Human leukocyte antigen genes and interferon beta preparations influence risk of developing neutralizing anti-drug antibodies in multiple sclerosis.
Human leukocyte antigen genes and interferon beta preparations influence risk of developing neutralizing anti-drug antibodies in multiple sclerosis.
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DOI：
10.1371/journal.pone.0090479
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Fogdell-Hahn A
中科院分区：
文献类型：
--
作者：
Link J;Lundkvist Ryner M;Fink K;Hermanrud C;Lima I;Brynedal B;Kockum I;Hillert J;Fogdell-Hahn A
接受贝塔干扰素(干扰素β)治疗的多发性硬化症患者中，有相当大一部分会产生中和抗体(NAB)，从而降低药物疗效。为了研究人类白细胞抗原I类和II类等位基因是否与针对干扰素β的NAB的发生有关，我们分析了903名瑞典多发性硬化症患者肌肉内注射干扰素β-1a、皮下注射干扰素β-1a或皮下注射干扰素β-1b后，NAB状态和NAB滴度的发展是否足够高，足以与人类白细胞抗原等位基因组携带率相关(>；150个单位/毫升)。携带HLADRB1*15与发生NAB和高NAB滴度的风险增加相关。根据干扰素β制剂的类型进行分层后，观察到携带HLADRB1*15增加了发生NAB的风险，并增加了皮下和肌肉内抗干扰素β-1a的高滴度。此外，在接受皮下干扰素的患者中，β-1a携带HLADQA1*05降低了高NAB滴度的风险。在干扰素β-1b治疗的患者中，HLADRB1*04增加了发生高滴度NAB的风险，在DRB1*04：01携带者中，DRB1*04等位基因的亚组分析增加了患NAB的风险。总而言之，如果在未来的研究中得到证实，存在特定于制剂的基因决定的风险，即产生足够高的针对干扰素β的NAB，从而在多发性硬化症患者的治疗决策中具有临床相关性。然而，干扰素β制剂的选择仍然是发生NAB风险的唯一最重要的决定因素。
A significant proportion of patients with multiple sclerosis who receive interferon beta (IFNβ) therapy develop neutralizing antibodies (NAbs) that reduce drug efficacy. To investigate if HLA class I and II alleles are associated with development of NAbs against IFNβ we analyzed whether NAb status and development of NAb titers high enough to be biologically relevant (>150 tenfold reduction units/ml) correlated with the HLA allele group carriage in a cohort of 903 Swedish patients with multiple sclerosis treated with either intramuscular IFNβ-1a, subcutaneous IFNβ-1a or subcutaneous IFNβ-1b. Carriage of HLA-DRB1*15 was associated with increased risk of developing NAbs and high NAb titers. After stratification based on type of IFNβ preparation, HLA-DRB1*15 carriage was observed to increase the risk of developing NAbs as well as high NAb titers against both subcutaneous and intramuscular IFNβ-1a. Furthermore, in patients receiving subcutaneous IFNβ-1a carriage of HLA-DQA1*05 decreased the risk for high NAb titers. In IFNβ-1b treated patients, HLA-DRB1*04 increased the risk of developing high NAb titers, and in a subgroup analysis of DRB1*04 alleles the risk for NAbs was increased in DRB1*04:01 carriers. In conclusion, there is a preparation-specific genetically determined risk to develop NAbs against IFNβ high enough to be clinically relevant in treatment decisions for patients with multiple sclerosis if confirmed in future studies. However, choice of IFNβ preparation still remains the single most significant determinant for the risk of developing NAbs.
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