近年来,随着单克隆抗体用于阻断导致潜在炎症的选择性靶标的开发,出现了最有希望的严重不受控制的哮喘(SUA)的治疗选择。如美泊利单抗和贝那利珠单抗。然而,治疗反应存在不完全控制的变异性.对美泊利单抗和贝那利珠单抗的反应变异性可能受单核苷酸多态性(SNP)的影响,检测这些并将其用作反应的预测生物标志物将是有用的。我们进行了一项回顾性观察性队列研究,纳入了来自三级医院的72名白种人患者,这些患者接受了美泊利单抗和贝那利珠单抗治疗,患有严重的嗜酸性粒细胞哮喘。IL5中的多态性(rs4143832,rs17690122),RAD50(rs11739623,rs4705959),IL1RL1(rs1420101,rs17026974,rs1921622),GATA2(rs4857855),IKZF2(rs12619285),FCGR2A(rs1801274),FCGR2B(rs3219018,rs1050501),FCGR3A(rs10127939,rs396991),FCER1A(rs2251746,rs2427837),FCER1B(rs1441586,rs573790,rs569108),使用Taqman探针通过实时聚合酶链反应(PCR)分析ZNF415(rs1054485)基因。在治疗12个月后分析反应。在接受mepolizumab治疗的患者中,定义为恶化减少的治疗反应与ZNF415rs1054485-T相关(p=0.042;OR=5.33;95%CI=1.06-30.02),定义为口服糖皮质激素使用减少的治疗反应与上一年的加重次数相关(p=0.029;OR=3.89;95%CI=1.24-14.92),定义为肺功能改善的治疗反应与生物治疗开始时的年龄相关(p=0.002;OR=1.10;95%CI=1.04-1.18),FCER1Brs569108-AA(p<0.001;OR=171.06;95%CI=12.94-6264.11),和FCER1Ars2427837-A(p=0.021;OR=8.61;95%CI=1.71-76.62)。另一方面,在接受贝那利珠单抗治疗的患者中,治疗反应,定义为减少恶化,与ZNF415rs1054485-T相关(p=0.073;OR=1.3×108;95%CI=1.8×10-19-NA),FCER1Brs569108-AA(p=0.050;OR=11.51;95%CI=1.19-269.78),过敏(p=0.045;OR=4.02;95%CI=1.05-16.74),和性别(p=0.028;OR=4.78;95%CI=1.22-20.63);治疗反应定义为肺功能改善与息肉病相关(p=0.027;OR=9.16;95%CI=1.58-91.4),IKZF2rs12619285-AA(p=0.019;OR=9.1;95%CI=1.7-75.78),IL5rs4143832-T(p=0.017;OR=11.1;95%CI=1.9-112.17),和FCER1Brs1441586-C(p=0.045;OR=7.81;95%CI=1.16-73.45)。这项研究的结果表明,所研究的多态性对美泊利单抗和贝那利珠单抗的反应的潜在影响,以及通过定义治疗反应的预测性生物标志物可以获得的临床益处。
The most promising treatment options for severe uncontrolled asthma (SUA) have emerged in recent years with the development of monoclonal antibodies for blocking selective targets responsible for the underlying inflammation, such as mepolizumab and benralizumab. However, there is variability in treatment response that is not fully controlled. The variability of the response to mepolizumab and benralizumab could be influenced by single-nucleotide
polymorphisms (SNPs), and it would be useful to detect these and use them as predictive biomarkers of response. We conducted a retrospective observational cohort study of 72 Caucasian patients recruited from a tertiary hospital with severe uncontrolled eosinophilic asthma treated with mepolizumab and benralizumab.
Polymorphisms in the IL5 (rs4143832, rs17690122), RAD50 (rs11739623, rs4705959), IL1RL1 (rs1420101, rs17026974, rs1921622), GATA2 (rs4857855), IKZF2 (rs12619285), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs569108), and ZNF415 (rs1054485) genes were analyzed by real-time polymerase chain reaction (PCR) using Taqman probes. The response was analyzed after 12 months of treatment. In patients under mepolizumab treatment, a treatment response defined as a reduction in exacerbations was associated with ZNF415 rs1054485-T (p = 0.042; OR = 5.33; 95% CI = 1.06-30.02), treatment response defined as a reduction in oral corticosteroids use was associated with the number of exacerbations in the previous year (p = 0.029; OR = 3.89; 95% CI = 1.24-14.92), and treatment response defined as improvement in lung function was associated with the age at the beginning of biological therapy (p = 0.002; OR = 1.10; 95% CI = 1.04-1.18), FCER1B rs569108-AA (p < 0.001; OR = 171.06; 95% CI = 12.94-6264.11), and FCER1A rs2427837-A (p = 0.021; OR = 8.61; 95% CI = 1.71-76.62). On the other hand, in patients under benralizumab treatment, treatment response, defined as a reduction in exacerbations, was associated with ZNF415 rs1054485-T (p = 0.073; OR = 1.3 × 108; 95% CI = 1.8 × 10-19-NA), FCER1B rs569108-AA (p = 0.050; OR = 11.51; 95% CI = 1.19-269.78), allergies (p = 0.045; OR = 4.02; 95% CI = 1.05-16.74), and sex (p = 0.028; OR = 4.78; 95% CI = 1.22-20.63); and treatment response defined as improvement in lung function was associated with polyposis (p = 0.027; OR = 9.16; 95% CI = 1.58-91.4), IKZF2 rs12619285-AA (p = 0.019; OR = 9.1; 95% CI = 1.7-75.78), IL5 rs4143832-T (p = 0.017; OR = 11.1; 95% CI = 1.9-112.17), and FCER1B rs1441586-C (p = 0.045; OR = 7.81; 95% CI = 1.16-73.45). The results of this study show the potential influence of the studied
polymorphisms on the response to mepolizumab and benralizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.