Identification of HLA-DRB1 association to adalimumab immunogenicity.
Identification of HLA-DRB1 association to adalimumab immunogenicity.
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DOI：
10.1371/journal.pone.0195325
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Waring JF
中科院分区：
文献类型：
--
作者：
Liu M;Degner J;Davis JW;Idler KB;Nader A;Mostafa NM;Waring JF
抗药抗体的形成与大多数生物制剂在疾病状态下发生，但其形成机制尚不清楚。阿达木单抗（AAA）的抗药抗体的形成可能会降低其在一些患者中的治疗效果。据报道，HLA等位基因与抗干扰素和其他TNF抑制剂的自身抗体形成有关，但与阿达木单抗无关。我们分析了634例类风湿关节炎（RA）或化脓性水疱炎（HS）患者的样本：37例（17例RA和20例HS）在阿达木单抗治疗期间发展为AAA (AAA+)， 597例（348例RA， 249例HS）在临床试验期间没有发展为AAA （AAA-）。利用新一代基于测序的HLA分型技术，我们发现AAA+人群中3个保护性HLA等位基因（HLA- dqb1 *05、HLA- drb1 *01和HLA- drb1 *07）的发生率低于AAA -人群（or分别为0.4、0.25和0.28，P值分别为0.012、0.012和0.018），2个高危HLA等位基因（HLA- drb1 *03和HLA- drb1 *011）的发生率高于AAA -人群（or分别为2.52、2.64，P值分别为0.006和0.019）。与Billiet等人发现HLA-DRB1*03等位基因在抗英夫利ximab抗体人群中携带更为普遍（OR = 3.6, p = 0.002, 95% CI:[1.5,8.6]）相似，我们发现HLA-DRB1*03等位基因在抗阿达木单抗阳性人群中也更为普遍（OR = 2.52, p = 0.006, 95% CI:[1.37,4.63]）。结果表明，特异性HLA等位基因可能在阿达木单抗治疗的RA和HS患者发生AAAs的过程中发挥关键作用。
Anti-drug antibody formation occurs with most biological agents across disease states, but the mechanism by which they are formed is unknown. The formation of anti-drug antibodies to adalimumab (AAA) may decrease its therapeutic effects in some patients. HLA alleles have been reported to be associated with autoantibody formation against interferons and other TNF inhibitors, but not adalimumab. We analyzed samples from 634 subjects with either rheumatoid arthritis (RA) or hidradenitis suppurativa (HS): 37 subjects (17 RA and 20 HS) developed AAA (AAA+) during adalimumab treatment and 597 subjects (348 RA, 249 HS) did not develop AAA (AAA-) during the clinical trials. Using next-generation sequencing-based HLA typing, we identified three protective HLA alleles (HLA-DQB1*05, HLA-DRB1*01,and HLA-DRB1*07) that were less prevalent in AAA+ than AAA–subjects (ORs: 0.4, 0.25 and 0.28, respectively; and P values: 0.012, 0.012 and 0.018, respectively) and two risk HLA alleles (HLA-DRB1*03 and HLA-DRB1*011) that were more abundant in AAA+ than AAA–subjects (ORs: 2.52, and 2.64, respectively; and P values: 0.006 and 0.019). Similar to the finding of Billiet et al. who found that carriage of the HLA-DRB1*03 allele was more prevalent in those with anti-infliximab antibodies (OR = 3.6, p = 0.002, 95% CI: [1.5,8.6]).), we found HLA-DRB1*03 allele was also more prevalent in anti-adalimumab positive (OR = 2.52, p = 0.006, 95% CI: [1.37,4.63]). The results suggest that specific HLA alleles may play a key role in developing AAAs in RA and HS patients treated with adalimumab.
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