早期抗TNFα治疗对克罗恩病患儿有效

一项观察性研究显示，在获得诊断后3个月内接受抗肿瘤坏死因子(TNF)α治疗的克罗恩病患儿，1年时的总体临床和生长结局优于接受免疫调节药物或不接受免疫调节药物的患儿。

加拿大多伦多病童医院的Thomas D. Walters医生领导的研究团队在《胃肠病学》2月刊上撰文指出，尽管对近期被诊断为克罗恩病(CD)的儿童的现行治疗标准涉及在启动皮质激素治疗后早期给予免疫调节药物，但一些儿科消化病学家受到成人试验数据的启发，“正在逐渐采纳对严重慢性活动性疾病风险较高的炎症性肠腔CD患者更早期引入抗TNFα治疗(即跳过免疫调节药物单药试治疗的步骤)”。

虽然抗TNFα治疗的效果已得到确证，但对特定儿科患者群(患有炎症性肠腔疾病)早期使用该治疗是否比经典的升阶梯方式更有助于改善患者结局尚有待证实。为此，研究者分析了来自仍在进行中的克罗恩病患儿风险分层与识别快速疾病疾病进展的免疫遗传、微生物标志物(RS)试验的数据。该试验于2008年启动，北美地区的28个儿科胃肠病中心参与了该试验。当前这项研究的目的是，确定在诊断后3个月内开始抗TNFα单药治疗与在诊断后3个月内开始免疫调节药物单药治疗或在此期间不给予免疫治疗相比能否改善1年结局。

研究者评估了2008~2012年期间参与RISK试验的552例患者的数据。他们采用倾向评分匹配法“以避免在采用观察性队列数据探讨治疗应当差异时常会遇到的混杂因素问题”。超过半数患者(61%)为男性，平均年龄为11.8岁，63%的患者的儿科克罗恩病活动性指数(PCDAI)评分＞30。主要结局为诊断后1年时无皮质激素临床缓解(定义为PCDAI≤10)且无肠腔切除(Gastroenterology 2013 [doi: 10.1053/j.gastro.2013.10.027])。

在552例患者中，68例接受了早期抗TNFα单药治疗，248例接受了早期免疫调节药物治疗，236例未接受早期免疫治疗。经过倾向评分匹配后，早期抗TNFα单药治疗组有85%的患者在1年时达到缓解，而早期免疫调节药物治疗组和无早期免疫治疗组的这一比例分别为60%和54%(P=0.0003)。当研究者将3个月后的治疗也作为一个协变量纳入考虑时，上述结果并未改变；抗TNFα单药治疗仍然明显优于早期免疫调节药物单药治疗(风险率[RR]，1.51；P=0.0004)，而早期免疫调节药物单药治疗与无早期免疫治疗之间无显著差异(RR，1.00；P=0.99)。

Walters医生及其同事还观察发现，三组患儿的体重和体重指数(BMI)评分均有改善，而身高z评分仅在早期抗TNFα单药治疗组患儿中得到改善。

研究者总结称：“尽管我们的数据有助于对诊断为克罗恩病的儿童进行治疗决策，但不应当认为这些数据证明某种早期治疗方案优于其他方案。我们未能用特定方法确定任何预测应答或失败的常用临床或实验室特征。如果能对我们的研究队列开展进一步遗传学、血清学和微生物组分析，并结合比较性疗效结果，将能更好地阐明不同治疗决策的价值。”

这项研究获得了美国克罗恩病与结肠炎基金会的支持。Walters医生及多位合著者披露称获得了多家药企提供的研究支持、咨询费或担任其讲者。

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By: DOUG BRUNK, Internal Medicine News Digital Network

Children with Crohn’s disease who received antitumor necrosis factor-alpha within 3 months of diagnosis experienced better overall clinical and growth outcomes at 1 year, compared with their counterparts who received an immunomodulator or those who received no immunomodulator therapy, results from an observational study demonstrated.

Although the current standard of practice for children recently diagnosed with Crohn’s disease (CD) involves early administration of immunomodulators after initial treatment with corticosteroids, some pediatric gastroenterologists, inspired by data from adult trials, "are adopting earlier introduction of anti-TNF-alpha therapy (without a trial of immunomodulators alone) in patients with inflammatory luminal CD judged to be at risk of serious chronically active disease," researchers led by Dr. Thomas D. Walters wrote in the February issue of Gastroenterology.

Dr. Walters of the Hospital for Sick Children in Toronto and his associates went on to note that while the efficacy of anti-TNF-alpha therapy is well established, "it has yet to be shown that the early use of this therapy in a specific group of pediatric patients (those with inflammatory luminal disease) is any more effective at improving patient outcomes than the classic step-up approach." In an effort to answer this question, the researchers analyzed data from the ongoing Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children With Crohn’s Disease (RS) trial, which was launched in 2008 at 28 pediatric gastroenterology centers in North America. The purpose of the current study was to determine whether anti-TNF-alpha monotherapy started within 3 months of diagnosis improves 1-year outcomes, compared with clinically similar patients who were treated with immunomodulator monotherapy started within 3 months of diagnosis or those who were treated with
no immunotherapy during that time frame.

The researchers evaluated data from 552 patients who participated in the trial RISK between 2008 and 2012. They used propensity score matching "to avoid the usual problem of confounding by indication when using observational cohort data to explore differences in treatment response." More than half of the patients (61%) were male, their mean age was 11.8 years, and 63% had a Pediatric Crohn’s Disease Activity Index (PCDAI) score of greater than 30. The primary outcome of interest was corticosteroid-free clinical remission (defined as a PCDAI of 10 or less) at 1 year after diagnosis without luminal resection (Gastroenterology 2013 [doi: 10.1053/j.gastro.2013.10.027]).

Of the 552 patients, 68 received early anti-TNF-alpha monotherapy, 248 received early immunomodulator therapy, and 236 received no early immunotherapy. After propensity score matching, 85% of patients treated with early anti-TNF-alpha monotherapy achieved remission at 1 year, compared with 60% of those who were treated with early immunomodulator monotherapy and 54% of those who received no early immunotherapy, a difference that reached statistical significance (P =.0003). When the researchers factored in therapy after 3 months as a covariate, the results did not change; treatment with anti-TNF-alpha monotherapy remained significantly superior to early immunomodulator monotherapy (risk ratio, 1.51; P =.0004), while early immunomodulator monotherapy was no different from no early immunotherapy (RR, 1.00; P =.99).

Dr. Walters and his associates also observed that while weight and body mass index scores improved in all three groups, the height z score only showed improvement in the early anti-TNF-alpha group.

"Although our data clearly have added to the evidence base guiding treatment decisions after a diagnosis of Crohn’s disease in children, they should not be taken as an endorsement of one early therapeutic regimen over another," the authors concluded. "We were not able to identify any common clinical or laboratory characteristic that predicted response or failure with a particular approach. Further genetic, serologic, and microbiome analysis of our study cohort in conjunction with comparative efficacy results will better elucidate the value of different treatment decisions."

The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Walters and many of his coauthors disclosed having received research support, consulting fees, or being on the speakers bureau for numerous pharmaceutical companies.