类风湿关节炎患者FCGR2A/FCGR3A基因多态性和临床变量对Tocilizumab和Rituximab反应的预测

IF 2.9 4区 医学 Journal of Clinical Pharmacology Pub Date : 2019-04-01 Epub Date: 2018-11-20 DOI:10.1002/jcph.1341
Alberto Jiménez Morales, Mar Maldonado-Montoro, Juan Enrique Martínez de la Plata, Cristina Pérez Ramírez, Abdelali Daddaoua, Carolina Alarcón Payer, Manuela Expósito Ruiz, Carlos García Collado
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引用次数: 32

摘要

我们评估了临床、生化和遗传因素对142例诊断为类风湿关节炎患者反应的影响,其中87例患者接受托珠单抗治疗(61.26%),55例患者接受利妥昔单抗治疗(38.7%),根据欧洲抗风湿病联盟(EULAR)在6个月、12个月和18个月28个关节(DAS28)的反应、缓解、低疾病活动性和改善等变量。进行回顾性前瞻性队列研究。携带FCGR3A rs396991-TT基因型的患者接受tocilizumab治疗显示出更高的EULAR反应(OR, 5.075;95%置信区间,1.20 - -21.33;P = 0.027)在12个月时,那些在治疗开始时首次使用生物疾病改善抗风湿药物(bDMARDs)的患者在6个月时显示出令人满意的EULAR反应,更高的缓解和更大的DAS28改善。托珠单抗治疗开始时较年轻的年龄与18个月时令人满意的EULAR反应以及6和18个月时更大的缓解相关。皮下注射tocilizumab与6个月时更高的缓解和12个月时改善的低疾病活动率相关。在接受利妥昔单抗治疗的患者中,FCGR2A rs1801274-TT基因型携带者在6个月时具有更高的EULAR应答(OR, 4.861;95%置信区间,1.11 - -21.12;P = 0.035), 12个月(OR, 4.667;p = 0.066, 95%CI, 0.90-24.12;P = 0.066), 18个月(OR, 2.487;95%置信区间,0.35 - -17.31;P = .357),更高的缓解(OR: 10.625;p = 0.044, CI95%: 1.07, 105.47), 12个月时DAS28有较大改善(B = 0.782;95%CI, -0.15 ~ 1.71;P = 0.098)和18个月(B = 1.414;95%置信区间,0.19 - -2.63;P = .025)。FCGR3A rs396991-G等位基因与低疾病活动性的改善相关(OR, 4.904;95%置信区间,0.84 - -28.48;P = 0.077), DAS28有较大改善(B = -1.083;95%CI, -1.98 ~ -0.18;P = 0.021)。既往生物治疗次数较少的患者在12个月时有较高的缓解。我们认为FCGR3A rs396991-TT基因型、较高的DAS28基线值、皮下给药、较年轻的开始治疗年龄和bDMARD初发与对tocilizumab的更好反应相关。在接受利妥昔单抗治疗的患者中,我们发现FCGR2A rs1801274-TT基因型、FCGR3A rs396991-G等位基因的患者疗效更好,既往生物治疗次数较少。
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FCGR2A/FCGR3A Gene Polymorphisms and Clinical Variables as Predictors of Response to Tocilizumab and Rituximab in Patients With Rheumatoid Arthritis.

We evaluated the influence of clinical, biochemical, and genetic factors on response in 142 patients diagnosed with rheumatoid arthritis, of whom 87 patients were treated with tocilizumab (61.26%) and 55 patients were treated with rituximab (38.7%;) according to the variables European League Against Rheumatism (EULAR) response, remission, low disease activity, and improvement in Disease Activity Score, 28 joints (DAS28) at 6, 12, and 18 months. A retrospective prospective cohort study was conducted. Patients carrying the FCGR3A rs396991-TT genotype treated with tocilizumab showed higher EULAR response (OR, 5.075; 95%CI, 1.20-21.33; P = .027) at 12 months, those who were naive for biological disease-modifying antirheumatic drugs (bDMARDs) at the beginning of treatment showed satisfactory EULAR response, higher remission, and greater improvement in DAS28 at 6 months. Younger age at start of tocilizumab treatment was associated with satisfactory EULAR response at 18 months and greater remission at 6 and 18 months. Subcutaneous tocilizumab administration was associated with higher remission at 6 months and improved low disease activity rate at 12 months. In patients treated with rituximab, carriers of the FCGR2A rs1801274-TT genotype had higher EULAR response at 6 months (OR, 4.861; 95%CI, 1.11-21.12; P = .035), 12 months (OR, 4.667; p = 0.066, 95%CI, 0.90-24.12; P = .066), and 18 months (OR, 2.487; 95%CI, 0.35-17.31; P = .357), higher remission (OR: 10.625; p = 0.044, CI95% : 1.07, 105.47) at 6 months, and greater improvement in DAS28 at 12 months (B = 0.782; 95%CI, -0.15 to 1.71; P = .098) and 18 months (B = 1.414; 95%CI, 0.19-2.63; P = .025). The FCGR3A rs396991-G allele was associated with improved low disease activity rate (OR, 4.904; 95%CI, 0.84-28.48; P = .077) and greater improvement in DAS28 (B = -1.083; 95%CI, -1.98 to -0.18; P = .021) at 18 months. Patients with a lower number of previous biological therapies had higher remission at 12 months. We suggest that the FCGR3A rs396991-TT genotype, higher baseline value of DAS28, subcutaneous tocilizumab administration, younger age at the beginning of treatment, and being bDMARD naive are associated with better response to tocilizumab. In patients treated with rituximab, we found better response in those patients with the FCGR2A rs1801274-TT genotype, the FCGR3A rs396991-G allele, and lower number of previous biological therapies.

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Journal of Clinical Pharmacology
Journal of Clinical Pharmacology PHARMACOLOGY & PHARMACY-
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期刊介绍: The Journal of Clinical Pharmacology (JCP) is a Human Pharmacology journal designed to provide physicians, pharmacists, research scientists, regulatory scientists, drug developers and academic colleagues a forum to present research in all aspects of Clinical Pharmacology. This includes original research in pharmacokinetics, pharmacogenetics/pharmacogenomics, pharmacometrics, physiologic based pharmacokinetic modeling, drug interactions, therapeutic drug monitoring, regulatory sciences (including unique methods of data analysis), special population studies, drug development, pharmacovigilance, womens’ health, pediatric pharmacology, and pharmacodynamics. Additionally, JCP publishes review articles, commentaries and educational manuscripts. The Journal also serves as an instrument to disseminate Public Policy statements from the American College of Clinical Pharmacology.
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