活动度和血浆 C 反应蛋白（CRP）、FXIII 和凝血酶片段 F1+2 的水平，采用免疫酶法。15 名性别和年龄匹配的健康受试者作为实验室测量的正常对照。
在基线时，确诊的 RA 患者的 DAS28 中位数为 4.8（3.2-8.3），与健康对照相比，他们的血浆 CRP 水平更高（p<0.0001）、FXIII（p=0.017）和 F1+2（p<0.0001）。在开始托珠单抗治疗 4 周后，根据 EULAR 反应标准，8 例患者可分类为应答者，7 例为无应答者。在应答者中，我们不仅观察到 DAS28 和 CRP 值显著降低（两者均为 p=0.012），还观察到 FXIII（p=0.05）和 F1+2（p=0.025）的血浆水平降低。在无应答者中，所有研究参数均无变化。
仅在对药物有反应的患者中观察到托珠单抗治疗后 FXIII 和 F1+2 水平降低，表明托珠单抗对血栓前状态的作用与控制炎症和疾病活动度有关，而不是与药物的直接作用有关，从而有助于降低心血管风险。
