Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study
Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn's disease: a prospective, multicentre, cohort study
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DOI：
10.1016/s2468-1253(19)30012-3
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发表时间：
2019-05-01
影响因子：
35.7
通讯作者：
Ahmad, Tariq
中科院分区：
文献类型：
--
作者：
Kennedy, Nicholas A.;Heap, Graham A.;Ahmad, Tariq
背景抗肿瘤坏死因子药物是治疗克罗恩病的有效方法，但治疗失败是常见的。我们的目的是确定临床和药代动力学因素，预测主要无反应在14周后开始治疗，非缓解在第54周，和不良事件导致drugwithdraw.Methods在克罗恩病研究（PANTS）的个性化抗TNF治疗是一个前瞻性的观察英国范围内的研究。我们入组了2013年3月7日至2016年7月15日期间首次暴露于英夫利西单抗或阿达木单抗时患有活动性管腔克罗恩病的抗TNF初治患者（年龄≥ 6岁）。对患者进行12个月的评估或直至停药。在基线时记录人口统计学数据、吸烟状况、诊断时的年龄、疾病持续时间、位置和行为、既往病史和药物史以及既往克罗恩病相关手术。在每次访视时，记录疾病活动评分、体重、治疗和不良事件;还测量药物和总抗药抗体浓度。治疗失败终点为第14周的主要无应答、第54周的无缓解和导致停药的不良事件。我们使用回归分析，以确定哪些因素与治疗failure.Findings相关我们招募了955例患者接受英夫利西单抗治疗（753与originator; 202与生物类似药）和655阿达木单抗治疗。在第14周可评估的1241例患者中，295例（23.8%，95% CI 21.4 - 26.2）发生原发性无应答。1211例可评估患者中有764例（63.1%，60.3 - 65.8）在第54周时未缓解，1610例患者中有126例（7.8%，6.6 - 9.2）因不良事件缩短治疗。在多变量分析中，与原发性无应答独立相关的唯一因素是第14周的低药物浓度（英夫利西单抗：比值比0.35 [95% CI 0.20 - 0.62]，p = 0.00038;阿达木单抗：0.13 [0.06 - 0.28]，p <0.0001）;与第14周和第54周的缓解相关的最佳第14周药物浓度对于英夫利昔单抗为7mg/L，对于阿达木单抗为12mg/L。在原发性无应答后继续标准给药方案很少有帮助; 113例患者中仅14例（12.4%[95% CI 6.9 - 19.9]）在第54周达到缓解。类似地，第14周药物浓度也与第54周未缓解独立相关（英夫利西单抗为0.29 [0.16 - 0.52];阿达木单抗为0.03 [0.01 - 0.12];两者p <0.0001）。英夫利西单抗组中产生抗药抗体（免疫原性）的患者比例为62.8%（95% CI 59.0 - 66.3），阿达木单抗组为28.5%（24.0 - 32.7）。对于两种药物，第14周的次优药物浓度预测免疫原性，抗药抗体的产生预测随后的低药物浓度。联合免疫调节剂（硫嘌呤或甲氨蝶呤）治疗降低了产生抗药抗体的风险（英夫利西单抗的风险比为0.39 [95% CI 0.32 - 0.46];阿达木单抗为0.44 [0.31 - 0.64];两者均为p <0.0001）。对于英夫利西单抗，免疫调节剂使用和第14周药物和抗药抗体浓度的多变量分析显示免疫调节剂使用对第54周非缓解的独立影响（优势比0.56 [95%CI 0.38 - 0.83]，p = 0.004）。需要进行临床试验来研究个体化诱导方案和目标剂量强化治疗是否能改善预后.
Background Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal.Methods The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged >= 6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14, nonremission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure.Findings We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23.8%, 95% CI 21.4-26.2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63.1%, 60.3-65.8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7.8%, 6.6-9.2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0.35 [95% CI 0.20-0.62], p= 0.00038; adalimumab: 0.13 [0.06-0.28], p< 0.0001); the optimal week 14 drug concentrations associated with remission at both week 14 and week 54 were 7 mg/L for infliximab and 12 mg/L for adalimumab. Continuing standard dosing regimens after primary non-response was rarely helpful; only 14 (12.4% [95% CI 6.9-19.9]) of 113 patients entered remission by week 54. Similarly, week 14 drug concentration was also independently associated with non-remission at week 54 (0.29 [0.16-0.52] for infliximab; 0.03 [0.01-0.12] for adalimumab; p< 0.0001 for both). The proportion of patients who developed antidrug antibodies (immunogenicity) was 62.8% (95% CI 59.0-66.3) for infliximab and 28.5% (24.0-32.7) for adalimumab. For both drugs, suboptimal week 14 drug concentrations predicted immunogenicity, and the development of anti-drug antibodies predicted subsequent low drug concentrations. Combination immunomodulator (thiopurine or methotrexate) therapy mitigated the risk of developing anti-drug antibodies (hazard ratio 0.39 [95% CI 0.32-0.46] for infliximab; 0.44 [0.31-0.64] for adalimumab; p< 0.0001 for both). For infliximab, multivariable analysis of immunododulator use, and week 14 drug and anti-drug antibody concentrations showed an independent effect of immunomodulator use on week 54 non-remission (odds ratio 0.56 [95% CI 0.38-0.83], p= 0.004).Interpretation Anti-TNF treatment failure is common and is predicted by low drug concentrations, mediated in part by immunogenicity. Clinical trials are required to investigate whether personalised induction regimens and treatmentto- target dose intensification improve outcomes.