Tony H-P, Roll P, Mei H E, Blümner E, Straka A, Gnuegge L, Dörner T
Department of Rheumatology and Immunology, University of Würzburg, Germany.
Hospital for Rheumatology and Clinical Immunology Berlin, and DRFZ, Berlin, Germany.
Clin Exp Rheumatol. 2015 Nov-Dec;33(6):887-94. Epub 2015 Oct 30.
Identification of B cell biomarkers predictive of response prior to therapy with rituximab (RTX) and evaluation of the efficacy of long-term treatment in patients with rheumatoid arthritis (RA).
302 RA patients failing one TNFi were treated with two applications of 1000 mg RTX (FIRST study). During the follow-up study (ReFIRST) the patients were treated for up to three more courses if they showed measurable clinical response but RA was still active. In a substudy on 154 RA patients peripheral B cell subsets were determined by flow cytometry before starting RTX. Rheumatoid factor (RF), RF-isotypes and anti-citrullinated protein antibodies (ACPA) were also measured.
Based on multivariate analyses patients with positive RF and normal (>lower limit) levels of CD19⁺ B cells (RF⁺CD19⁺) showed better treatment effects compared to patients who had only one or none of those parameters. Considering the RF status of the patients, analysis of B cell subpopulations yielded a correlation between higher ER rates and "double negative" CD19+CD27⁻IgD⁻ B cells. Lowest ER rates were observed for RF negative patients in combination with low numbers of CD19⁺CD27⁻IgD⁻ B cells as independent risk factors, thus defining a group with lower responses. Conversely, higher CD19⁺CD27⁻IgD⁻ B cells identified a responder group within RF negative patients.
The data of this large biomarker study suggest that beyond RF positivity, normal levels of CD19⁺ B cells together with increased CD19⁺CD27⁻IgD⁻ B cells predict response to RTX in RA, in particular when all parameters were present.
鉴定在使用利妥昔单抗（RTX）治疗前可预测反应的B细胞生物标志物，并评估类风湿关节炎（RA）患者长期治疗的疗效。
302例对一种肿瘤坏死因子抑制剂（TNFi）治疗无效的RA患者接受了两次1000mg RTX治疗（FIRST研究）。在随访研究（ReFIRST）中，如果患者显示出可测量的临床反应但RA仍处于活动期，则对其进行最多三个疗程的额外治疗。在一项针对154例RA患者的子研究中，在开始RTX治疗前通过流式细胞术测定外周血B细胞亚群。还检测了类风湿因子（RF）、RF亚型和抗瓜氨酸化蛋白抗体（ACPA）。
基于多变量分析，与仅具有其中一个或不具有这些参数的患者相比，RF阳性且CD19⁺B细胞水平正常（>下限）（RF⁺CD19⁺）的患者显示出更好的治疗效果。考虑患者的RF状态，对B细胞亚群的分析显示较高的缓解率与“双阴性”CD19⁺CD27⁻IgD⁻B细胞之间存在相关性。RF阴性患者与低数量的CD19⁺CD27⁻IgD⁻B细胞联合作为独立危险因素时观察到最低的缓解率，从而确定了一个反应较低的组。相反，较高的CD19⁺CD27⁻IgD⁻B细胞在RF阴性患者中确定了一个反应者组。
这项大型生物标志物研究的数据表明，除了RF阳性外，CD19⁺B细胞的正常水平以及CD19⁺CD27⁻IgD⁻B细胞的增加可预测RA患者对RTX的反应，特别是当所有参数都存在时。
