OBJECTIVES HLA DQA1*05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNF) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data. METHODS We analyzed banked serum from patients with CD < 21 years of age enrolled in COMBINE, a multi-center, prospective randomized trial of anti-TNF monotherapy vs. combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development. RESULTS A trend towards increased treatment failure among HLA DQA1*05 positive participants was not significant (HR 1.58, 95% CI 0.95-2.62; p=0.08). After stratification by HLA DQA1*05 and by methotrexate vs. placebo, patients who were HLA DQA1*05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1*05 positive patients on placebo (HR 0.31, 95% CI 0.13-0.70; p=0.005).A trend toward increased ADA development among HLA DQA1*05 positive participants was not significant (odds ratio [OR] 1.96, 95% CI 0.90-4.31, p=0.09). After further stratification, HLA DQA1*05 negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1*05 positive patients on placebo (OR 0.12, 95% CI 0.03-0.55; p=0.008). CONCLUSIONS In a randomized trial of children with CD initiating anti-TNF, 40% were HLA DQ-A1*05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1*05 is an important biomarker for prognosis and risk stratification.

中文翻译：

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HLA DQA1*05 和克罗恩病患儿抗 TNF 治疗失败和抗药抗体产生的风险：HLA DQA1*05 和小儿克罗恩病。


目的 HLA DQA1*05 与肿瘤坏死因子拮抗剂 （anti-TNF） 抗药抗体 （ADA） 的产生和成人克罗恩病 （CD） 治疗失败有关。然而，其他研究的结果与有限的儿科数据不一致。方法 我们分析了参加 COMBINE 的 21 岁 CD < 患者的库存血清，COMBINE 是一项抗 TNF 单一疗法与甲氨蝶呤联合治疗的多中心、前瞻性随机试验。主要结局是表明治疗失败的因素的综合。次要结局是 ADA 发展。结果 HLA DQA1*05 阳性参与者治疗失败增加的趋势不显著 （HR 1.58,95% CI 0.95-2.62;p=0.08）。经 HLA DQA1*05 和甲氨蝶呤与安慰剂分层后，HLA DQA1*05 阴性且分配到甲氨蝶呤组的患者治疗失败率低于安慰剂组的 HLA DQA1*05 阳性患者 （HR 0.31,95% CI 0.13-0.70;p=0.005）。HLA DQA1*05 阳性参与者中 ADA 发展增加的趋势不显著 （比值比 [OR] 1.96,95% CI 0.90-4.31，p=0.09）。进一步分层后，相对于安慰剂组的 HLA DQA1*05 阳性患者，分配到甲氨蝶呤组的 HLA DQA1*05 阴性参与者发生 ADA 的可能性较小 （OR 0.12,95% CI 0.03-0.55;p=0.008）。结论 在一项针对 CD 儿童启动抗 TNF 的随机试验中，40% 的 HLA DQ-A1*05 阳性，这与治疗失败和 ADA 风险增加的趋势相关。这些风险通过加用口服甲氨蝶呤而减轻，但并未消除。HLA DQ-A1*05 是预后和风险分层的重要生物标志物。