风湿性疾病患者HLA单倍型与抗药抗体发展的相关性

IF 5.3 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Biologics : Targets & Therapy Pub Date : 2018-01-31 eCollection Date: 2018-01-01 DOI:10.2147/BTT.S145941

Maurizio Benucci, Arianna Damiani, Francesca Li Gobbi, Francesca Bandinelli, Maria Infantino, Valentina Grossi, Mariangela Manfredi, Guillaume Noguier, Francesca Meacci

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引用次数: 21

摘要

前言:本研究的目的是研究风湿性疾病患者中人类白细胞抗原(HLA)单倍型与抗药抗体(ADAs)发展的相关性。患者和方法:我们评估了248例炎症性风湿病患者在接受抗tnf药物治疗6个月后ADAs的存在:26例患者接受英夫利昔单抗(IFX)治疗;类风湿性关节炎(RA) 3例，强直性脊柱炎(AS) 13例，银屑病关节炎(PsA) 10例;83例阿达木单抗(ADA;RA 24例，AS 36例，PsA 23例);依那西普治疗88例(ETA;RA 35例，AS 27例，PsA 26例);certolizumab (CERT;RA 25例，AS 2例，PsA 5例);19例用golimumab (GOL;3例RA, 7例AS, 9例PsA)。采用Lisa-Tracker Duo检测血清药物和ADA水平，ADA阳性样本进行抑制试验，真阳性样本进行HLA基因分型。为了有一个均匀的对照人群，我们还对11例ada阴性患者进行了遗传HLA分型。结果:经抑制试验，IFX组ADA发生率为2/26 (7.69%)，ADA组ADA发生率为4/83 (4.81%)，ETA组ADA发生率为0/88 (0%)，CERT组ADA发生率为4/32 (12.5%)，GOL组ADA发生率为1/19(5.26%)。检测患者HLA等位基因频率分别为HLA- dr β-11 0.636、HLA- dq -03 0.636、HLA- dq -05 0.727。ada阳性患者与ada阴性患者的相对危险度分别为HLA-DRβ-11 2.528 (95% CI 0.336 ~ 19.036)、HLA-DQ-03 1.750 (95% CI 0.289 ~ 10.581)、HLA-DQ-05 2.424 (95% CI 0.308 ~ 15.449)。结论:本研究首次发现HLA与风湿性疾病患者ADAs发生相关的遗传因素相关，但样本量太少，无法得出明确的结论。

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Correlation between HLA haplotypes and the development of antidrug antibodies in a cohort of patients with rheumatic diseases.

Introduction: The aim of this study was to investigate the correlation between human leukocyte antigen (HLA) haplotypes and the development of antidrug antibodies (ADAs) in a cohort of patients with rheumatic diseases.

Patients and methods: We evaluated the presence of ADAs in 248 patients with inflammatory rheumatic diseases after 6 months of treatment with anti-TNF drugs: 26 patients were treated with infliximab (IFX; three with rheumatoid arthritis [RA], 13 with ankylosing spondylitis [AS], 10 with psoriatic arthritis [PsA]); 83 treated with adalimumab (ADA; 24 with RA, 36 with AS, 23 with PsA); 88 treated with etanercept (ETA; 35 with RA, 27 with AS, 26 with PsA); 32 treated with certolizumab (CERT; 25 with RA, two with AS, five with PsA); and 19 treated with golimumab (GOL; three with RA, seven with AS, nine with PsA). Serum drug and ADA levels were determined using Lisa-Tracker Duo, the ADA-positive samples underwent an inhibition test, and the true-positive samples underwent genetic HLA typing. To have a homogeneous control population, we also performed genetic HLA typing of 11 ADA-negative patients.

Results: After inhibition test, the frequency of ADAs was 2/26 patients treated with IFX (7.69%), 4/83 treated with ADA (4.81%), 0/88 treated with ETA (0%), 4/32 treated with CERT (12.5%), and 1/19 treated with GOL (5.26%). The frequency of HLA alleles in the examined patients was HLA-DRβ-11 0.636, HLA-DQ-03 0.636, and HLA-DQ-05 0.727. The estimated relative risks between the ADA-positive patients and the ADA-negative patients were HLA-DRβ-11 2.528 (95% CI 0.336-19.036), HLA-DQ-03 1.750 (95% CI 0.289-10.581), and HLA-DQ-05 2.424 (95% CI 0.308-15.449).

Conclusion: This is the first study that shows an association between HLA and genetic factors associated with the occurrence of ADAs in patients with rheumatic diseases, but the number of samples is too small to draw any definite conclusion.

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