Mark Reppell, Xiuwen Zheng, Ingeborg Dreher, Jonas Blaes, Elina Regan, Tobias Haslberger, Heath Guay, Valerie Pivorunas, Nizar Smaoui
{"title":"HLA-DQA1*05 与 SERENE UC 和 CD 研究中炎症性肠病患者的抗肿瘤坏死因子免疫原性和低阿达木单抗谷浓度有关。","authors":"Mark Reppell, Xiuwen Zheng, Ingeborg Dreher, Jonas Blaes, Elina Regan, Tobias Haslberger, Heath Guay, Valerie Pivorunas, Nizar Smaoui","doi":"10.1093/ecco-jcc/jjae129","DOIUrl":null,"url":null,"abstract":"<p><strong>Background & aims: </strong>Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's Disease (CD) and Ulcerative Colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADA). Understanding the factors associated with immunogenicity in anti-TNF treated patients can help guide treatment. The Humira SERENE studies were phase 3 trials studying adalimumab induction regimens in CD and UC patients.</p><p><strong>Methods: </strong>We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We tested these alleles for association with time to immunogenicity. We then tested loci significantly associated with immunogenicity for association with patients that had consistently low drug-serum concentrations.</p><p><strong>Results: </strong>This study replicated the association of HLA-DQA1*05 with time to immunogenicity (Hazard Ratio (HR) 1.42, P=2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, P=2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, P=2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 were both associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05 OR 1.98, P=0.0049; HLA DRB1*01:02 OR 7.06, P=7.44E-05).</p><p><strong>Conclusions: </strong>We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug-serum concentrations in large clinical studies of CD and UC patients. This work extends previous results in Crohn's disease to ulcerative colitis and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest genetic screening as a useful tool for clinicians concerned with patient anti-TNF immunogenicity.</p>","PeriodicalId":94074,"journal":{"name":"Journal of Crohn's & colitis","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"HLA-DQA1*05 associates with anti-TNF immunogenicity and low adalimumab trough concentrations in inflammatory bowel disease patients from the SERENE UC and CD studies.\",\"authors\":\"Mark Reppell, Xiuwen Zheng, Ingeborg Dreher, Jonas Blaes, Elina Regan, Tobias Haslberger, Heath Guay, Valerie Pivorunas, Nizar Smaoui\",\"doi\":\"10.1093/ecco-jcc/jjae129\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background & aims: </strong>Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's Disease (CD) and Ulcerative Colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADA). Understanding the factors associated with immunogenicity in anti-TNF treated patients can help guide treatment. The Humira SERENE studies were phase 3 trials studying adalimumab induction regimens in CD and UC patients.</p><p><strong>Methods: </strong>We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We tested these alleles for association with time to immunogenicity. We then tested loci significantly associated with immunogenicity for association with patients that had consistently low drug-serum concentrations.</p><p><strong>Results: </strong>This study replicated the association of HLA-DQA1*05 with time to immunogenicity (Hazard Ratio (HR) 1.42, P=2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, P=2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, P=2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 were both associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05 OR 1.98, P=0.0049; HLA DRB1*01:02 OR 7.06, P=7.44E-05).</p><p><strong>Conclusions: </strong>We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug-serum concentrations in large clinical studies of CD and UC patients. This work extends previous results in Crohn's disease to ulcerative colitis and directly shows a genetic association in patients with low drug concentrations. 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引用次数: 0
摘要
背景与目的:抗肿瘤坏死因子(anti-TNF)疗法是治疗克罗恩病(CD)和溃疡性结肠炎(UC)的常用处方药。许多接受抗肿瘤坏死因子治疗的患者最终会产生抗药性抗体(ADA)。了解与抗肿瘤坏死因子治疗患者免疫原性相关的因素有助于指导治疗。Humira SERENE研究是在CD和UC患者中研究阿达木单抗诱导方案的3期试验:我们对 SERENE CD 和 SERENE UC 试验中 1100 名患者的 7 个 HLA 基因的等位基因进行了估算。我们检测了这些等位基因与免疫原性时间的相关性。然后,我们检测了与免疫原性明显相关的位点与药物血清浓度持续偏低的患者的关联性:本研究证实了 HLA-DQA1*05 与免疫原性时间的关系(危险比 (HR) 1.42,P=2.22E-06)。具体来说,HLA-DQA1*05:05与免疫原性时间密切相关(HR 1.76,P=2.02E-10),我们还发现了以HLA-DRB1*01:02为代表的新的关联(HR 3.16,P=2.92E-07)。携带HLA-DQA1*05:05和HLA-DRB1*01:02与阿达木单抗谷浓度持续偏低的患者有关(HLA-DQA1*05:05 OR 1.98,P=0.0049;HLA DRB1*01:02 OR 7.06,P=7.44E-05):在对CD和UC患者进行的大型临床研究中,我们发现人类HLA位点基因的等位基因与阿达木单抗免疫原性的形成和阿达木单抗药物-血清低浓度之间存在明显关联。这项工作将之前在克罗恩病中的研究成果推广到了溃疡性结肠炎,并直接显示了低药物浓度患者的遗传关联。这项工作以现有文献为基础,建议临床医生将基因筛查作为关注患者抗肿瘤坏死因子免疫原性的有用工具。
HLA-DQA1*05 associates with anti-TNF immunogenicity and low adalimumab trough concentrations in inflammatory bowel disease patients from the SERENE UC and CD studies.
Background & aims: Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's Disease (CD) and Ulcerative Colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADA). Understanding the factors associated with immunogenicity in anti-TNF treated patients can help guide treatment. The Humira SERENE studies were phase 3 trials studying adalimumab induction regimens in CD and UC patients.
Methods: We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We tested these alleles for association with time to immunogenicity. We then tested loci significantly associated with immunogenicity for association with patients that had consistently low drug-serum concentrations.
Results: This study replicated the association of HLA-DQA1*05 with time to immunogenicity (Hazard Ratio (HR) 1.42, P=2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, P=2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, P=2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 were both associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05 OR 1.98, P=0.0049; HLA DRB1*01:02 OR 7.06, P=7.44E-05).
Conclusions: We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug-serum concentrations in large clinical studies of CD and UC patients. This work extends previous results in Crohn's disease to ulcerative colitis and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest genetic screening as a useful tool for clinicians concerned with patient anti-TNF immunogenicity.