The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers
The TTTT B lymphocyte stimulator promoter haplotype is associated with good response to rituximab therapy in seropositive rheumatoid arthritis resistant to tumor necrosis factor blockers
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DOI：
10.1002/art.37707
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发表时间：
2013-01-01
影响因子：
--
通讯作者：
De Vita, Salvatore
中科院分区：
文献类型：
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作者：
Fabris, Martina;Quartuccio, Luca;De Vita, Salvatore
目的探讨类风湿关节炎（RA）患者B淋巴细胞刺激因子（BLyS）基因启动子区多态性与利妥昔单抗（RTX）疗效的关系。方法本研究首先在152例意大利RA患者中进行，然后在另外117例RA患者（73例意大利人，44例英国人）中重复。使用欧洲抗风湿联盟反应标准评估RTX第一个周期后第4个月和第6个月的反应率，通过使用红细胞沉降率对28个关节进行疾病活动性评分;根据第4个月和第6个月之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，然后分析限制性片段，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试验分析BLyS血清水平。计算比值比（OR）和95%置信区间（95% CI）。结果TTTT BLyS启动子单倍型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）中与RTX反应显著相关。复制研究证实，这种关联仅限于血清阳性的RA患者，在这些患者中，抗肿瘤坏死因子（抗TNF）药物治疗失败。在抗TNF药物治疗失败的血清学阳性患者中，携带TTTT BLyS启动子单倍型的患者在良好应答者中更常见。（43例中的18例[41.9%]）（20/83 [24.1%]）或无应答者（1/21 [4.8%]）（良好应答者vs无应答者，OR 14.4 [95% CI 1.77117.39]，P = 0.0028）。此外，多变量分析选择TTTT BLyS启动子单倍型作为RTX良好反应的独立标志物（对于良好反应者与无反应者，OR 16.2 [95%CI 1.7152.5]，P = 0.01;对于良好反应者与中度反应者和无反应者组合，OR 3.1 [95%CI 1.27.8]，P = 0.02）。BLyS多态性与血清BLyS水平之间的关系尚不清楚。结论BLyS启动子基因分型可能适用于血清学阳性的RA患者，这些患者在抗TNF药物治疗失败后可能对RTX有良好的反应。
Objective 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). Methods 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). Results 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 anticyclic citrullinated peptide). The replication study confirmed that this association was limited to seropositive RA patients in whom treatment with antitumor 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 1.77117.39], 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 1.7152.5], P = 0.01; for good responders versus moderate responders and nonresponders combined, OR 3.1 [95% CI 1.27.8], P = 0.02). The relationship between BLyS polymorphisms and BLyS serum levels remained unclear. Conclusion 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.