ImmunoScience, Nordic Bioscience, Herlev Hovedgade 207, DK-2730, Herlev, Denmark.
Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen N, Denmark.
Arthritis Res Ther. 2021 Jan 7;23(1):13. doi: 10.1186/s13075-020-02378-7.
Associations between rheumatoid arthritis (RA) and effect of treatment at the tissue levels are poorly understood. We investigated the scope of released extracellular matrix (ECM) metabolites as a consequence of tissue remodelling in patients treated with methotrexate (MTX) and tocilizumab (TCZ) compared to placebo.
Tissue metabolites from 387 RA patients treated with either TCZ (8 mg/kg) or MTX monotherapy (7.5-20 mg/kg) were measured at baseline and 8 weeks sera by validated ELISA assays. The levels of collagen biomarkers (C1M, C2M, C3M and C4M) together with C-reactive protein (CRP) and CRP metabolite (CRPM) were investigated. Baseline levels of biomarkers have been compared with 72 age- and gender-matched healthy controls. Comparison between treatment and response groups were done by ANCOVA, Spearman's correlation and logistic regression adjusted for age, gender, BMI and disease duration.
C1M and C3M were significantly (P < 0.05) inhibited by TCZ and C3M by MTX (P < 0.01) compared to placebo. C1M and C3M inhibition with TCZ was respectively 23% and 16% greater than that of MTX (P < 0.01 and P < 0.0001). C4M was inhibited by TCZ and MTX, but the effect of TCZ was 22% greater than MTX (P < 0.0001). TCZ and MTX had minimal effect on C2M levels. MTX had no effect on CRP and CRPM, whereas TCZ reduced their levels to 69% and 27% from baseline. Investigated biomarkers revealed a significant (P < 0.05) difference in biomarker profiles of MTX ACR50 treatment responders and non-responders. Change to week 8 in levels of C3M, C4M, CRP and CRPM in MTX patients correlated significantly (rho = 0.41 to 0.18, P < 0.0001 to 0.039) with change in disease activity (DAS28) at weeks 8, 16 and 24, whereas only CRP in TCZ patients (rho = 0.32 to 0.21, P < 0.0001 to 0.01).
Patients receiving TCZ treatment for 8 weeks had higher suppression of tissue remodelling and inflammatory biomarkers over patients treated with MTX. Measured biomarkers enabled for a discrimination of biomarker profiles of ACR50 treatment responding patients and identification of those who benefit at the early time point. Week 8 change in levels of C3M, C4M, CRP and CRPM significantly predicted clinical response to treatment and correlated with DAS28 at all time points.
ClinicalTrials.gov, NCT00109408 . Date of registration: July 2005. Name of the registry: A Study to Assess the Safety and Efficacy of Tocilizumab in Patients with Active Rheumatoid Arthritis.
类风湿关节炎（RA）与组织水平治疗效果之间的关联尚未完全阐明。我们研究了接受甲氨蝶呤（MTX）和托珠单抗（TCZ）治疗与安慰剂相比，组织重塑导致细胞外基质（ECM）代谢物释放的范围。
通过验证的 ELISA 检测，在基线和第 8 周时，对 387 名接受 TCZ（8mg/kg）或 MTX 单药治疗（7.5-20mg/kg）的 RA 患者的组织代谢物进行测量。研究了胶原蛋白生物标志物（C1M、C2M、C3M 和 C4M）以及 C 反应蛋白（CRP）和 CRP 代谢物（CRPM）的水平。将生物标志物的基线水平与 72 名年龄和性别匹配的健康对照者进行了比较。通过 ANCOVA、Spearman 相关性和逻辑回归对年龄、性别、BMI 和疾病持续时间进行调整，对治疗和反应组进行了比较。
与安慰剂相比，TCZ 显著抑制了 C1M 和 C3M（P<0.05），MTX 显著抑制了 C3M（P<0.01）。与 MTX 相比，TCZ 对 C1M 和 C3M 的抑制作用分别高出 23%和 16%（P<0.01 和 P<0.0001）。C4M 被 TCZ 和 MTX 抑制，但 TCZ 的作用比 MTX 高 22%（P<0.0001）。TCZ 和 MTX 对 C2M 水平的影响最小。MTX 对 CRP 和 CRPM 没有影响，而 TCZ 将其水平降低至基线的 69%和 27%。研究的生物标志物显示，MTX ACR50 治疗反应者和无反应者的生物标志物谱有显著差异（P<0.05）。MTX 患者在第 8 周时，C3M、C4M、CRP 和 CRPM 水平的变化与第 8、16 和 24 周时疾病活动度（DAS28）的变化显著相关（rho 值为 0.41 至 0.18，P<0.0001 至 0.039），而在 TCZ 患者中仅 CRP 相关（rho 值为 0.32 至 0.21，P<0.0001 至 0.01）。
接受 TCZ 治疗 8 周的患者对组织重塑和炎症生物标志物的抑制作用高于接受 MTX 治疗的患者。测量的生物标志物能够区分 ACR50 治疗反应患者的生物标志物谱，并确定早期受益的患者。第 8 周时 C3M、C4M、CRP 和 CRPM 水平的变化可显著预测治疗反应，并与所有时间点的 DAS28 相关。
ClinicalTrials.gov，NCT00109408。注册日期：2005 年 7 月。注册名称：一项评估托珠单抗在活动性类风湿关节炎患者中的安全性和疗效的研究。
