Fabris Martina, Quartuccio Luca, Vital Ed, Pontarini Elena, Salvin Sara, Fabro Cinzia, Zabotti Alen, Benucci Maurizio, Manfredi Mariangela, Ravagnani Viviana, Biasi Domenico, Atzeni Fabiola, Sarzi-Puttini Piercarlo, Morassi Pia, Fischetti Fabio, Bazzicchi Laura, Saracco Marta, Pellerito Raffaele, Cimmino Marco, Carraro Valeria, Semeraro Angelo, Schiavon Franco, Caporali Roberto, Bortolotti Roberto, Govoni Marcello, Fogolari Federico, Tonutti Elio, Bombardieri Stefano, Emery Paul, De Vita Salvatore
DSMB, Azienda Ospedaliero Universitaria of Udine, Udine, Italy.
Arthritis Rheum. 2013 Jan;65(1):88-97. doi: 10.1002/art.37707.
To investigate the polymorphisms in the promoter region of the B lymphocyte stimulator (BLyS) gene as markers of response to rituximab (RTX) in rheumatoid arthritis (RA).
The study was first conducted in 152 Italian RA patients and then replicated in an additional 117 RA patients (73 Italian, 44 British). The European League Against Rheumatism response criteria were used to evaluate the response rate at months 4 and 6 after the first cycle of RTX, by means of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate; patients were classified according to the best response shown between months 4 and 6. BLyS promoter polymorphisms were analyzed by polymerase chain reaction followed by the analysis of the restriction fragments, BLyS promoter haplotypes were analyzed using the expectation-maximization algorithm, and BLyS serum levels were analyzed using enzyme-linked immunosorbent assay. Odds ratios (ORs) were calculated with 95% confidence intervals (95% CIs).
The TTTT BLyS promoter haplotype appeared to be significantly associated with response to RTX only in the subset of seropositive patients (those positive for rheumatoid factor and/or anti-cyclic citrullinated peptide). The replication study confirmed that this association was limited to seropositive RA patients in whom treatment with anti-tumor necrosis factor (anti-TNF) agents had previously failed. In the whole series of seropositive patients in whom anti-TNF agents had previously failed, patients carrying the TTTT BLyS promoter haplotype were more prevalent in good responders (18 of 43 [41.9%]) than in moderate responders (20 of 83 [24.1%]) or in nonresponders (1 of 21 [4.8%]) (for good responders versus nonresponders, OR 14.4 [95% CI 1.77-117.39], P=0.0028). Furthermore, multivariate analysis selected the TTTT BLyS promoter haplotype as an independent marker of good response to RTX (for good responders versus nonresponders, OR 16.2 [95% CI 1.7-152.5], P=0.01; for good responders versus moderate responders and nonresponders combined, OR 3.1 [95% CI 1.2-7.8], P=0.02). The relationship between BLyS polymorphisms and BLyS serum levels remained unclear.
BLyS promoter genotyping may be suitable for identifying seropositive RA patients who may have a good response to RTX after anti-TNF agents have failed.
研究B淋巴细胞刺激因子（BLyS）基因启动子区域的多态性，作为类风湿关节炎（RA）患者对利妥昔单抗（RTX）反应的标志物。
该研究首先在152例意大利RA患者中进行，然后在另外117例RA患者（73例意大利患者，44例英国患者）中重复进行。采用欧洲抗风湿病联盟反应标准，通过28个关节疾病活动评分（使用红细胞沉降率）评估RTX第一周期后第4个月和第6个月的反应率；根据第4个月至第6个月期间显示的最佳反应对患者进行分类。通过聚合酶链反应分析BLyS启动子多态性，随后分析限制性片段，使用期望最大化算法分析BLyS启动子单倍型，并使用酶联免疫吸附测定法分析BLyS血清水平。计算比值比（OR）及其95%置信区间（95%CI）。
仅在血清阳性患者亚组（类风湿因子和/或抗环瓜氨酸肽阳性患者）中，TTTT BLyS启动子单倍型似乎与对RTX的反应显著相关。重复研究证实，这种关联仅限于先前使用抗肿瘤坏死因子（抗TNF）药物治疗失败的血清阳性RA患者。在先前抗TNF药物治疗失败的所有血清阳性患者中，携带TTTT BLyS启动子单倍型的患者在良好反应者中更为常见（43例中的18例[41.9%]），而在中度反应者中（83例中的20例[24.1%]）或无反应者中（21例中的1例[4.8%]）则较少（良好反应者与无反应者相比，OR为14.4[95%CI为1.77 - 117.39]，P = 0.0028）。此外，多变量分析选择TTTT BLyS启动子单倍型作为对RTX良好反应的独立标志物（良好反应者与无反应者相比，OR为16.2[95%CI为1.7 - 152.5]，P = 0.01；良好反应者与中度反应者和无反应者合并相比，OR为3.1[95%CI为1.2 - 7.8]，P = 0.02）。BLyS多态性与BLyS血清水平之间的关系仍不清楚。
BLyS启动子基因分型可能适用于识别在抗TNF药物治疗失败后可能对RTX有良好反应的血清阳性RA患者。
